Neonatal diabetes is rare and may be transient or permanent.³⁷ Several genetic defects have been identified in these patients, most notably mutations in the adenosine triphosphate (ATP)-sensitive potassium channel (K_ATP) of the β cell. The K_ATP channel comprises two subunits (Kir6.2 and SUR1), and mutations in these can result in loss of function (leading to channel closure and neonatal hyperinsulinemic hypoglycemia) or gain of function (leading to channel opening and neonatal diabetes). Although rare, elucidation of these conditions and the molecular mechanisms underlying them has improved our understanding of this area of human biology.³⁸

Other genetic disorders that are associated with impaired β cell function include certain maternally inherited forms of diabetes with a mutation in mitochondrial DNA,³⁹ disorders that lead to impaired conversion of proinsulin to insulin,⁴⁰ and disorders that lead to synthesis of an aberrant form of the insulin molecule.⁴¹ Of the former conditions, diabetes associated with an A-to-G transition at the nucleotide pair 3243 in mitochondrial transfer RNA (tRNA) has been best characterized and appears to have a wide phenotypic expression from type 2 through to type 1 diabetes. The latter two conditions are inherited in an autosomal dominant manner and are associated with relatively mild glucose intolerance.

GENETIC DEFECTS IN INSULIN ACTION

For insulin to exert its biological effect, it first must bind to its receptor on the cell surface. Following receptor binding, a complex series of postreceptor signaling reactions take place, leading to the hormone’s metabolic and mitogenic effects. Disruption of some of these postreceptor mediators (e.g., insulin receptor substrate-1) has been shown to cause diabetes in animals.⁴² However, very few human forms of diabetes have been linked clearly to specific genetic defects in the insulin signaling cascade. Leprechaunism and Rabson-Mendenhall syndrome represent rare congenital disorders of the insulin receptor.⁴³ Both syndromes are associated with diabetes and hyperinsulinemia and altered growth in utero. As the insulin signaling cascade is further defined, it is likely that additional forms of diabetes will be found to be caused by genetic defects in insulin action.

The nomenclature associated with clinical syndromes of severe insulin resistance can be confusing.⁴⁴ The term type A insulin resistance has been used to describe a syndrome in which severe insulin resistance is associated with a skin condition called acanthosis nigricans and with hyperandrogenism in females. Glucose intolerance or overt diabetes may or not be present. The term type B insulin resistance describes a rare syndrome in which autoantibodies to the insulin receptor lead to insulin resistance and hyperinsulinemia (see later). Also associated with insulin resistance are the lipodystrophies; several forms of lipodystrophic diabetes have been characterized,⁴⁵ and in some cases, their genetic basis has been established and novel therapeutic interventions have been utilized.⁴⁶

DISEASES OF THE EXOCRINE PANCREAS

Hyperglycemia can occur during an episode of acute pancreatitis and is associated with a poor prognosis. It is unusual for permanent diabetes to develop following a single episode of acute pancreatitis. Furthermore, removal of up to 90% of the pancreas does not always cause diabetes. On the other hand, diabetes has been reported in association with very small pancreatic adenocarcinomas, leading some investigators to speculate that these tumors produce some diabetogenic factor or factors.⁴⁷ Five percent to 15% of patients with cystic fibrosis develop diabetes.⁴⁸ Up to half of these patients require insulin chronically or at times of added stress, such as glucocorticoid therapy. Hemochromatosis can cause diabetes.⁴⁹ Because glucose tolerance may improve with phlebotomy, this condition represents an important, potentially reversible cause of diabetes. Fibrocalculous pancreatic diabetes is seen mainly in the tropics and is associated with abdominal pain and calcification of the pancreas on abdominal imaging.⁵⁰ The natural history of this form of diabetes has been established recently,⁵¹ along with a genetic marker of the disease.⁵²

ENDOCRINOPATHIES

Cortisol, growth hormone, glucagon, and the catecholamines (epinephrine and norepinephrine) can antagonize insulin action. Tumors that produce these hormones in excess lead to Cushing’s syndrome, acromegaly, glucagonoma, and pheochromocytoma, respectively. Although all of these conditions are associated with a degree of glucose intolerance, overt diabetes develops only in a subset of patients. The importance of recognizing these secondary forms of diabetes lies in the fact that resection of the underlying tumor can cure diabetes. The hyperglycemia that is seen in the setting of aldosterone-producing adenomas and somatostatinomas results from alteration of insulin secretion.

DRUG- OR CHEMICAL-INDUCED DIABETES

Certain compounds are toxic to β cells. These include the rat poison vacor and the anti-Pneumocystis drug pentamidine. The hyperglycemia that results from these agents is usually not reversible. Thiazide diuretics can inhibit insulin secretion by causing hypokalemia. Glucocorticoids and nicotinic acid cause hyperglycemia by impairing insulin action. Protease inhibitors used in the treatment of persons with human immunodeficiency virus infection can cause hyperglycemia via an as yet undetermined mechanism. The so-called atypical or second-generation antipsychotics are associated with metabolic disorders such as overt diabetes mellitus. The ADA recently published a consensus statement highlighting this association and identifying the need for clinical research in this area.⁵³ The pathophysiologic mechanisms underlying the metabolic derangements are beginning to be elucidated.⁵⁴

INFECTIONS

Certain viral infections, including rubella⁵⁵ and coxsackie B virus,⁵⁶ have been associated with diabetes. Some studies suggest that a viral infection can trigger autoimmune destruction of β cells in genetically predisposed individuals, leading to autoimmune type 1 diabetes.

