Treatment With Growth Hormone and Dexamethasone in Mice Transgenic for Human Islet Amyloid Polypeptide Causes Islet Amyloidosis and β-Cell Dysfunction

Abstract

Islet amyloid derived from islet amyloid polypeptide (IAPP) is a well-recognized feature of type II diabetes. However, the mechanism of islet amyloidogenesis is unknown. In vitro studies suggest that amino acid residues 20-29 in human, but not mouse, IAPP confer amyloidogenicity consistent with the absence of spontaneous islet amyloidosis in mice. Several clinical and in vitro studies suggest that increased synthetic rates of IAPP predispose to IAPP-amyloidosis. In the present study, we sought to test the hypothesis that pharmacological induction of insulin resistance in a mouse transgenic (TG) for human IAPP would induce islet amyloid and beta-cell dysfunction. TG and non-transgenic (N-TG) control mice were treated with both rat growth hormone (12 micrograms/day) and dexamethasone (0.24 mg/day) (dex/GH) or received no treatment for 4 weeks, after which animals were killed to examine islet morphology. Treatment with dex/GH caused hyperglycemia (7.3 +/- 0.4 vs. 5.2 +/- 0.1 mmol/l, TG vs. N-TG, P < 0.001) associated with a decreased plasma insulin concentration (595 +/- 51 vs. 996 +/- 100 pmol/l, TG vs. N-TG, P < 0.05) in TG versus control mice. Islet amyloid was induced in treated TG mice but not in control mice. Islet amyloid was identified in both intra- and extracellular deposits, the former being associated with evidence of beta-cell degeneration. We conclude that dex/GH treatment in mice TG for human IAPP induces IAPP-derived islet amyloid, hyperglycemia, and islet dysfunction. The present model recapitulates the islet morphology and phenotype of type II diabetes.

Islet Amyloid Develops Diffusely Throughout the Pancreas Before Becoming Severe and Replacing Endocrine Cells

“…These transgenic mice do not develop islet amyloid spontaneously (12,13), in accordance with the fact that only small amounts of islet amyloid are observed in a few isolated islets in old nondiabetic primates and cats (3,4). However, islet amyloid occurs when these transgenic mice are exposed to other diabetogenic factors, including increased dietary fat (16), insulin resistance induced by growth hormone and dexamethasone (14), or obesity caused by crossbreeding with genetically obese mice (15,17).…”

“…Therefore, to investigate the mechanism of islet amyloidosis in a mouse model, we and others have generated transgenic mice expressing the human IAPP (hIAPP) gene in their pancreatic ␤-cells (12)(13)(14)(15). These transgenic mice do not develop islet amyloid spontaneously (12,13), in accordance with the fact that only small amounts of islet amyloid are observed in a few isolated islets in old nondiabetic primates and cats (3,4).…”

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

“…Remarkably, the majority of in vivo animal studies and clinical reports show that, in addition to hyperinsulinaemia, GC treatment induces higher plasma levels of glucagon and amylin and may probably affect somatostatin. The increased plasma amylin levels might also be considered diabetogenic because enhanced IAPP concentrations may lead to increased rates of toxic amylin aggregation (Couce et al 1996). In addition, the hyperglucagonaemia observed with GC treatment opposes insulin actions and may aggravate steroid-induced hyperglycaemia by increasing hepatic glucose output, as indicated in diabetes (Quesada et al 2008).…”

IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants

“…commonly used in islet transplants (Couce et al 1996, Mulder et al 1996. Another practice that may exacerbate islet amyloid formation in islet grafts is the use of heparin to prevent clotting during islet infusion.…”