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Genetic Epidemiology Of Diabetes

Jun 7, 2005

How many times do your patients ask you “is there a diabetes heredity” or “am I going to pass on the diabetes genes to my kids”. What do you tell them? Yes, No, or Maybe? What about all that stuff that says Type 1 is an autoimmune disease, does that mean it is not heredity or does it mean that you can pass on auto-immunity and therefore pass on diabetes? M. Alan Permutt, Jonathon Wasson and Nancy Cox, researchers from both Washington University and The University of Chicago, just completed a total review of what is known. Their feature, Genetic Epidemiology takes a full look at how to answer the questions.

Genetic Epidemiology Of Diabetes
M. Alan Permutt, Jonathon Wasson and Nancy Cox
Department of Endocrinology, Metabolism and Lipids, Washington University
School of Medicine Department of Human Genetics, The University of Chicago


Conventional genetic analysis focuses on the genes that account for specific phenotypes, while traditional epidemiology is more concerned with the environmental causes and risk factors related to traits. Genetic epidemiology is an alliance of the 2 fields that focuses on both genetics, including allelic variants in different populations, and environment, in order to explain exactly how genes convey effects in different environmental contexts and to arrive at a more complete comprehension of the etiology of complex traits. In this review, we discuss the epidemiology of diabetes and the current understanding of the genetic bases of obesity and diabetes and provide suggestions for accelerated accumulation of clinically useful genetic information.

Definition of the problem

Diabetes is a metabolic condition in which the body fails to produce enough insulin. Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing ß cells, which leaves the patient dependent on insulin injections for survival (1) T2D, formerly known as adult-onset diabetes, occurs when impaired insulin effectiveness (insulin resistance) is accompanied by the failure to produce sufficient ß cell insulin. Patients can be placed on regimens to reduce weight or manage diet or treated with medication and, less often, insulin injections. This latter form of diabetes accounts for as much as 95% of cases. Gestational diabetes is another form of diabetes, defined as a state of glucose intolerance during pregnancy that usually subsides after delivery but has major implications for subsequent risk of T2D, as pregnancy serves as an "environmental" stressor that reveals a genetic predisposition.

Other less common forms of diabetes include the rare, genetically determined disease maturity onset diabetes of the young (MODY), diabetes resulting from surgery, and other illnesses that constitute only 1–5% of cases. Based on plasma glucose measurements, 2 conditions have been identified with increased risk of the disease (2): (a) impaired glucose tolerance (IGT) is defined as hyperglycemia intermediate between normal and diabetic levels following a glucose load; (b) impaired fasting glucose (IFG), like IGT, is associated with increased cardiovascular disease (CVD) and future diabetes. Because complications of diabetes may develop years before overt disease, many consider the disease part of a cluster of CVD risk factors that include hypertension, hyperinsulinemia, dyslipidemia, visceral obesity, hypercoagulability, and microalbuminuria. This collection of risk factors is also known as the metabolic syndrome (3, 4).

While insulin therapy can reverse many of the metabolic disturbances, and numerous improvements in management have been introduced (5), the disease has reached epidemic proportions. According to the WHO (6), it is likely to be one of the most substantial threats to human health in the 21st century.


The prevalence of diabetes in the United States has risen 40%, from 4.9% in 1990 to 6.9% in 1999 (7). A breakdown of the prevalence of diabetes by state from 1990 through 2001 and of obesity by state from 1991 through 2003 is shown in Figure 1, A and B, respectively (8, 9). The disease affects various groups differently, occurring 10 times more commonly in those older than 65 years compared with those younger than 45 years. Minority racial groups including Hispanics, African Americans, and Native Americans are generally affected at a rate 2–4 times that for white individuals. The recent increased prevalence has also been noted in children and adolescents, where T2D may now occur more commonly than T1D (10). The estimated lifetime risk of developing diabetes for individuals born in the United States in 2000 is 33% for males and 39% for females (7). It is highest among Hispanic females, at 53%. Diabetes is associated with large reductions in life expectancy, on the order of 11 years in males diagnosed at age 40. While an estimated 18.2 million persons had diabetes in the United States in 2002 (11), diabetes worldwide has been estimated to affect 151 million persons, and that number projected to increase to 324 million by 2025 (2).

