Altered beta-Cell Distribution of pdx-1 and GLUT-2 After a Short-Term Challenge With a High-Fat Diet in C57BL/6J Mice.

Mechanisms involved in the islet adaptation to insulin resistance were examined in mice of the C57BL/6J strain challenged with a high-fat (58%) diet for 8 weeks. Basal hyperglycemia commenced after 1 week, whereas hyperinsulinemia evolved after 8 weeks. Glucose elimination after an intravenous glucose challenge (1 g/kg) was significantly delayed after 1, 4, and 8 weeks on the high-fat diet compared with normal-diet--fed mice. This result was associated with unchanged insulin responses. However, glucose-stimulated insulin secretion from isolated islets was increased in a compensatory fashion at all glucose levels over a wide range (3.3--22 mmol/l) after 8 weeks on the high-fat diet, whereas no compensatory hypersecretion of insulin was evident after 1 or 4 weeks, except at 22 mmol/l glucose. Immunohistochemistry revealed that the islet architecture of insulin and glucagon cells remained intact in islets from mice fed a high-fat diet. However, the nuclear translocation of the homeobox transcription factor, pdx-1, and the plasma membrane translocation of GLUT2 were both impaired in high-fat--fed animals after 1 week. In contrast, the expression of the full-length leptin receptor (ObRb) was not affected by high-fat feeding. The study thus shows that 8 weeks are required for the development of a compensatory hypersecretion of insulin after high-fat feeding in mice, and even then the in vivo insulin secretion is insufficient to normalize impaired glucose tolerance. The early-onset islet dysfunction is accompanied by impaired beta-cell trafficking of two factors, pdx-1 and GLUT-2, which are involved in beta-cell proliferation and glucose recognition. The mechanisms compromising this beta-cell trafficking remain to be established

Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice.

OBJECTIVES: Inhibitors of the glucagon-like peptide-1 (GLP-1)-degrading enzyme, dipeptidyl peptidase IV (DPPIV), are being explored in the treatment of diabetes. We examined the long-term influence of a selective, orally active inhibitor of DPPIV (NVP DPP728), in normal female C57BL/6J mice and such mice rendered glucose-intolerant and insulin-resistant by feeding a high-fat diet. DESIGN: In mice fed a standard diet (11% fat) or a high-fat diet (58% fat), NVP DPP728 (0.12 micromol/g body weight) was administered in the drinking water for an 8 week period. RESULTS: DPPIV inhibition reduced plasma DPPIV activity to 0.01+/-0.03 mU/ml vs 3.26+/-0.19 mU/ml in controls (P<0.001). Glucose tolerance after gastric glucose gavage, as judged by the area under the curve for plasma glucose levels over the 120 min study period, was increased after 8 weeks by NVP DPP728 in mice fed normal diet (P=0.029) and in mice fed a high-fat diet (P=0.036). This was accompanied by increased plasma levels of insulin and intact GLP-1. Glucose-stimulated insulin secretion from islets isolated from NVP DPP728-treated animals after 8 weeks of treatment was increased as compared with islets from control animals at 5.6, 8.3 and 11.1 mmol/l glucose both in mice fed normal diet and in mice fed a high-fat diet (both P<0.05). Islet insulin and glucagon immunocytochemistry revealed that NVP DPP728 did not affect the islet architecture. However, the expression of immunoreactive glucose transporter isoform-2 (GLUT-2) was increased by DPPIV inhibition, and in mice fed a high-fat diet, islet size was reduced after treatment with NVP DPP728 from 16.7+/-2.6 x 10(3) microm(2) in controls to 7.6+/-1.0 x 10(3) microm(2) (P=0.0019). CONCLUSION: Long-term DPPIV inhibition improves glucose tolerance in both normal and glucose-intolerant mice through improved islet function as judged by increased GLUT-2 expression, increased insulin secretion and protection from increased islet size in insulin resistance

Enhanced Insulin Sensitivity by Adipose Tissue Browning Alters Islet Morphology and Hormone Secretion in Response to Autonomic Nervous Activation in Female Mice.

Insulin resistance results in compensatory increase in insulin secretion to maintain normoglycemia. Conversely, high insulin sensitivity results in reduced insulin secretion to prevent hypoglycemia. The mechanisms for this inverse adaptation are not well understood. We utilized highly insulin sensitive mice, due to adipocyte specific overexpression of the FOXC2 transcription factor, to study mechanisms of the reversed islet adaptation to increased insulin sensitivity. We found that Foxc2TG mice responded to mild hyperglycemia with reduced insulin secretion compared to wild type mice, however when severe hyperglycemia was induced, Foxc2TG mice demonstrated insulin secretion equal to or greater than that of wild type mice. In response to autonomic nervous activation the acute suppression of insulin seen in wild-type mice was absent in Foxc2TG mice suggesting impaired adrenergic signaling in the islet. Basal glucagon was increased in Foxc2TG mice but they displayed severely impaired glucagon responses to cholinergic and autonomic nervous stimuli. These data suggest that the autonomic nerves contribute to the islet adaptation to high insulin sensitivity which is compatible with a neuro-adipo regulation of islet function being instrumental for maintaining glucose regulation

Local growth factors are beneficial for the autonomic reinnervation of transplanted islets in rats

Introduction: Transplanted islets, being avascular and denervated, receive blood vessels and nerves from the recipient. Reinnervation may account in part for the normalization of islet function in islet transplants. Whether reinnervation is possible to augment is not known. Aims and Methodology: To explore whether reinnervation of transplanted islets is augmented by local addition of growth factors to the graft, syngeneic islets were transplanted to the pancreas of streptozotocin-diabetic Lewis rats with or without pellets locally releasing nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), alone or in combination. The pellets released growth factors for 14 days at a rate of 20 ng/day. After 7 weeks, pancreatic tissue was processed for immunofluorescence of insulin and the neural markers neuropeptide Y (NPY) and tyrosine hydroxylase (TH). Results: Islets were larger and more numerous after treatment with NGF (p = 0.024) and with NGF in combination with VEGF (p = 0.044). Similarly, immunostaining for TH and the C-terminal flanking peptide of NPY (C-PON) was more pronounced after treatment with NGF in combination with VEGF than in controls (both p < 0.05). Conclusion: Local growth factor treatment has a beneficial effect on autonomic reinnervation as well as islet integrity and survival of the graft after islet transplantation in rats