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Оглавление1 Diabetes Mellitus: An Introduction
F.A. Gries, J. Eckel, P. Rösen, and D. Ziegler
The aim of this introduction is to provide a general understanding of diabetes mellitus and its impact on the diabetic individual. It will focus on aspects of epidemiology, pathobiochemistry, prevention, and therapy. Given the scope covered, selectivity and bias of topics and citations have been accepted as unavoidable.
Definition
The term “diabetes mellitus” comprises a number of chronic diseases characterized by hyperglycemia due to absolute or relative insulin deficiency. Hyperglycemia is only the most obvious biochemical marker of complex metabolic disorders that affect carbohydrate, lipid, protein, and electrolyte metabolism and may impair numerous organs and functions of the organism.
Diagnosis
The diagnosis of diabetes mellitus is based on classical symptoms (weight loss, polyuria, thirst, muscular weakness and fatigue) and persistent hyperglycemia. Glucosuria and elevated glycosylated hemoglobin (HbAlc) levels should not be used for diagnosis. The criteria for diagnosis of hyperglycemia and the classification of diabetes mellitus are not uniformly accepted. Some physicians use the criteria of the United States National Diabetes Data Group of 1979 [1], which was endorsed by the World Health Organization Study Group on Diabetes Mellitus in 1985 [2], while others prefer the criteria of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus of the American Diabetes Association 1998 [3] (Table 1.1).
The criteria published in 1998 tend to diagnose diabetes in younger and more obese subjects than the WHO 1985 criteria, while subjects with postprandial hyperglycemia, microalbuminuria, and those with other predictors of cardiovascular disease are less likely to receive this diagnosis despite the fact that they are at similar risk of premature death [4–8].
Classification
The diabetes mellitus classification of 1979 [1] was based “in large part on the pharmacological treatment used in its management.” This was reflected in the terms “insulin-dependent diabetes mellitus” (IDDM) and “non-insulin-dependent diabetes mellitus” (NIDDM) and the further subdivision of patients with the latter into obese and nonobese. The typing of 1998 is based on etiology and pathogenetic mechanisms (Table 1.2). About 50 different types of diabetes mellitus have been identified, the majority of cases being type 1, type 2, or gestational diabetes mellitus.
Table 1.1 Criteria for the diagnosis of diabetes according to the World Health Organization [2] and the American Diabetes Association [3]
| World Health Organization | American Diabetes Association |
|---|---|
| Clinical: | |
| Increased thirst and urine volume, unexplained weight loss, established by casual blood glucose | Polyuria, polydipsia and unexplained weight loss plus casual plasma or capillary blood glucose ≥ 200 mg/dl (11.1 mmol/l) |
| or | or |
| Biochemical: | |
| Casual venous plasma glucosea > 200mg/dl (11.1 mmol/l), fasting venous or capillary plasma glucose b ≥ 140 mg/dl (7.8 mmol/l) and 2 h venous or capillary plasma or capillary whole blood glucose c ≥ 200 mg/dl (11.1 mmol/l) after glucose loadd | Fasting plasma glucose ≥ 126 mg/dl (7.0 mmol/l) or capillary blood glucose ≥ 110 mg/dl or 2 h plasma or capillary blood glucose ≥ 200 mg/dl (11.1 mmol/l) during an oral glucose tolerance test |
a Values for capillary plasma > 220 mg/dl, for venous whole blood >180 mg/dl. for capillary whole blood > 200 mg/dl
b Value for venous and capillary whole blood ≥ 120 mg/dl
c Value for venous whole blood ≥ 180 mg/dl
d Performed as described by WH01985 [2] using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water
There is a great similarity between type 1 diabetes and IDDM and between type 2 diabetes and NIDDM. However, these pairs of terms should not be used indiscriminately as being respectively synonymous. Type 1 diabetes mellitus may for a limited time after manifestation remain non-insulin-dependent, particularly when it begins in an adult (latent autoimmune diabetes in adults. LADA; see page 10). On the other hand, NIDDM, like any type of diabetes mellitus, may become insulin-dependent at an advanced or critical stage.
Epidemiology
Epidemiological research on diabetes mellitus is hampered by methodological problems. The criteria and methods for both the diagnosis and the classification of diabetes mellitus have changed over time. Population-based studies are rare, studies based on subgroups are usually biased, and even random samples are not always representative. The epidemiology of diabetes mellitus shows considerable regional variation, so that when data from different regions are compared, the ethnicity, gender, and age structure of the groups that had been studied need to be considered-but frequently these have not been communicated. These problems are more relevant to studies on type 2 respectively NIDDM than type 1 respectively IDDM.
Type 1 Diabetes/IDDM
The incidence of IDDM varies considerably with geography and ethnicity. In Japan, China, and in African Americans the incidence (number of new cases per 100 000 person-years) in the age group of 0-14 years is below 5. In most European regions it is about 1020 per 100 000 person-years, and in Finland and Sardinia it is above 30 [2,9,10,11].
The highest incidence of IDDM is found in children below the age of 15, but IDDM or type 1 diabetes may become manifest at any age. The estimated incidence in adults is about half that observed in children of the respective population. However, the figure may be much higher if cases of LADA are included, which may comprise about 10% of all patients initially diagnosed as having type 2 diabetes mellitus [12]. Worldwide a trend to increasing incidence in children and adolescents has been observed [13–15]. According to a Finnish study the incidence is increasing more in younger than older age groups [16]. Firstborn children are at highest risk. The risk increases with the age of the mother [17].
Table 1.2 Shortened version of the classification of diabetes according to the Expert Committee on the Diagnosis and Classification of Diabetes mellitus [3]
| I. Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency) A. Immune-mediated B. Idiopathic II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) III. Other specific types A. Genetic defects of β-cell function B. Genetic defects in insulin action C. Disease of the exogenic pancreas D. Endocrinopathies E. Drug- or chemical-induced F. Infections G. Uncommon forms of immune-mediated diabetes H. Other genetic syndromes sometimes associated with diabetes IV. Gestational diabetes (GDM) |
Reliable data about the prevalence of IDDM/type 1 diabetes mellitus are not available. Type 1 diabetes is associated with genetic as well as environmental factors. The rising incidence can hardly be explained by a change in the gene pool, so environmental factors must be playing a major role. However, it is impossible at present to decide what these environmental factors are.
The life expectancy of IDDM subjects is reduced. The number of lost years of life depends on the age at diagnosis (it is highest in early-onset IDDM) and on the quality of care as well as on chronic complications [18–20]. In the USA, mortality “among males was 5.4 times higher and in females it was 11.5 times higher than in the total US population.” “Among people with age at diagnosis < 30 years, IDDM reduces life expectancy by at least 15 years.” In 70-90% the cause of death is related to diabetes [21]. In long-term type 1 diabetes vascular complications are the most important predictors and causes of death[22–24] (Table 1.3). In the USA, ketosis has been the cause of death in about 10% of people with IDDM who died at 0-44 years of age. Hypoglycemia may be the undiagnosed cause of sudden death. It was noted as an underlying cause of death in about 1 of 300 deaths due to diabetes [25]. Others have estimated that 2-4% of all deaths in IDDM subjects are due to hypoglycemia [26].
Type 2 Diabetes/NIDDM
Type 2 diabetes mellitus is by far the most common type of diabetes. By extrapolation from the incidence of diabetic retinopathy in recently diagnosed subjects it may be concluded that the disease will manifest a couple of years before it is diagnosed. Most cases are diagnosed in individuals under the age of 60 years. The highest prevalence is found in the age group of 65-75 years.
Since type 2 diabetes develops insidiously, it is difficult to determine its incidence. Most reliable are prevalence data of clinical NIDDM/type 2 diabetes and of impaired glucose tolerance (IGT), which is assumed to precede clinical NIDDM/type 2 diabetes. Considerable regional differences exist in the prevalence of NIDDM/type 2 diabetes depending on relative body weight, life style, ethnic origin, nutritional habits, social status, education, and the age structure of the population [27,28]. Type 2 diabetes/NIDDM used to be the disease of affluent societies in highly developed industrialized regions. This is no longer true. The highest prevalence is now found in Fiji, Micronesia, and among the Pima Indians. There is a worldwide trend towards both increasing prevalence and incidence and a lowering of the age at manifestation. It has been predicted that the number of diabetic subjects worldwide will double during the next two decades. This will be due not only to a rising incidence but also to increasing life expectancies in the growing world population.
Type 2 diabetes is associated with an increased mortality. In western countries the loss of life years is about 30% of normal life expectancy (Table 1.4). Because the NIDDM/type 2 diabetes population is older as a whole, the average absolute number of lost years is smaller than in type 1 diabetes and becomes insignificant in the very old. The main cause of death is cardiovascular disease [22,29] (Table 1.3).The association between blood glucose control and the risk of dying is rather weak [30].
Other types of diabetes mellitus, such as gestational diabetes mellitus (GDM), maturity-onset diabetes in the young (MODY), malnutrition-related diabetes mellitus (MRDM), and endocrine syndromes associated with diabetes mellitus will not be discussed in this chapter.
Etiology and Pathogenesis of Diabetes
Type 1 Diabetes
More than 20 different regions of the human genome show some linkage with type 1 diabetes mellitus [31]. Many of these genes carry a risk, others protect.
The strongest linkage is seen for the major histo-compatibility complex, which is located on chromosome 6 (IDDM1 locus). The importance of some HLA class II genes (e.g., DR7, DR9, DQA1 0301, DQB1 0201) differs among ethnic groups [9], as may be true for HLA class I genes. The physiological role of HLA molecules is to present foreign and self antigens to T lymphocytes and to other cells involved in the initiation of insulitis. The region of the insulin genes on chromosome IIp15 (IDDM2 locus) may also be involved. The importance of other type 1 diabetes mellitus-associated gene loci remains open.
Even in monozygotic twins the concordance for diabetes is not more than 50%, which indicates the importance of nongenetic factors. Environmental factors have been mainly studied in laboratory animals. The spontaneous diabetic NOD mouse is the star model, where numerous modulations of the environment or immunomodulatory protocols have been reported to lower the incidence of diabetes mellitus [32]. The ease of this success in preventing diabetes in a mouse model means that the observations cannot be simply transferred to the human situation.
In humans some seasonal variations of incidence with peaks in winter and early spring have been reported [11,33], but they seem to be absent in HLADR 3-positive and very young children [51]. The introduction of cow-milk-based diets before 3 months of age has been accused as a diabetogenic factor, but the epidemiological data remain controversial [34]. A homology of bovine serum albumin and human islet proteins and of immunogenic epitopes on β casein Al which resemble β-cell epitopes (immunogenic mimicry) have been suggested to be responsible for the induction of insulitis. Prospective or controlled intervention studies comparing feeding with cow-milk proteins and breastfeeding will be needed to answer this question [34]. Nitrosamines, various toxins, and infection with rubella, German measles, mumps, coxsackievirus B1, Epstein-Barr virus, and cytomegalovirus have also been discussed as possible causes. With the exception of congenital rubella virus infection [35], definite evidence of a causal role remains to be established.
Type 1 diabetes mellitus is an insulin deficiency syndrome caused by β-cell destruction. This is the result of an immune-mediated disease which leads to chronic inflammation of the islets of Langerhans, called insulitis. Various types of mononuclear cells are involved. On the basis of animal experiments, two types of insulitis may be distinguished [36–38]:
• Benign Th-2 (T-heiper-2 cell) type insulitis is characterized by secretion of interleukin (IL)-4, IL-10, and IL-13 and absence of aggressive immune cells. Cellular infiltration is located in the periphery of the islets and little β-cell destruction is seen.
• Destructive Th-1 (T-helper-1 cell) type insulitis is characterized by secretion of interferon (IFN)-γ;, tumor necrosis factor (TNF)-α, and IL-2 and the presence of cytotoxic T cells and activated macrophages, which migrate into the islets and cause β-cell damage by induction of apoptosis or necrosis.
As a rule, insulitis is a chronic process which may begin in early childhood [39]. Its earliest sign seems to be the appearance of islet autoantibodies in blood, which may be detected many years before clinical diabetes can be diagnosed. Whether insulitis will proceed to clinical diabetes, and how rapidly this may occur, seems to depend on a variety of hitherto hypothetical immune modulatory factors. Th-2 cytokines suppress Th-1 cells and vice versa [40,41]. IF the Th-2/ Th-1 balance is shifted towards a Th-1 dominance, β-cell destruction will proceed until insulin release has dropped so low that blood glucose can no longer be regulated within the normal range, and clinical diabetes will become manifest [42] (Fig. 4.1).
Fig. 1.1a, b Development of type 1 diabetes mellitus. a Insulin secretion in relation to clinical signs. b Insulin secretion in relation to type of insulitis. (Adapted by permission from Martin and Kolb [43])
In recent-onset diabetes, histological analysis of the pancreas shows infiltration by mononuclear cells, mostly T lymphocytes and monocytes/macrophages. Insulin-producing β cells are preferentially attacked. Other lobules of the pancreas may contain either completely insulin-deficient small islets which consist of A, D, and PP cells (A cells secrete glucagon, D cells somatostatin, and PP cells pancreatic polypeptide) or apparently normal islets. Such normal islets may persist for several years after diagnosis and could explain the remission or “honeymoon” phase and different grades of severity of the disease.
