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 [1–9]. 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 is insulin-independent and becomes saturated at a plasma glucose concentration of approximately 40 mg/dL [10]. Another 25% of glucose disposal occurs in the splanchnic area (liver plus gastrointestinal tissues), which is also insulin-independent. The remaining 25% of glucose use in the postabsorptive state takes place in insulin-dependent tissues, primarily muscle, and to a lesser extent adipose tissue. Basal glucose use, approximately 2.0 mg/kg/min, is precisely matched by the rate of endogenous glucose production (Fig. 1). Approximately 85% of endogenous glucose production is derived from the liver, and the remaining 15% is produced by the kidney. Glycogenolysis and gluconeogenesis contribute equally to the basal rate of hepatic glucose production.
Following glucose ingestion, the increase in plasma glucose concentration stimulates insulin release, and the combination of hyperinsulinemia and hyperglycemia (1) stimulates glucose uptake by splanchnic (liver and gut) and peripheral (primarily muscle) tissues and (2) suppresses endogenous (primarily hepatic) glucose production (Box 1) [1–9].
The majority (80%–85%) of glucose uptake by peripheral tissues occur in muscle, with a small amount (4%–5%) metabolized by adipocytes. Although fat tissue is responsible for only a small amount of total body glucose disposal, it plays a very important role in the maintenance of total body glucose homeostasis by regulating the release of free fatty acids (FFA) from stored triglycerides (see discussion below) and through the production of adipocytokines that influence insulin sensitivity in muscle and liver [11–14]. Insulin is a potent antilipolytic hormone, and even small increments in the plasma insulin concentration markedly inhibit lipolysis, leading to a decline in the plasma level of free fatty acid [12]. The decline in plasma FFA concentration augments muscle glucose uptake and contributes to the inhibition of hepatic glucose production. Thus, changes in the plasma FFA concentration in response to increased plasma levels of insulin and glucose play an important role in the maintenance of normal glucose homeostasis [11–14].
Glucagon also plays a central role in the regulation of glucose homeostasis [9,15]. Under postabsorptive conditions, approximately half of total hepatic glucose output is dependent on the maintenance of normal basal glucagon levels, and inhibition of basal glucagon secretion with somatostatin causes a reduction in hepatic glucose production and plasma glucose concentration. After a glucose-containing meal, glucagon secretion is inhibited by hyperinsulinemia, and the resultant hypoglucagonemia contributes to the suppression of hepatic glucose production and maintenance of normal postprandial glucose tolerance.
The route of glucose entry into the body also plays an important role in the distribution of administered glucose and overall glucose homeostasis [9,16,17]. Intravenous insulin exerts only a small stimulatory effect on splanchnic (liver plus gut) glucose uptake, whereas intravenous glucose augments splanchnic glucose uptake in direct proportion to the increase in plasma glucose concentration. In contrast, oral glucose administration markedly enhances splanchnic glucose uptake. The portal signal that stimulates hepatic glucose uptake after glucose ingestion is directly proportional to the negative hepatic artery–portal vein glucose concentration gradient [9].As this gradient widens, the splanchnic nerves are stimulated, and this activates a neural reflex in which vagal activity is enhanced, and sympathetic nerves innervating the liver are inhibited. These neural changes augment liver glucose uptake and stimulate hepatic glycogen synthase, while simultaneously inhibiting glycogen phosphorylase. In contrast to intravenous glucose/insulin administration, in which muscle accounts for the majority (80%–85%) of glucose disposal, the splanchnic tissues are responsible for the removal of approximately 30%–40% of an ingested glucose load. Glucose administration through the gastrointestinal tract also has a potentiating effect on insulin secretion. Thus, the plasma insulin response following oral glucose is approximately twice as great as that following intravenous glucose, despite equivalent increases in the plasma glucose concentration. This increase in effect is related to the release of glucagon-like peptide (GLP)-1 and glucosedependent insulinotropic polypeptide (GIP) (previously called gastric inhibitory polypeptide) from the intestinal tissues cells [18,19].
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...