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Chapter 2

The Diagnosis and Classification of Diabetes in Nonpregnant Adults

Irl B. Hirsch, MD, MACP,¹ and Linda M. Gaudiani, MD, FACP, FACE²

¹Professor of Medicine, University of Washington School of Medicine, Seattle, WA. ²Medical Director, Braden Diabetes Center, Marin Endocrine Care and Research, Greenbrae, CA; Associate Clinical Professor of Medicine, University California San Francisco, CA.

DOI: 10.2337/9781580406086.02

Much has been learned about the diverse pathogenesis of diabetes over the previous two decades resulting in alterations in the traditional classification of this disease. Although former classifications focused largely on age at onset of initial clinical presentations, such as acute diabetic ketoacidosis (DKA) versus chronic hyperglycemia, the newer position statements on classification by the American Diabetes Association (ADA) have focused on etiologies rather than phenotype. New genetic testing capabilities, expanded immunologic characterizations, and case reports of novel presentations in special disease states have further expanded diagnostic and classification schemes. This has resulted in nomenclature that is more complex than type 1 diabetes (T1D) and type 2 diabetes (T2D), recognizing the heterogeneous characteristics of the major classes of diabetes as well as the phenotypic and mechanistic overlap both initially and over the course of the disease state. Although assigning a type of diabetes to any given patient may be confounded by the circumstances at the time of diagnosis or by acute illness in the hospitalized patient, misdiagnosis of the type of diabetes, failure to attempt to classify the patient accurately, or failure to recognize that the hospitalized patient has diabetes all are critical errors that may affect treatment decisions in the hospital and following discharge and also may contribute to readmissions. An incorrect diabetes classification during the hospital admission and discharge could have especially significant consequences in our current protocol-driven system of diabetes management and certainly on safe transitions of aftercare.

Unfortunately, misclassification of diabetes is not uncommon. Reasons include the fact that age and obesity are traditional discriminating factors for T1D and T2D. Although the exact number is not known, it is estimated that as many as 50% of patients with T1D are diagnosed after the age of 18 years. The impact of this change in the demographics of T1D is not yet clear; however, misdiagnosis of T1D is responsible for admissions for DKA and the development of DKA in the hospital setting.

Several other issues are contributing to a more complex classification of diabetes type. The recent increase in the use of insulin to treat T2D has blurred the prior differentiating schemes based on therapy, as has the expanded uses of noninsulin injectable and oral agents to augment insulin therapy in select individuals with T1D. Additionally, the expanded descriptions and differentiations of the various forms of monogenic diabetes, pancreatic diabetes, and lipodystrophic and syndromic diabetes now often require the assistance of sophisticated laboratory testing for diagnosis^1-3 and often provoke controversy even among endocrinologists. Even with appropriate genetic or antibody analysis, classification is not always clear, available, or timely, resulting in movement between diagnostic categories over time.⁴

It is critical that significant hyperglycemia in the hospitalized patient be promptly recognized and addressed with therapies and education to ensure safe glycemic targets that support best clinical outcomes for the admission. An adequate history must be obtained and testing tailored to guide inpatient management and discharge planning. These goals can be best met by thoughtful consideration of accurate diabetes classification and reconsideration of patients’ prior classification as they present clinically.

This chapter reviews the current diagnostic criteria and classification scheme of diabetes for nonpregnant adults with a focus on areas of special interest in the hospital setting. We also hope to acknowledge the areas of controversy and confusion in the current nomenclature and to clarify and further define the various nomenclatures in a schema that is useful, intuitive, and flexible. It is our expectation that as understanding about the pathogenesis and genetic influences of the various forms of diabetes expands, future classifications will continue to evolve.⁵