B lymphocytes and islet cell autoantibodies are not essential for β-cell destruction [433]. In the early stages of insulitis, glucose metabolism and stimulated insulin secretion are normal. When stimulated, early insulin secretion drops in autoantibody-positive subjects to the 1st percentile of normal, this indicates a loss of more than 80% of the β cells and the manifestation of diabetes mellitus in the very near future [44].
Type 2 Diabetes
Genes and Determination Factors
Type 2 diabetes mellitus is a heterogeneous group of disorders that result from the combination of insulin resistance and impaired insulin secretion. Their etiology “may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance” [3]. A widely accepted pathogenetic model assumes that diabetes develops in carriers of susceptibility genes if they are exposed to determination factors. The idea of a genetic basis is supported by both twin studies and differences in prevalence between ethnic groups [45]. The genetic influence is stronger than in type 1 diabetes (Table 1.5). Multiple candidate genes have been nominated, including “thrifty genes” related to the metabolic syndrome [47,48], but the type 2 diabetes genes are not yet established. The mutations that have been found in MODY [49] play no role in ordinary type 2 diabetes.
Most determination factors are related to insulin resistance (Table 1.6). Some of these factors, such as age, are beyond our control, but most can be influenced. Of outstanding importance is the metabolic syndrome, which was first described in 1967 [50] (Table 1.7). Its multifactorial etiology is not yet fully understood [52]. The metabolic syndrome precedes and accompanies overt diabetes. Its components also constitute risk factors for vascular complications. This explains why many subjects already show angiopathies at the time of diagnosis of diabetes mellitus. For this reason, it is reasonable to expand the concept of type 2 diabetes to the early disorders of the preclinical phase, which traditionally have been neglected.
Obesity is closely related to physical inactivity. Both physical inactivity and obesity are associated with type 2 diabetes [53–56]. The relationship is most pronounced in the visceral (android, truncal, abdominal central) type of obesity [57–59]. This type of obesity is in its turn related to aging [60] and to physical inactivity [61]. Increasing abdominal adipose tissue mass and weight gain are predictors of impaired glucose tolerance, dyslipoproteinemia, hypertension, and hyperuricemia [55]. Weight reduction predicts improvement of these risk factors [62] and of life expectancy [63]. This direct relationship indicates that obesity and physical activity are causal determininants rather than being accidentally associated with these disorders.
Table 1.6 Determination factors of type 2 diabetes mellitus
| Family history of diabetes mellitus Age Metabolic syndrome Physical inactivity Western life style Diabetogenic drugs Endocrinopathies and pregnancy |
The importance of life style has been shown in longitudinal studies on, for example. Indians who emigrated to South Africa [64], and Japanese people who emigrated to North America [65], where they developed not only obesity but also diabetes. Thus, a genetic predisposition to diabetes may be revealed only under the influence of a diabetogenic life style. This concept has been confirmed in other populations [66,67] and by intervention studies (see p. 19). It has also been suggested that fetal malnutrition may predispose to the metabolic syndrome [68–71], but this hypothesis has been challenged [72,73].
Insulin Sensitivity
In the majority of type 2 diabetic individuals insulin resistance seems to be a very early or indeed the primary metabolic disorder [74–76]. In the general population insulin sensitivity varies over a wide range. The variation between members of a family is smaller than that between families [91], indicating a genetic determination.
The mechanisms of insulin resistance most likely involve polygenic defects [76] (Table 1.8), which cannot be discussed in this chapter. However, insulin resistance may also be acquired [77]. Some factors that enhance insulin resistance are identical with determination factors of type 2 diabetes (Table 1.6).
The biochemistry of insulin resistance has been extensively studied. Insulin acts through binding to a specific receptor which is composed of two extracellular insulin-binding α-subunits (135 kDa) and two cytoplasmic β-subunits (95 kDa) that carry a tyrosine kinase domain. Insulin binding initiates a conformational change which results in the activation of a tyrosine kinase. Important substrates of this kinase are the receptor itself and the insulin receptor substrates IRS-1 to IRS-4. Processes which are not completely understood connect the hormone to different signaling cascades which trigger either metabolic or mitogenic stimulation (Fig. 1.2).
The effects of insulin are cell-specific (Table 1.9). Insulin stimulates glucose uptake and glycogen synthesis in muscle. Insulin resistance of the muscle may precede impaired glucose tolerance. It usually begins with an impairment of nonoxidative glucose metabolism; later, oxidative glucose metabolism is also involved [91–93]. These defects may contribute to postprandial hyperglycemia.
Table 1.7 The metabolic syndrome originally [50] and today
| 1969 | 2000 |
|---|---|
| Obesity | aObesity, abdominal typeaInsulin resistance |
| Hyperinsulinemia | Hyperinsulinemia |
| Impaired glucose tolerance | aImpaired glucose tolerance, type 2 diabetes Dyslipoproteinemia |
| Hypertriglyceridemia | aHypertriglyceridemiaaLow-HDL cholesterol Small, dense LDL |
| Hyperlipidacidemia | Hyperlipidacidemia |
| Abnormal adipose tissue metabolism | HypertensionActivated hemostasisPlatelet activationLowPAI-1 Low thromboplastinHyperfibrinogenemiaHyperuricemiaHyperandrogenemia in womenaAlbuminuria |
a WHO criteria [51]
HDL, High-density lipoprotein; LDL, low-density lipoprotein; PAI-1, plasminogen activator inhibitor-1
Table 1.8 Causes and candidate genes of primary insulin resistance
| Insulin receptor Insulin binding site (α-subunit) Tyrosine kinase activity (β-subunit) |
| Insulin receptor substrate IRS-1 (polymorphism) [79,80] |
| Glucose utilization CLUT-4 (decreased expression and/or translocation) [81] Glycogen synthase? Hexokinase II? |
| Others Rad [82] Glucagon receptor [83] Fatty acid binding protein (FABP) [84] β3-Adrenergic receptor [85] Tumor necrosis factor α (TNF-α) [86–88] |
| Calpain-10 [89] |
Adapted from [78]
It has been suggested that genetically determined insulin resistance of the muscle is the primary defect in the majority of type 2 diabetic individuals [74,94]. However, in cell culture, muscle cells from lean, non-diabetic, insulin-resistant subjects do not preserve their insulin resistance, suggesting that environmental factors may be of pivotal importance in the insulin sensitivity of muscle [95].
Fig. 1.2 Hypothetical insulin signaling pathways. Insulin signaling is initiated at the level of the insulin receptor. The insulin receptor tyrosine kinase activity leads to tyrosine phosphorylation of insulin receptor substrates (IRS1, IRS2, She). The phosphotyrosine residues of these proteins transfer the signal via SH2 domains and adapter molecules (Grb2, SOS, Syp) onto signal mediators like PI-3 kinase and the RAS complex. The PI-3 kinase pathway leads to translocation of glucose transporter 4 GLUT-4) and stimulation of glycogen synthesis; the RAS complex is a mediator for the activation of the MAP kinase, which is important for insulin-dependent cell growth and protein synthesis. (Adapted by permission from Holman and Kasuga [90] and from J. Eckel, personal communication)
PI 3-kinase. phosphatidylinositol 3-kinase; IRS, insulin receptor substrate; Shc, adaptor protein Shc; SH2, Src homology 2; PKB, protein kinase B; SOS. son-of-sevenless; Ras, small GTP-binding protein; Raf proteins, serine-threonine kinases with homology to PKC; MAP kinase, mitogen activated protein kinase; GSK3, glycogen synthase kinase 3; GRB2, growth factor receptor binding protein 2: Syp, SH2 domain-containing protein-tyrosine-phosphatase
Table 1.9 Effects of insulin on different tissues
| Effect | Tissue |
|---|---|
| Stimulation of membrane transport | |
| Glucose | Muscle, adipose tissue |
| Amino acids | Muscle, adipose tissue |
| Ions | Muscle, adipose tissue, liver |
| Stimulation of synthesis | |
| Glycogen | Muscle, adipose tissue |
| Protein | Muscle, adipose tissue, lactating mammary gland |
| Fatty acids | Liver, adipose tissue, lactating mammary gland |
| Triglycerides | Liver, adipose tissue, lactating mammary gland |
| Inhibition of | |
| Lipolysis | Adipose tissue |
| Proteolysis | Muscle, liver |
| Gluconeogenesis and glucose production | Liver |
| Cell proliferation and differentiation | Stem cells, preadlpocytes, fibroblastsDifferentiated cells? |
In the liver insulin suppresses gluconeogenesis and hepatic glucose release. Insulin resistance may unleash hepatic glucose output, which plays a role in fasting hyperglycemia.
In adipocytes insulin inhibits lipolysis and stimulates glucose uptake, lipid synthesis, and esterification of fatty acids. Therefore, insulin resistance results in elevated plasma free fatty acids (FFA), which in their turn contribute to insulin resistance, increased gluconeogenesis, hepatic glucose output, and very-low-density lipoprotein (VLDL) production.
The mechanism of the relationship between obesity and insulin resistance is still a matter of debate. FFA could play a major role [100]. High plasma FFA concentrations induce insulin resistance in muscle and liver [96]. The augmentation of adipose mass results in increased FFA release. Since visceral fat cells are metabolically more active and more sensitive to lipolytic stimuli, the increase of FFA is most pronounced in persons with visceral obesity. This is in line with the high diabetes rate in this type of obesity.
At the molecular level, the Randle mechanism, the inhibition of the glycogen synthase [96], the inhibition of the insulin signal cascade [97], or genomic effects which could be mediated through peroxisome proliferator-activated receptor (PPAR)-α have been discussed as possibly implicated in insulin resistance [98].
The Randle mechanism, also called the glucose-fatty acid cycle, postulates an inhibition of muscular glucose utilization by FFA [99]. Its relevance in humans is debated [92,100]. FFA are also important stimulators of hepatic gluconeogenesis and hepatic glucose output [101], which is unleashed in early impaired glucose tolerance [102]. This effect allows the enhanced hepatic glucose output to be explained without postulating genuine hepatic insulin resistance.
Another link between obesity and insulin resistance could be related to the hormonal activity of adipose tissue. Fat cells produce a variety of molecules with endocrine and paracrine activity. Some of them, including leptin, estrogens, IGF-I, FFA, and complement factors are released into the circulation. The cytokines TNF-α, interieukin-6, and angiotensinogen or angiotensin may act locally. Since metabolically active fat cells are located not only in adipose tissue but also inside the muscle, in close vicinity to myocytes, signals from these fat cells may have effects on adipocytes or muscle cells without being detectable in the circulation.
There is some evidence that signals released from fat cells are involved in insulin resistance. In laboratory animals the expression of TNF-α in adipocytes is linked to insulin resistance [86]. This cytokine stimulates phosphorylation of the serine residues of IRS-1, leading to reduced activity of the insulin receptor tyrosine kinase [88,103]. An inhibition of insulin signaling at the phosphatidylinositol 3-kinase (PI-3 kinase) level has been shown in human fat cells [88]. It could explain why TNF-α inhibits insulin-stimulated glucose transporter 4 (GLUT-4) expression and translocation [88,104,105] and may thereby impair glucose utilization. In obesity and type 2 diabetes, the expression of TNF-α and its receptors is increased in adipose and muscle tissue [86,104].
Physical activity has major effects on glucose and lipid metabolism. The sequence of metabolic changes during exercise can be summarized as follows: white muscle fiber metabolism dominates during the first few minutes of exercise. During endurance exercise red fibers dominate. Their aerobic glycolysis is increased and all endogenous and exogenous substrates are oxidized. Muscle and liver glycogen is mobilized and used up. Glucose uptake may increase up to 20-fold. Serum insulin decreases, indicating enhanced insulin sensitivity. After about 10 minutes' exercise, oxidation of FFA becomes more important and may increase to up to 50-fold of the basal level. Finally, energy metabolism is fueled mainly by FFA and β-hydroxybutyrate/acetoacetate. After strenuous exercise (e.g., marathon), plasma FFA may stay elevated and glucose uptake may remain reduced for several hours (“post-exercise insulin resistance”). A paradoxical increase in blood glucose is seen after short-term exhaustive exercise, which is the result of stress hormone release [106,107].
Increased insulin sensitivity during exercise is due to increased muscular blood flow with greater insulin delivery to muscle, opening of closed capillaries, which enhances the surface area for glucose uptake, and translocation of glucose transporters, mainly GLUT-4 [108]. Physical training stimulates GLUT-4 synthesis [109]. Enhanced insulin sensitivity vanishes in periods of physical inactivity. This occurs as early as after a few days of strict bed rest.
Clinical experience shows that in poorly controlled diabetic individuals insulin sensitivity is decreased. It improves when metabolic control is restored towards normal. This metabolic insulin resistance has been described by the term “glucose toxicity.” The mechanism of glucose toxicity is not fully understood. One explanation is increased synthesis of glucosamine, which could cause insulin resistance by inhibition of the translocation of GLUT-4 in muscle [110–112]. Glucosamine seems also to inhibit glucose-induced insulin secretion [110]. Thus, this metabolite would mimic both the major pathogenetic mechanisms in type 2 diabetes. However, since poor metabolic control is characterized by high plasma FFA levels, the aforementioned effects of plasma FFA on liver and muscle metabolism could also explain some signs of metabolic insulin resistance.