Figure 1

(A) Diabetes trends among adults in the US. *Includes gestational diabetes. Adapted from ref. 8. (B) Obesity trends among US adults. **BMI 30 (about 30 pounds overweight for a 5-ft 4-in. individual). Adapted from ref. 9

The burden of diabetes is to a large extent the consequence of macrovascular and microvascular complications of the disease, which result in large increases in morbidity and mortality. For example, the prevalence of ischemic heart disease is 2–14 times the rate in age-matched nondiabetics (12). Diabetic retinopathy is the chief cause of blindness in the US. In 2000, diabetic renal disease accounted for 40% of new cases of end-stage renal disease, and diabetics are the largest group receiving dialysis (more than 50% of all cases) and renal transplants (approximately 25%). Lower extremity disease resulting from a combination of peripheral vascular disease and neuropathy causes an increase in lower extremity amputations. While improved glycemic control has been shown to reduce the incidence of microvascular complications, episodes of severe symptomatic hypoglycemia were 3 times higher in those receiving intensive insulin management therapy (13). Along with experiencing physical and cognitive disabilities, adults with diabetes have an age-adjusted mortality rate estimated to be twice that of nondiabetics (12). Risk factors for CVD, including systolic hypertension, elevated cholesterol levels, and cigarette smoking, independently predict CVD mortality, and any 1 risk factor affects outcomes more in persons with diabetes (14).

Although increase in diabetes prevalence occurs mostly in middle-aged and older adults, there is strong evidence of an increase in the prevalence of T2D in children (10). For example, in Japan the incidence in school children (6–15 years old) has doubled over a 20-year period, such that T2D is now more common than T1D (15). In the US, up to 45% of the newly diagnosed diabetics in the pediatric age group have T2D (10). This rise in diabetes rates in children reflects, at least in part, the growing prevalence of obesity in this age group (16).

Direct medical expenditures and lost productivity due to diabetes were estimated to cost the US $132 billion in 2002 (17). The per capita expenditures were twice those for individuals without the disease. While the prevalence of diagnosed diabetes is less than 5% of the population, almost $1 of every $5 spent on health care in the US is for patients with diabetes. As the prevalence of diabetes increases with age, and because of the increasing diabetes-prone populations, it has been estimated that the number of diagnosed cases will increase. Thus the projected total cost in 2002 dollars could be as high as $192 billion by 2020.

Etiology of the Diabetes Epidemic

The sudden increase in diabetes in the last few years is due not to genetic factors but rather to the increase in obesity. This phenomenon is currently being documented in Africa, where the incidence of diabetes is rising with urbanization. The incidence is also rising among Africans who have immigrated to the US (18, 19). Epidemiological studies have regularly shown the relationship between diabetes and obesity, mediated in part by nutritional and lifestyle factors (20, 21). The most common measure of obesity, body mass index (BMI), combines measurements of height and weight. People with a BMI greater than 25 are said to be overweight, while those with a BMI greater than 30 are defined as obese (22). The Nurses Health Study showed that the risk for developing diabetes increased sharply for individuals observed as having a BMI greater than 23 for 16 years and was increased 20-fold for those with a BMI greater than 30 (18). In a recent study of measures of obesity and CVD risk factors in Australian adults, the prevalence of T2D rose from 5% in normal-weight to 16% in obese males; of hypertension, from 20% to 49%; and of dyslipidemia, from 18% to 61%, with even higher prevalence in females (23).

The molecular and physiological relationships between obesity and diabetes are not fully understood, and this subject is an area of intense investigation (see ref. 22 for review). The "thrifty genotype" hypothesis was proposed to account for a genetic advantage of accelerated fat deposition during times of restricted availability of calories, which leaves individuals faced with harmful consequences given the abundant food supply and reduced levels of physical activity in developed countries today (24). Noting an association between low birth weight and increased incidence of diabetes in later life, Hales and Barker have hypothesized that intrauterine malnutrition result in reduced birth weight and to subsequent changes leading to disease in adults (25, 26). This phenomenon, also known as the "thrifty phenotype" hypothesis, proposes that fetal malnutrition results in impaired pancreatic ß cell development and insulin resistance. Offspring are subsequently more prone to diabetes and the metabolic syndrome when exposed to abundant nutrition later in life. In this regard, the increased prevalence of T2D in offspring of diabetic mothers may be a consequence of environmental factors operating on a genetic background, i.e., an altered intrauterine environment superimposed on a genetic predisposition in the fetus. While epidemiological studies have confirmed these observations, virtually nothing is known of their mechanisms, and this is an active area of investigation (27). If the relationship between obesity and diabetes could be understood, or obesity effectively prevented with treatment, then therapies directed at these mechanisms might curtail the increasing incidence of the disease.