Diagnosis

Because more than 8 million people (nearly a third) in the U.S. with diabetes are not diagnosed,⁶ many patients admitted with hyperglycemia will have undiagnosed diabetes. Those with previously undiagnosed diabetes are more likely to require admission to the hospital compared with those without diabetes.⁷ Furthermore, at each level of hyperglycemia, those without a previous diagnosis of diabetes have been shown to be less likely to receive insulin and have greater adverse events compared with those with known diabetes before admission.⁸ Unfortunately, diabetes can remain undiagnosed or unattended during hospitalization⁹ and the nondiagnosis of diabetes or the undertreatment of stress-induced hyperglycemia in the hospital represents a “missed opportunity” and confers increased mortality risk.¹⁰

The current diagnostic criteria for diabetes mellitus pose special challenges for the admitting health-care provider. All of the three recently proposed diagnostic glucometric tests for diabetes, except for the HbA_1c, are specific for nonill, nonstressed individuals, rendering a new diagnosis of diabetes during hospitalization problematic. The traditional glucose tolerance tests are impractical in the hospital setting and random plasma and fasting plasma glucose values can be distorted by dextrose-containing intravenous (IV) fluids, steroids, stress, illness, and fluctuations in nutrition. The HbA_1c test has the advantages of speed, convenience (fasting is not required), and fewer perturbations from recent stress and illness. Table 2.1 notes the current ADA criteria for diabetes.⁵

Table 2.1—Criteria for the Diagnosis of Diabetes

HbA1c >6.5% (The test should be performed in a laboratory using a method that is National Glycohemoglobin Standardization Program certified* and standardized to the Diabetes Control and Complications Trial assay.**)

OR

Fasting plasma glucose >126 mg/dL (fasting is defined as no caloric intake for at least 8 h)

OR

2-h postprandial plasma glucose >200 mg/dL during a 75-g oral glucose tolerance test

OR

In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose >200 mg/dL

*See NGSP.org; **in the absence of unequivocal hyperglycemia, the results should be confirmed by repeat testing.

Of the three diagnostic glucose tests for diabetes, all of which have limitations in hospitalized patients, the most recently added is HbA_1c.⁵ Despite its advantages, a number of cautions still pertain to the reliability and accuracy of this test in the acutely ill population, especially when critical illness is superimposed on chronic comorbidities.¹¹ There are numerous clinical scenarios in which the HbA_1c may be falsely high or more commonly low and therefore not actually reflect the glycemic history that usually relates to changes in red blood cell survival times (Table 2.2). This obviously makes the HbA_1c difficult to utilize as a diagnostic tool in the hospital setting without careful consideration. In one study, just treating an iron-deficiency anemia can lower the HbA_1c from 10.1% to 8.2% in a population with diabetes and from 7.6% to 6.2% in a population without diabetes.¹²

Cardiac valvulopathies and valve replacements with both aortic or mitral valves can cause a microhemolysis resulting in a falsely low HbA_1c.¹¹ Thus, despite the fact many hospitals now require admission HbA_1c measurements on patients with and without known diabetes entering the hospital, the test has inherent problems, resulting in the potential for misdiagnosis and mismanagement. Nonetheless, a significantly high HbA_1c level (e.g., >8.0%) in the context of hyperglycemia (>180–200 mg/dL) makes the diagnosis of diabetes highly probable.

Table 2.2—Etiologies of Falsely High or Low HbA1c Levels

Falsely high

—Iron deficiency (with or without anemia)

—Anemia

—Hemoglobinopathies

—Race: African American, Hispanic, Asian

Falsely low

—Hemolysis

—Reticulocytosis

—Hemoglobinopathies

—Posthemorrhage or post-transfusion

—Drugs: iron, erythropoietin, dapsone

—Uremia

—Splenomegaly

Plasma glucose is another test that can be used for the diagnosis of diabetes. In the outpatient setting, a fasting glucose of 126 mg/dL or higher or a 75-g oral glucose tolerance test with a 2-h glucose ≥200 mg/dL confirms the diagnosis of diabetes.⁵ It is recommended that two such tests are performed in the absence of unequivocal hyperglycemia. The third diagnostic test using glucose is a random plasma glucose >200 mg/dL with classic symptoms of hyperglycemia (polyuria, polydipsia).⁵ In addition to a significantly high HbA_1c, only this last diagnostic test can be used definitively to confirm the diagnosis of diabetes for the hospitalized patient.