Insulin Secretion
Instead of postulating insulin resistance and peripheral underutilization of glucose as the primary defect, some investigators have proposed that impaired insulin secretion and impaired suppression of hepatic glucose production are the important determinants of glucose intolerance [102,113]. Gerich [114] based his view on the evaluation of insulin secretion after an oral glucose load. In subjects with impaired glucose tolerance, and even more in those with clinical N1DDM, early insulin secretion is reduced and late insulin secretion increased [115]. Defective early insulin release is responsible for impaired glucose tolerance, which on its part triggers late hyperinsulinemia. The suppression of hepatic glucose production is impaired [102,116], resulting in increased hepatic glucose output. Under steady-state conditions this is equal to increased glucose disposal. Indeed, forearm muscle glucose uptake is not impaired in person with impaired glucose tolerance [116]. From these observations, Gerich concluded that peripheral insulin resistance cannot be an important pathogenetic factor [114].
Hepatic glucose output is directly related to fasting plasma glucose, supporting the view that the liver plays a major role in fasting hyperglycemia. However, increased hepatic glucose output may not be a primary defect. As mentioned before, increased hepatic glucose output can be explained as a response to enhanced lipolysis, with the primary defect being ascribed to insulin resistance of the adipocyte.
Recently, in order to elucidate the sequence of events, body weight and body composition, insulin secretion, insulin action, and endogenous glucose output were continuously monitored in a longitudinal study over several years in Pima Indians in whom normal glucose tolerance progressed to diabetes [117]. Progression to impaired glucose tolerance was associated with an increase in body weight and fat mass and a decline in both early insulin response to a glucose stimulus and insulin-stimulated glucose disposal. Progression to diabetes was accompanied by progression of these two disorders and, in addition, by an increase in basal endogenous glucose output. Subjects who retained a normal glucose tolerance in spite of weight gain (nonprogressors) were insulin-resistant but improved their early insulin secretion. According to this study, the ability to improve early insulin secretion decides progression to diabetes. Increased endogenous glucose output is a later event in the development of type 2 diabetes [117].
Genes responsible for defects of early insulin secretion and insulin secretory capacity have not yet been identified. However, the familial nature of type 2 diabetes leaves little doubt that they play a role. On the other hand, secretory defects may also be acquired due to glucose toxicity or hyperlipacidemia [118]. Thus, there is evidence for primary genetic and secondary environmental influences on insulin secretion and insulin sensitivity, respectively.
Clinical Picture of Diabetes Mellitus
Acute Symptoms
Mild hyperglycemia usually does not cause symptoms and may not be noticed by the patient, but severe hyperglycemia will always cause clinical symptoms.
People with untreated diabetes develop progressive hyperglycemia. When the renal threshold for plasma glucose of about 7 mmol/l is surpassed, glucose is excreted with the urine. Glucosuria goes along with osmotic diuresis and results in large urine volume, thirst, exsiccosis, and electrolyte disorders. Together with these effects of insulin deficiency, electrolyte imbalance is accentuated by cellular loss and renal excretion of potassium. Protein synthesis is lowered and accelerated proteolysis results in protein loss from muscle and other tissues. Increased amino acid levels in blood may be utilized for energy metabolism and gluconeogenesis. Lipid storage is blocked, while lipolysis is increased. This results in the massive appearance of FFA in blood. They are in part incorporated into lipoproteins, thus inducing hyper- and dyslipidemia. FFA also swamp into the energy metabolism. This process is enhanced by elevated levels of plasma glucagon, which activates the enzyme carnitine-palmitoyltransferase (CPT-1) and the transport of long-chain fatty acids into the mitochondria. Here they compete with glucose for the oxidative chain, thus decreasing glucose oxidation. The supply of FFA is greater than the energy need. The FFA surplus is only degraded to the level of β-hydroxybutyrate and α-ketoglutarate, which may accumulate and cause ketoacidosis.
FFA also stimulate gluconeogenesis and hepatic glucose output, they modulate signal chains (e.g., PI-3 and IRS phosphorylation depressed. PKC activated), and contribute to metabolic insulin resistance (pages 6–8).
These disorders result in the classical symptoms of insulin deficiency: polyuria, thirst, polydipsia, exsiccosis, muscle wasting, loss of lipid stores, weight loss, polyphagia, fatigue, and nausea. At diagnosis, about 1% of the subjects have developed ketoacidosis with hyperventilation and eventual coma.
Type 1 Diabetes
Five phases of type 1 diabetes mellitus may be distinguished.
Prediabetes is characterized by the presence of islet cell autoantibodies in blood serum without metabolic disorders. Clinically important types are antibodies against islet cell cytoplasm (ICA), glutamic acid decarboxylase(LGAD), and tyrosinphosphatase (IA-2) (Table 1.10). Islet cell autoantibodies can often be detected many years before clinical manifestation. Transient presence of antibodies may have no relevance, but persisting antibodies indicate that type 1 diabetes will follow with a probability that increases if more than one autoantibody is detected and if they are present at high titers. In antibody-positive persons they should be monitored once or twice per year. Tests for insulin secretory capacity may have additional predictive value [44].
At manifestation symptoms are more frequent in younger than in older individuals. In young subjects it may be only hours or a few days from the first signs until a serious clinical syndrome develops. In later adulthood, the progression from insulin deficiency to overt clinical diabetes is often retarded [120–122]. The clinical picture of these people may resemble that of type 2 diabetes, but they are islet cell antibody-positive and will usually need insulin during the first year after diagnosis. It can be expected that about 10% of newly diagnosed diabetic subjects originally classified as having type 2 in fact have this form of type 1 diabetes [12]. The term “latent autoimmune diabetes inadults” (LADA) has been used to describe this subgroup.
Table 1.10 Islet cell specific autoantibodies in type 1 diabetes. Prevalence at manifestation
| Antibodies to | Prevalence (%) |
|---|---|
| Islet cell cytoplasm (ICA, IgICA, ICCA) | 60-90 |
| Glutamic acid decarboxylase (GAD) | 70-90 |
| IA-2 | 70-90 |
| IA-2β | >50% |
| Insulin (IAA) | 20-100 |
| Proinsulin (PAA) | 10-20 |
| BSA | 60-100 |
| ICA 69 | 60 |
| 38-kDa insulin granules | > 30 |
| Glucose transporter | 80-100 |
| Carboxy peptidase H | 30-50 |
| Polar antigen | 30-50 |
| 52-kDa protein | > 30 |
| 150-kDa protein | 80-100 |
| Islet cell surface (ICSA) | 60-80 |
Adapted from [120]
Frequently the manifestation of type 1 diabetes seems to be precipitated by coincident diseases that increase the insulin requirement, such as infections, pregnancy, hyperthyroidism, glucocorticoid treatment, or severe somatic stress (myocardial infarction, major surgery, etc,).
In about two-thirds of subjects a remission will follow the initiation of therapy. The required insulin dose decreases and metabolism stabilizes due to some recovery of insulin and C-peptide secretion together with improved insulin sensitivity. The remission period can be prolonged by experimental immunomodulatory therapy [123]. However, sooner or later the individual will become C-peptide-negative. After some weeks or months, remission is usually followed by a relapse and the development of irreversible clinical diabetes, which under unfavorable conditions may proceed to end-stage diabetes with chronic complications.
If diabetes mellitus is suspected, the diagnosis should immediately be checked by laboratory tests. If the diagnosis is confirmed, it is advisable to start therapy and normalize the metabolism promptly, because this seems to improve the chances of inducing a remission [124].
Treated type 1 diabetes mellitus is not associated with hypertension, lipid disorders, or obesity. However, this does not rule out their existence at diagnosis or that they may develop later. The further course of the disease is determined by the lability of the metabolism, problems of insulin substitution, glucose monitoring, hypoglycemia, and hyperglycemia. The quality of metabolic control is the main determinant of the prognosis.
Type 2 Diabetes
In the majority of cases the disease begins as a metabolic syndrome. In this early stage most symptoms are reversible. Progression to clinical diabetes is not inevitable. The progress of the blood glucose disorder from impaired fasting glucose or impaired glucose tolerance to overt diabetes may take years. Even when diagnostic criteria are reached, hyperglycemia may not cause the classical symptoms, and glucosuria may be minimal or lacking due to an elevated renal threshold. Other symptoms will often be misinterpreted as a normal attribute of aging. Thus, it may take a couple of years until diabetes is diagnosed.
In contrast to type 1 diabetes mellitus, glucose metabolism in type 2 diabetes mellitus is usually fairly stable. However, treatment is usually more difficult than in type 1 diabetes because it requires life-style changes. The disorder tends to increasing severity, and over the years it becomes more and more difficult to achieve near-normal metabolic control [125]. As in the case of type 1 diabetes, the prognosis of type 2 diabetes depends on the quality of metabolic control. However, in addition to glucose metabolism, the other components of the metabolic syndrome such as obesity, hypertension, and dyslipoproteinemia, and life style are equally important.
Chronic Complications
The chronic complications of diabetes - mainly microangiopathy, neuropathy, and macroangiopathy - are major problems, because they determine the prognosis and quality of life of the patients. Although the details of their pathogenesis are not fully understood, there is no doubt that the diabetic condition is the major cause. Epidemiological studies have shown that their incidence increases with poor metabolic control [126–132] and can be reduced by lowering HbA1c[127,130,131,133]; however, the beneficial effect of strict metabolic control on macroangiopathy is rarely significant [127,130,133–135]. Many proposals have been put forward to explain “diabetes the risk factor,” which forms a network of potentially pathogenetic mechanisms. Recent articles have covered specific topics and the reader is referred to these publications [136–145]. It is not the aim of this short introduction to add another review.
In addition to insulin deficiency/hyperglycemia. other pathogenic factors such as adverse life style, hypertension, lipid disorders, proteinuria, unfavorable hemorrheology, and activated hemostasis are also involved. These will be mentioned in the context of the various clinical manifestations.
The following section outlines the role of hyperglycemia in the pathogenetic network leading to microangiopathy [146–149].
Introduction to the Pathogenesis of Microangiopathy
Hyperglycemia has three important effects that are to some extent interdependent: nonenzymatic glycation, activation of the polyol pathway, and generation of reactive oxygen species (ROS).
The formation of early glycation endproducts (Schiff base and Amadori products) is reversible, but glycated long-lived molecules like DNA and matrix/basement membrane proteins may undergo irreversible cross-linking and other not yet fully understood complex reactions to form advanced glycation endproducts (AGE).
This process leads to considerable changes in their three-dimensional structure and function. Glycated LDL (low-density lipoproteins) are more atherogenic than nonglycated LDL The charge of matrix proteins may be altered, leading to increased permeability, and basement membrane proteins may become resistant to degradation andincrease in thickness and stiffness. AGE may impair the relaxation of vessels by quenching nitric oxide [150]. Moreover, they favor coagulation and thrombosis and initiate atherosclerosis by stimulating macrophages to express AGE receptors (RAGE) and to release cytokines such as TNF-α. IL-1. and IGF.
The activation of the polyol pathway leads to the accumulation of sorbitol, which is followed by myoinositol depletion and inactivation of Na+-K+-ATPase channels. In addition, the production of fructose and sorbitol, which contribute to the formation of AGE, is increased.
There is much evidence that both advanced glycation endproducts (AGE) and high glucose are able to induce the generation of ROS in various types of vascular cells and that this process plays an important role in the initiation of vascular complications in diabetes. In addition to the autoxidation of glucose, three different mechanisms of ROS production are presently under debate:
1. Activation of a membrane-bound, macrophage-like NADH-oxidase. Activation of NADH-oxidase in endothelial cells and smooth muscle cells has been reported in subjects with hypertension and hypercholesterolemia. AGE and angiotensin II are strong activators of this enzyme in vascular cells.
2. Alternatively, it has been suggested that the electron flux in endothelial nitric oxide synthase (NOS III) becomes uncoupled in diabetes and hyperglycemia. In this uncoupled state the electrons flowing from the reductase domain to the oxygenase domain of the NOS complex are diverted to molecular oxygen rather than to L-arginine. In line with this assumption, production of ROS was prevented in human and rat endothelial cells in the presence of inhibitors of NOS.
3. Recently, Nishigawa et al. [146] demonstrated in cultured bovine aortic endothelial cells that in hyperglycemic conditions the mitochondrial electron flux becomes uncoupled from ATP synthesis, resulting in increased ROS production. ROS production was prevented by various uncouplers of the mitochondrial electron chain and overexpression of the uncoupling protein (UCP-2). The activation of protein kinase C, the polyol pathway, the transcription factor NFkB, and the increased formation of AGE and glucosamine were clearly dependent on the formation of ROS, suggesting that at least in these cultured endothelial cells the formation of ROS is the central, initiating step for the transformation of endothelial cells into an active, prothrombotic state. According to these observations, an accelerated substrate flow from either glucose or fatty acids seems to be the final cause for the generation of ROS and oxidative stress.
Against this background, the great importance of accelerated conversion of glucose to fructose by the so-called sorbitol pathway and the changes in the cellular redox state by these processes is obvious. The conversion of glucose consumes NADPH and leads to increased flow of NADH to mitochondria. Since an important cofactor of glutathione peroxidase is diminished, the regeneration of glutathione is impaired, which may limit the antioxidative capacity of the cells and contribute to the occurrence of oxidative stress in diabetes.
