Abstract
The epidemic of type 2 diabetes mellitus is increasing in most nations. This illness is a major cause of cardiovascular disease, stroke, blindness, renal failure, and amputations. Because available interventions have failed to show durability, new modes of therapy need to be directed at the underlying causes of abnormal glucose metabolism. The development of such modes of therapy will require an improved understanding of how the β-cell mass compensates for changes in insulin resistance and why β cells lose the capacity to secrete insulin. In addition, new therapeutic modalities need to address α-cell dysregulation, because the inability to suppress glucagon production results in ongoing elevated levels of hepatic glucose.
Diabetes mellitus is a worldwide epidemic. Global projections suggest that most nations will have a doubling of the incidence of diabetes mellitus within 20 years.
1 Wild et al
1 estimated, based on data from the World Health Organization and United Nations, that there were approximately 171 million people with type 2 diabetes mellitus (T2DM) in 2000, and that this number would grow to 366 million by 2030. This epidemic involves all parts of the globe—with India, China, and the Middle East impacted more than Europe, Africa, and North and South America.
1
The most important risk factor for the development of T2DM is obesity. Although the detailed mechanisms for the genesis of T2DM are not known, the association with obesity is strong. Colditz et al
2 estimated that a body mass index (BMI) of 31 results in a 40-fold increased risk of T2DM, while a BMI greater than 35 yields a 90-fold increased risk, compared with a BMI of 22.
Despite these statistics, obesity is not the ultimate cause of T2DM, because most obese or overweight people do not have T2DM. Investigations into the factors that determine if T2DM will develop are a major thrust of current research.
No single etiologic factor has been defined as the cause of T2DM. Thus, we cannot predict with certainty in whom T2DM will develop. Besides obesity, other important risk factors for T2DM include age, ethnicity, and family history.
2,3 Although T2DM has a strong genetic component, research has shown that an individual's genetic profile only “sets the stage,” and that the individual's lifestyle largely determines if the disease will be expressed.
3 For example, T2DM never develops in many obese individuals, though they may have insulin resistance.
4 Such people may produce as much as twofold to threefold more insulin than normal to overcome their resistance, thereby maintaining healthy blood glucose levels for many years.
4 However, about 20% of obese people do have T2DM.
5 Conversely, approximately 85% of people with T2DM are overweight or obese.
6
Understanding why T2DM develops in certain individuals is also complicated by the fact that diabetes mellitus is a heterogeneous disease. Some people exhibit features of both type 1 and type 2 diabetes mellitus and have had their disease diagnosed as type 1.5 diabetes mellitus.
7 Other people may appear to have T2DM, but they actually have latent autoimmune diabetes of adults (LADA) and require insulin therapy. There is also a presentation known as atypical, or ketosis-prone, diabetes, which occurs primarily in African American teenagers and young adults.
8 This condition mimics type 1 diabetes mellitus (T1DM), but it does not include the autoantibodies typical of T1DM, and it can be managed with oral agents after euglycemia is reestablished with a short course of insulin therapy.
8 Yet another form of diabetes mellitus with a pronounced genetic component is maturity-onset diabetes of the young (MODY).
9
Diabetes mellitus is also heterogeneous with regard to ethnic groups—and even to expression within families.
10 Diabetes mellitus is not inherited in a simple Mendelian manner; there is no unique set of genes that determines the development of T2DM. Rather, many genes have been identified as T2DM risk factors.
10 Skadek et al
10 recently presented data on a genome-wide search that revealed four previously unknown genes that confer T2DM risk. Additional T2DM-related genes are expected to be found. However, to reiterate, genes may confer risk for T2DM, but the major factor determining the expression of T2DM is lifestyle—particularly overeating and physical inactivity.