Consider the patient with an HbA_1c of 6.8%, anemia, and renal insufficiency who is admitted with pneumonia and fasting and postprandial glucose levels in the 130–140 mg/dL and 200–220 mg/dL range, respectively. This patient may or may not meet the criteria for diabetes once discharged from the hospital. Nonetheless, the inpatient strategy for the treatment of this patient’s hyperglycemia should be to meet the goals for optimal inpatient glycemic control and should not be influenced by diagnostic ambiguity. It is critical that “stress hyperglycemia versus diabetes” be included on the discharge problem list so both the patient and the outpatient care team appreciates the specific diagnosis clarifications to be investigated once the acute illness has resolved.

In addition to the diagnostic categories of diabetes and stress-induced hyperglycemia, the Expert Committee on Diagnosis and Classification of Diabetes now recognizes a significant group of patients who are at increased risk of developing future diabetes. The term “prediabetes” is used to describe these individuals with impaired fasting glucose or impaired glucose tolerance (Table 2.3).⁵ Although these patients do not meet the diagnostic criteria for diabetes, their glucose values are too high to be considered normal, and numerous prospective studies have shown a strong association between HbA_1c and progression to diabetes. In the hospital setting, these patients can develop significant hyperglycemia and are at increased risk for complications while hospitalized and subsequently for cardiovascular disease.

Table 2.3—Categories of Increased Risk for Diabetes (Prediabetes)*

Fasting plasma glucose 100–125 mg/dL (impaired glucose tolerance)

OR

2-h plasma glucose in the 75-g oral glucose tolerance test 140–199 mg/dL

OR

HbA1c 5.7–6.4%

*For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at higher ends of the range.

Classification

The goal of classifying a patient with a particular type of diabetes in the hospital setting should be to provide useful information about the pathogenesis, natural history, genetics, and phenotype of their disease to optimize safe and appropriate treatments, monitoring, education, patient expectations, and quality of life. Additionally, proper classification of hospitalized patients with hyperglycemia assists in appropriate transitions of aftercare.

Recent classifications have broadly distinguished the types of diabetes into two groups—autoimmune (T1D) and nonautoimmune (T2D)—with all other types being classified in an “other” category. The other category includes monogenic, gestational, pancreatic, steroid-induced, HIV-associated, hepatitis C–associated, polycystic ovarian syndrome–related, and endocrinopathy-associated (acromegaly and Cushing’s syndrome) diabetes. This general schema is useful despite considerable overlap in classic phenotypic presentation in each major class and will guide the knowledgeable health-care provider to make prudent decisions on whom to consider for more specific assignment. In addition to sophisticated testing, it is highly useful to obtain accurate and detailed histories of presentation and family history to advise further evaluation.

Type 1 Diabetes

T1D accounts for ~5–10% of diabetes and is the result of cellular-mediated autoimmune destruction of the pancreatic β-cells,¹³ resulting in moderate to severe insulin deficiency. It classically but not invariably manifests with acute and severe symptoms of hyperglycemia, dehydration, and ketoacidosis. Although the presence of autoantibodies assists in identifying autoimmune versus nonautoimmune diabetes, these antibodies usually but not always disappear over a variable amount of time. The most common antibody in the adult population is glutamic acid decarboxylase 65 (GAD65).¹⁴ Other antibodies that are quickly becoming commercially available include antibodies to tyrosine phosphatase IA-2 and zinc transporter 8 (ZnT8). Traditional islet cell antibodies (ICA) generally are not used because of the assay’s subjectivity. Insulin autoantibodies rarely are seen in adults (although they cross-react with antibodies from exogenous insulin). T1D has strong human leukocyte antigen (HLA) associations, which may be either predisposing or protective in most cases.

