Diabetes mellitus
Diabetes mellitus comprises a group of chronic metabolic disorders characterized by abnormalities in insulin secretion or action (or both) resulting in hyperglycemia. These conditions are associated with disordered carbohydrate, fat, and protein metabolism and can lead to long-term complications involving the nervous, cardiovascular, renal, and sensory organ systems. The types of diabetes are summarized in Table 1-1.
TABLE 1-1.
| Type 1 (T1DM) | Results from an absolute deficiency of insulin secretion due to beta-cell destruction (immune-mediated, 90% [type 1 A], or idiopathic [type 1B]). Patients require insulin and are prone to ketoacidosis. |
| Type 2 (T2DM) | Results from a combination of insulin resistance and insulin deficiency, which is often preceded by a period of abnormal carbohydrate metabolism (prediabetes). Patients are typically overweight, may not immediately require insulin, and are not usually prone to ketoacidosis. |
| Gestational (GDM) | Represents diabetes diagnosed during pregnancy and is based on specific screening protocols. |
| Other specific types | Diabetes caused by other conditions (chronic pancreatitis, pancreatectomy, acromegaly, hemochromatosis, hypercortisolism) or by medications (glucocorticoids, atypical antipsychotics, antiretrovirals), and monogenetic diabetes, also called maturity-onset diabetes of the young [MODY). |
2. What is the prevalence of diabetes?
According to 2011 statistics compiled by the U.S. Centers for Disease Control, 25.8 million children and adults, or 8.3% of the U.S. population, have diabetes. Of those, 18.8 million have been diagnosed, and 7.0 million Americans have diabetes but are unaware of it. Of individuals 20 years or older, 25.6 million (11.3%) have diabetes. In 2010, 1.9 million adults were newly diagnosed with diabetes. Additionally, an estimated 35% of adults were classified as prediabetic.
3. What is monogenic diabetes?
In contrast to type 2 diabetes, which is clearly polygenic, monogenic diabetes is hyperglycemia due to a single gene mutation. Monogenic diabetes is relatively rare, accounting for only 1% to 2% of all cases in Europe. It is loosely divided into neonatal diabetes (diabetes appearing within the first 6 months of life) and maturity-onset diabetes of the young (MODY; diagnosed outside the neonatal period and generally prior to 25 years of age). Mutations involving the beta-cell adenosine triphosphate–sensitive potassium channel (KATP channel) account for most cases of neonatal diabetes, and the disease in patients with these mutations responds to sulfonylureas, which block the persistently open, mutated KATP channels, thus allowing insulin secretion. MODY is associated with mutations involving glucokinase or genes coding transcription factors that are important in insulin signaling.
4. Who should be screened for diabetes?
Screening for type 1 diabetes is not feasible. Despite many studies, there is no effective means of preventing diabetes in patients who test positive for autoantibodies associated with type 1 diabetes without an abnormality in glucose tolerance, and there is no consensus as to what should be done about positive results.
The risk for development of type 2 diabetes increases with age, obesity, and sedentary lifestyle. There is an increased risk with a family history of diabetes, in certain ethnic groups, and in women with a history of gestational diabetes. Current recommendations are to screen the general population at 3-year intervals starting at age 45. Earlier or more frequent screening should be performed in adults with a body mass index (BMI) 25 kg/m2 or greater and additional risk factors (Table 1-2).
TABLE 1-2.
ADDITIONAL RISK FACTORS PROMPTING SCREENING FOR TYPE 2 DIABETES MELLITUS IN ADULTS
Physical inactivity
Diabetes in a first-degree relative
High-risk ethnicity: African American, Native American, Latino, Pacific Islander, Asian
History of gestational diabetes or of delivering a baby weighing > 9 lbs
Hypertension: blood pressure ≥ 140 mm Hg systolic/90 mm Hg diastolic or current hypertension therapy
Lipid disorders: High-density lipoprotein (HDL) cholesterol < 35 mg/dL or triglycerides > 250 mg/dL
Polycystic ovarian syndrome (PCOS)
History of abnormal glucose metabolism noted in prior testing: fasting glucose ≥ 100 mg/dL; hemoglobin A1C ≥ 5.7%; 2-hour oral glucose tolerance test (OGTT) result > 140 mg/dL
Clinical evidence of insulin resistance: acanthosis nigricans, pronounced obesity
There are four different testing options for the diagnosis of diabetes: a fasting plasma glucose (FPG) test, a 75-g oral glucose tolerance test (OGTT), a hemoglobin A1C (HbA1C) measurement, and random plasma glucose measurement. Both the HbA1C measurement and FPG test are more convenient and less expensive and are, therefore, preferred. In a patient with a positive test result, the test should be repeated on a different day to confirm the diagnosis. Table 1-3 describes diagnostic criteria.
