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Pathogenesis of type 2 diabetes mellitus
David K McCulloch, MD
R Paul Robertson, MD

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UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.1 is current through December 2006; this topic was last changed on December 29, 2006. The next version of UpToDate (15.2) will be released in June 2007.

INTRODUCTION — 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 (show 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].

PATHOPHYSIOLOGY — 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 ß-cell function and exacerbate insulin resistance, leading to a viscous 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. As an example, in a five-year prospective study of 137 initially nondiabetic Japanese-American men, impaired insulin secretion preceded insulin resistance and visceral adiposity in those who became diabetic [10]. In addition, a seven-year prospective study of 714 non-diabetic 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 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 [13] and suggests a possible mechanism for the link between high fat diet and the development of diabetes [14].

Insulin resistance may be the best predictor of type 2 diabetes [5,6]. The vast majority of patients appear to have a genetic risk for type 2 diabetes (see below). It is possible, for example, that insulin resistance becomes more severe with increasing age and weight, thereby unmasking a concurrent defect in insulin secretion in susceptible subjects to cause impaired glucose tolerance and eventually overt hyperglycemia. In normal-weight nondiabetic subjects at high risk for type 2 diabetes, both fasting and post-glucose hyperinsulinemia predict future weight gain, which in turn predisposes to hyperglycemia [15,16]. Hyperglycemia itself may contribute to further progression by a toxic effect on beta-cells, possibly by decreasing insulin gene expression [17].

Insulin resistance may, at least in part, be related to substances secreted by adipocytes ("adipokines" including leptin adiponectin, tumor necrosis factor alpha, and resistin) (see "Factors released from adipocytes" below).

The importance of genetic factors in the pathogenesis of type 2 diabetes is suggested by the observation that lean, normoglycemic offspring of parents with type 2 diabetes have reduced nonoxidative glucose metabolism associated with reduced muscle glycogen synthesis [18]. Thus, insulin resistance is present years before the onset of hyperglycemia. An increase in intracellular lipid content in muscle has been identified in these insulin-resistant offspring, suggesting that dysregulation of fatty acid metabolism may mediate the insulin resistance in these individuals. In one study, this dysregulation appeared to be due to an inherited defect in mitochondrial function [19].

The importance of the combination of genetic and environmental factors is suggested by another study of nondiabetic offspring of two parents with type 2 diabetes [6]. Their insulin sensitivity was similar to that of normal subjects with no first-degree relatives with type 2 diabetes at near ideal body weight; with increasing degrees of obesity, however, the progressive decrease in insulin sensitivity was much more pronounced in those with a family history of type 2 diabetes (show figure 2) [6].

Impaired insulin processing — Insulin production in normal subjects involves cleavage of insulin from proinsulin; 10 to 15 percent of secreted insulin is proinsulin and its conversion intermediates. In contrast, the proportion of immunoreactive insulin that is proinsulin in type 2 diabetes is increased considerably in the basal state (>40 percent) [20]. The difference between normal and diabetic subjects becomes even more pronounced after stimulation with arginine or glucagon [21]. The increase in proinsulin secretion persists after matching for degree of obesity, suggesting that it represents beta cell dysfunction, and not merely the response to the increased secretory demand imposed by the insulin resistance of obesity [21]. These finding s suggest that the processing of proinsulin to insulin in the beta cells is impaired in type 2 diabetes, or that there is insufficient time for granules to mature properly so that they release more proinsulin.

Role of islet amyloid polypeptide — Islet amyloid polypeptide (amylin) is stored in insulin secretory granules in the pancreatic beta-cells. It is cosecreted with insulin, resulting in serum concentrations about one tenth those of insulin, and is present in increased amounts in the pancreas of many patients with type 2 diabetes [22]. First-phase serum insulin and amylin concentrations are lower in patients with impaired glucose tolerance compared with patients with normal glucose tolerance, and the concentrations are very low in patients with type 2 diabetes [23].

High concentrations of amylin decrease glucose uptake and inhibit endogenous insulin secretion, suggesting that amylin may be directly involved in the pathogenesis of type 2 diabetes [24]. However, administration of physiologic amounts of amylin has no acute effect on insulin secretion or insulin action in humans [25]. On the other hand, the administration of an amylin antagonist to rats results in a fall in blood glucose and an increase in insulin secretion, suggesting that amylin may tonically inhibit insulin secretion [26].

