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1: Overview of Diagnosis, Classification, and Pathophysiology of Diabetes

DOI: 10.2337/9781580406192.01

Diabetes

Diabetes refers to a group of metabolic disorders that result in hyperglycemia. These disorders have different underlying processes but their common manifestation is hyperglycemia, regardless of underlying process. More than 29 million Americans have diabetes and approximately 8 million of these individuals are undiagnosed. Diabetes is a major public health problem because of the long-term complications (such as blindness, amputations, kidney failure, heart disease, and stroke) that could occur if the condition is inadequately controlled. Fortunately, the complications of diabetes can be prevented by maintaining excellent glycemic control, using comprehensive diabetes management.^1,2

Diagnosis of Diabetes and Prediabetes

The diagnosis of diabetes (Figure 1.1) can be established using any of the following American Diabetes Association criteria:

• Plasma glucose of ≥126 mg/dL after an overnight fast. A repeat test on a different day is required to confirm the diagnosis of diabetes.³

• Symptoms of diabetes and a random (nonfasting) plasma glucose of ≥200 mg/dL.

• A standard oral glucose tolerance test (OGTT) showing a plasma glucose level of ≥200 mg/dL at 2 h after ingestion of a 75-g glucose load, provided all testing protocols are followed.

• A hemoglobin A1c level of >6.5%.

In the absence of unequivocal hyperglycemia with typical symptoms, abnormal test results should be confirmed by repeat testing.³

Figure 1.1—Fasting plasma glucose (FPG), oral glucose tolerance test (OGTT), random blood glucose (RBG), and HbA_1c criteria for diagnosis of diabetes and prediabetes.

Prediabetes

The term prediabetes is used to describe persons with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). IGT is defined by a 2-h OGTT plasma glucose level >140 mg/dL but <200 mg/dL, and IFG is defined by a fasting plasma glucose level of ≥100 mg/dL but <126 mg/dL.³ Approximately 86 million Americans have prediabetes, and studies have shown that people with prediabetes tend to develop type 2 diabetes (T2D) at a rate of ~10% per year. Recently, it was observed that initially normoglycemic offspring of parents with T2D develop incident prediabetes at a rate of ~10% per year.⁴ Lifestyle modifications (dietary restriction and exercise) and certain medications can prevent the development of diabetes in people with prediabetes.⁵

Classification of Diabetes

Type 1 diabetes (T1D) accounts for <10% of all cases of diabetes, occurs in younger people, and is caused by absolute insulin deficiency resulting from an immune-mediated destruction of the insulin-producing cells of the pancreas, known as β-cells. T2D accounts for >90% of all cases of diabetes (Figure 1.2). Usually a disease of adults, T2D is being diagnosed increasingly in younger age-groups. Obesity, insulin resistance, and relative insulin deficiency are characteristic findings. Insulin resistance refers to a decreased ability of insulin to drive the uptake of glucose from the blood into the cells and to produce the other appropriate metabolic effects of insulin. People with insulin resistance alone do not develop diabetes, because their pancreatic β-cells compensate by increasing insulin secretion to levels that can maintain normoglycemia. Therefore, a second defect—an inability to maintain compensatory hyperinsulinemia—is required to precipitate T2D. Other specific types of diabetes include those that result from surgical resection or diseases of the exocrine pancreas (such as cystic fibrosis), glandular disorders (e.g., Cushing’s syndrome, acromegaly), and monogenic syndromes (e.g., maturity-onset diabetes of the young). Gestational diabetes occurs during the second half of pregnancy and tends to resolve once the baby and placenta have been delivered (although the mother remains at high risk for future T2D).³

Figure 1.2—The two major types of diabetes mellitus.

