Review articlePathogenesis of type 2 diabetes mellitus
Section snippets
Normal glucose homeostasis
A discussion of the pathogenesis of type 2 diabetes mellitus must start with a review of mechanisms involved in the maintenance of normal glucose homeostasis in the basal or postabsorptive state (10–12 h overnight fast) and following ingestion of a typical mixed meal [1], [2], [3], [4], [5], [6], [7], [8], [9]. In the postabsorptive state the majority of total body glucose disposal takes place in insulin-independent tissues. Thus, approximately 50% of all glucose use occurs in the brain, which
Glucose homeostasis in type 2 diabetes mellitus
Type 2 diabetic subjects manifest multiple disturbances in glucose homeostasis, including: (1) impaired insulin secretion; (2) insulin resistance in muscle, liver, and adipocytes; and (3) abnormalities in splanchnic glucose uptake [1], [2], [20], [21].
Site of insulin resistance in type 2 diabetes
Maintenance of normal whole-body glucose homeostasis requires a normal insulin secretory response and normal tissue sensitivity to the independent effects of hyperinsulinemia and hyperglycemia to augment glucose uptake [1], [2], [3], [4], [5], [6], [7]. The combined effects of insulin and hyperglycemia to promote glucose disposal are dependent on three tightly coupled mechanisms (see Box 1): (1) suppression of endogenous (primarily hepatic) glucose production; (2) stimulation of glucose uptake
Dynamic interaction between insulin sensitivity and insulin secretion in type 2 diabetes
Insulin resistance is present in approximately 25% of the adult population [138], [139], [140]. The majority of these individuals, however, have normal glucose tolerance because the pancreatic beta cells are able to read the severity of insulin resistance and appropriately augment their insulin secretory rate. This dynamic interaction between insulin sensitivity and insulin secretion is demonstrated by results obtained in healthy, lean, young normal-glucose-tolerant women who received a
Role of the adipocyte in the pathogenesis of type 2 diabetes mellitus: the harmonious quartet
The majority (≥ 80%–90%) of type 2 diabetics in the United States are overweight or obese [147]. Both lean and especially obese type 2 diabetics are characterized by day-long elevation in plasma free fatty-acid concentration, which fails to suppress normally following ingestion of a mixed meal or oral glucose load [30]. FFA are stored as triglycerides in adipocytes and serve as an essential energy source during fasting conditions. Insulin is a potent antilipolytic hormone and restrains the
Cellular mechanisms of insulin resistance
The cellular events through which insulin initiates its stimulatory effect on glucose metabolism start with binding of the hormone to specific receptors that are present on the cell surface of all insulin target tissues [2], [160], [161], [162]. After insulin has bound to and activated its receptor, “second messengers” are generated, and these second messengers activate a cascade of phosphorylation-dephosphorylation reactions that eventually result in the stimulation of intracellular glucose
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