Thus, it remains unclear whether amylin has a causative role in type 2 diabetes or is merely present in increased amounts as a consequence of the defect in insulin secretion. There is no apparent association between the amylin gene and type 2 diabetes [27].

Pramlintide is a synthetic analog of human amylin that slows gastric emptying, reduces postprandial rises in blood glucose concentrations, and improves A1C concentrations in patients with type 1 and type 2 diabetes when given subcutaneously. (See "Amylin and GLP-1-based therapies for the treatment of diabetes").

GENETIC SUSCEPTIBILITY — Type 2 diabetes most likely represents a complex interaction among many genes and environmental factors. Monogenic causes of type 2 diabetes represent only a small fraction of cases and commonly inherited polymorphisms individually contribute only small degrees of risk for, or protection from, diabetes. Most of the genetic risk for type 2 diabetes results from complex polygenic risk factors.

Observations which demonstrate a genetic influence on the development of type 2 diabetes include: The prevalence of type 2 diabetes varies remarkably between ethnic groups living in the same environment [28]. Type 2 diabetes is two to six times more prevalent in African Americans, Native Americans, Pima Indians, and Hispanic Americans in the United States than in whites [29,30]. Thirty-nine percent of patients with type 2 diabetes have at least one parent with the disease [31]. Among monozygotic twin pairs with one affected twin, approximately 90 percent of unaffected twins eventually develop the disease [32]. First-degree relatives of patients with type 2 diabetes frequently have impaired nonoxidative glucose metabolism (indicative of insulin resistance) long before they develop type 2 diabetes [33]. In addition, they may have beta-cell dysfunction, as evidenced by decreases in insulin and amylin release in response to glucose stimulation [34]. The lifetime risk for a first-degree relative of a patient with type 2 diabetes is five to ten times higher than that of age- and weight-matched subjects without a family history of diabetes [28].

Even among groups with increased genetic risk for diabetes, however, environmental factors play a major role in the development of diabetes. As an example, the prevalence of diabetes among Pima Indians in Mexico is less that one-fifth that in US Pima Indians (6.9 versus 38 percent) [35].

The search for plausible candidate genes has focused upon genes coding for proteins that might be involved in insulin secretion or action [6].

Genes affecting insulin release

  Transcription factor genes — One gene variant, representing single nucleotide polymorphisms at one of two loci (rs7903146 and rs12255372) in the transcription factor 7-like 2 gene (TCF7L2), was found to significantly increase risk for type 2 diabetes in a case control study of a population in Iceland [36]. It was also shown to increase diabetic risk in two other populations, including in the United States (US) where the gene variant is widely prevalent: 38 percent of the US cohort studied were heterozygous and 7 percent homozygous for the variant allele. Compared with non-carriers, the relative risk for type 2 diabetes was 1.45 for heterozygotes and 2.41 for homozygotes. The population attributable risk for diabetes for this gene is estimated at 21 percent. The gene is postulated to regulate expression of a proglucagon gene in enteroendocrine cells, and alter levels of glucagon-like peptide (GLP-1).

Subsequent analysis for this variant gene in samples from participants (n = 3548) in the Diabetes Prevention Program (DPP trial) found that homozygotes for the variant TCF7L2 gene were more likely to progress from impaired glucose tolerance to diabetes over three years than those without the variant gene (HR 1.55; CI 1.2 to 2) [37]. The impact was strongest in the placebo DPP group where the incidence of diabetes per 100 person-years for the homozygous variant genotype at rs7903146, compared to heterozygous and nonvariant genotypes, was 18.5, 10.7, and 10.8, respectively. The variant genotype was associated with impaired insulin secretion.