The generation of ROS seems to be the initiating factor for a number of processes known to be relevant to the development of vascular complication:
1. Activation of protein kinase C(PKC). The activation of PKC in cells and tissues that take up glucose independently of insulin is mediated not only by a hyperglycemia-dependent increase in diacylglycerol (DAG), but also by the enhanced formation of ROS. Activation of PKC seems to be a common downstream mechanism to which multiple cellular and functional abnormalities in the diabetic vascular tissue can be attributed, including changes in vascular blood flow, vascular permeability, extracellular matrix components, and cell growth.
2. Activation of redox-sensitive transcription factors by AGE and hyperglycemia. AGE formation has so far mostly been in discussion as a process of protein modification. From recent studies it follows, however, that interactions of AGE-modified proteins with specific AGE receptors serve not only to eliminate AGE proteins, but also to induce signal transaction pathways which lead to the generation of ROS, depletion of cellular antioxidant defense mechanisms (e. g., glutathione, ascorbate) and the activation of redox-sensitive transcription factors such as NFkB [144,151]. The activation of NFkB and presumably also other redox-sensitive transcription factors promotes the expression of a variety of kinins, such as the procoagulant tissue factor, endothelin-1, and the adhesion molecules VCAM-1 (vascular cellular adhesion molecule 1), ICAM-1 (intercellular adhesion molecule 1), and MCP-1 (monocyte chemoattracting protein 1), all of which have been found to be increased in the diabetic state. The concept of AGE-induced oxidative stress which activates transcription factors could explain the concomitant occurrence of oxidative stress and changes in the dynamic endothelial balance from an anticoagulant to a procoagulant state, from vasodilatation to vasoconstriction and impaired microcirculation.
3. Activation of the hexosamine pathway and activation of the transcription factor SP-1. ROS have been shown to inhibit glyceraldehyde 3-P-dehydrogenase. In consequence, more glucose will be metabolized to glutamine 6-phosphate. This molecule has been shown to play a role in the induction of insulin resistance. It also enhances glycosylation and activation of the transcription factor SP-1, which accelerates synthesis of plasminogen activator inhibitor 1 (PAI-1) and transforming growth factor β1 (TGF-β1), both of which contribute to the pathogenesis of vascular complications by changes in the hemostatic balance and remodeling processes of the vessel wall.
4. Quenching of nitric oxide. Oxidative stress seems thereby to initiate a vicious cycle reinforcing the imbalance in the redox state of cells and the generation of ROS. These therefore counterbalance the cytoprotective effects of nitric oxide on microcirculation, on the permeability and adhesiveness of the vessel wall, and growth inhibition of smooth muscle cells.
5. Taken together, ROS activate interrelated processes and mechanisms which play a major role in the development of vascular complications in diabetes. However, it must be borne in mind that the outcome of the processes may vary depending the site affected (large vessels, resistance vessels, capillaries).
Following the metabolic concept of pathogenesis, one would expect that the extracellular changes are ubiquitous systemic disorders and that all insulinindependentcells (for only these are exposed to intracellular hyperglycemia) are affected. However, microangiopathy is clinically evident only in the kidney and the eye, and is thought to play a role in neuropathy. Microangiopathy usually begins with reversible functional disorders and may end with irreversible loss of organ function. For this reason, early detection (screening) and monitoring are of paramount importance.
Retinopathy
Epidemiology
The prevalence of diabetic retinopathy is highest in early-onset insulin-treated diabetic subjects and lowest in late-onset non-insulin-treated diabetic subjects. The prevalence increases with the duration of diabetes. In early-onset insulin-treated subjects proliferative diabetic retinopathy is rarely seen within the first five years of diabetes, but after 15 years it is found in 25% of patients and after 20 years in more than 50%. Beyond 20 years, almost 100% of people with diabetes mellitus will develop diabetic retinopathy [152]. In late-onset diabetes retinopathy may be observed at the time the diabetes is diagnosed, but proliferative diabetic retinopathy is rare. The 10-year incidence and progression rates reflect these trends (Table 1.11). Macular edema is more common in late-onset diabetes [153]. Senilecataracts, which will not be further discussed, appear earlier in life and progress faster than in nondiabetic subjects.
Pathology
Diabetic retinopathy is a disease of the retinal vasculature. In the early stages capillary blood flow is increased. The capillary basement membrane is thickened, its composition and charge are altered, its permeability to blood-borne particles and molecules is increased, and pericytes are lost. This process is related to hyperglycemia [127,130–132] and modified by hypertension [158,159], smoking [160,161], and pregnancy [162–164].
Table 1.11 Ten years cumulative incidence of diabetic retinopathy or progression to proliferative diabetic retinopathy (PDR)
| Diabetic group | 10-Year Incidence (%) | 10-Year progression to PDR (%) |
|---|---|---|
| Younger-onset taking insulin:MaleFemaleTotal | 938589 | 293130 |
| Older-onset taking insulin:MaleFemaleTotal | 778079 | 252324 |
| Older-onset not taking insulin:MaleFemaleTotal | 696567 | 71210 |
Data from the Wisconsin Epidemiologic Study of Diabetic Retinopathy [434]
An early morphological sign is the presence of microaneurysms. These have been interpreted as abortive attempts to vascularize ischemic areas. Other early signs are intraretinal (flame-shaped or dotted) hemorrhages and lipoprotein deposits (hard exudates). They are indicative of increased capillary permeability, which could be due to modified LDL, free radical damage of endothelial cells, or AGE formation in the endothelial matrix proteins, which attract platelets and macrophages and stimulate the expression of vascular permeability factor (VPF) and other cytokines. Disruption and fenestrations of the endothelial layer and vascular proliferation may occur. Another important clinical sign of vascular permeability is focal or diffuse macular edema.
A later morphological sign is capillary closure. This may be caused by the activated hemostasis with expression of adhesion molecules in platelets and leukocytes as well as by procoagulatory changes of the endothelium and matrix areas exposed to the blood flow because of endothelial disrupture.
Capillary closure is followed by ischemia, which is a potent trigger of new vessel formation. This process is normally suppressed by collagen IV, but it is stimulated by collagen fragments, fibronectin, and local growth factors such as vascular endothelial growth factor (VEGF; secreted in response to hypoxia), fibroblast growth factor(FGF), and TGF-β. Formation of new vessels may not be restricted to the retina. They may grow into the preretinal space and vitreous and eventually cause retinal detachment. New vessel formation may also occur in the iris, where it causes rubeosis iridis and possibly neovascular glaucoma.
Classification
For the purposes of therapy and prognosis, diabetic retinopathy may be classified according to the Early Treatment Diabetic Retinopathy Study Research Group [165] as follows:
1. Background retinopathy, characterized by microaneurysms, hard exudates, generalized venous dilatation, intraretinal hemorrhages, and occasional cotton wool spots (retinal infarcts). Background diabetic retinopathy does not necessarily progress to more advanced stages.
2. Preproliferative retinopathy, characterized by localized irregularities of venous caliber (beading), which are strong predictors of neovascularization; venous looping and reduplication: multiple (≥ 5) cotton wool spots; and intraretinal microvascular abnormalities (IRMAs—abnormally branched vessels within the retina).
3. Proliferative retinopathy, characterized by abnormal new vessels growing into the preretinal space, vitreous, or, occasionally, on the iris. Bleeding from these vessels, retinal detachment due to contraction of fibrotic structures that develop in the hemorrhages, and neovascular glaucoma may cause impairment of vision.
Another cause of impaired vision is maculopathy due to capillary leakage (edematous, wet maculopathy) or to ischemia (dry maculopathy).
Management
The different classes of diabetic retinopathy require different action depending on the risk of loss of vision. In general, the best primary prevention is near-normal metabolic control, normal blood pressure, and giving up smoking [127,130,158,159,166,167]. In secondary prevention, abrupt normalization of poor metabolic control of long duration should be avoided because of the so-called normoglycemic re-entry phenomenon [168,169]. Dyslipoproteinemia increases the risk of hard exudates, maculopathy [170], and vascular proliferations [171] and should be effectively treated. Guidelines for ophthalmological intervention have been developed (for references see [172–174]). The most important technical methods of treating diabetic retinopathy are photocoagulation and vitreous surgery, which may save useful vision in up to 70% of cases of severe proliferative diabetic retinopathy. A difficult problem is dry (ischemic) maculopathy. Treatments based on improving the microcirculation are still experimental [175].
Any diabetic person requires an ophthalmological checkup at diagnosis and annually thereafter. Background retinopathy should be monitored every 6 months. Referral to the ophthalmologist is indicated soon in the case of preproliferative diabetic retinopathy or maculopathy. Referral is urgent if new vessels develop, particularly if they originate from the optic disk. Immediate referral is indicated if retinal detachment, vitreous hemorrhage, or neovascular glaucoma is suspected.
Nephropathy
Diabetic nephropathy is a microvascular disease of the glomerulus (diabetic glomerulosclerosis). It begins with hyperfiltration followed by proteinuria, hypertension, and progressive renal failure. The pathogenesis and clinical course of diabetic nephropathy are better known in type 1 than in type 2 diabetes. They appear to be similar but not identical.
Epidemiology
The prevalence of microalbuminuria or any more advanced stage of nephropathy in IDDM increases during the first 20 years after diagnosis (or, in children, after puberty) to > 50% and levels off thereafter. During this time only about half of the microalbuminuric subjects will develop macroproteinuria and only a minority will develop end-stage renal disease [176]. The cumulative incidence of persistent macroproteinuria is about 35% in both IDDM and NIDDM. However, endstage renal disease after 30 years of diabetes is more often present in IDDM (>20%) than in NIDDM (10%) [177–179]. About 30–50% of all patients on chronic dialysis have diabetes (which does not imply that the reason is always the diabetes). Since type 2 diabetes is much more frequent than type 1 diabetes, it contributes the majority of these subjects.
The incidence and progression of diabetic nephropathy are related to metabolic control [127,130–133] and blood pressure [158,159]. A threshold phenomenon was postulated [180], but was rejected [181,182]. Mortality is high in subjects with diabetic nephropathy. Microalbuminuria has been identified as a strong predictor of cardiovascular disease.
In proteinuric subjects coronary artery disease is about 15 times more frequent than in diabetic subjects without proteinuria [154], and cardiovascular mortality is increased nine-fold [183,184]. Ten-year survival of subjects with persistent proteinuria used to be only 20-50% [179,185]. Antihypertensive treatment and renal replacement therapy have effectively improved the prognosis. In recent studies, eight-year survival after the onset of persistent proteinuria rose to 70-87% [176,186,187].
Before renal replacement therapy was available, the main cause of death in subjects with proteinuria was uremia. About 25% died from myocardial infarction or stroke. Renal replacement therapy reduced deaths from uremia but increased deaths from cardiovascular causes [188].
Pathology
As in diabetic retinopathy, there is no doubt about the influence of hyperglycemia on the development of diabetic nephropathy. However, the causal relationship is less clear. There is no linear relation between the cumulative incidence of any sign of diabetic nephropathy and the duration of diabetes, and more than half of diabetic subjects never develop such nephropathy [176,189]. Normal kidneys transplanted into diabetic recipients may develop typical lesions, but the rate of development varies and is independent of metabolic control [155]. These observations suggest that hyperglycemia is necessary but not sufficient for the development of diabetic nephropathy. Other important pathogenetic factors are hypertension, protein intake, renal hemodynamics, smoking, and genetics.
The hyperglycemia-related pathogenetic effects discussed on pages 11 and 12 are also found in diabetic nephropathy. In addition, synthesis of the glucosaminoglycan heparan sulfate and glycoproteins is impaired [136]. These molecules contribute to the negative charge of the glomerular capillary membranes and are involved in the selectivity of glomerular filtration, which consequently may be reduced. Hemodynamics are another important pathogenetic factor. The impact of hypertension on diabetic nephropathy has been shown in epidemiological and antihypertensive treatment studies [156–159,190,191]. A significant example of direct jeopardizing of the kidney by hypertension is seen in people with unilateral renal artery stenosis, where only the kidney with the patent artery develops glomerulosclerosis [155].
Evidence for a genetic influence comes from family studies. Siblings of probands with nephropathy develop signs of nephropathy several times more often than do siblings of probands without nephropathy [192,193]. Recently epidemiological studies showed an increased incidence of diabetic nephropathy at level of a protein intake exceeding 20% of total energy [194], suggesting a pathogenetic role of nutritional protein.
The clinical picture of diabetic nephropathy is dominated by functional disorders, which may be classified according to Mogensen [195] (Table 1.12). The functional disorders correspond to morphological changes. The early increase in glomerular filtration rate has been explained by the ubiquitously increased blood flow and peripheral vasodilation. It correlates to increased kidney size, glomerular volume, and capillary filtration surface area.
Microalbuminuria develops without apparent morphological changes. It seems to be caused by increased glomerular capillary pressure and a loss of negative charge of the glomerular basement membrane. When the pores of this membrane enlarge, filtration selectivity is lost, and (macro-)proteinuria develops. With mesangial expansion due to continuous deposition of indigestible matrix proteins (formation of AGE on collagen, laminin, fibronectin) and thickening of the endothelial layer, vascular obstruction will occur, which results in a decrease of the filtering area. Histological studies show diffuse or nodular glomerulosclerosis [196–198]. In this situation blood pressure increases, glomerular filtration rate decreases, and progressive renal failure with end stage renal disease will develop.
