Thompson & Thompson Genetics in Medicine, 8th Edition

Case 35. Non–Insulin-Dependent (Type 2) Diabetes Mellitus (Insulin Deficiency and Resistance, MIM 125853)



• Polygenic disease

• Environmental modifiers

Major Phenotypic Features

• Age at onset: Childhood through adulthood

• Hyperglycemia

• Relative insulin deficiency

• Insulin resistance

• Obesity

• Acanthosis nigricans

History and Physical Findings

M.P. is a 38-year-old healthy male member of the Pima Indian tribe who requested information on his risk for development of non–insulin-dependent (type 2) diabetes mellitus (NIDDM or T2D). Both of his parents had had T2D; his father died at 60 years from a myocardial infarction and his mother at 55 years from renal failure. His paternal grandparents and one older sister also had T2D, but he and his four younger siblings did not have the disease. The findings from M.P.'s physical examination were normal except for mild obesity; he had a normal fasting blood glucose level but an elevated blood insulin level and abnormally high blood glucose levels after an oral glucose challenge. These results were consistent with early manifestations of a metabolic state likely to lead to T2D. His physician advised M.P. to change his lifestyle so that he would lose weight and increase his physical activity. M.P. sharply reduced his dietary fat consumption, began commuting to work by bicycle, and jogged three times per week; his weight decreased 10 kg, and his glucose tolerance and blood insulin level normalized.


Disease Etiology and Incidence

Diabetes mellitus (DM) is a heterogeneous disease composed of type 1 (also referred to as insulin-dependent DM, IDDM, or T1D) (Case 26) and Type 2 (also referred to as non–insulin-dependent DM, NIDDM, or T2D) diabetes mellitus (see Table). NIDDM/T2D (MIM 125853) accounts for 80% to 90% of all diabetes mellitus and has a prevalence of 6% to 7% among adults in the United States. For as yet unknown reasons, there is a strikingly increased prevalence of the disease among Native Americans from the Pima tribe in Arizona, in whom the prevalence of T2D is nearly 50% by the age of 35 to 40 years. Approximately 5% to 10% of patients with T2D have maturity-onset diabetes of the young (MODY, MIM 606391); 5% to 10% have a rare genetic disorder; and the remaining 70% to 85% have “typical T2D,” a form of type 2 diabetes mellitus characterized by relative insulin deficiency and resistance. Despite significant efforts to identify genes that influence the risk for T2D (see Chapter 10), the molecular and genetic bases of typical T2D remain poorly defined.

Comparison of Type 1 and Type 2 Diabetes Mellitus


Type 1 (IDDM)

Type 2 (NIDDM)


Female = male

Female > male

Age at onset

Childhood and adolescence

Adolescence through adulthood

Ethnic predominance


African Americans, Mexican Americans, Native Americans



 Monozygotic twins



 Dizygotic twins



Family history






Body habitus

Normal to wasted


Acanthosis nigricans



Plasma insulin

Low to absent

Normal to high

Plasma glucagon

High, suppressible

High, resistant

Acute complication


Hyperosmolar coma

Insulin therapy


Resistant or responsive

Oral hypoglycemic therapy




T2D results from a derangement of insulin secretion and resistance to insulin action. Normally, basal insulin secretion follows a rhythmic pattern interrupted by responses to glucose loads. In patients with T2D, the rhythmic basal release of insulin is markedly deranged, responses to glucose loads are inadequate, and basal insulin levels are elevated, although low relative to the hyperglycemia of these patients.

Persistent hyperglycemia and hyperinsulinemia develop before T2D and initiate a cycle leading to T2D. The persistent hyperglycemia desensitizes the islet β-cell such that less insulin is released for a given blood glucose level. Similarly, the chronic elevated basal levels of insulin down-regulate insulin receptors and thereby increase insulin resistance. Furthermore, as sensitivity to insulin declines, glucagon is unopposed and its secretion increases; as a consequence of excessive glucagon, glucose release by the liver increases, worsening the hyperglycemia. Ultimately, this cycle leads to T2D.

Typical T2D results from a combination of genetic susceptibility and environmental factors. Observations supporting a genetic predisposition include differences in concordance between monozygotic and dizygotic twins, familial clustering, and differences in prevalence among populations. Whereas human inheritance patterns suggest complex inheritance, identification of the relevant genes in humans, although made difficult by the effects of age, gender, ethnicity, physical fitness, diet, smoking, obesity, and fat distribution, has met with some success. Genome-wide screens and analyses showed that an allele of a short tandem repeat polymorphism in the intron of the gene for a transcription factor, TCF7L2, is significantly associated with T2D in the Icelandic population. Heterozygotes (38% of the population) and homozygotes (7% of the population) have an increased relative risk for T2D of approximately 1.5-fold and 2.5-fold, respectively, over noncarriers. The increased risk due to the TCF7L2 variant has been replicated in other population cohorts, including in the United States. The risk for T2D attributable to this allele is 21%. TCF7L2 encodes a transcription factor involved in the expression of the hormone glucagon, which raises the blood glucose concentration and therefore works to oppose the action of insulin in lowering blood glucose.

