Lack of Effect of Islet Amyloid Polypeptide in Causing Insulin Resistance in Conscious Dogs During Euglycemic Clamp Studies

Abstract

In this study, we administered constant intravenous infusions of human islet amyloid polypeptide (hIAPP) to conscious dogs during euglycemic glucose-clamp studies. The doses of hIAPP used (5 and 50 pmol.kg-1.min-1) raised the circulating IAPP levels approximately 12- and 50-fold above basal levels, respectively. Studies were conducted at two different insulin infusion rates, resulting in steady-state plasma insulin levels of approximately 600 and 2800 pM. According to our results, the hIAPP infusions did not lead to any measurable change in the insulin-stimulated glucose disposal rate at either insulin infusion rate. Additionally, we observed no effect of IAPP on hepatic glucose production. Although we did not observe any effect of hIAPP on any of the aspects of glucose or insulin metabolism measured, we did find a consistent hypocalcemic effect of this peptide at the 50-pmol.kg-1.min-1 infusion rate. Shortly after the onset of hIAPP infusion, serum calcium levels fell by 10-15% and remained at these levels throughout the course of the hIAPP infusion. In summary, 1) infusion of hIAPP at doses of 5 or 50 pmol.kg-1.min-1 in conscious dogs raised the circulating IAPP level 12- to 50-fold above basal; 2) during these infusion studies, no effect of hIAPP was observed on any of the aspects of glucose or insulin homeostasis measured; 3) 50 pmol.kg-1.min-1 hIAPP lead to a prompt reduction in plasma calcium concentrations with intravenous administration.

Effects of the amylin analogue pramlintide on hepatic glucagon responses and intermediary metabolism in Type 1 diabetic subjects

“…It is possible that an effect of pramlintide would have been seen if these studies had been conducted in the postprandial state. In agreement with this, some [12], but not all [13], animal studies have found evidence that amylin reduces insulin sensitivity. Native amylin at high concentrations has been reported to inhibit muscular glycogen synthesis and stimulate glycogenolysis in isolated rat muscle, presumably via a reduction of glycogen synthase and stimulation of glycogen phosphorylase [12,30].…”

“…Native amylin at high concentrations has been reported to inhibit muscular glycogen synthesis and stimulate glycogenolysis in isolated rat muscle, presumably via a reduction of glycogen synthase and stimulation of glycogen phosphorylase [12,30]. In agreement with this, some [12], but not all [13], animal studies have found evidence that amylin reduces insulin sensitivity. In terms of the effect of native amylin on insulin sensitivity in humans, amylin has been suggested both to reduce and not to affect insulin sensitivity [10,31].…”

“…The human amylin analogue pramlintide has been demonstrated to improve overall glycaemic control in Type 1 diabetic subjects [5,6], an effect primarily based on the ability of amylin (and pramlintide) to suppress circulating glucagon concentrations [6,7], to slow gastric emptying [8] and to act as a satiety factor [9]. In human [10,11], as well as in in vivo animal studies [12,13] native amylin has been found both to reduce and not affect insulin sensitivity (peripherally and/or in the liver). Pramlintide administered acutely, and in short-term studies has previously been shown to have no effect on insulinstimulated glucose uptake or on insulin suppression of endogenous glucose production (EGP) in Type 1 diabetic subjects [11,14,15].…”

Islet amyloid polypeptide: actions and role in the pathogenesis of diabetes

“…IAPP, like CGRP, has been shown to decrease insulininduced glycogenesis in skeletal muscle in vitro and has therefore been proposed as a regulator of glucose disposal with an important role in insulin resistance in diabetes [25]. However, this hypothesis could not be substantiated in vivo in humans and other animal experiments: glucose disposal after an infusion was not reduced by very high circulating concentrations of synthetic IAPP in humans and experimental animals [26,27]. In addition, it has been suggested that I M P , by promoting lactate formation in muscle, potentiates hepatic glycogenesis from lactate [28,29]: this potential effect of IAPP is the basis of a putative therapy for Type-1 diabetes to maintain hepatic glycogen stores and reduce insulin-induced hypoglycaemia.…”

Islet amyloid in type 2 (non-insulin-dependent) diabetes

“…1993;Bretherton-Watt et al 1992;Wilding et ul. 1993;Kassir et al 1991). Despite the high circulating concentrations of IAPP in transgenic mice, there was no evidence for the formation of fibrillar islet amyloid (de Koning et ul.…”