Diabetes Mellitus

Laura M. Kester

Donald P. Orr

Tamara S. Hannon

Diabetes mellitus (DM) constitutes a group of metabolic diseases, characterized by hyperglycemia due to defects in insulin secretion, insulin action, or both. The metabolic derangements associated with untreated or undertreated diabetes lead to acute complications, including diabetic ketoacidosis (DKA) and nonketotic hyperosmolar coma. Chronic hyperglycemia is associated with long-term microvascular (retinopathy, nephropathy, and neuropathy), accelerated macrovascular (coronary artery disease and stroke), and neurocognitive complications. Data obtained from the Diabetes Control and Complications Trial (DCCT)¹ and Epidemiology of Diabetes Interventions and Complications study² indicate that intensive blood glucose (BG) control in individuals with type 1 diabetes cost-effectively reduces the risk of diabetes-related complications. Comparable clinical trials of intensified treatment and glycemic control for individuals with type 2 diabetes have also demonstrated a significant reduction in risk for microvascular complications. In aggregate, the available evidence supports initiating intensive, multidisciplinary therapy in persons with diabetes at the onset of diagnosis with the goal of treating evidence-based recommended glycemic, blood pressure, and lipid targets.

CLASSIFICATION AND ETIOLOGY

DM (or more commonly, diabetes) includes a spectrum of disorders with overlapping characteristics, making classification difficult in some cases, especially in the face of the obesity epidemic. Currently, classification of diabetes is based on the presumed etiology, rather than the mode of treatment.³ The more common types of diabetes include the following (see Table 13.1):

Type 1 diabetes is the result of pancreatic β-cell destruction, leading to absolute insulin deficiency. Adolescents and young adults (AYAs) are typically symptomatic (i.e., have polyuria, polydipsia, and weight loss) at presentation, and are at risk for DKA.
- Immune-mediated type 1A diabetes: The most common form of diabetes in AYAs, type 1A diabetes, is linked to genetic susceptibility associated with the major histocompatibility genes, most notably human leukocyte antigen class II immune recognition molecules (DR and DQ) located on chromosome 6. One or more environmental factors are likely necessary to trigger the onset of the disease. Autoimmune-mediated destruction of the β-cells involves T cells that recognize β-cell-specific antigens resulting in insulitis and circulating immune markers. Associated immune markers may be detected many months to years before the onset of diabetes and include antibodies directed against islet cells (islet cell antibody), insulin, glutamate decarboxylase (anti-GAD₆₅), receptor-linked tyrosine phosphatases (IA-2, IA-2_β), and zinc transporter ZnT8. Antibodies are present in 85% to 90% of children and adolescents with type 1 diabetes at the time of diagnosis.
- Ketosis-prone, idiopathic, or type 1B: Persons with insulin deficiency without evidence of autoimmunity and no other cause of β-cell destruction are described as having ketosis-prone diabetes.⁴
- Latent autoimmune diabetes in adults: Approximately 10% of phenotypic type 2 diabetic patients are positive for at least one of the islet autoantibodies.⁵ This form of diabetes is characterized by circulating autoantibodies against β-cell antigens and progressive β-cell failure to insulin dependence after several months to years of relatively mild diabetes.
Type 2 diabetes comprises a spectrum of disorders characterized by varying degrees of hyperglycemia associated with insulin resistance in combination with relative impairment in insulin secretion in the absence of circulating immune markers.⁶ Type 2 diabetes disproportionally affects people of minority race and ethnicity; genetic susceptibility is an important risk factor and represents complex interaction among numerous genes and environmental factors.⁷,⁸ It is characterized by decreased muscle glucose uptake, increased hepatic glucose production, impaired and progressively deteriorating insulin secretion, and overproduction of free fatty acids. Prevalence has increased dramatically mirroring the increase in obesity throughout the world.

Congenital genetic defects (leading to various forms of diabetes):

Monogenic diabetes (also known as maturity-onset diabetes) of the young, or MODY, comprises a group of autosomal dominantly inherited disorders associated with disordered β-cell function, impaired insulin secretion, with minimal or no defects in insulin action, and lack of autoantibodies.⁹ It represents <5% of cases of diabetes and is seen in all racial/ethnic groups. Six specific types of gene defect have been characterized as forms of MODY.

Hepatocyte nuclear factor-4-alpha (MODY 1)—Insulin secretory defect with good initial response to treatment with sulfonylureas.¹⁰

Glucokinase (MODY 2)—Reduced or delayed glucose sensing leads to a higher threshold for glucose-stimulated insulin secretion. Results in mild diabetes, which can be controlled with diet.⁹

TABLE 13.1 Characteristics of Common Forms of Diabetes

	Type 1A	Type 2, Ketosis-Prone	Type 2	Monogenic^a
Age	Childhood	Pubertal	Pubertal	Usually <age 25
Onset	Acute; severe	Acute; severe	Mild to severe; often insidious	Mild; insidious
Insulin secretion	Very low	Moderately low	Variable	Variable
Insulin sensitivity	Normal	Normal	Decreased	Normal
Insulin dependence	Permanent	Variable	Progression from variable to permanent	Usually no, until late
Groups at increased risk	Non-Hispanic Whites	Non-Hispanic Blacks	Minority race/ethnicity	All
Genetics	Polygenic	Autosomal dominant	Polygenic	Autosomal dominant
Association with obesity	No	Variable	Strong	No
Acanthosis nigricans	No	Variable	Yes	No
Autoimmune etiology	Yes	No	No	No
^aMaturity-onset diabetes of youth (MODY).

Hepatocyte nuclear factor-1-alpha (MODY 3)—Insulin secretory defect with good initial response to treatment with sulfonylureas. Mutations also result in a low renal threshold for glucose leading to detectable glycosuria after a glucose load.¹¹
Insulin promoter factor 1 (MODY 4)—Reduced binding of the protein to the insulin gene promoter leads to disordered β-cell function.⁹
Hepatoctye nuclear factor-1-beta (MODY 5)—Results in pancreatic atrophy, abnormal renal development progressive renal insufficiency, hypomagnesemia, elevated serum aminotransferases, and genital abnormalities.¹²
Neurogenic differentiation factor-1 (MODY 6)—Faulty pancreatic development, also associated with permanent neonatal diabetes.¹³

Mitochondrial: This very rare form of diabetes is caused by a rare sporadic or maternally inherited mitochondrial genetic mutation at position 3243 in transfer RNA.¹⁴ It is almost always associated with other symptoms—deafness, neurological disorders, cardiac failure, renal failure, and myopathy.
Various genetic defects of insulin action include type A insulin resistance, leprechaunism, Rabson-Mendenhall syndrome, and lipoatrophic diabetes.¹⁵

Diseases of the exocrine pancreas leading to destruction of endocrine function include pancreatitis, trauma/pancreatectomy, neoplasia, hemochromatosis, and cystic fibrosis-related diabetes (CFRD). CFRD is associated with decreased pulmonary function, protein catabolism, poor growth, and weight loss.¹⁶ It results primarily from insulinopenia, although insulin resistance may be observed during periods of infection and with glucocorticoid therapy. Insulin treatment is associated with increased body weight and improvement in pulmonary function.
Genetic syndromes that may be associated with diabetes include Down syndrome, Klinefelter syndrome, Turner syndrome, Wolfram syndrome, Friedreich ataxia, Huntington chorea, Laurence-Moon syndrome, myotonic dystrophy, and Prader-Willi syndrome.
Gestational DM: Pregnancy leads to both insulin resistance and increased insulin requirements, which results in diabetes in women whose pancreatic function is insufficient to withstand these requirements for the growing fetus.¹⁷