The Genetic Basis of Diabetes

Interactions between genetic and environmental factors are well recognized in the pathogenesis of T1D and T2D (Figure 1.3). In T1D, the expression of inherited disease susceptibility markers of the major histocompatibility (HLA) gene family predisposes individuals to islet β-cell damage, classically through autoimmune-mediated mechanisms. The environmental triggers for such autoimmune destruction of the β-cells are believed to include certain viruses.⁶ A family history of diabetes in first-degree relatives (parents, siblings, and offspring) is one of the strongest risk factors for the development of diabetes. The genetic transmission of diabetes risk from parents to offspring is rather complex, however, and familial concordance is stronger for T2D than T1D. Among monozygotic (identical) twins, the concordance rate of T2D is ~80%, and the lifetime risk of development of T2D among offspring and siblings of affected patients has been estimated at ~40%.⁷ If both parents are affected the risk approaches 80% in offspring.⁸ Current understanding indicates that multiple genes are involved in this process, and rarely have single genes been discovered that explained the entire processes underlying the development of diabetes.^9,10

Figure 1.3—Genetic and environmental interactions in the pathophysiology of type 1 and type 2 diabetes. Source: Adapted from Dagogo-Jack.¹⁰

Pathophysiology of Type 2 Diabetes

In genetically susceptible persons, the development of T2D is characterized ultimately by three underlying mechanisms: impaired insulin action (also known as insulin resistance), which is expressed in skeletal muscle and fat cells; impaired insulin secretion by the pancreatic β-cells; and increased hepatic (liver) glucose production (HGP).^11–13 The transition from normal glucose regulation to T2D is punctuated by a variable interlude (usually lasting several years) in the intermediate state of prediabetes (IGT and IFG).

There is general agreement that insulin resistance and impaired insulin secretion are present in most individuals before the onset of diabetes.¹² Longitudinal studies in which initially healthy Pima Indians (a population that has the highest known prevalence of T2D) underwent metabolic assessments repeatedly over several years showed that subjects who progressed from the normal state to prediabetes (IGT) had lost ~12% of their insulin sensitivity but 27% of their insulin secretion; the further progression from prediabetes to T2D was preceded by a 31% decline in insulin sensitivity and a 78% decline in insulin secretion.¹⁴

Demographic Factors

Age

In 2012, the Centers for Disease Control and Prevention (CDC) estimated that about 208,000 people <20 years old had diagnosed diabetes (T1D or T2D). This represents 0.25% of all people <20 years of age, a sharp contrast from the 25.9% prevalence of diabetes among Americans ≥65 years old.¹⁵ The SEARCH for Diabetes in Youth, a multicenter study funded by CDC and the National Institutes of Health (NIH), found that in 2008–2009, an estimated 18,436 people <20 years old in the U.S. were newly diagnosed with T1D annually, and 5,089 people <20 years old were newly diagnosed with T2D annually. Although still uncommon, the rates of new cases of T2D were greater among people age 10–19 years old than in younger children. In national surveys and epidemiological studies, older age always emerges as a robust risk factor for the development of T2D.^16,17

Gender

The global prevalence of diabetes is fairly balanced by gender.^18,19 During the evolution of T2D, male preponderance occurs at the stage of prediabetes: this has been reported in two cross-sectional surveys (the National Health and Nutrition Examination Survey [NHANES] 1999–2002 and 2005–2006)^20,21 and in the prospective Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study.⁴ [AU: Please confirm correct reference number.] The lack of a major gender difference among people who eventually develop T2D indicates that gender equilibration occurs during transition from prediabetes to T2D.²²

Race and Ethnicity

The markedly high prevalence of T2D in Pima Indians (~50% by ≥35 years old) has been noted for a long time.²³ Cross-sectional national surveys also have reported higher prevalence rates of T2D among African Americans, Hispanic Americans, and other ethnic minority groups as compared with non-Hispanic whites.^24–28 However, prospective studies of individuals with prediabetes showed no racial or ethnic differences in progression from prediabetes to T2D during 3 years⁵ or 9 years²⁹ of follow-up. Similarly, in the SHIELD study, race and ethnicity was not a significant predictor of incident diabetes among initially normoglycemic persons followed for ~5 years.³⁰ In the POP-ABC study, initially normoglycemic African Americans and European Americans with parental history of T2D developed incident prediabetes at a similar rate.⁴