  MODY2 and MODY 4 — MODY is a rare cause of type 2 diabetes which has autosomal dominant transmission and features of both impaired insulin secretion and insulin resistance. One form, MODY2, appears to be due to mutations in the glucokinase gene on chromosome 7 [38]. Markers in this region have been linked to type 2 diabetes in American blacks [39] and some other ethnic groups, but not in whites [40]. Glucokinase, which phosphorylates glucose to glucose-6-phosphate, probably acts as the glucose sensor within pancreatic ß-cells, and therefore glucokinase defects likely result in decreased insulin secretion. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on Genetic defects of beta-cell function).

Another form of MODY (MODY4) is associated with mutations in insulin promoter factor-1 (IPF-1/PDX-1), a pancreatic ß-cell transcription factor [41]. These mutation result in decreased insulin secretion in response to glucose due to reduced binding of the protein to the insulin gene promoter [41,42] and perhaps by altering fibroblast growth factor signaling in beta cells [43]. Less severe mutations in IPF-1/PDX-1 may predispose to late onset type 2 diabetes [42,44]. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on Genetic defects of beta-cell function).

  Other genes — Several other genes that might affect insulin secretion, including the insulin gene and the genes for amylin and glucose transporters, have not been found to have any relationship to type 2 diabetes [6,27]. On the other hand, a mutation in mitochondrial DNA has been associated with a rare subtype of type 2 diabetes that has been called maternally inherited diabetes and deafness; insulin secretion is impaired via an uncertain mechanism in this disorder. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on Genetic defects in mitochondial DNA)

Genes affecting insulin action — Insulin exerts its effects by first binding to a specific insulin receptor that is present on many cells throughout the body. The insulin receptor is a large transmembrane protein composed of two extracellular alpha subunits and two transmembrane and intracellular beta subunits that have intrinsic tyrosine kinase activity. When insulin binds to the extracellular portion of the receptor, the tyrosine kinase is activated, initiating a sequence of intracellular responses mediated in part by insulin receptor substrates [45,46].

Several genetic syndromes of severe insulin resistance have been identified, many of which are associated with point mutations of the insulin-receptor gene [45]. These patients have marked hyperinsulinemia and sometimes other abnormalities, such as acanthosis nigricans and hyperandrogenism. However, as noted above, impaired glucose tolerance or overt diabetes only occurs in humans or in animals if compensatory increases in insulin secretion are inadequate [45,47,48].

None of the syndromes associated with an insulin receptor defect plays an important role in the common forms of type 2 diabetes [6]. Thus, the decrease in insulin responsiveness in type 2 diabetes is probably due to a postreceptor defect, presumably affecting one of the intracellular enzymes involved in glucose metabolism. In animals, for example, the gene for glycogen synthase (which promotes the conversion of glucose-6-phosphate to glycogen; show figure 3) is involved in the susceptibility to diet-induced hyperglycemia [49].

This observation may be relevant to humans, because impaired glycogen synthesis is responsible for the early insulin resistance in nondiabetic first-degree relatives of patients with type 2 diabetes [5,33], and an association has been noted between a polymorphism of the glycogen synthase gene and the presence of diabetes in a subgroup of patients with a strong family history of type 2 diabetes, hypertension, and marked insulin resistance [50]. However, a relationship between type 2 diabetes and the promoter or coding regions of the glycogen synthase gene has not been confirmed [6,51]. Furthermore, there is evidence that impaired insulin-stimulated glucose transport is responsible for the reduced muscle glycogen synthesis in patients with this disorder [52].

Other genes that may affect susceptibility to type 2 diabetes are the genes for insulin-receptor substrates, the beta-3-adrenergic receptor, and peroxisome-proliferator-activated receptor gamma-2. Insulin-receptor substrates are a common substrate for insulin receptor tyrosine kinases. Disruption of the IRS-2 gene in mice results in insulin resistance in the liver and skeletal muscle and hyperglycemia because of an inadequate compensatory increase in insulin secretion [53]. In another mouse study, upregulation of IRS-2 in pancreatic beta cells could prevent the onset of diabetes caused by IRS-2 disruption or diet-induced obesity [54]. Other tissue-specific IRS-2 knockout mouse models suggest that IRS-2 signaling may play an important role in hypothalamic regulation of leptin, peripheral insulin sensitivity, and possibly, regeneration of beta cells [55,56]. (See "Physiology of leptin" and see "Structure and function of the insulin receptor").

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