Acute effects of the human amylin analog AC137 on basal and insulin-stimulated euglycemic and hypoglycemic fuel metabolism in patients with insulin-dependent diabetes mellitus.

Abstract

Amylin has been reported to decrease glycogen storage in rodent skeletal muscles and produce insulin resistance in intact rats. To test the acute effect of a human amylin analog (AC137) on glucose metabolism in man, seven IDDM patients were infused in a randomized, double blind, cross-over study with AC137 (100 micrograms/h, n = 1; 50 micrograms/h, n = 6) or placebo for 330 min during a two-step euglycemic clamp (insulin infusion rates, 0.2 and 0.6 mU/kg.min; basal and hyperinsulinemic period, respectively) followed by a hyperinsulinemic hypoglycemic clamp (insulin infusion rate, 1.5 mU/kg.min; hypoglycemic period). During euglycemia, no differences were found in glucose disposal (step 1, 2.43 +/- 0.20 vs. 2.03 +/- 0.26; step 2, 4.28 +/- 0.54 vs. 4.11 +/- 0.45 mg/kg.min; AC137 vs. placebo, mean +/- SEM), arteriovenous substrate balances across the forearm, or hepatic glucose production. During hypoglycemia, glucose fluxes were also similar. However, lactate release from the forearm was more pronounced (P < 0.05) with the analog than with placebo (area under the curve, -11.2 +/- 4.6 vs. -1.4 +/- 2.2 mmol/min.L). Despite similar plasma glucose nadirs (2.7 +/- 0.0 vs. 2.6 +/- 0.1 mmol/L; AC137 vs. placebo), circulating cortisol and GH rose to significantly higher levels during hypoglycemia with the amylin analog (P < 0.05). In conclusion, acute administration of the amylin analog AC137 did not influence insulin-stimulated glucose metabolism during euglycemic conditions. During imposed hypoglycemia, lactate release from skeletal muscle was, however, enhanced, and the rise in cortisol and GH was augmented.

Plasma amylin concentration in suckling goat neonates and its relationship with C-reactive protein, selected biochemical and hormonal indicators

“…Chmielowska et al (2005) demonstrated that amylin administered centrally and peripherally produced a significant decrease in prolactin release in rats. Together, our results show that the interactions between plasma amylin and prolactin, a reproductive hormone, in goat neonates are not consistent with the findings in rats (Nyholm et al 1996). The observed differences between rats and goat neonates may be due to distinct receptor subtypes of amylin in each species.…”

“…Nyholm et al (1996) showed that amylin analogue AC 137 caused an increase in circulating cortisol during hypoglycaemia in patients with insulin-dependent diabetes mellitus. Our data suggest that the interactions between plasma amylin and cortisol, a metabolic hormone, in goat neonates are consistent with those observed with the amylin analogue in humans.…”

Amylin Agonists: A Novel Approach in the Treatment of Diabetes

“…A similar observation was also made in insulin-treated type 2 diabetic patients (45). There is no evidence of an effect of pramlintide administration on insulin sensitivity in either peripheral tissues or the liver in type 1 diabetic patients (46), which reiterates the observations made in healthy individuals using native amylin (34) and which is further supported indirectly using an amylin antagonist (47) in obese type 2 diabetic and nondiabetic individuals. The latter study also demonstrated that the amylin antagonist was able to increase insulin secretion in lean and obese individuals, suggesting a possible physiological role of amylin to restrain insulin secretion.…”

A Randomized Study and Open-Label Extension Evaluating the Long-Term Efficacy of Pramlintide as an Adjunct to Insulin Therapy in Type 1 Diabetes

“…The mechanisms underlying the lack of increase in severe hypoglycemia with pramlintide are not yet fully established but may involve an increase in liver glycogen stores (21), a reduction in diurnal glucose fluctuations (22), and/or an improved hormonal counter-regulatory response to hypoglycemia (23). Of note, both preclinical studies (24,25) and studies in patients with type 1 diabetes (26) indicate that the effects of pramlintide on gastric emptying and glucagon secretion are overcome in the presence of insulin-induced hypoglycemia. Although pramlintide itself does not cause hypoglycemia, even at high Data are % or means Ϯ SEM.…”