This chapter describes a physiological and profound effect of
amylin to inhibit meal-related
glucagon secretion.
Glucagon is processed from a large precursor,
proglucagon, in a tissue-specific manner in pancreatic alpha-cells. In addition to
amino acid nutrient stimuli,
glucagon is also secreted in response to stressful stimuli, such as
hypoglycemia and
hypovolemia.
Glucagon primarily acts on liver to initiate glycogenolysis and gluconeogenesis, resulting in a rapid increase in endogenous production of
glucose. With longer stimulation,
glucagon action at the liver results in a
glucose-sparing activation of
free fatty acid oxidation and production of
ketones. During
hypoglycemia,
glucagon secretion is clearly a protective feed-back, defending the organism against damaging effects of low
glucose in brain and nerves (neuroglycopenia).
Amino acid-stimulated
glucagon secretion during meals has a different purpose:
amino acids stimulate insulin secretion, which mobilizes
amino acid transporters and effects their storage in peripheral tissues. At the same time,
insulin obligatorily recruits GLUT4
glucose transporters in muscle and fat. The
hypoglycemic potential of such GLUT4 mobilization is averted only by the simultaneous liberation of endogenous
glucose in response to feedforward (anticipatory)
glucagon secretion. The effect of
amylin and its agonists to inhibit
amino acid-stimulated
glucagon secretion is both potent (EC50 = 18 pM) and profound (approximately 70% inhibition). This glucagonostatic action appears to be extrinsic to the pancreatic islet, occurring in intact animals and in patients, but not in isolated islets or isolated perfused pancreas preparations. On the other hand, the effect of
hypoglycemia to stimulate
glucagon secretion, which is intrinsic to the islet and occurs in isolated preparations, is not affected by
amylin or its agonists. The physiological interpretation of these actions fits with the general concept, illustrated in Fig. 1, that
amylin and
insulin secreted in response to meals shut down endogenous production as a source of
glucose, in favor of that derived from the meal.
Amylin and
insulin secreted in response to nutrients already absorbed act as a feedback switch for
glucose sourcing. The insulinotropic (
incretin) gut
peptides,
GLP-1 and GIP, secreted in response to yet-to-be-absorbed intraluminal nutrients, amplify beta-cell secretion and thereby activate the
glucose sourcing switch in a feedforward manner.
Hypoglycemia-stimulated
glucagon secretion and nutrient (
amino acid)-stimulated
glucagon secretion are two clearly different processes, differently affected by
amylin. The balance of
glucose fluxes is disturbed in diabetic states, partly as a result of inappropriate
glucagon secretion. Although
glucose production due to
glucagon secreted in response to
hypoglycemia is normal or even reduced in diabetic patients, the secretion of
glucagon (and production of endogenous
glucose) in response to
protein meals is typically exaggerated. Absence of appropriate beta-cell suppression of alpha-cell secretion has been invoked as a mechanism that explains exaggerated
glucagon responses, especially prevalent in patients with deficient beta-cell secretion (
type 1 diabetes and insulinopenic
type 2 diabetes). A proposed benefit of
insulin replacement
therapy is the reduction of absolute or relative hyperglucagonemia. High
glucagon is said to be necessary for
ketosis in severe forms of diabetes. A further benefit of reversing hyperglucagonemia is reduction of the excessive endogenous
glucose production that contributes to fasting and
postprandial hyperglycemia in diabetes. The idea that
amylin is a part of the beta-cell drive that normally limits
glucagon secretion after meals fits with the observation that
glucagon secretion is exaggerated in
amylin-deficient states (diabetes characterized by beta-cell failure). This proposal is further supported by the observation that postprandial
glucagon suppression is restored following
amylin replacement
therapy in such states. These observations argue for a therapeutic case for
amylin replacement in patients in whom excess
glucagon action contributes to fasting and
postprandial hyperglycemia and
ketosis. The selectivity of
amylin's glucagonostatic effect (wherein it is restricted to meal-related
glucagon secretion, while preserving
glucagon secretion and
glucagon action during
hypoglycemia) may confer additional benefits; the patient population amenable to
amylin replacement
therapy is likely to also be receiving
insulin replacement
therapy, and is thereby susceptible to
insulin-induced
hypoglycemia. Most explorations of the biology of
amylin have used the endogenous
hormone in the cognate species (typically rat
amylin in rat studies). Clinical studies have typically employed the amylinomimetic agent
pramlintide. Studies of amylinomimetic effects on
glucagon secretion include effects of rat
amylin in anesthetized non-diabetic rats (Jodka et al., 2000; Parkes et al., 1999; Young et al., 1995), effects of rat
amylin in isolated perfused rat pancreas (Silvestre et al., 1999), effects of
pramlintide in anesthetized non-diabetic rats (Gedulin et al., 1997b,c,d, 1998), effects of
pramlintide in patients with type l diabetes (Fineman et al., 1997a,b,c,d, 1998a; Holst, 1997; Nyholm et al., 1996, 1997a,b,c; Orskov et al., 1999; Thompson and Kolterman, 1997), and effects in patients with
type 2 diabetes (Fineman et al., 1998b). In addition, effects of
amylin antagonists have been observed in isolated preparations (Silvestre et al., 1996), and effects of antagonists or
neutralizing antibody have been determined in whole-animal preparations (Gedulin et al., 1997a,e,f).