UNCOMMON FORMS OF IMMUNE-MEDIATED DIABETES

The stiff-man syndrome is a rare neurologic syndrome characterized by spasticity of the axial muscles. It is associated with very high titers of anti-GAD antibodies, and up to one third of patients develop diabetes.⁵⁷ Autoantibodies directed against the insulin receptor represent another rare cause of diabetes (referred to as type B insulin resistance).⁵⁸ These antibodies have the potential to change from being receptor antagonists (causing insulin resistance) to being receptor agonists (leading to potentially life-threatening hypoglycemia). Spontaneous remission of antibody production can occur. The syndrome is typically seen in African American females in association with other autoimmune diseases (most commonly systemic lupus erythematosus).

OTHER GENETIC SYNDROMES SOMETIMES ASSOCIATED WITH DIABETES

Many of the genetic syndromes listed under H in Table 39-1 are known to be associated with diabetes. Wolfram’s syndrome, also known as DIDMOAD (reflecting the components of the disorder; diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is a rare autosomal recessive disorder caused by mutations in the WFS1 gene on the short arm of chromosome 4. Recently, polymorphisms in the WFS1 gene have been linked to an increased risk for type 2 diabetes,⁵⁹ providing another example of the study of rare disorders improving our understanding of common conditions.

GESTATIONAL DIABETES

Gestational diabetes is defined as diabetes with onset or first recognition during pregnancy. The prevalence of gestational diabetes increases in parallel with the prevalence of type 2 diabetes in a population. Recent data from a large U.S. health care organization revealed a prevalence of 7.4 cases per 100 pregnancies.⁶⁰ Risk factors include age (it is more common among older women), ethnicity (higher rates are seen among women from ethnic groups with a high incidence of type 2 diabetes), prepregnancy body mass index (the risk increases with degree of obesity), parity (the risk increases with the number of previous pregnancies), and family history of diabetes. A previous pregnancy that was complicated by gestational diabetes or a history of delivery of a macrosomic infant also represents a strong risk factor for future gestational diabetes. The diagnosis of gestational diabetes is important because if it is left untreated, adverse fetal or maternal outcomes can occur. The main adverse fetal outcomes are macrosomia and neonatal hypoglycemia.⁶¹ Maternal complications include higher rates of dystocia and cesarean section, as well as increased risk for future development of type 2 diabetes⁶² (among women who revert to normal glucose tolerance after completion of the pregnancy).

No uniformly agreed upon criteria have been identified for the diagnosis of gestational diabetes.⁶³ The criteria that are used most widely in North America were developed on the basis of the ability of plasma glucose levels measured during pregnancy to predict future development of type 2 diabetes and not adverse outcomes of that pregnancy. In addition, the 100 g glucose load that is used in North America is different from the 75 g load that is used in other parts of the world. Finally, no consensus exists as to who should be screened.⁶⁴ In some countries (e.g., the United States), universal screening is undertaken routinely, whereas in other countries (e.g., those in Europe), only women who are believed to be at high risk are screened.

Diagnosis

DIAGNOSTIC CRITERIA

In addition to recommending changes in the classification system for diabetes, the Expert Committee of the ADA, in their 1997 report, recommended changes in the diagnostic criteria used for diabetes.⁷ These recommendations were subsequently endorsed by the WHO⁸ (Table 39-3). Major changes included a reduction in the fasting plasma glucose cut point used to diagnose diabetes from 140 mg/dL to 126 mg/dL and a recommendation to use fasting plasma glucose rather than an oral glucose tolerance test (OGTT) for diagnosis. The ability to use casual (i.e., random) plasma glucose levels in patients with hyperglycemic symptoms was retained, as was the requirement that in asymptomatic individuals, a diagnosis should be based on testing carried out on more than one occasion. The ADA report based its criteria on use of the fasting plasma glucose level, and the WHO report included equivalent cut points for whole-blood venous and capillary glucose.⁸ The ADA report introduced the terms normal fasting glucose and impaired fasting glucose. The latter describes patients with fasting plasma glucose levels in the intermediate zone between normal and overt diabetes. Considerable controversy and debate followed publication of the 1997 report, and the ADA re-convened its expert committee in 2003.⁶⁵ Major areas of controversy, how they were dealt with in the 2003 report, and the current status of the diagnostic criteria are discussed in the remaining sections of this chapter.

Table 39-3. Diagnostic Thresholds for Diabetes and Lesser Degrees of Impaired Glucose Regulation*

Category	Fasting Plasma Glucose	2 Hour Plasma Glucose
Normal	<100 mg/dL (<5.6 mmol/L)	<140 mg/dL (<7.8 mmol/L)
IFG	100–125 mg/dL (5.6–6.9 mmol/L)	—
IGT	—	140–199 mg/dL (7.8–11.0 mmol/L)
Diabetes†	≥126 mg/dL (≥7.0 mmol/L)	≥200 mg/dL (≥11.1 mmol/L)