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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #130: Pathogenesis of Type 2 Diabetes Mellitus Part 1

Jun 19, 2018

Normal glucose homeostasis

Any discussion of the pathogenesis of type 2 diabetes mellitus (T2DM) must start with a review of mechanisms involved in the maintenance of normal glucose homeostasis in the basal o postabsorptive state (10–12-h overnight fast) and following ingestion of a typical mixed meal [1–4]. In the postabsorptive state the great majority of total body glucose disposal takes place in insulin independent tissues.Thus, ∼50% of all glucose utilization occurs in the brain, which is insulin independent and becomes saturated at a plasma glucose concentration of about 40 mg dL−1 [4,5]. Another 25% of glucose disposal occurs in the splanchnic area (liver plus gastrointestinal tissues) and is also insulin independent. The remaining 25% of glucose utilization in the postabsorptive state takes place in insulin-dependent tissues, primarily muscle, and to a lesser extent adipose tissue. Basal glucose utilization, ∼2.0mg kg−1 min−1, is precisely matched by the rate of endogenous glucose production (Figure 25.1). 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 (i) stimulates glucose uptake by splanchnic (liver and gut) and peripheral (primarily muscle) tissues (Table 25.1), and (ii) suppresses endogenous (primarily hepatic) glucose production [1–4,6–10]. The majority (∼80–85%) of glucose uptake by peripheral tissues occurs in muscle, with a small amount (∼4–5%) being 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 later) and through the production of adipocytokines that influence insulin sensitivity in muscle and liver [11–13]. 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 FFA level [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 [11–13].

Glucagon also plays a central role in the regulation of glucose homeostasis [14,15]. Under postabsorptive conditions approximately half of total hepatic glucose output is dependent upon 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 [14,16,17]. Intravenous (i.v.) insulin exerts only a small stimulatory effect on splanchnic (liver plus gut) glucose uptake, while i.v. glucose augments splanchnic glucose uptake in direct proportion to the increase in plasma glucose concentration [6]. 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 i.v. glucose/insulin administration, where muscle accounts for the majority (∼80–85%) of glucose disposal, the splanchnic tissues are responsible for the removal of ∼30–40% of an ingested glucose load.

Glucose administration via the gastrointestinal tract also has a potentiating effect on insulin secretion. Thus, the plasma insulin response following oral glucose is about twice as great as that following i.v. glucose despite equivalent increases in the plasma glucose concentration. This incretin effect is related to the release of glucagon-like peptide-1 (GLP-1) from the L cells in the large intestine and glucose-dependent insulinotropic polypeptide (previously called gastric inhibitory polypeptide) (GIP) from the K cells in the early part of the small intestine [18–20]. GLP-1 also inhibits glucagon secretion and the decline in plasma glucagon concentration contributes to suppression of hepatic glucose production following meal ingestion. GLP-1 and GIP are released in response to nutrient absorption by the L and K cells [18–20], and in response to a meal increased circulating levels of GLP-1 and GIP can be detected within minutes, before nutrients can reach the K cells in the duodenum and long before they reach the L cells in the distal small intestine and early large intestine. This early release of GLP-1 and GIP is mediated via neural impulses that are carried to centers in the hypothalamus and back to the intestinal cells via the vagus nerve [21]. GLP-1 and GIP have their own receptors on the β cell and augment insulin secretion by activation of adenyl cyclase [18–20]. Importantly, the stimulation of insulin secretion by GLP1 and GIP is glucose-dependent, that is, insulin

release is augmented in the presence of hyperglycemia and the stimulatory effect of both GLP-1 and GIP wanes as the blood glucose concentration returns to normoglycemic levels.