Maintenance of the postabsorptive plasma glucose concentration: insulin or insulin plus glucagon?

Abstract

The prevalent view is that the postabsorptive plasma glucose concentration is maintained within the physiological range by the interplay of the glucose-lowering action of insulin and the glucose-raising action of glucagon. It is supported by a body of evidence derived from studies of suppression of glucagon (and insulin, among other effects) with somatostatin in animals and humans, immunoneutralization of glucagon, defective glucagon synthesis, diverse mutations, and absent or reduced glucagon receptors in animals and glucagon antagonists in cells, animals, and humans. Many of these studies are open to alternative interpretations, and some lead to seemingly contradictory conclusions. For example, immunoneutralization of glucagon lowered plasma glucose concentrations in rabbits, but administration of a glucagon antagonist did not lower plasma glucose concentrations in healthy humans. Evidence that the glycemic threshold for glucagon secretion, unlike that for insulin secretion, lies below the physiological range, and the finding that selective suppression of insulin secretion without stimulation of glucagon secretion raises fasting plasma glucose concentrations in humans underscore the primacy of insulin in the regulation of the postabsorptive plasma glucose concentration and challenge the prevalent view. The alternative view is that the postabsorptive plasma glucose concentration is maintained within the physiological range by insulin alone, specifically regulated increments and decrements in insulin, and the resulting decrements and increments in endogenous glucose production, respectively, and glucagon becomes relevant only when glucose levels drift below the physiological range. Although the balance of evidence suggests that glucagon is involved in the maintenance of euglycemia, more definitive evidence is needed, particularly in humans. glucose metabolism; hypoglycemia; diabetes GIVEN EVIDENCE of absolute or relative hyperglucagonemia in patients with type 1 and type 2 diabetes (27,29,37,38), Unger and Orci (48) first proposed that glucagon, in the setting of absolute or relative insulin deficiency, plays a role in the pathogenesis of diabetes. Their bihormonal hypothesis was based on three lines of evidence: 1) endogenous hyperglycemia had never been observed in the absence of glucagon; 2) when both insulin and glucagon were suppressed with somatostatin, hyperglycemia did not occur; and 3) somatostatin-induced suppression of glucagon reduced glycemia in humans with diabetes. With respect to the last, somatostatin has been shown to reduce, but not normalize, fasting and postprandial hyperglycemia (15) and to delay increments in plasma glucose (as well as in plasma nonesterified fatty acids, glycerol, and ␤-hydroxybutyrate) concentrations following withdrawal of insulin in patients with type 1 diabetes (14). Although these findings are entirely consistent with a role of glucagon in the pathogenesis of hyperglycemia (and ketosis) in type 1 diabetes, control studies with somatostatin administration and replacem...

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Interaction of fast and slow dynamics in endocrine control systems with an application to β-cell dynamics

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