Transgenic overexpression of human islet amyloid polypeptide inhibits insulin secretion and glucose elimination after gastric glucose gavage in mice

Abstract

Islet amyloid polypeptide (IAPP, also designated amylin) is a 37 amino acid polypeptide which is synthesized in islet beta cells and co-stored and co-released with insulin [1±6]. Exogenous treatment with the peptide inhibits insulin secretion in the perfused rat pancreas [7], in isolated rat islets [8,9] and in vivo in rats [10] and humans [11], and a specific IAPP antagonist increases insulin secretion from islets [12]. It has also been shown that IAPP inhibits glycogen formation in skeletal muscle [13] and induces insulin resistance in rats [14,15]. This would suggest it inhibits both insulin secretion and action and, consequently, if overexpressed in a prediabetic stage, could add to the pathogenesis of Type II (non-insulin-dependent) diabetes mellitus. It has, however, also been claimed that IAPP does not impair insulin secretion [16,17] or insulin sensitivity [18]. Therefore, its physiological function is not yet established. In addition to its putative physiological actions, IAPP is also of interest in diabetes pathogenesis due to its ability to form fibrils, which are constituents of the islet amyloid characteristically accompanying Type II diabetes [19,20].To study the physiological function of IAPP as a circulating peptide, transgenic mice overexpressing Diabetologia (1998) Summary Islet amyloid polypeptide (IAPP) is synthesized in islet beta cells and has been implicated in diabetes pathogenesis because it can inhibit insulin secretion and action and form fibrils leading to islet amyloidosis. Its physiological function has, however, not been established. We therefore examined insulin secretion and glucose elimination after i. v. or gastric gavage of glucose in transgenic mice overexpressing human IAPP (hIAPP) resulting in considerably increased circulating IAPP concentrations. The insulin response to and the glucose elimination after i. v. glucose (1 g/kg) were not different in transgenic mice compared with wild type animals, neither in males nor in females. In contrast, the insulin response to gastric glucose (150 mg/mouse) was reduced and the glucose elimination was inhibited in both male and female transgenic mice. The area under the 30 min insulin curve (AUC insulin ) was 21 ± 2 nmol/l in 30 min in transgenic males (n = 24) vs 43 ± 3 nmol/l in 30 min in wild type males (n = 26; p < 0.001) and the respective areas under the glucose curve (AUC glucose ) were 1.90 ± 0.12 and 1.62 ± 0.09 mol/l in 120 min (p < 0.05). Similarly, in females, the AUC insulin was 17 ± 2 nmol/l in 30 min in transgenic mice vs 25 ± 3 nmol/l in 30 min in wild type mice (p < 0.05) and the respective AUC glucose was 1.62 ± 0.7 and 1.12 ± 0.07 mol/l in 120 min (p < 0.001). Hence, endogenous hIAPP inhibits insulin secretion and glucose elimination after gastric glucose gavage in both male and female mice, indicating that overexpression of hIAPP could be a diabetogenic factor, via effects on the intestinal tract or the gut-islet axis or both. [Diabetologia (1998

Extensive islet amyloid formation is induced by development of Type II diabetes mellitus and contributes to its progression: pathogenesis of diabetes in a mouse model

“…In this study, both hyperinsulinaemia and hyperglycaemia were indeed evident in NT ob/ob mice at the first point in time investigated, i. e. at 3.5 months of age. Even in homozygous transgenic hIAPP mice of lines No14 and No18, which are normoinsulinaemic and normoglycaemic, no islet amyloid could be detected at 4 months of age [18]. Therefore, insulin resistance in 3.5-month-old heterozygous transgenic hIAPP ob/ob mice most probably developed in the absence of islet amyloid.…”

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

“…In this study, we explored the effects vildagliptin in the mouse model of targeted β-cell overexpression of human IAPP, which is associated with impaired insulin secretion and glucose intolerance (12). We found that in this model, vildagliptin improves glucose tolerance and the insulin response to gastric glucose in mice with transgenic overexpression of hIAPP.…”

“…IAPP of the human form may form fibrils leading to islet amyloid deposition, β-cell dysfunction and type 2 diabetes (17,18). We have previously shown that mice with β -cell specific overexpression of hIAPP have severe glucose intolerance and defective insulin response to gastric glucose (12). In the present study, we explored whether DPP-4 inhibition improves glucose tolerance and insulin secretion in these mice.…”

“…We previously showed no gender difference in glucose tolerance or insulin secretion after gastric or intravenous glucose in mice with β-cell overexpression of hIAPP (12). When mice were 2 months of age, half of the mice were given the DPP-4 inhibitor, vildagliptin (a kind gift from Novartis Institutes for BioMedical Research, Cambridge, U.S.A.) in the drinking water (0.3mg/ml, ∼3µmol vildagliptin/day/mouse).…”

“…This was previously demonstrated in transgenic mice with ß-cell targeted dominantnegative mutant hepatocyte nuclear factor (HNF)-1α, a model of severe islet dysfunction underlying the genetic syndrome known as maturity-onset diabetes of the young (variant 3), and in which DPP-4 inhibition has weak and compromised effect (11). In the present study, we explored the effects of DPP-4 inhibition in mice with a targeted β-cell overexpression of human islet amyloid polypeptide (hIAPP) (12,13). IAPP is produced in the β-cells and inhibits insulin secretion (14)(15)(16).…”