Although severe insulin deficiency and the tendency to ketosis and acute onset of symptoms are the hallmarks of T1D, the time of progression to absolute insulin deficiency is variable. Particularly in adults with newly diagnosed T1D, residual endogenous insulin secretion may still be present decades after the diagnosis¹⁵ and appears to be protective to the complications of the disease.¹⁶ This is significant to the health-care provider in the hospital setting because the measurement of c-peptide, while helpful in some circumstances, does not necessarily differentiate T1D from T2D as previously thought and may be misleading. Because a number of factors significantly influence the accurate measurement of c-peptide (antecedent hyperglycemia leading to glucotoxicity, nonstandardization of c-peptide measurement and assay), it generally is not recommended as a helpful test to classify the inpatient with hyperglycemia and may be misleading.

Age and BMI do not invariably discriminate T1D and T2D. Although most commonly presenting in childhood and adolescence, T1D can manifest at any decade of life and with extended life spans in the T1D population combined with the increased frequency of T2D in the young adult obese population, age is no longer a reliable discriminatory factor in the classification between T1D and T2D. Similarly, recent data show that the BMI breakdown for the T1D population is now identical to that of the general population, a shift thought to be related to more intensive insulin regimens and secondary weight gain in the T1D population.¹⁷

Patients with T1D may have personal or family histories of one or more autoimmune disorders. These include Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, celiac disease, myasthenia gravis, vitiligo, and pernicious anemia. Other historical features may be helpful, such as family history of associated endocrinopathies, or features at initial disease presentation, but these facts may not be available to the treating health-care provider in the hospital setting.

Classic T1D is now appreciated to include factors of β-cell dysfunction as well as β-cell loss and the understanding of the mechanisms that trigger these processes is still incomplete but rapidly expanding.

One of the most confusing controversies in the nomenclature of T1D classification is latent autoimmune diabetes of adults (LADA). Originally described in patients over the age of 30 years, who were GAD65 antibody positive,¹⁸ but who did not require insulin treatment in the first 6 months after diagnosis, these patients eventually required insulin for survival similarly to what was seen in individuals with complete insulin deficiency. LADA also has been called “slowly progressive insulin dependent diabetes,” “latent T1D,” “antibody-positive, noninsulin-dependent diabetes,” and “type 1.5 diabetes.” Not all adults who develop autoimmune diabetes have LADA, however, progression to complete β-cell deficiency and even ketosis can be rapid in some adults or may be provoked suddenly by acute illness, infection, hyperthyroidism, or other stress.

It is estimated that between 2 and 12% of all diabetes in adults is LADA. In the United Kingdom Prospective Diabetes Study (UKPDS), ~10% of adults presumed to have T2D at diagnosis had evidence of positive GAD or ICA¹⁹ and most of these progressed to require insulin within 6 years. These patients should be sought for accurate diagnosis because they require vigilance as to the timing of beginning insulin and optimal therapies to preserve β-cell function. Some authors consider all adult-diagnosed patients with diabetes who are antibody positive to have LADA or type 1.5 diabetes. We suggest it may be useful to differentiate the classical nonobese (noninsulin-resistant) adult with positive diabetes autoantibodies and not requiring insulin 6 months after diagnosis as LADA,¹⁸ and those adults who are antibody positive but exhibit classic insulin resistance with phenotypic features of metabolic syndrome as type 1.5 diabetes. This differentiation may inform more effective and specific treatment strategies based on pathogenesis. Despite widespread use of these diabetes classifications in the literature, neither LADA nor type 1.5 diabetes is included in the current ADA classification scheme.⁵

For the typical LADA patient, basal-bolus insulin therapy has been shown to retard the progression to more profound β-cell failure.²⁰ The obese, antibody-positive patients classified as having type 1.5 diabetes may respond to all of the T2D agents, although these individuals will likely progress to profound insulin deficiency more rapidly than if they were antibody negative.²¹ Patients with LADA and type 1.5 diabetes generally will require insulin in the hospital setting.