Management
It is essential to detect diabetic nephropathy at a reversible stage. At Mogensen's stages 1-3 (Table 1.12) the disorders are reversible and renal function may be kept normal if effectively treated. In stages 4 and 5 it may only be possible to delay or possibly halt progression.
The most relevant diagnostic sign is microproteinuria. Microalbuminuria screening should be started not later than five years after diagnosis of type 1 diabetes, and at the time of diagnosis of type 2 diabetes. For correct diagnosis and follow-up monitoring, quantitative determination of albumin in urine collected over precisely measured time periods is essential. An albumin excretion rate (AER) below 30 mg per 24 hours (20 μg/min) is considered normal, whereas an AER above 300 mg per24 hours (200 μg/min) is considered to define macroalbuminuria or proteinuria. In between these two extremes is the range of microalbuminuria. Alternatively, the urinary albumin/creatine ratio may be determined [189].
Prevention and treatment of diabetic nephropathy is based on achieving near-normal metabolic control [127,129–131,199–202], lowering elevated blood pressure to values below 130/80 mmHg [157,158,191], a normal protein intake of 0.8-1.2 g/kg body weight [203,204], cessation of smoking (if applicable), and diagnosis and treatment of nondiabetic renal or urinary tract disease.
In normotensive diabetic subjects ACE inhibitors do not reliably prevent the development of microalbuminuria [205]. In normotensive patients with microalbuminuria, captopril and calcium channel blockers [206–212] retard the progression of nephropathy. In hypertensive subjects both the ACE inhibitor captopril and the β-adrenergic blocker atenolol retard the development of microalbuminuria [158,206]. In hypertensive diabetic subjects with micro- or macroalbuminuria, lowering blood pressure with ACE inhibitors, β-adrenergic blockers, or calcium channel blockers retards the progression of albumin excretion [213–221]. While the UK Prospective Diabetes Study (UKPDS) suggested that blood pressure reduction itself may be more important for nephroprotection than the type of drug used for treatment, recent secondary prevention studies in type 2 diabetic subjects suggest that inhibition of the renin - angiotensin system may be more advantageous than other antihyperintensive therapy. In studies with ACE inhibitors [222] and with angiotensin receptor blockers [223–225] the nephroprotective effect was beyond that attributable to blood pressure control.
Cardiovascular risk is increased at any stage of diabetic nephropathy, and the majority of patients with such nephropathy will die not of uremia but of macrovascular complications [183,184,188,226]. Prevention of these complications is mandatory, and risk factors for macroangiopathy other than hypertension should also be treated.
Diabetic nephropathy is accompanied by lipid disorders which are believed to contribute essentially to the high cardiovascular risk [227]. Treatment of dyslipoproteinemia is mandatory, as are “stop smoking” programs for smokers.
Platelet aggregation inhibition with aspirin is recommended in diabetic patients with albuminuria [228]. Radiopaque media should only be used after careful hydration of the patient [229].
Patients with endstage renal disease will need renal replacement therapy. Chronic hemodialysis, peritoneal dialysis (intraperitoneal, continual ambulatory), and renal transplantation in combination with pancreas transplantation [230] are presently the methods of choice. The prognosis of patients who have undergone transplantation has recently been improved but still is not as good as in non-diabetic subjects [176,187,230].
Almost 100% of patients with endstage renal disease also have diabetic retinopathy and/or diabetic neuropathy. Monitoring and treatment of these complications is equally important.
Macroangiopathy
The term “macroangiopathy” was introduced by Lundbaek [231] to draw attention to the fact that large-vessel disease in diabetes is not just a matter of atherosclerosis occurring in a diabetic subject, but is a facet of diabetic angiopathy as important as microangiopathy. The major clinical complications of macroangiopathy are coronary artery disease, stroke, and amputation. Only coronary artery disease will be discussed in more detail in this chapter.
Epidemiology
Due to the insidious course of macroangiopathy and the difficulties of early diagnosis, reliable population-based data on its incidence and prevalence are lacking. Some epidemiological data on the clinical manifestations are available [232]. The figures for their incidence and prevalence in diabetes depend on their occurrence in the general population to which they belong and differ considerably between countries [233]. However, clinical, epidemiological [154,234–236], and autopsy studies [237,238] and cause-of-death statistics [29,239] agree that the figures are higher in people with type 1 diabetes/IDDM and type 2 diabetes/ NIDDM than in the general population. After 30 years of IDDM, cardiovascular disease accounts for two-thirds of all deaths [21]. Macroangiopathy develops earlier in life and occurs almost independently of gender [154,240]. The increase in risk is higher in women than in men [236,241,242]. Thrombotic complications of macroangiopathy are the leading cause of death in diabetes [29,243–245].
Coronary artery disease is 3.3 times more frequent in diabetic than in nondiabetic people [246]. Myocardial infarction is 3.7 times more frequent in diabetic men and 5.9 times more frequent in diabetic women [242]. In another study [247] the increase was 6.7 times in type 2 and 12.2 times in type 1 diabetic women. The higher risk of women goes along with more atherogenic lipid profiles (see below). The standardized mortality rate (corrected for age and gender) for any heart disease is 9.1 times higher if diabetes mellitus is diagnosed before the age of 30 and 2.3 times higher if it is diagnosed later [248]. As a rough estimate, in western societies about half of diabetic people die of premature cardiac death. Stroke is about twice as frequent as in the general population, and two out of three amputations are performed in diabetic people.
Pathology
The histology of lesions in the arterial wall of diabetic subjects is similar to what is seen in the general population. However, lesions tend to be located in more distal regions of the vasculature. In diabetic subjects, the established sequence of early events in atherogenesis seems to be the same as in nondiabetic subjects:-adhesion of monocytes to endothelial cells, mediated by VCAM-1-penetration of monocytes into the vessel wall, mediated by MCP-1-activation of monocytes to form macrophages/foam cells/fatty streaks, mediated by MCSF (macrophage colony stimulating factor). The classical risk factors of atherosclerosis are also effective in diabetes mellitus [135,154,249–251], and diabetes enhances the impact of these risk factors. Hyperglycemia contributes to the pathogenesis of macroangiopathy. However, the correlation with the duration of diabetes and HbA1c is weak. There must be additional specific risk factors in diabetic people, which are absent or only weakly expressed in non-diabetic people (Table 1.13).
Activated hemostasis seems to play an important role. It results from increased plasma coagulation and decreased fibrinolysis together with a loss of physiological endothelial platelet resistance, increased thrombogenicity of the subendothelial matrix, and platelet activation [138,140,252–255]. The plasma factors involved in hypercoagulation have been summarized by Ceriello [256,257]: increase of plasma fibrinogen, factor VII and VIII, α2-macroglobulin, and PAI-1, decrease of protein C. protein S, and prostacycline, and increase in the activity of factor X, antithrombin III, heparin cofactor II. and von Willebrand factor. Only some of the mechanisms underlying these disorders are known, e.g., the regulation of PAI-1 by TNF-α, insulin. VLDL, AGE, and endothelial injury [258].
Table 1.13 Risk factors of atherosclerosis and diabetic macroangiopathy
| Classical risk factors of atherosclerosis | Additional specific risk factors of diabetic macroangiopathy |
|---|---|
| Hypertension, systolic and diastolic | Hyperglycemia |
| Dyslipidemia | Abnormal lipoproteins |
| Obesity | Platelet activation |
| Smoking | Endothelial dysfunction |
| Stress | Hypercoagulation (increased fibrinogen and PAI-1) |
| Physical inactivity | Albuminuria |
| Family history of atherosclerosis | Hyperhomocystinemia |
| Age | Insulin? |
| Previous myocardial infarction | Duration of diabetes? |
Platelet activation, which is well documented [259–261], is in part constitutional and results from the priming of megakaryocytes [262,263]. However, it may also be induced reactively by LDL [264] and by endothelial injury through thromboxane A2 which is increased in diabetes [265]. Platelet activation goes along with increased expression of adhesion molecules. It favors thrombogenesis and the formation of circulating aggregates of platelets and platelets with leukocytes that are large enough to occlude small vessels [266]. This process is promoted by dyslipoproteinemia [267]. The expression of adhesion molecules contributes to the unfavorable rheological properties of the blood.
After interaction of activated platelets with injured endothelial cells, various growth factors are released which are known to be involved in atherogenesis, such as platelet-derived growth factor (PDGF), TGF-β, endothelium-derived relaxing factor (EDRF), endothelial, and others [268]. Thus, platelet activation may favor thrombogenesis, atherogenesis, capillary occlusion, and microvascular proliferation.
Endothelial dysfunction is another key factor in the pathogenesis of diabetic angiopathies [140,269]. The balanced interaction between blood and vessel wall, which regulates blood flow, hemostasis and vessel wall metabolism, is disturbed in diabetes. Loss of normal endothelial function and activation of abnormal reactions [270] may initially be caused by endothelial injury, and this may finally result in loss of cellular integrity and in cell death.
Endothelial dysfunction is a ubiquitous defect which is not limited to the regions of clinical angiopathy. Its early clinical marker seems to be microalbuminuria.
Blood flow is mainly regulated by vasodilatory EDRF (EDRF = nitric oxide) and the prostaglandin derivative prostacyclin, while endothelin-1, angiotensin II and the platelet factors thromboxane and serotonin are vasoconstrictive. In diabetes the balance of this system is disturbed. The main cause seems to be nitric oxide quenching by AGE [150] and other oxidative stress [271,272].
Lipids and lipoproteins are predictors of coronary artery disease [273]. Discussions of their role in the pathogenesis of atherosclerosis usually emphasize high triglycerides and cholesterol and low HDL-cholesterol levels. These abnormalities are frequently observed in diabetes, and their impact on risk of coronary artery disease is at least as high as in the nondiabetic population [274–278]. The significance of postprandial hypertriglyceridemia in diabetes may have been underestimated in the past [279–281]. Insulin substitution favors an antiatherogenic lipoprotein pattern [282]. In well-controlled type 1 diabetes, lipids tend to be fairly normal. By contrast, dyslipidemia is usually observed as a part of the metabolic syndrome in obese subjects with impaired glucose tolerance and type 2 diabetes [276]. It also develops in poorly controlled type 1 diabetes and in subjects with nephropathy [283,284] (Table 1.14). Lipid abnormalities seem to be more pronounced in women than in men [285,286].
In the presence of insulin and under the influence of high serum glucose, free fatty acids, and amino acids, VLDL synthesis is increased in the liver. Peripheral triglyceride uptake is delayed because of low lipoprotein lipase activity, resulting in hypertriglyceridemia. Hypertriglyceridemia correlates with PAI-1 activity and is associated with low HDL-cholesterol and alterations in the metabolism of other lipoproteins.
In addition to these quantitative alterations, the generation of abnormal lipoproteins seems to be very important [287,288]. The dyslipoproteinemia of diabetes is characterized by the formation of triglyceriderich particles (VLDLI) and abnormal LDL [274,289,290], Small, dense LDL (LDL III) are susceptible to lipid oxidation and strongly related to cardiovascular risk [291–295]. Another effect is the lowering of cardioprotective HDL2, usually measured as low HDL-cholesterol [290,296–298].
Lipoproteins are also subject to glycation of their apoproteins and phospholipids [227]. Glycation promotes lipid oxidation and markedly changes the functional properties of lipoproteins. They become immunogenic and bind to specific scavenger receptors. This excludes them from the regulated lipid metabolism [299] and drains them into foam cell formation. They also act as stimulators of kinin release from endothelial cells and monocytes/macrophages. Thus, diabetic dyslipoproteinemia is related to a variety of factors that may enhance the risk of macroangiopathy [290,295,298].
The correlation of insulin and its precursors with macroangiopathy has received much attention [300]. It has been shown that insulin stimulates the migration, proliferation, LDL binding, and cholesterol synthesis of vascular smooth muscle cells. It may also raise blood pressure by enhancing sodium reabsorption and the sympathetic tone of vessel walls. Insulin is a prerequisite of increased VLDL synthesis, which is an important early step in the development of dyslipoproteinemia. Insulin, proinsulin, and hypertriglyceridemia stimulate PAI-1 synthesis in endothelial cells and liver and inhibit fibrinolysis [301]. However, the possible role of insulin in the pathogenesis of macroangiopathy remains a matter of debate. It may make a difference whether insulin is being used to restore insulin deficiency or whether it occurs as hyperinsulinemia in insulin-resistant states.
Clinical Picture and Management of Coronary Heart Disease
Considering the high mortality associated with myocardial infarction and the high risk of reinfarction, primary and secondary prevention of coronary heart disease (CHD) is of utmost importance.