The relationship between obesity and diabetes has been extensively studied in inbred strains of mice (28). Mice from a single inbred strain fed a high-fat diet all became insulin resistant, yet only about half became both obese and diabetic. Interestingly, 10% became diabetic but resisted obesity, and 10% became obese but not diabetic. The mechanisms responsible are unlikely to be purely genetic, and the results are consistent with the hypothesis that epigenetic changes and stochastic factors contribute to the phenotypic diversity. More recently, ER stress was shown to be the etiology of obesity-induced insulin resistance and diabetes in experimental mouse models, and this mechanism promises to be a rewarding area of investigation in the near future (29). If the degree of ER stress varies among mice, then perhaps this could explain the phenotypic differences in mice that are genetically identical.

As it has long been noted that levels of FFAs are increased in obese individuals, their accumulation in skeletal muscle has been proposed to compete with circulating glucose resulting in hyperglycemia, hyperinsulinemia, and ultimately insulin resistance (30). Recently, using magnetic resonance spectroscopy in patients with obesity and/or T2D, Shulman et al. have shown a reduction in the rate of insulin-stimulated glucose metabolism secondary to reduced muscle glycogen synthesis, associated with a blunted increase in intramuscular glucose 6 phosphate relative to concentration in insulin-resistant offspring of diabetic parents compared to control individuals (31, 32). Increased intracellular fatty acid metabolites were found to result in decreased insulin signaling and impaired glucose transport. Other factors contributing to the insulin resistance of obesity include the tendency to store fat in the abdominal region as opposed to the extremities and defects in adipocyte fatty acid metabolism and mitochondrial fatty acid oxidation. While impaired mitochondrial activity in insulin-resistant offspring of patients with T2D has been observed (33), the genetic basis for reduced mitochondrial biogenesis has not been elucidated. Reduced mitochondrial activity results in reduced energy expenditure, obesity, increased intramuscular fatty acid accumulation, and insulin resistance and has therefore been incorporated into the thrifty gene hypothesis (32).

Heritability of Diabetes

The recent increased prevalence of obesity and diabetes must be largely attributable to changes in nongenetic risk factors. Yet environmental aspects must certainly accelerate the disease in those with genetic predisposition. There is a clear need to understand the genetic basis for the regulation of food intake, energy expenditure, and variations in energy balance in various individuals. In the long run, it may be more beneficial to develop treatments based on these genetic mechanisms than to rely on the use of will power to modify lifestyle. Moreover, different aspects of environment may be more critical in different subsets of individuals. We know from the natural history of diabetes complications that when patients are first diagnosed, there may already be marked progression of microvascular and macrovascular complications (34). The overwhelming majority of obese individuals have insulin resistance, yet only 5–10% develop pancreatic ß cell failure and diabetes. Discovering the genetic risk factors for the disease will likely have many positive consequences.

The familial occurrences of both T1D and T2D have been long noted. A sibling’s risk of developing T1D (5–10%) is perhaps 12- to 100-fold greater than the risk in the general population (0.1–0.4%) (35). Concordance in monozygotic (MZ) twins has been consistently shown to be greater than that in dizygotic (DZ) twins (36). For T2D, the concordance among MZ twins has been observed to be 50–92%, higher than the 37% concordance in DZ twins (36). Thus while the relative risk to a sibling, a measure of the genetic contribution, is considerably greater for T1D than for T2D, the concordance and absolute risk are substantially greater for T2D, which perhaps underscores the importance of the environmental contribution to the latter (37).
Quantitative phenotypes related to glucose homeostasis are also known to be heritable (38). In families with an increased genetic susceptibility to T2D, heritability estimates for ß cell function and features of the insulin resistance syndrome of 72% and 78%, respectively, were calculated (39). The heritability of other features of the insulin resistance syndrome, including BMI, blood pressure, and serum lipid and insulin sensitivity levels, was also estimated to be high. Evidence for heritability of these metabolic phenotypes was reported in studies of Pima Indians (40) and nondiabetic Japanese Americans (41); in the Insulin Resistance Atherosclerosis Study (IRAS) among family members of African American and Hispanic heritage (42); and in a study of the familial aggregation of the amount and distribution of subcutaneous fat and responses to exercise training in the HERITAGE Family Study (43). These studies strongly support the role of both genetic and environmental factors in the etiology of diabetes and the insulin resistance syndrome.

Now that we have the basics down, next week we will discuss further the idea of genetic disposition and what type 1 and 2 studies have shown us.

This article first as J. Clin. Invest. 115:1431-1439 (2005). doi:10.1172/JCI24758.
Copyright ©2005 by the American Society for Clinical Investigation

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