Another group of adult autoantibody-positive patients is seen more frequently in the early 21st century with a phenotype rarely seen 30 years ago and variously called “double diabetes” or “hybrid diabetes,” but to keep the nomenclature consistent, we call this “type 3 diabetes.” This class refers to adults who developed classic T1D autoimmune diabetes as children but because of all of the genetic and environmental issues that have resulted in the current obesity epidemic, as they reach adolescence and adulthood, these individuals also become obese and develop features of the metabolic syndrome.²² Although they may appear to be the same, the factor differentiating these patients from those with type 1.5 diabetes is the history of being diagnosed initially with classic childhood diabetes and having relatively rapid β-cell failure as opposed to the more recently diagnosed adults with autoimmune diabetes who tend to have less profound β-cell destruction and slower development of insulin deficiency.

Admittedly, there is no consensus on these various T1D subcategories as yet, but classifying patients as LADA (diagnosed as an adult, normal body weight, normal insulin resistance, gradually deficient in endogenous insulin, and antibody positive), type 1.5 (diagnosed as an adult, obese, insulin resistant, and antibody positive), or type 3 (diagnosed as a child, obese, insulin deficient, and resistant) may be useful if this classification results in a more clear appreciation of the pathogenesis and institution of optimal treatments

A minority of T1D occurs without evidence of autoimmunity as in the cause of the insulin deficiency, which nonetheless can be profound and develop rapidly. This is referred to as idiopathic diabetes, previously called “type 1b diabetes.” Included in the category of idiopathic diabetes is “fulminant type 1 diabetes,”²³ most commonly described in Asian patients²⁴ and usually presenting after a viral infection or during pregnancy. Onset is acute, usually with DKA despite HbA_1c levels that are near normal because of the rapid onset of the hyperglycemia. Of special relevance to treating health-care providers in the emergency room and hospital, death from DKA may occur within 24 h if insulin therapy is not initiated immediately upon presentation.²³

Type 2 Diabetes

T2D accounts for the majority of diabetes in the world, accounting for ~90% of all cases. Uncontrolled hyperglycemia in T2D often goes undiagnosed for many years because of the absence of symptoms or presence of vague symptoms. In the hospitalized setting, DKA can occur, but it is almost always associated with stress of another illness, such as infection or ischemia. Undiagnosed diabetes is particularly common in patients admitted for myocardial infarction.²⁵ An inpatient admission can be an important opportunity for diagnosis and initiation of treatment in such high-risk individuals. Even patients with previously well-controlled T2D usually will require discontinuation of prior diabetes oral agents and noninsulin injectable therapies during hospitalizations and treatment with IV or subcutaneous insulin therapies to optimally and safely control hyperglycemia.

Individuals with T2D are resistant to insulin and have relative, as opposed to absolute, insulin deficiency. Over time, they can become profoundly insulin deficient. Depending on the individual and the situation, insulin and c-peptide levels may be high, normal, or low. Autoimmune destruction of the β-cells does not occur, and patients are antibody negative. The risk of developing T2D increases with age, obesity, sedentary lifestyle, and positive family history. It occurs more frequently in women with previous gestational diabetes and polycystic ovarian syndrome; postmenopause, it is seen in individuals with dyslipidemia and hypertension; and it is seen in many ethnic groups (African American, Native American, Hispanic, Pacific Islander, and Asian American). Approximately 85% of individuals with T2D are obese or overweight, and those who are not obese often have an increased percentage of body fat distributed in the abdominal region. The obesity definition is ethnicity-related. For example, although Caucasians are considered obese with a BMI >30 kg/m², the World Health Organization defines obesity <30 kg/m² for most Asians and the recent ADA standards changed the BMI cut point for screening overweight Asian Americans for T2D to 23 kg/m², from the previous 25 kg/m².⁵

Multiple genetic mutations have been associated with T2D but in clinical practice it is not possible to identify a specific genetic abnormality. One specific example of a poorly understood genetic entity of T2D is atypical diabetes, also called Flatbush diabetes. This is a ketosis-prone diabetes, initially described in African Americans who presented with DKA, but the subsequent disease course more closely resembles classic T2D.²⁶ The underlying pathogenesis is unclear, but studies have shown a transient secretory defect of β-cells at the time of presentation with remarkable recovery of insulin-secretory capacity.²⁷ Ketosis-prone diabetes also has been described in other ethnicities.