In both types of diabetes mellitus, myocardial infarction and macroangiopathy are related to metabolic control, but a significant lowering of risk by lowering HbA1c alone could not be shown [127,130]. Treatment of obese type 2 diabetic subjects with metformin significantly lowered the incidence of myocardial infarction [133], indicating that this drug has not only anti-diabetic effects, but also others. In type 2 diabetes myocardial infarction is also associated with hypertension [159]. However, as shown in the UKPDS [158], which used calcium channel and β-receptor blockers, lowering of blood pressure by itself was not able to reduce significantly the risk of myocardial infarction. In contrast, studies with ACE inhibitor ramipril significantly lowered the risk of myocardial infarction, stroke, and cardiovascular death [222,302], indicating that other than blood pressure lowering effects must be important.
Primary and secondary prevention with aspirin has been recommended [138,303,304], and dyslipidemia should also be treated. In secondary prevention, clinical data showed that β-blockers [305] and ACE inhibitors [306,307] were beneficial.
From the list of known risk factors (Table 1.13) it is evident that primary prevention of macroangiopathy should pay attention to more than just the risk factors considered in the Diabetes Control and Complications Study (DCCT) and UKPDS. The need for a holistic view [308] is underlined by intervention studies in diabetic populations [309,310].
In myocardial infarction in diabetic subjects, most frequently the left coronary artery is occluded, and often two or three arteries are involved. The lesions tend to be localized distally; unstable plaques are frequent.
The most frequent complications of myocardial infarction in diabetes mellitus are left ventricular dysfunction, congestive heart failure, cardiogenic shock, arrhythmias, and sudden death [311–313]. Silent infarction is frequent and seems to be more closely related to the severity of the coronary artery disease than to cardiac autonomic neuropathy [314–316].
The prognosis depends on age, acute metabolic control, and duration of diabetes [317–319]. Early and late mortality is increased 1.5- to 2.5-fold in men and four-fold in women [29,320]. Recently one-year mortality was reduced by infusion of glucose with insulin and potassium [321]. The benefit of thrombolytic therapy is debated [322,323]. A considerable reduction of late mortality has been achieved by surgical therapy [324]. The indication for interventional therapy of myocardial infarction in diabetes is the same as in the general population. In most studies the early mortality associated with percutaneous transluminal coronary angioplasty, stent implantation, and coronary bypass surgery was no higher than in nondiabetic subjects, but long-term survival is still lower [325–330].
In addition to coronary artery disease, diabetic subjects may have cardiac problems even when the coronary arteries are intact. They have been attributed to diabetic cardiomyopathy and microvascular dysfunction characterized by reduced coronary flow reserve [331,332].
Management of Diabetes Mellitus
Prevention
Since diabetes mellitus has taken on epidemic dimensions, with an incidence that continues to rise, prevention is indispensable if we are to gain control of this disease. In the etiology of both types of diabetes, genes and environmental factors complement one another. Genes will most likely not become the target of preventive measures in the foreseeable future. However, environmental factors could offer the chance for successful intervention.
At present we do not know the environmental factors involved in the pathogenesis of type 1 diabetes mellitus. Ongoing prevention studies are aiming at the elimination of potential triggers of the autoimmune process and intervention studies at the level of the insulitis, or the basic mechanisms of autoimmunity [43,333,334]. The results remain to be seen.
In type 2 diabetes mellitus the determination factors are known (Table 1.6). Only early detection and treatment of the metabolic syndrome will reverse the epidemic trend of type 2 diabetes and its major complications. Among the factors that can be influenced, adverse life style, obesity, and physical inactivity are highly significant [53–56,335–338]. Their correction is the best prevention and causal treatment of type 2 diabetes mellitus.
Societies with increasing prevalence of type 2 diabetes seem to be characterized by a Western life style that includes little physical activity and in which overeating is common. Therefore, prevention of type 2 diabetes should start with population-wide awareness campaigns and counseling about a healthy life style. The management of “civilization-dependent” diseases is not just a medical problem but also a cultural one. The particular situations in different geographic regions must be taken into account. Voluntarily changing a life style which people have found comfortable and pleasant is a life-long task. It is not enough to face people with rational arguments. They need to be offered emotional rewards as well. The ideal would be to make healthy life style fashionable [339].
Various strategies have been proposed in the past [340]. Holistic approaches have been the most promising [337,338].They have proved to be effective under study conditions, but the epidemic trend has not yet been reversed. One reason for the failure may be that intervention is usually targeted at adults, whereas a life style is often shaped in childhood and prevention should be started at that age.
Treatment
Treatment Aims
The primary goals of treatment are identical for all types of diabetes mellitus (Table 1.15).
The impact of diabetes both on the affected subjects and their families and on the health services is important. Mortality is increased. Although recent studies have shown that the prognosis can be improved, it appears to be difficult to replicate the study experiences in the diabetic population in general. For economic reasons this will be impossible in developing regions of the world.
Quality of life is decreased. Reduced life expectancy and the risk of disabling complications frighten many diabetic people, even though their fear may remain unconscious. It is a strain for many diabetic people tointegrate regular self-management into their daily lives. It is burdensome to have to abstain from certain social activities and pleasures, to accept the limitation of fitness and working capacity, and to realize that society tends to consider people with diabetes less reliable and fit for use. Being diabetic may also impair one's chances of employment, and the cost of health insurance may be higher than normal. Psychological problems, both obvious and hidden, and social discrimination are important causes of reduced quality of life.
Table 1.15 Primary goals of diabetes management
| Relief of symptoms |
|---|
| Improvement of quality of life |
| Prevention of acute and chronic complications |
| Reduction of mortality |
| Treatment of accompanying disorders |
| Prevention of discrimination |
| Prevention of psychological, social and economic problems |
Chronic complications of diabetes are a major burden. This is evident in respect of loss of vision, renal failure, or diabetic neuropathies with pain, the diabetic foot syndrome, and autonomic failure such as erectile dysfunction. Concomitant diseases such as the metabolic syndrome also constitute a burden.
The best way to avoid complications of diabetes and early death seems to be near-normal metabolic control, with effective treatment of hypertension, dyslipoproteinemia, and adverse life style (Table 1.16). Both fasting and postprandial hyperglycemia are predictors of chronic complications [3,7,341,342]. For prevention of chronic complications, the Kumamoto study elaborated the following glycemic thresholds: HbA1c <6.5%, fasting blood glucose <110mg/dl (<11.1 mmol/l), 2-hour postprandial glucose >180mg/dl(<10mmol/l).
Basically, the goals shown in Table 1.16 are valid for ail types of diabetes mellitus except for gestational diabetes. They may be modified under certain conditions, for example, if strict metabolic control would mean an increased risk of hypoglycemia, if life expectancy is short for other reasons than diabetes, or in geriatric patients with multiple morbidity in whom diabetes is a second-order problem. Sometimes these goals may also be incompatible with well-being, because changing a comfortable life style will often be necessary to achieve the goals. In these cases a compromise should be agreed upon between the diabetic patient and his/her care team.
Near-normal metabolic control plays a pivotal role not only in chronic, but also in acute hyperglycemia of people who have not had diabetes mellitus. Such conditions occur frequently after major surgery or other major somatic stress such as multiple trauma or severe burns. In the past, these critically ill people were usually treated only in the presence of hyperglycemia exceeding 200mg/dl(11 mmol/l) with the aim of keeping blood glucose below this level. This standard of treatment is insufficient, since a recent study has shown that lowering morning blood glucose from an average of 153 mg/dl (8.5 mmol/l) to 103 mg/dl (5.7 mmol/l) reduces mortality by almost 50% [343]
Table 1.16 Medical goals of diabetes management according to Deutsche Diabetes Gesellschaft [344]
| Capillary blood glucose | ||
| Postprandial | 130–160 mg/dl | 7.2–8.9 mmol/l |
| Fasting | 90–120 mg/dl | 5.0–6.7 mmol/l |
| Bedtime | 110–140mg/dl | 6.1–7.8mmol/l |
| HbA,1c (%) | 6.5 | |
| Triglycerides(mg/dl) | ≤150mg/dl | ≤1.71 mmol/l |
| LDL cholesterol (mg/dl) | ≤130 mg/dl | ≤3.45 mmol/l |
| HDL cholesterol (mg/dl) | ≥40 mg/dl | ≥1.04 mmol/l |
| BMI (female/male) | 25/26 | |
| Blood pressure (mmHg) | ≤140/85120/80a | |
| Healthy life style | ||
| Well-being |
a In subjects with microangiopathy
Nonpharmacological Treatment
The goals of treatment can seldom be attained by conventional methods of patient care, where the doctor makes out a prescription and the patient has to follow it. In order to keep metabolism in a near-normal range, it is necessary to check actual glycemic control frequently, often several times a day. Values that are too high or too low must be corrected, and to plan treatment according to the events of the day. These daily therapeutic measures are unpredictable and cannot be carried out by doctors and their team, only by the diabetic subjects (or those around them) themselves. Consequently, people with diabetes should no longer be seen as “patients” “suffering from” their disease, but must become active partners of their doctors (Table 1.17). To be qualified for this role, they must be knowledgeable and motivated to take on the responsibility for managing their own diabetes. Teaching, training, and empowerment of people with diabetes mellitus is thus believed to be essential, even though this has not always been proven [345–348].
The role of the doctors and their team will be to teach people with diabetes, design therapeutic options for the individual diabetic person, and arrange regular checkups (Table 1.17). Their role is also to encourage and support the patients, give ongoing advice, and help in acute and chronic problems. However, the doctors cannot take responsibility for the correctness of daily management and for therapeutic failures due to noncompliance on the part of the patients.
Teaching should enable the diabetic subjects (and if possible people in their social environment) to understand the disease and its treatment and to detect and manage complications early on (Table 1.18). Transferring knowledge and abilities is important. More important, however, is empowerment. The diabetic persons should not simply take on the doctors recommendations, but should develop their own health beliefs. Instead of obeying prescriptions, they should want to attain good control and wish to practice self-monitoring, treatment adaptation, and a healthy life style. In other words, they should be able to develop appropriate self-care behavior.
Table 1.17 Nonpharmacological management of diabetes mellitus
| A. The role of the patients: Learn about diabetes Develop health consciousness and self-management behavior Set goals for your therapy Express and discuss your wishes and expectations with your health care team Control and correct yourself regularly Adopt a healthy life style Profit from the expertise of your health care team Don't “suffer” from your diabetes Decide to want what you have realized as being good for you |
| B. The role of the doctor and the diabetes team: Teaching and training, ongoing advice, back-up. empowerment, and motivation of the persons with diabetes Discussion and consensus on goals of individual therapy Design of individual therapy Nutrition counseling and self-management plan |
Table 1.18 Topics for teaching and training of people with diabetes
| What does diabetes mellitus mean? (causes, symptoms, natural course, prevention, rights and roles) |
| Sensible eating (what to eat, nutrients and energy content, metabolic effect, shopping, cooking) |
| Physical activity (pros and cons of different activities, metabolic and cardiovascular effects, joint loading, monitoring) |
| Self-monitoring (blood glucose, body weight, skin, blood pressure, how and when to do, how to document) |
| Hypoglycemia (causes, symptoms, prevention, treatment) |
| a Oral antidiabetic drugs (action, when to take, side effects) |
| a Isulin (action, how to inject, pens and other devices, schedule, dosage) |
| Care of skin and feet (how to examine, instruments for care) |
| a Not smoking (importance, how to give up smoking) |
| Blood pressure (importance, measurement, how, when, actions at high blood pressure) |
| Chronic complications (symptoms, regular check-ups, risk, prevention, treatment) |
| When to contact the doctor or diabetes care team |
| Special situations (traveling, being ill) |
| Social problems (driver's license, insurance, diabetes risk of descendants) |
a If reasonable
An important aim of patient teaching and training is regular self-monitoring of blood glucose, body weight, skin, particularly of the feet, and blood pressure (Table 1.19). Urinary glucose determination is inadequate as the only method. Aglucosuria does not constitute proof of good metabolic control, because the renal threshold for glucose may be far above the treatment goal. Furthermore, only blood glucose self-monitoring can show the risk of hypoglycemia, which is the greatest obstacle to strict metabolic control.
Nutrition of diabetic people should contain no more than 30% of energy as fat and only 10% as saturated fatty acids. This is much less than is usually consumed in Western diets. Protein intake should not exceed 20% of energy. The majority of energy intake should be in the form of carbohydrates, preferentially complex carbohydrates. However, trained people with good metabolic control may also take some sugar (about 50 g per day) in several portions combined with food rich in fibers. Alcohol should be limited to 15 g per day for women and 30 g per day for men. Salt should be used in moderation [203,349]. About 80% of diabetic people are obese. For these people, restriction of energy intake combined with physical activity is essential in order to achieve slow but continuous weight loss. Nutritional advice must aim to keep eating enjoyable and to help diabetic subjects to satisfy their nutritional preferences within the limits of sensible eating.
Nonpharmacological treatment is the basis for management of all types of diabetes mellitus. Whether it will be successful depends not only on the commitment of the doctor and his team, but also on the cultural background and the all-round educational level of the diabetic person. Only educated, well-trained, independent-minded patients will claim their right to choose among different therapeutic options, will know what kind of service they are entitled to demand from the health care system, and will realize what they themselves have to contribute to the management of their diabetes. Only these patients will have a realistic chance of effective diabetes management and a good long-term prognosis.