Much of the racial and ethnic demographic information on prevalent diabetes in the U.S. was generated from cross-sectional survey data that relied on self-report during telephone interviews. In the 2005–2006 NHANES,²¹ 516 persons who reported having ever been told by a health care professional that they have diabetes were classified as having “diagnosed diabetes,” and 3,107 persons who did not report preexisting diabetes underwent evaluation with blood glucose measurements, to estimate the prevalence of undiagnosed diabetes and prediabetes. Among adults 20 years or older, the self-reported prevalence of diagnosed diabetes was 12.8% in non-Hispanic blacks, 8.4% in Mexican Americans, and 6.6% in non-Hispanic whites.^21,28 In contrast, the prevalence of undiagnosed diabetes and that of prediabetes, both of which were based on measured fasting and 2-h post-OGTT plasma glucose values, showed no significant racial or ethnic differences.^21,28

Thus, national data based on blood glucose measurements are in discord with the twofold black–white difference in self-reported diagnosed diabetes. In fact, these data show lower values for measured fasting and 2-h post-OGTT plasma glucose levels in African Americans compared with white persons.^17,21,28 Furthermore, results of the prospective SHIELD study showed that race or ethnicity was not a significant predictor of incident T2D during 5 years of follow-up of a diverse cohort of initially normoglycemic subjects.³¹ The recent use of HbA_1c for diagnosis probably inflates the magnitude of racial and ethnic differences in the prevalence of diabetes and prediabetes, as ethnic differences in HbA_1c values may be explained, at least in part, by nonglycemic factors.^16,32,33

Genetic and environmental risk factors contribute to diabetes susceptibility in different populations (Figure 1.3 and Table 1.1).³⁴ The evidence, however, for significant racial differences in major diabetes risk alleles of genome-wide significance has not been compelling.^9,10 Thus, no clear biological mechanisms explain why objective estimates of undiagnosed diabetes would follow a different racial pattern from that of self-reported prevalence of diagnosed diabetes. Undoubtedly, among people with diagnosed diabetes in the U.S., there are marked ethnic disparities in the quality of diabetes control and complications from diabetes. It is most likely that suboptimal glycemic control, rather than race or ethnicity per se, underlies much of the greater burden of diabetes complications among U.S. ethnic minority populations.^32,34,35

Table 1.1—Risk Factors for Type 2 Diabetes

• Genetic, familial, race/ethnicity

• Increasing age

• Being overweight or obese

• Habitual physical inactivity

• Having dyslipidemia (elevated triglycerides or decreased HDL cholesterol)

• Having hypertension

• History of gestational diabetes or birth of child weighing 9 lb or more

• History of polycystic ovary syndrome

• History of vascular disease

• History of impaired fasting glucose or impaired glucose tolerance

Insulin Resistance

The binding of insulin to its receptor triggers a series of phosphorylation reactions in the cytosol. The initial phosphorylation occurs on tyrosine residues within the cytoplasmic tail of the insulin receptor, followed by phosphorylation of multiple other intracellular proteins, including insulin receptor substrates (IRS)-1, 2, 3, and 4. In insulin-sensitive tissues (skeletal muscle and adipose), phosphorylation of the IRS proteins activates the enzyme phosphatidylinositol 3-kinase (PI3-kinase), leading to downstream activation of Akt/protein kinase B (PKB) and the translocation of an intracellular pool of glucose transporter molecules (GLUT4) to the plasma membrane, where they form vesicles that mediate glucose transport into the cell (Figure 1.4). Thus, insulin lowers blood glucose by stimulating the transport of glucose across cell membranes through a series of complex chemical reactions. Failure of this mechanism at any level between the binding of insulin to its cell membrane receptor and the eventual translocation of GLUT4 and internalization of glucose results in insulin resistance. Phosphorylation of serine or threonine residues (instead of tyrosine) interferes with insulin signaling, and is a common molecular mechanism that leads to insulin resistance.