Monogenic Diabetes Syndromes

These patients represent a small fraction of diabetes (<5%), which is the result of a single genetic defect and generally presents before the age of 25 years. They usually are negative for the antibodies commonly found in T1D. The two main subtypes of monogenic diabetes are neonatal diabetes and maturity onset diabetes of youth (MODY). When diagnosed within the first 6 months of life, diabetes is called neonatal diabetes, which is not a form of T1D. The diabetes in these neonates may be transient or permanent, with the latter most commonly having a mutation on the gene encoding the Kir6.2 subunit of the β-cell K_ATP channel. Despite the early onset, these individuals can be well managed with sulfonylureas instead of insulin as children and, if eventually diagnosed later, even as adults. For this reason, all patients diagnosed with diabetes before the age of 6 months should have genetic screening for neonatal diabetes, even if the history of age of onset is discovered decades later.

MODY is a heterogeneous group of antibody-negative, autosomal-dominant inherited, youth-onset disorders of the β-cell. MODY is characterized by impaired insulin secretion but no (or minimal) defects in insulin action. To date, six different gene mutations are identified on different chromosomes, each one resulting in a different clinical entity.²⁸ One of these genes encodes the enzyme glucokinase (associated with MODY 2), whereas the other five loci encode transcription factors. The most common is hepatic nuclear factor 1-a (associated with MODY 3). Differentiating MODY from T1D is important given the autosomal-dominant inheritance of the former and the observation that many of these patients can be controlled with sulfonylureas. Furthermore, those with glucokinase MODY generally need no therapy (except during pregnancy). Specialty commercial lab testing is now available to identify the gene mutations for clinical (nonresearch) diagnosis to accurately diagnose youth who have MODY and to facilitate prompt identification of other potentially affected family members.

Pancreatic Diabetes

Many diseases of the pancreas affect endocrine function. Formally termed “pancreatic diabetes,” the etiologies, degree of insulin sensitivity, and the subsequent risk for hypoglycemia vary.

For example, cystic fibrosis (CF) patients have a high frequency of diabetes called cystic fibrosis–related diabetes (CFRD). This occurs in 40–50% of adult patients with CF.²⁹ Insulin sensitivity is generally normal or only slightly decreased except in the setting of acute illness when insulin resistance can be severe.³⁰ The frequent intervention of lung transplantation requiring use of corticosteroids and calcineurin inhibitors further increases the prevalence of diabetes in this population. Conversely, the diabetes secondary to chronic pancreatitis mainly occurs from the destruction of islet cells by pancreatic inflammation. There is also an idiopathic variety of chronic, calcific pancreatitis associated with malnutrition that has been termed “tropical chronic pancreatitis.” Both of these latter forms of chronic pancreatitis also are associated with glucagon deficiency and thus more marked sensitivity to insulin with increased risks of hypoglycemia associated with insulin therapy.

Hereditary hemochromatosis is another etiology of pancreatic diabetes, with up to 23% of hemochromatosis patients in one study diagnosed with diabetes.³¹

Surgical pancreatectomy is particularly common in hospitals with busy oncology centers. Immediately after surgery, insulin deficiency in these patients can be reasonably easy to control with basal-bolus insulin therapy. These patients, however, are extremely prone to the risk of devastating hypoglycemia because of glucagon deficiency, and reducing insulin dosing by 20–25% at discharge from the hospital is suggested.

Ideally, patients scheduled for pancreatectomy should meet with a diabetes team or endocrinologist before the surgery and focused diabetes education is needed after this procedure. Because the pancreatectomy is due to a malignancy (or in some cases pancreatic dysplasia³²), the diabetes often is not the main focus of the patient or the family. Especially for those patients who have a good prognosis, the importance of good glycemic control and avoidance of hypoglycemia, even more so than the newly diagnosed patient with T1D, should be stressed. The glucagon deficiency, besides leading to abnormal glucose counterregulation, also results in overall increased insulin sensitivity, meaning extra precaution is required for exercise. Although exact data are not available, there are anecdotal reports of death resulting from hypoglycemia in this population possibly related to physical activity, lack of blood glucose testing, alcohol, or a combination. Continuous glucose monitoring should be strongly considered for these patients.

