In vivo prevention of hyperglycemia also prevents glucotoxic effects on PDX-1 and insulin gene expression.

Abstract

Chronic exposure of pancreatic islet beta-cell lines to supraphysiologic glucose concentrations causes defects in insulin gene expression and insulin secretion. To determine whether these in vitro phenomena have pathophysiologic relevance in vivo, we studied the Zucker diabetic fatty (ZDF) rat, an animal model of type 2 diabetes. The ZDF animals had relatively higher levels of glycemia and islet insulin mRNA at 6 weeks of age than age-matched Zucker lean control (ZLC) rats. As glycemia increased in 12- and 16-week-old ZDF rats, we observed decrements in glucose-induced insulin secretion during static incubations of pancreatic islets and in insulin mRNA levels, PDX-1 mRNA levels, and PDX-1 protein binding to the insulin promoter compared with age-matched ZLC rats and 6-week-old ZDF rats. To determine whether normalization of blood glucose levels would prevent these defects, ZDF rats were treated with troglitazone beginning at 6 weeks of age. Troglitazone prevented ZDF rats from becoming hyperglycemic and preserved glucose-induced insulin responses. Furthermore, troglitazone-treated ZDF animals had greater levels of insulin and PDX-1 mRNAs compared with untreated ZDF animals of the same ages at 12 and 16 weeks. Our results demonstrate that chronic and progressive hyperglycemia resulting from type 2 diabetes in ZDF rats is associated with loss of insulin and PDX-1 mRNAs and loss of glucose-stimulated insulin secretion. Prevention of hyperglycemia prevented the associated defects in insulin and PDX-1 gene expression and improved insulin secretion. These findings provide the first in vivo evidence that prevention of progressive hyperglycemia in a model of type 2 diabetes preserves insulin and PDX-1 gene expression.

High Glucose Causes Apoptosis in Cultured Human Pancreatic Islets of Langerhans

“…Excessive cell death through apoptosis or necrosis may contribute to acute organ failure as well as chronic diseases involving the loss of postmitotic cells (44). Several studies in the past decade have shown that chronic elevation of blood glucose concentrations in both humans and experimental animal models leads to ␤-cell dysfunction in terms of insulin secretion and insulin synthesis (45)(46)(47). Both in vivo and in vitro studies on rodent islets have suggested that hyperglycemia is associated with features of apoptosis when the architecture of the islet is maintained (11)(12)(13)(14)(15)(16)(17).…”

β-Cell Glucose Toxicity, Lipotoxicity, and Chronic Oxidative Stress in Type 2 Diabetes

“…Nomikos et al (22) demonstrated that in vivo treatment with superoxide dismutase and catalase protected islet tissue from oxygen metabolites induced by transplantation of islet allografts. Metformin or troglitazone, both of which have antioxidant properties, prevent hyperglycemia in the ZDF rat (23,24 (29) found that vitamin E failed to restore glucose-induced insulin secretion in rat pancreatic islets transplanted under the kidney capsule in streptozotocininduced diabetic rats. On the other hand, Ihara et al (11), who had previously noted increased immunostaining for 8-OH-deoxyglucose and HNE-modified proteins in GK islets, found that vitamin E had beneficial effects on glycemic control in GK rats, which was accompanied by significant improvement in insulin secretion and lower levels of HbA 1c (30).…”

“…These findings support chronic oxidative stress as a potential mechanism of action for glucose toxicity and point away from nitric oxide species as a candidate ROS in this animal model. In this context, it is interesting to recall that troglitazone, a drug that prevents glucotoxic decreases in insulin RNA levels in the ZDF animal (23,24), is also an antioxidant. Gene overexpression experiments have been designed to test whether increased levels of antioxidant enzymes in pancreatic islets might protect against oxidative stress.…”

Role of Peroxisome Proliferator-Activated Receptor-γ in the Glucose-Sensing Apparatus of Liver and β-Cells

“…Currently, the reports on the effects of PPAR-␥ on insulin secretion are contradictory. PPAR-␥ agonists can decrease insulin secretion in diabetic animal models, whereas activation of PPAR-␥ does not acutely improve insulin secretion in isolated human islets (Table 1) (4,5,30,(33)(34)(35)(36)(37)(38)(39)(40). However, it is reported that PPAR-␥ agonists can protect the ␤-cells from apoptosis and restore the function of ␤-cells, including GSIS (39,41,42).…”

“…53, SUPPLEMENT 1, FEBRUARY 2004 TZDs can prevent glucotoxic effects on PDX-1 expression in diabetic ␤-cells, indirectly resulting in an increase in the expression of GLUT2 and ␤GK (40). Oral administration of TZDs increases the expression of GLUT2 and ␤GK in the ␤-cells of diabetic ZDF rats.…”