Insulin resistance can be inherited or acquired. Obesity, aging, physical inactivity, overeating, and accumulation of nonestrified (free) fatty acids (NEFAs) are known causes of insulin resistance. Normally, cytoplasmic NEFAs in the form of long-chain fatty acyl coenzyme A (LCFA-CoA) are transported into mitochondria for β-oxidation, a process that is gated by carnitine palmitoyl transferase (CPT)-1 and CPT-2 (the shuttle enzymes located in the outer and inner mitochdrial membrane; Figure 1.4). This shuttle process ensures that NEFAs do not accumulate excessively in the cytoplasm. Inhibition of that process leads to the accumulation of LCFA-CoA, which can lead to lipotoxicity.¹³ Also, intracellular accumulation of fatty acids can activate protein kinase C (PKC) via diacylglycerol (DAG), leading to aberrant phosphorylation at serine or threonine residues instead of tyrosine (Figure 1.4). As noted, serine or threonine phosphorylation produces insulin resistance by short-circuiting the normal insulin signal transduction that leads to GLUT4 translocation and glucose transport into cells. Interestingly, acetyl CoA, a product of glycolysis in the Krebs cycle, can be converted to malonyl CoA by the enzyme acetyl CoA carboxylase (ACC). Malonyl CoA is a potent inhibitor of CPT-1, a process that thwarts mitochondrial fat oxidation and promotes the accumulation of fatty acids in the cytosol.³⁶ Glucose abundance also increases the formation of intracellular DAG. Thus, multiple metabolic pathways link intracellular glucose abundance (usually derived from carbohydrate consumption) to impaired fat oxidation, cytosolic fat accumulation, risk of lipotoxicity, and insulin resistance (Figure 1.4). Caloric restriction through the reduction of carbohydrate and fat intake has been shown to improve insulin sensitivity and prevent T2D.^37,38

Figure 1.4—Schema showing insulin signaling and interactions with glucose (G) and fatty acid metablism.

Increased Lipolysis

As a consequence of insulin resistance in adipocytes, the inhibitory effects of insulin on plasma NEFA levels and adipocyte NEFA turnover are markedly impaired.^13,39,40 The net effect is increased lipolysis and NEFA turnover in the setting of insulin resistance. Thus, patients with T2D are exposed to chronic elevation in plasma NEFA levels, which leads to increased gluconeogenesis, exacerbation of insulin resistance in hepatocytes and myocytes, and impairment of insulin secretion.^41,42 Furthermore, a morphological shift to a larger adipocyte size occurs in the setting of insulin resistance along with aberrant adipocyte function, resulting in the increased secretion of proinflammatory molecules and decreased production of adiponectin, a protective adipocytokine. Notably, the enlarged adipocytes in insulin-resistant subjects have a reduced capacity for storing fat, which causes excessive lipid deposition at ectopic sites, such as muscle, liver, β-cells, and vascular smooth cells.^13,43 As noted, the intracellular accumulation of fatty acids leads to lipotoxicity, with dire consequences for cellular function, insulin sensitivity, and insulin secretion.¹³

Insulin Secretion

Under normal conditions, the pancreatic β-cells secrete insulin in response to glucose stimulation through a series of transmembrane electrical reactions. Glucose metabolism in β-cells generates bursts of action potentials that ultimately lead to calcium influx. The adenosine triphosphate (ATP)–sensitive potassium channel (K_ATP) normally maintains the β-cell resting membrane potential, thereby preventing calcium entry. The K_ATP channel is closed when the ratio of ATP to adenosine diphosphate rises within the β-cells as occurs during glucose metabolism. The resultant depolarization (change in electrical charge) of the β-cell membrane drives calcium into the cell, which then triggers insulin secretion (Figure 1.5). Agents that open the K_ATP channel (e.g., diazoxide) reverse the depolarization and inhibit insulin secretion by the β-cells. The β-cell mass is reduced in T2D patients because of apoptosis induced by toxic islet amyloid, oxidative stress, inflammatory cytokines, and other mechanisms.^44–46

Figure 1.5—Process of glucose-stimulated insulin secretion by the pancreatic β-cell.