Drug-Induced Diabetes

Many drugs are known to cause diabetes. Some drugs, such as streptozotocin and IV pentamidine can permanently destroy pancreatic β-cells. More commonly, the ubiquitously useful glucocorticoid therapies (including IV, oral, intra-articular, inhaled, and even topical) can result in hyperglycemia or frank diabetes. Glucocorticoids cause hyperglycemia by increasing insulin resistance by several mechanisms, including inducing an increase in visceral fat and direct actions on muscle and liver resulting in decreased insulin activity. Atypical antipsychotics also can result in diabetes in part because of the effects of increasing appetite and food intake resulting in obesity, although the exact mechanisms are complex.³³ DKA has been described as resulting from these agents and should be considered by the health-care providers when someone taking one of these medications presents with this metabolic emergency.³⁴ Table 2.4 lists medications often used in the hospital that can cause hyperglycemia or diabetes.

Table 2.4—Drugs Often Used in the Hospital That Can Cause Hyperglycemia or Diabetes

Antibiotics

—Quinolones

Gantifloxicin (can also cause hypoglycemia)

Levofloxicin

Atypical antipsychotics

—Most risky

Clozapine

Olanzapine

—Intermediate

Paliperidone

Risperidone

β-Blockers (carvedilol not associated with hyperglycemia)

—Atenolol

—Metoprolol

—Propranolol

Calcineurin inhibitors

—Cyclosporin

—Sirolimus

—Tacrolimus

Corticosteroids

Diazoxide

Nicotinic Acid

Protease inhibitors

Thiazide and thiazide-like diuretics

Lipodystrophic Diabetes

Lipodystrophies are heterogeneous-heterogeneously acquired or inherited disorders characterized by selective loss of adipose tissue. These patients have severe insulin resistance, dyslipidemia, and hepatic steatosis.³⁵ Interestingly, insulin resistance but not hyperglycemia is the norm in those patients with lipodystrophy related to protease inhibitors. Conversely, congenital generalized lipodystrophy usually is associated with severe hypertriglyceridemia prone to pancreatitis.

Other Forms of Diabetes Often Seen in the Hospital

The etiology of the diabetes is multifactorial. As noted, other conditions are associated with diabetes, and one that often is seen in the hospital is diabetes associated with hepatitis C infection.³⁶ These patients are at high risk for stress hyperglycemia or already may have undiagnosed T2D when admitted.

Conclusion

The classification of diabetes remains a work in progress. Attempts to classify our patients will lead to better understanding of the pathophysiology of the common diabetes types, the genetic mutations causing diabetes in rare forms of diabetes, and greater recognition of the vast heterogeneity in this disease. It is clear that for some patients, accurately classifying diabetes in the hospital may not be possible, whereas for others, more sophisticated lab testing may be required to confirm both diagnosis as well as classification. Occasional patients will be difficult to classify. Nevertheless, while in the hospital, the primary goal will remain to thoughtfully consider classification of diabetes and to treat the hyperglycemia to accepted targets, and this usually will require insulin therapy.

We acknowledge that the various subtypes of autoimmune diabetes have an evolving consensus in their classification. Figure 2.1 illustrates our conceptualization for how a health-care provider in the hospital can think about the classification of diabetes, taking into account what is now accepted by the ADA and what often is used clinically.

Figure 2.1—A conceptual classification for diabetes mellitus. Above the dark line are those classes not included in the 2015 ADA classification; below the line are those that are included. Moving left to right moves to greater degrees of insulin resistance.

*Depending on etiology, may have different degrees of insulin resistance and does not include CFRD; **wide degrees of insulin resistance depending on etiology.

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