Screens of Finnish and Mexican American groups have identified another predisposition variant, a Pro12Ala mutation in the PPARG gene, apparently specific to those populations and accounting for up to 25% of the population-attributable risk for T2D in these populations. The more common proline allele has a frequency of 85% and causes a modest increase in risk (1.25-fold) for diabetes. PPARG is a member of the nuclear hormone receptor family and is important in the regulation of adipocyte function and differentiation.

Evidence for an environmental component includes a concordance of less than 100% in monozygotic twins; differences in prevalence in genetically similar populations; and associations with lifestyle, diet, obesity, pregnancy, and stress. The body of experimental evidence suggests that although genetic susceptibility is a prerequisite for T2D, clinical expression of T2D is likely to be strongly influenced by environmental factors.

Phenotype and Natural History

T2D usually affects obese individuals in middle age or beyond, although an increasing number of children and younger individuals are affected as more become obese and sedentary. Depending on the apparent severity of the genetic susceptibility, some T2D patients are only mildly obese or not obese at all.

T2D has an insidious onset and is diagnosed usually by an elevated glucose level on routine examination. In contrast to patients with T1D, patients with T2D usually do not develop ketoacidosis. In general, the development of T2D is divided into three clinical phases. First, the plasma glucose concentration remains normal despite elevated blood levels of insulin, indicating that the target tissues for insulin action appear to be relatively resistant to the effects of the hormone. Second, postprandial hyperglycemia develops despite elevated insulin concentrations. Third, declining insulin secretion causes fasting hyperglycemia and overt diabetes.

In addition to hyperglycemia, the metabolic dysregulation resulting from islet β-cell dysfunction and insulin resistance causes atherosclerosis, peripheral neuropathy, renal disease, cataracts, and retinopathy (Fig. C-35). One in six patients with T2D will develop end-stage renal disease or will require a lower extremity amputation for severe vascular disease; one in five will become legally blind from retinopathy. The development of these complications is related to the genetic background and degree of metabolic control. Chronic hyperglycemia can be monitored by measurements of the percentage of hemoglobin that has become modified by glycosylation, referred to as hemoglobin A1c (HbA1c). Rigorous control of blood glucose levels, as determined by HbA1c levels as close to normal as possible (<7%), reduces the risk for complications by 35% to 75% and can extend the average life expectancy, which now averages 17 years after diagnosis, by a few years.


FIGURE C-35 Nonproliferative diabetic retinopathy in a patient with type 2 diabetes. Note the multiple “dot and blot” hemorrhages, the scattered “bread crumb” patches of intraretinal exudate- and, superonasally, a few cotton-wool patches. See Sources & Acknowledgments.


Weight loss, increased physical activity, and dietary changes help many patients with T2D by markedly improving insulin sensitivity and control. Unfortunately, many patients are unable or unwilling to change their lifestyle sufficiently to accomplish this control and require treatment with oral hypoglycemic agents, such as sulfonylureas and biguanides. A third class of agent, thiazolidinediones, reduces insulin resistance by binding to PPARG. A fourth category of medication, α-glucosidase inhibitors, which act to slow intestinal absorption of glucose, can also be used. Each of these classes of drugs has been approved as monotherapy for T2D. As they fail with progression of disease, an agent from another class can be added. Oral hypoglycemics are not as effective as weight loss, increased physical activity, and dietary changes for achieving glycemic control. To achieve glycemic control and possibly reduce the risk for diabetic complications, some patients require treatment with exogenous insulin; however, insulin therapy accentuates insulin resistance by increasing hyperinsulinemia and obesity.

Inheritance Risk

The population risk for T2D is highly dependent on the population under consideration; in most populations, this risk is 1% to 5%, although it is 6% to 7% in the United States. If a patient has one affected sibling, the risk increases to 10%; an affected sibling and another first-degree relative, the risk is 20%; and an affected monozygotic twin, the risk is 50% to 100%. In addition, because some forms of T2D are antecedents to T1D (Case 26), children of parents with T2D have an empirical risk of 1 in 10 for development of T1D.

Questions for Small Group Discussion

1. How could civil engineering have a major impact on the treatment of patients with T2D?

2. What counseling should members, including children, of T2D families be given?

3. What factors are contributing to the rising prevalence of T2D?


Bonnefond A, Froguel P, Vaxillaire M. The emerging genetics of type 2 diabetes. Trends Mol Med. 2010;16:407–416.

Diabetes Genetics Replication and Meta-analysis Consortium, et al. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet. 2014;46:234–244.

Thomsen SK, Gloyn AL. The pancreatic β cell: recent insights from human genetics. Trends Endocrinol Metab. 2014;S1043–S2760.