Evolution of β-Cell Dysfunction in the Male Zucker Diabetic Fatty Rat

Abstract

The molecular basis for the beta-cell dysfunction that characterizes non-insulin-dependent diabetes mellitus (NIDDM) is unknown. The Zucker diabetic fatty (ZDF) male rat is a rodent model of NIDDM with a predictable progression from the prediabetic to the diabetic state. We are using this model to study beta-cell function during the development of diabetes with the goal of identifying genes that play a key role in regulating insulin secretion and, thus, may be potential targets for therapeutic intervention aimed at preserving or improving beta-cell function. As a first step, we have characterized morphology, insulin secretion, and pattern of gene expression in islets from prediabetic and diabetic ZDF rats. The development of diabetes was associated with changes in islet morphology, and the islets of diabetic animals were markedly hypertrophic with multiple irregular projections into the surrounding exocrine pancreas. In addition, there were multiple defects in the normal pattern of insulin secretion. The islets of prediabetic ZDF rats secreted significantly more insulin at each glucose concentration tested and showed a leftward shift in the dose-response curve relating glucose concentration and insulin secretion. Islets of prediabetic animals also demonstrated defects in the normal oscillatory pattern of insulin secretion, indicating the presence of impairment of the normal feedback control between glucose and insulin secretion. The islets from diabetic animals showed further impairment in the ability to respond to a glucose stimulus. Changes in gene expression were also evident in islets from prediabetic and diabetic ZDF rats compared with age-matched control animals. In prediabetic animals, there was no change in insulin mRNA levels. However, there was a significant 30-70% reduction in the levels of a large number of other islet mRNAs including glucokinase, mitochondrial glycerol-3-phosphate dehydrogenase, voltage-dependent Ca2+ and K+ channels, Ca(2+)-ATPase, and transcription factor Islet-1 mRNAs. In addition, there was a 40-50% increase in the levels of glucose-6-phosphatase and 12-lipoxygenase mRNAs. There were further changes in gene expression in the islets from diabetic ZDF rats, including a decrease in insulin mRNA levels that was associated with reduced islet insulin levels. Our results indicate that multiple defects in beta-cell function can be detected in islets of prediabetic animals well before the development of hyperglycemia and suggest that changes in the normal pattern of gene expression contribute to the development of beta-cell dysfunction.

Induction of Hepatic Glucose-6-Phosphatase Gene Expression by Lipid Infusion

“…It is suggested that prolonged hyperlipidemia may contribute to the increased production of glucose via increased expression of this protein. Taken together with numerous other reports on the impact of lipids on carbohydrate metabolism in skeletal muscle (7)(8)(9), liver (8)(9)(10)12,13), and pancreatic (3-cells (11,38,39), our finding provides experimental support for the role of hyperlipidemia in the pathogenesis of NIDDM (40,41).…”

Induction of c-Myc Expression Suppresses Insulin Gene Transcription by Inhibiting NeuroD/BETA2-mediated Transcriptional Activation

“…The toxic effect of hyperglycemia on ␤-cells has been demonstrated with in vivo (2)(3)(4)(5) and in vitro models (6, 7). Previously we found that hyperglycemia induces the expression of c-Myc in islets in several different diabetic models (5,13).…”

“…Once hyperglycemia becomes apparent, ␤-cell function deteriorates (1). The adverse effects of chronic hyperglycemia on ␤-cells, called glucose toxicity, have been demonstrated by various in vivo (2)(3)(4)(5) and in vitro studies (6,7). After chronic exposure to hyperglycemia, insulin gene transcription and glucose-stimulated insulin secretion are suppressed.…”

“…Under chronic hyperglycemic conditions in vivo, the expression of many ␤-cell-associated genes is decreased (3)(4)(5), but, in contrast, the expression of some suppressed genes is markedly up-regulated. In normal adult islets, the c-Myc expression level is very low, but c-Myc is induced in diabetic rats following partial pancreatectomy and in rats made hyperglycemic with glucose clamps (5,13).…”

High glucose and hydrogen peroxide increase c-Myc and haeme-oxygenase 1 mRNA levels in rat pancreatic islets without activating NF?B

“…Chronic hyperglycaemia induces phenotypic alterations of rodent beta cells, including GSIS abnormalities, reduced expression of specific genes (loss of beta cell differentiation), hypertrophy, slight increase in apoptosis, and increased expression of genes normally repressed in fully differentiated beta cells [6,[8][9][10][11][12][13][14]. These phenotypic alterations may contribute to the progressive worsening of GSIS in type 2 diabetes [15,16].…”