Islet glucose metabolism and insulin release in two animal models of glucose intolerance

Abstract: Type 2 diabetes is a complex and heterogenous disease resulting from the interaction of defects of both genetic and environmental origin. Abnormalities contributing to the pathogenesis of type 2 diabetes include impaired [beta]-cell function, peripheral insulin resistance and increased hepatic glucose production. In the present study we have mainly used two animal models of glucose intolerance, i.e., spontaneously diabetic GK rats and transgenic mice with overexpressed glucocorticoid receptors in the [beta]-cell. In GK rats islet glucose utilization, oxidation and lactate output were significantly higher than in control rat islets. Oxidation of mitochondrial ubstrates, e.g. leucine and actate was also significantly higher in GK rat islets. However, the mitochondrial function measured by determining the rate of ATP production by different substrates was normal in GK rat islets. Improvement of hyperglycemia by long-term phlorizin treatment improved insulin secretion and normalized islet glucose-6-phosphatase (G6Pase) activity while it had no effect on islet glucose utilization and oxidation. In transgenic mice (TG mice), overexpression of glucocorticoid receptors in the [beta]-cell resulted in impaired glucose tolerance and decreased acute insulin response. Glucose utilization and oxidation were similar in TG and control mouse islets while insulin secretion was significantly decreased and islet G6Pase activity as well as the rate of islet glucose cycling (GC) were increased in TG mice. This inhibition of insulin secretion as well as the augmentation of G6Pase activity and the rate of GC involved the [alpha]2-adrenergic signalling pathways. Thus, [alpha]2-adrenergic antagonist benextramine normalized insulin secretion in islets from TG mice while it had no effect in control Mice. [alpha]2-adrenergic agonist UK 14304 decreased insulin release both in TG and control mouse islets but the inhibitory effect was more potent in TG mouse islets. Furthermore, benextramine decreased islet G6Pase activity in TG mice whereas UK 14304 increased the enzyme activity in TG mice. In conclusion, we have demonstrated multiple abnormalities in islet glucose metabolism in GK rats which may be involved in the development of hyperglycemia. Hyperglycemia per se can also contribute to the impairment of insulin release in GK rats possibly by increasing the activity of islet G6Pase. In addition to hyperglycemia, glucocorticoids play an important role in the regulation of islet G6Pase activity. Thus overexpression of glucocorticoid receptors in the [beta]-cell as well as in vivo or in vitro treatment with glucocorticoids agument islet G6Pase activity and inhibits insulin release. Glucocorticoids may exert these effects at least partially by enhanced signalling by [alpha]2-adrenergic receptors.