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Pathogenesis of type 2 diabetes mellitus

David K McCulloch, MD
R Paul Robertson, MD
Section Editor
David M Nathan, MD
Deputy Editor
Jean E Mulder, MD


Type 2 diabetes mellitus is characterized by hyperglycemia, insulin resistance, and relative impairment in insulin secretion. It is a common disorder with a prevalence that rises markedly with increasing degrees of obesity (figure 1) [1]. The prevalence of type 2 diabetes has risen alarmingly in the past decade [2], in large part linked to the trends in obesity and sedentary lifestyle [3].


Understanding the pathogenesis of type 2 diabetes is complicated by several factors [4]. Patients present with a combination of varying degrees of insulin resistance and relative insulin deficiency, and it is likely that both contribute to type 2 diabetes [5-7]. Furthermore, each of the clinical features can arise through genetic or environmental influences, making it difficult to determine the exact cause in an individual patient. Moreover, hyperglycemia itself can impair pancreatic beta-cell function and exacerbate insulin resistance, leading to a vicious cycle of hyperglycemia causing a worsening metabolic state [8].

Type 2 diabetes is often accompanied by other conditions, including hypertension, high serum low-density lipoprotein (LDL) cholesterol concentrations, and low serum high-density lipoprotein (HDL) cholesterol concentrations that, like type 2 diabetes, increase cardiovascular risk. This constellation of clinical conditions is referred to as the metabolic syndrome [9]. Hyperinsulinemia occurring in response to insulin resistance may play an important role in the genesis of these abnormalities. Increased free fatty acid levels, inflammatory cytokines from fat, and oxidative factors have all been implicated in the pathogenesis of metabolic syndrome, type 2 diabetes, and their cardiovascular complications. (See "The metabolic syndrome (insulin resistance syndrome or syndrome X)".)

Impaired insulin secretion and insulin resistance — The relative importance of impaired insulin release and insulin resistance in the pathogenesis of type 2 diabetes has been evaluated in several studies [10-12]. As an example, in a prospective study of over 6500 British civil servants without diabetes at baseline, 505 subjects were diagnosed with diabetes during 9.7 years (median) of follow-up [13]. In those who developed diabetes compared with those who did not, there was a marked decrease in insulin sensitivity during the five years prior to diagnosis. Beta-cell function (insulin secretion) increased three to four years prior to diagnosis and then decreased until diagnosis. In addition, a seven-year prospective study of 714 nondiabetic Mexican-Americans suggested that decreased insulin secretion and insulin resistance were independent risk factors for type 2 diabetes [11]. Among Pima Indians, in whom the frequency of diabetes is very high, the transition from normal glucose tolerance to impaired glucose tolerance to diabetes is characterized by concomitant decreases in insulin-stimulated glucose disposal and glucose-stimulated insulin secretion [12].

Insulin secretion — Insulin secretion by beta cells requires glucose transport into the cell, which is, at least in part, mediated by the glucose transporter 2 (GLUT-2). A mouse model with a genetic alteration affecting GLUT-2 expression produced mice with glucose intolerance; similar changes in GLUT-2 could be induced in normal mice fed a high-fat diet [14] and suggests a possible mechanism for the link between high-fat diet and the development of diabetes [15].

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Literature review current through: Nov 2017. | This topic last updated: Nov 17, 2016.
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