Diabetes Risks from Prescription and Nonprescription Drugs. Samuel Dagogo-Jack

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