6. What are the genetics of type 1 diabetes?
The exact role of genetics versus environment in the development of type 1 diabetes is unknown. Monozygotic twins have a 20% to 50% concordance for type 1 diabetes. The cumulative risk for siblings of diabetic patients is 6% to 10%, versus 0.6% for the general population. Regarding the effect of parental genes, the offspring of women with type 1 diabetes have a lower risk of disease (2.1%) than those of men with type 1 diabetes (6.1%). The reason for this disparity is unknown. The susceptibility for type 1 diabetes is associated with the genetic expression of certain proteins coded by the human leukocyte antigen (HLA) region of the major histocompatibility complex. These proteins are present on the surfaces of lymphocytes and macrophages and are considered essential for triggering the autoimmune destruction of beta cells. Although all of the genetic markers (HLA and others) for type 1 diabetes are not known, future progress in this field will allow population screening for genetic susceptibility. Type 1 diabetes is a major element of autoimmune polyglandular syndrome type 2 (APS-2; see Chapter 52).
7. What are the genetics of type 2 diabetes?
As with type 1 diabetes, the exact interaction of genetics and environment in the development of type 2 diabetes is unclear. However, the familial clustering of type 2 diabetes suggests a strong genetic component. Monozygotic twins have a 60% to 90% concordance for type 2 diabetes. The cumulative risk for type 2 diabetes in siblings of diabetic patients is 10% to 33%, versus 5% for the general population. Offspring of women with type 2 diabetes have a twofold to threefold greater risk of diabetes than offspring of men with the disease. The exact mode of inheritance for type 2 diabetes is not known but is thought to be polygenic. Specific mutations that are associated with risk for type 2 diabetes have been identified, but many of these genes are widely found in the population at large. Because type 2 diabetes is so commonly associated with obesity, many investigators suspect that genes that predispose to obesity are associated with type 2 diabetes as well. There appears to be a strong interplay between genetic and environmental influences in the cause of type 2 diabetes. One illustration is the demonstration of higher fasting insulin levels for every weight category in the offspring of two parents with type 2 diabetes than in control subjects. High insulin levels are a marker for insulin resistance and are predictive of progression to type 2 diabetes.
8. Describe the pathogenesis of type 1 diabetes.
Type 1 diabetes results from host T-cell destruction of beta cells within the pancreas, which causes absolute insulin deficiency. Markers of this autoimmune process include antibodies to islet cells, insulin, and glutamic acid decarboxylase. The autoimmune destruction is believed to be related to genetic predispositions (HLA-DR/DQ alleles) in combination with poorly defined environmental factors. Patients with type 1 diabetes are prone to other autoimmune disorders (Grave’s disease and Hashimoto’s thyroiditis, celiac sprue, etc.).
9. Describe the pathogenesis of type 2 diabetes.
The pathogenesis of type 2 diabetes is multifactorial, although specific etiologies are unknown. Autoimmune beta-cell destruction does not occur in this form of diabetes, which accounts for 90% to 95% of all cases of diabetes. Instead, type 2 diabetes is characterized by both a defect in insulin action (known as insulin resistance) and a relative insulin deficiency. Years of hyperglycemia often precede the diagnosis, which typically occurs only after non-autoimmune beta-cell failure has begun. Loss of first-phase insulin secretion is the initial defect, with resulting postprandial glucose elevations. Eventually beta-cell death accelerates, and glucose levels rise. It is estimated that by the time of diagnosis of diabetes, patients have lost nearly 50% of their beta-cell mass.