Hepatic Glucose Production

In the prospective study of Pima Indians, HGP remained normal during the transition from normal glucose tolerance to IGT, but increased by 15% with further progression to T2D.¹⁴ In patients with established T2D, the rate of hepatic gluconeogenesis is not suppressed postprandially (as occurs normally). Thus, the upregulated HGP becomes a key determinant of fasting as well as postprandial glucose excursions in T2D. The increased HGP is triggered by an increased flux of lipolytic products and other glucose precursors and is exacerbated by hepatic insulin resistance.

Glucagon and Incretins

Glucagon hypersecretion by the pancreatic α-cells is a characteristic of both T1D and T2D.⁴⁷ The hyperglucagonemia in patients with diabetes is particularly inappropriate in the postprandial period when glucon levels are expected to be suppressed. The failure of postprandial glucagon suppression in patients with T1D and T2D results from loss of pulsatile intraislet insulin secretion and leads to exaggerated postprandial glucose excursions.⁴⁸ Autopsy studies in patients with T2D further show preservation of α-cell mass, despite marked depletion of β-cell mass.⁴⁴ Incretin hormones (glucagon-like peptide [GLP]-1 and glucose-dependent insulinotropic peptide [GIP]), normally secreted by the enterocytes in response to food, amplify postprandial insulin secretion and suppress glucagon secretion. Emerging data indicate that T2D is associated with impaired incretin secretion and relative resistance to the action of incretin hormones. The major pathophysiological defects in T2D are summarized in Figure 1.6.¹³

Figure 1.6—Major pathophysiological defects in type 2 diabetes.

Renal Glucose Reabsorption

Under normal conditions, ~180 g of glucose are filtered by the glomerulus, but no glycosuria ensues because of efficient reabsorption by renal tubules. Renal tubular glucose reabsorption is mediated by specialized adluminal sodium glucose cotransporters (SGLT)-1 and SGLT2 (the latter being the major transporter) and basolateral glucose transporters GLUT1 and GLUT2 molecules. In patients with diabetes, hyperglycemia exceeds renal tubular maximum, leading to glycosuria commensurate with the degree of hyperglycemia. Mutations in the SGLT2 gene have been described in patients with familial renal glycosuria, a benign condition that is not associated with diabetes or hyperglycemia.⁴⁹ It appears that renal glucose reabsorption may be inappropriately efficient in the setting of hyperglycemia and that SGLT2, GLUT1, and GLUT2 may be upregulated in the kidney of patients with T2D.^13,50,51 Indeed, several SGLT2 inhibitors have now been approved for the treatment of T2D and are effective in decreasing hyperglycemia by promoting renal glucose excretion.

Central Dopaminergic Pathways

Emerging data indicate that central nervous system dopaminergic pathways modulate food intake, and glucose, energy, and weight homeostasis. Decreased dopaminergic tone and polymorphisms of the dopamine D2 receptor are associated with increased risks of obesity and T2D.^52,53 Conversely, augmentation of dopaminergic activity has been shown to improve glucose tolerance and insulin sensitivity, reduce adiposity, and improve lipid profile.^54,55 A quick-release form of bromocriptine (BQR) has been approved for the treatment of T2D on the basis of its ability to “reset” central dopaminergic tone and improve related neurotransmission pathways.⁵⁶ An ancillary mechanism of action of BQR may be its ability to reduce adrenergic tone, thus mitigating adrenergic-related increase in insulin resistance, glucose, and blood pressure.^56,57

Conclusion

Current understanding indicates that multiple pathophysiological defects underlie T2D. The exact sequence of evolution of individual defects has not been determined precisely; many of the defects coevolve during the pathogenesis of T2D and are demonstrable even at the stage of prediabetes (Figure 1.6).^4,11,13,14

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