Table 1.19 Rules for self-monitoring of metabolic parameters
| • Blood glucose testing is preferable for metabolic control. It is mandatory for patients on insulin or oral antidiabetic drugs that stimulate insulin secretion. It is a vital safeguard against hypoglycemia. Perform urine ketone tests during illness or when blood glucose increases above 20 mmol/l. Document all results. |
| • In well-controlled, stable patients: Fasting, before main meals, at bedtime. 1-2 times per week. |
| • In poorly controlled, unstable patients or during illness: Fasting, postprandially. before meals, at bedtime, daily until stabilized. |
| • During intensified insulin treatment: Before each insulin dose, if necessary postprandially. |
| • If hypoglycemia is suspected. |
| Other self-monitoring: |
| • Check body weight, inspect feet at least weekly. |
| • Check blood pressure, if normal monthly, if elevated more often, possibly several times per day until targets of control are achieved. |
| • Record special events. |
The benefit of nonpharmacological treatment has been shown. Weight reduction reduces mortality considerably [63]. Teaching improves metabolic control and may reduce the need for pharmacotherapy [347,350]. Well-established tools of pharmacological treatment of diabetes cannot be used without teaching, training, and empowerment of the patient.
Pharmacological Treatment of Type 1 Diabetes
General Aspects
The person with type 1 diabetes mellitus needs insulin from the very start of the disease. It is useless and may be dangerous to try a treatment without insulin. Different types of insulin treatment are presently practiced, which may be described as: (1) conventional insulin therapy, (2) intensified or functional insulin therapy, either by means of multiple subcutaneous injections, or by continuous subcutaneous insulin infusion. Other therapies, such as intraperitoneal or intraportal insulin infusion, are still experimental.
Conventional insulin therapy is characterized by a prescribed insulin formulation, dosage, and time of application. The quality of metabolic control is monitored by the diabetes care team. The patient performs blood glucose self-monitoring to prevent hypoglycemia but not as a basis for adapting treatment. Nutrition is inflexible, as the amount of carbohydrates and the time of eating are fixed in order to compensate for the blood glucose-lowering effect of insulin and physical work, and are mainly dictated by the pharmacokinetics of the injected insulin. Metabolic control in type 1 diabetes is poorer with conventional therapy than it is with intensified therapy [127]. For this reason, conventional therapy should be avoided in type 1 diabetes. For type 2 diabetes, it may be satisfactory.
By contrast, intensified (functional) insulin therapy is flexible. This aims to imitate physiological insulin secretion (but without combining insulin with C-peptide and amylin and without releasing insulin into the portal vein). The nutrition-independent (basal) insulin requirement is covered by an injection of long-acting insulin or several injections of intermediate-acting insulin or by continuous subcutaneous infusion at a basal insulin rate. In addition, bolus insulin is given to correct hyperglycemia or to cover nutrition-dependent insulin requirements. This method allows nutrition and physical activity to remain variable and also allows immediately correction of blood glucose deviations. However, it requires frequent self-monitoring of blood glucose and the diabetic subject must be able to adjust the insulin properly. The risk of weight gain is increased.
Practical Aspects
When type 1 diabetes mellitus is diagnosed, the patients need much attention, because they need to realize that they have acquired a life-long disease that will change their life. Usually the diagnosis is made because of deranged metabolism. These patients should initially be treated as inpatients. The ketoacidotic patient must be treated as an emergency case. The initial inpatient period should be used for intensive teaching and training which will be continued on an outpatient basis. To make insulin therapy easier, the use of insulin pens should be favored.
If insulin therapy is not initiated on a ward, it may for the purpose of training be started as conventional insulin therapy.
Conventional insulin therapy (CT) is usually performed with intermediate-acting human NPH insulin (NPH = neutral protamine Hagedorn) or mixtures of human NPH insulin and short-acting regular insulin (Table 1.20). Since the duration of action of NPH insulin is less than 24 hours it must be given twice a day or more often. Because there is a delay before NPH insulin begins to act, it is usually given 30-45 minutes before breakfast and dinner. In view of the nutrition-dependent insulin need over the course of the day, about two-thirds of the daily dose is given in the morning and one-third in the evening. If the postprandial blood glucose increment is unacceptably high, mixed insulins are given in the morning or also in the evening. The proportion of regular insulin in mixtures may be chosen anywhere in the range between 10% and 50%.
To compensate for the action of insulin, carbohydrate intake must be properly distributed over the day. The dietary regimen also depends on physical activity and must be developed by trial and error. As a proposal to start with, total daily carbohydrate intake may be divided in eight parts with two-eighths given at breakfast, one-eighth about 3-4 hours later, one-eighth at lunch, one-eighth in the afternoon, two-eighths at dinner, and one-eighth at bedtime. Unless there is an emergency, it is advisable to start insulin therapy with a low dose. The effect of this very first dose should be monitored by repeated blood glucose measurements. Thereafter, the insulin dose may be swiftly adjusted.
Given the appropriate social and educational background in the patient, type 1 diabetes should be treated with intensified insulin therapy (ICT) from the very beginning. At first, the diabetes care team will be responsible for the enterprise, while the patient is learning. After the teaching and training phase, the diabetic subject will take over responsibility step by step. According to the basis/bolus concept, basal insulin needs will be covered by two to three injections of NPH. The aim is to guarantee a permanent, fairly constant supply with insulin without causing hypoglycemia and to take into account the circadian variation of the insulin demand. Since the insulin demand usually begins to increase in the early morning at 3-4 A.M., the last dose of NPH is often given at bed time. The basal insulin dose is usually about 50% of the total daily insulin dose, or 0.7-1.0 U per hour. If it is difficult to find the right dosage, this can be tested over a 24-hour fasting period with close blood glucose monitoring. However, this procedure is rarely necessary.
The bolus injection should be used for correction of hyperglycemia. It should also be related to carbohydrate intake and should take account of the fact that in a circadian pattern the need for a carbohydrate unit is highest at breakfast time, being then about 1.3 times as high as in the afternoon and evening. The bolus is given subcutaneously either in the form of regular human insulin 15-30 minutes before the meal or in the form of the insulin analogues insulin lispro or insulin aspart at the beginning of the meal. If food intake is unpredictable, the injection of the fast-acting insulin analogues may be given immediately after the meal according to how much was actually eaten.
On average, 1.3-1.5 U insulin are needed to compensate for 10-12 g carbohydrates or for a hyperglycemia of 40-50 mg/dl. Vice versa, about 10-12 g carbohydrates are needed to elevate blood glucose by 40-50 mg/dl. Insulin therapy should always be accompanied by blood glucose monitoring, preferably self-monitoring by the diabetic subject (see Table 1.19).
In continuous subcutaneous insulin infusion (CSII), pump insulin is infused by means of a programmable precision insulin pump and infusion system. The action kinetics of pump insulin are similar to those of subcutaneously injected insulin. The amounts of basal and bolus insulin and the timing of the infusion are similar to those in ICT. CSII has the advantage that the action kinetics remain constant as long as the infusion site is not changed and that basal insulin infusion can exactly be adjusted to the circadian needs. The risk of hypoglycemia is usually lower than with ICT, but unnoticed pump errors with loss of insulin supply may result in rapidly developing ketoacidosis. Other technical problems can usually be easily solved without any danger to the patient.
For emergency treatment of ketoacidosis and other unusual situations, treatment handbooks should be consulted.
Various insulins and insulin analogues are available to meet the different pharmacokinetic requirements (Table 1.20). Insulin should be given strictly subcutaneously. Intracutaneous injection or injection into tendons and muscle sheaths will delay insulin action, while injection into the muscle will accelerate the action. The kinetics of insulin action also depend on the region into which insulin is injected-relatively fast in the abdominal region and slower in the arm or thigh. Even in the same region, the peak time of insulin action may vary considerably from day to day. The action of regular insulin starts much slower than physiological insulin secretion. For this reason, regular insulin should be given 15-30 minutes before meals. The duration of action is longer than the average duration of food digestion and absorption and usually requires a snack 3-4 hours after the injection in order to avoid hypoglycemia.
New insulins have been developed with the aim of improving the concept of physiological insulin substitution. Insulin glargine is a 30B-Arg-Arg insulin analogue with almost constant insulin kinetics over 24 hours [351]. The risk of hypoglycemia can be kept low. Insulin glargine seems to be useful as basal insulin in ICT and may be used for the evening dose in type 2 diabetes.
For meal-time insulin demand the bioavailability of regular subcutaneously injected human insulin is too sluggish. Two insulin analogues avoid this problem: insulin lispro (28B-lysine-29B-proline human insulin) and insulin aspart (28B-aspartic acid human insulin). The action kinetics of these insulin analogues are fast enough to allow treatment without an interval between injection and meal and without a snack between main meals [352,353]. No benefit with regard to the risk of hypoglycemia could be established [354]. These analogues have also been used in CSH treatment [355].
Recently inhaled insulin was developed as a noninvasive alternative to subcutaneous insulin administration. From a proof-of-concept study in type 1 diabetic individuals [356] and an observation study in patients with type 2 diabetes [357] it was concluded that inhaled insulin may offer a practical, noninvasive alternative to insulin injections, because it maintains glycemic control without major side effects and may provide greater patient satisfaction than subcutaneously injected insulin. These first clinical studies will stimulate the development of this new form of insulin therapy [358,359].
The insulin analogues glargine, lispro, and aspart have only recently been introduced into clinical practice. Data on their long-term safety and benefit are not yet available and must be awaited before their advantages and disadvantages can be finally assessed. This may not be a theoretical argument, since the binding properties of the analogues to the insulin and IGF-I receptors are not always identical with those of human insulin [360–362]. However, postmarketing surveys of more than a million treatment-years have provided no evidence for any increase in mitogenic risk with lispro (T. Krause. personal communication, 2001).
While the DCCT [127] has clearly shown that intensified insulin therapy is superior to conventional insulin therapy, no long-term studies in type 1 diabetic subjects using combinations of insulin and oral drugs such as metformin or α-amylase inhibitors are available.
Pharmacological Treatment of Type 2 Diabetes
Glucose Metabolism
About 25% of newly diagnosed type 2 diabetic individuals can initially have their condition controlled by nonpharmacological treatment [125]. The others need additional pharmacological therapy. Metabolic control deteriorates continuously from the very start of the disease. For this reason, the number of subjects who need drugs will increase, and those who were initially on monotherapy will eventually need combination drug therapy [125].
Five classes of oral antidiabetic drugs (Table 1.21) and insulin (Table 1.20) are available for pharmacological treatment of type 2 diabetes.
The competitive α-amylase inhibitors (acarbose, miglitol) delay digestion of complex carbohydrates. By this mechanism they reduce the postprandial rise of glucose, serum insulin, and gastric inhibitory polypeptide (GIF) and stimulate release of glucagon-like peptide 1 (GLP-1) [363]. The antidiabetic effect is seen promptly after the first dose. Their efficacy is well documented [364–368].
Major adverse drug effects are flatulence, abdominal discomfort, and bloating, which usually occur during the first 2-3 weeks of treatment, particularly if the dosage is increased too rapidly. These effects are promptly reversible after discontinuation of treatment but may cause noncompliance problems. It is therefore strongly recommended to start with a very low dose (e. g., 50 mg acarbose at breakfast) and titrate the dose very slowly upwards according to how it is tolerated. Other adverse events are very rare. Monotherapy with α-amylase inhibitors does not cause hypoglycemia nor weight gain 1365-368]. There is no risk of tachyphylaxia. These drugs may be combined with sulfonylurea, metformin, or insulin. Their effect is additive. If hypoglycemia occurs during combination therapy, monosaccharides must be given as antidote.
The main metabolic effect of metformin is inhibition of hepatic glucose production, with little effect on peripheral insulin sensitivity [369,370]. The molecular mechanisms of this effect are not known. Fasting and daytime blood glucose are reduced by metformin. It may take a couple of days or even weeks until the full therapeutic effect has developed.
The antidiabetic effect of metformin alone [133,371,372] and in combination [373,374] is well documented.
Metformin monotherapy does not cause hypoglycemia or weight gain. There is no risk of tachyphylaxia. The drug may be combined with insulin, glitazones, glinides, sulfonylurea, and α-amylase inhibitors. In combination with sulfonylurea or insulin it is able to reduce weight gain [133].
However, in the UKPDS, the addition of metformin treatment to poorly controlled patients receiving sulfonylurea significantly increased the risk of diabetes-related and all-cause mortality [133]. A recent retrospective analysis has cast further doubt on the benefit of this combination [375]. This finding of the UKPDS has been criticized on methodological grounds [376] and the relevance of this observation has been questioned. The American Diabetes Association decided not to change the guidelines on the pharmacological treatment of hyperglycemia in NIDDM [377], because the study had not provided assurance about the risk or benefit of the combination of sulfonylurea and metformin.
A rare but possibly fatal adverse event is lactic acidosis. The risk of this complication increases with overdose or reduced elimination of metformin (serum creatinine > 1.2 mg/dl) and in all conditions in which lactate production is increased or lactate utilization decreased, such as shock, sepsis, hypoxia, alcohol abuse, or narcosis. Ketosis may be aggravated by metformin. Frequent but harmless adverse events include reversible gastrointestinal discomfort and diarrhea. The contraindications for metformin must be carefully taken into account.
Sulfonylurea stimulates endogenous insulin secretion, leading to a decrease in postprandial and fasting blood glucose. The effect is mediated by the closing of ATP-dependent potassium channels in the plasma membrane of pancreatic β cells. This mechanism explains why the efficacy of sulfonylurea depends on the existence of an endogenous insulin reserve. Although administration of sulfonylurea makes the β cells more sensitive to glucose stimulation, the impaired first-phase insulin secretion, which is the most important defect in type 2 diabetes, is not restored [378,379].
The efficacy of sulfonylurea tends to vanish during long-term therapy (late or secondary failure). This may be due to progressive exhaustion of the endogenous insulin reserve. To manage this problem sulfonylurea may be combined with insulin, glitazones, and α-amylase inhibitors. The antidiabetic effect of sulfonylurea treatment alone or in combination is well documented [380,381].
The most frequent adverse event is hypoglycemia, which may begin insidiously and last longer than a day. Sulfonylurea-treated patients usually experience weight gain. Other adverse events are rare. Drug interactions which modulate the efficacy of sulfonylurea are frequent [382].
New oral drugs have recently been developed in order to better mimic physiological insulin secretion and to improve insulin sensitivity.
The glinides (repaglinide and nateglinide) are benzoic acid derivatives which belong to a new class of insulin secretagogues referred to as “prandial glucose regulators.” Compared with glibenclamide these drugs are rapidly absorbed and excreted (tmax of plasma concentration: glibenclamide 300 minutes [383], repaglinide 45 minutes [384], nateglinide 45-60 minutes [385]; t½ of plasma elimination: glibenclamide nine hours [383], repaglinide one hour [384], nateglinide one hour [385]. These drugs bind to specific receptors on the pancreatic β cell, heart, and peripheral muscle cells. In comparison with glibenclamide and gliburide, the binding of nataglinide is much more specific for β cells [386].
The mechanism of action, action profile, and pharmacokinetics of repaglinide and nateglinide are similar but not identical [387]. The binding of repaglinide or nateglinide is rapidly followed by closing of ATP-dependent K+ channels, discontinuous depolarization of the cell membrane, and Ca++ influx, resulting in a rapid insulin release of short duration. In vitro, the insulin-stimulatory effect of repaglinide is enhanced by the presence of physiological concentrations of glucose. Under these conditions repaglinide is several times more potent than glibenclamide [386]. After stimulation with glinides the kinetics of postprandial insulin secretion are more similar to physiological insulin secretion than they are after stimulation with sulfonylurea [388,389].
These drugs cut off postprandial glucose peaks, lower HbAlc, and can be effectively combined with metformin [390–392].
In poorly controlled type 2 diabetic patients formerly treated with metformin, repaglinide monotherapy was as effective as metformin. The combination of repaglinide or nateglinide with metformin seems to be superior to monotherapy [391–393].
Adverse effects of glinides are hypoglycemia, gastrointestinal symptoms, blurred vision, and, rarely, elevated liver enzymes and hypersensitive reactions of the skin. Interactions with drugs metabolized by the cytochrome P450 system may occur. Efficacy is modulated by drug interaction in a similar way as with sulfonylurea.
The thiazolidinediones (glitazones) rosiglitazone and pioglitazone are called “insulin sensitizers.” They lower blood glucose by improving the insulin sensitivity of liver, adipose tissue, and muscle [394,395]. Glitazones develop their metabolic effect through binding to the peroxisome proliferator-activated nuclear receptor-γ (PPAR-γ). This glitazone-activated receptor may become effective as a transcription factor for proteins involved in the regulation of glucose and lipid metabolism. Glitazones improve insulin signaling by increasing the phosphorylation of the insulin receptor, the insulin receptor substrate 1 (IRS-1), and phosphatidylinositol-3 (PI-3) kinase [395]. They also stimulate the expression of glucose transporters GLUT-1 and GLUT-4 [397,398], enhance glucose utilization [399], and suppress hepatic glucose output [400]. Rosiglitazone inhibits the expression of the leptin gene in rat adipocytes [401,402] and stimulates the expression of uncoupling proteins 1 and 3 (UCP1 and UCP3) in preadipocytes [403]. Pioglitazone reduces the expression of TNF-α in muscle and adipose tissue [404]. This effect may be responsible for the favorable influence on the insulin receptor tyrosine kinase and the serine phosphorylation of the insulin receptor [405]. However, a reduced availability of free fatty acids in blood and tissues may also improve insulin sensitivity [406]. The significance of the glitazone effects on proliferation and differentiation of various cell types is unknown. A possible beneficial effect may be inhibition of LDL-induced growth of vascular smooth muscle cells [407].
Adverse effects of glitazones include fluid retention, edema, cardiac failure, anemia, and slight increase in LDL cholesterol and body weight.
Troglitazone, which has been withdrawn from the market, showed severe (fatal) liver toxicity. Rosiglitazone and pioglitazone have been claimed not to be liver toxic, but cases of new liver disease during therapy with rosiglitazone have been reported [408–411], and minor functional disorders may occur. There is at present no proof of a causal relationship, but careful monitoring of liver function is indicated.
Interactions with drugs metabolized by the cytochrome P450 system are possible. Since glitazones have a broad spectrum of effects (there are more than those mentioned in this chapter) and since not all the genes regulated by PPAR-γ seem to be completely known, their safety profile cannot be definitively assessed.
Significant lowering of blood glucose has been reported with glitazones used alone [412]. However, the effect is smaller than with metformin or sulfonylurea [413]. Better effects are seen in combination with metformin [414], sulfonylurea [415], and possibly insulin [416]. At present most clinical information is available only in the form of abstracts. The official regulations for the use of glitazones differ between countries.
The efficacy of the new drugs has only been tested using surrogate markers such as blood glucose and HbA1c. Cardiac benefits have been claimed [417], but so far none of these drugs has been tested in large-scale, long-term prospective studies on safety and efficacy such as the UKPDS using ultimate clinical endpoints or other patient-oriented outcomes.
For most clinicians insulin monotherapy is a second choice in type 2 diabetes mellitus, usually in the form of conventional insulin therapy. Since type 2 diabetes is associated with insulin resistance, high doses are usually necessary [418,419].
The insulin dose may be reduced by the addition of oral antidiabetic drugs [381,420,421]. Recently, intensified insulin treatment has been recommended [422]. However, the metabolic control achieved using different insulin regimens was comparable [423,424]. The most important adverse effects of insulin in the treatment of type 2 diabetes are hypoglycemia and weight gain. Weight gain may be reduced by combining insulin with metformin [133,425].
Clinical Aspects
Pharmacological therapy should be evidence-based, achieve the goals of therapy, be safe and causal rather than symptomatic, easy and comfortable for the patient, and inexpensive. Only two landmark studies on pharmacological therapy of type2 diabetes mellitus have used mortality and diabetes-related morbidity as ultimate endpoints. The Kumamoto study [131,426] evaluated the effects of intensive insulin therapy on prevention and progression of retinopathy, nephropathy, and neuropathy, and studied the cost-benefit relationship. The UKPDS [130,133,368] compared standard and intensive treatment with human insulin, chlorpropamide, glibenclamide and other sulfonylurea drugs, metformin, and acarbose. Three aggregate endpoints were used: (1) any diabetes-related endpoint, which includes various cardiac diseases, renal failure, amputations, and eye problems; (2) diabetes-related death; and (3) all-cause mortality. The UKPDS also analyzed the cost-benefit relationship and treatment of hypertension.
The main points that can be drawn from these studies are:
1. Intensive blood glucose lowering therapy with glibenclamide, metformin, or insulin (NB not with chlorpropamide [130]) delays the onset and progression of microvascular complications in type 2 diabetes.
2. The HbAlc lowering potency of these drugs was comparable.
3. Intensive treatment of obese type 2 diabetic subjects with metformin can also reduce the risk of macrovascular complications.
In none of the studies was diabetes management ideal. The goals of blood glucose control were rarely met, the rates of chronic complications of diabetes remained high, and adverse events were frequent during sulfonylurea and insulin treatment. The need for combination therapy was realized [125], but the addition of metformin to sulfonylurea had adverse effects. Other combinations were not systematically studied. New drugs could not be investigated. These shortcomings make it difficult to select the best therapy for each individual patient solely on the basis of these important studies. For this reason, the therapeutic options will now also be considered from the practical and patho-physiological points of view.
Intensive treatment with sulfonylurea or insulin has adverse effects. It increases the risk of hypoglycemia. In the past this used to be a minor problem, but it becomes a question of safety and quality of life if the goal of therapy is near-normoglycemia. The other adverse effect is weight gain. Most type 2 diabetic subjects are overweight and are advised to lose weight. The patients experience both hypoglycemia and weight gain as causing distress and impairing their quality of life [130]. Weight gain is a precipitating factor for diabetes and a macrovascular risk factor. Therefore, it is legitimate to ask whether the benefit of lowering HbA1c by insulin or glibenclamide is not jeopardized by the risk of this side effect. Therapy with either drug alone may not be a first choice.
Another concern is the fact that neither human insulin nor sulfonylurea corresponds with the pathogenetic defects of type 2 diabetes. They do not restore early insulin secretion because they are too sluggish; that is, the meal-related early phase of insulin action comes too late and the postprandial insulin action lasts too long.
Both types of drugs may overcome insulin resistance but they do not restore insulin sensitivity. If insulin sensitivity improves, this is not a direct drug effect but a nonspecific effect of lowering blood glucose and decreasing glucose toxicity. In the future, rather than insulin and sulfonylurea, rapid-and short-acting insulin analogues and glinides should be considered to initiate a more physiological insulin substitution, and metformin and glitazones to improve insulin sensitivity. However, the new drugs urgently need to be evaluated in controlled prospective studies using hard endpoints.
Intensive treatment with oral drugs or insulin over three years will lower HbA1c below 7% in only half of the patients. In the majority, combination therapy is indicated. Combinations of oral antidiabetic drugs have already been discussed. The combination of insulin with oral antidiabetic drugs may be even more important. The combination of insulin with sulfonylurea has been extensively studied [381,420,421,427,428]. It is convenient and may save some insulin. If postprandial hyperglycemia after breakfast is the main problem, the morning sulfonylurea dose may be replaced by regular or mixed insulin or short-acting insulin analogues. If fasting hyperglycemia is the main problem, the evening oral antidiabetic drug dose may be replaced by NPH insulin at bedtime. Metabolic control can be improved by various combinations without increasing the risk of hypoglycemia [423,424,427,428]. The combination of insulin with metformin is also possible. This combination offers the advantage of avoiding weight gain [133,425].
Fig. 1.3 Proposed stepwise treatment algorithm based on the pathophysiology of type 2 diabetes. For the rationale of this proposal, see text. The warnings with respect to possible unknown long-term side effects must be taken into account.(Modified after Matthaei et al. [395])
A proposed rationale for the selection of drugs in the treatment of type 2 diabetes mellitus is given in Figure 1.3.
Metabolic Syndrome
The outstanding significance of treating the metabolic syndrome to prevent type 2 diabetes mellitus has already been discussed. The metabolic syndrome usually persists in clinical type 2 diabetes, and therefore its treatment remains important.
The impact of overweight/obesity and the importance of weight reduction have been repeatedly confirmed. Weight reduction is not easy. Even more difficult is maintaining reduced body weight over long periods of time. The ideal aim is normal body weight, which will very seldom be achieved. However, much lesser weight reduction is also beneficial [53,54,62,336]. In support of nonpharmacological treatment with nutrition and physical activity, two drugs have recently been introduced: the intestinal lipase inhibitor orlistat, which reduces nutritional fat absorption, and the serotonin/norepinephrine reuptake inhibitor sibutramine, which is an appetite suppressant. Both drugs have been shown to enhance weight loss during conventional weight reduction programs. Orlistat may inhibit absorption not only of fat but also of lipid-soluble drugs and essential nutrients. Sibutramine may evoke psycho-neurological symptoms and increase arterial blood pressure. The drug also has the drawback of a variety of contraindications and drug interactions.
The beneficial effect of lowering elevated blood pressure and specific drug effects on nephropathy and coronary artery disease have already been discussed. The UKPDS [158] has shown that lowering blood pressure from 154/87 to 144/82 mmHg significantly reduced diabetes-related endpoints by 24%, microvascular endpoints by 37%, and stroke by 44%. The epidemiological analysis of this study offers the conclusion that the lowest risk will be “in those with systolic blood pressure less than 120 mm Hg” [159].
Dyslipoproteinemia that does not respond to weight reduction should be corrected by pharmacological therapy. Statins are the first-choice drug if serum cholesterol is elevated. They have favorable effects on small, dense LDL and lower the risk of macroangiopathy complications [429,430]. Fibrates (and analogues) should be favored if triglycerides are increased. These drugs also lower plasma fibrinogen and are beneficial for hypercoagulation and impaired microcirculation. However, the combination of statins and fibrates (and analogues) should definitely be avoided, because it increases the risk of myositis and other severe adverse drug effects.
Prophylactic treatment of hypercoagulation with aspirin or other drugs that reduce platelet aggregation has been recommended [228,304].
Treatment of the metabolic syndrome requires lifestyle changes. Physical activity should be integrated into everyday life, and every smoker should be offered a course in giving up smoking.
This kind of broad approach has been proven to be effective both in preventing [337,338] and in managing [431] type 2diabetes mellitus. The task for the future will be to integrate this experience into public health.
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