No abstract

The endocrine part of the pancreas plays a central role in blood-glucose regulation. It is well established that an elevation of glucose concentration reduces secretion of the hyperglycaemia-associated hormone glucagon from pancreatic alpha 2 cells. The mechanisms involved, however, remain unknown. Electrophysiological studies have demonstrated that alpha 2 cells generate Ca2+-dependent action potentials. The frequency of these action potentials, which increases under conditions that stimulate glucagon release, is not affected by glucose or insulin. The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is present in the endocrine part of the pancreas at concentrations comparable to those encountered in the central nervous system, and co-localizes with insulin in pancreatic beta cells. We now describe a mechanism whereby GABA, co-secreted with insulin from beta cells, may mediate part of the inhibitory action of glucose on glucagon secretion by activating GABAA-receptor Cl- channels in alpha 2 cells. These observations provide a model for feedback regulation of glucagon release, which may be of significance for the understanding of the hypersecretion of glucagon frequently associated with diabetes.

Although patients with type 2 diabetes have elevated risks of liver, pancreatic, kidney, and endometrial cancer, little is known about the risk of cancer for patients with type 1 diabetes. We conducted a cohort study to examine cancer incidence among 29 187 patients in Sweden who were hospitalized for type 1 diabetes from 1965 through 1999. Relative risks of cancer were estimated by age-, sex- and calendar year of follow-up--adjusted standardized incidence ratios (SIRs), using data for the entire Swedish population as a reference. After excluding cancers diagnosed during the first year after hospital discharge, we observed 355 incident cases of cancer, which corresponded to a 20% increase in overall cancer incidence among type 1 diabetes patients (SIR = 1.2, 95% confidence interval [CI] = 1.0 to 1.3). Patients with type 1 diabetes had elevated risks of cancers of the stomach (SIR = 2.3, 95% CI = 1.1 to 4.1), cervix (SIR = 1.6, 95% CI = 1.1 to 2.2), and endometrium (SIR = 2.7, 95% CI = 1.4 to 4.7). Type 1 diabetes is associated with a modest excess cancer risk overall and risks of specific cancers that differ from those associated with type 2 diabetes.

Abnormalities contributing to the pathogenesis of non-insulin-dependent diabetes mellitus include impaired ␤ cell function, peripheral insulin resistance, and increased hepatic glucose production. Glucocorticoids are diabetogenic hormones because they decrease glucose uptake and increase hepatic glucose production. In addition, they may directly inhibit insulin release. To evaluate that possible role of glucocorticoids in ␤ cell function independent of their other effects, transgenic mice with an increased glucocorticoid sensitivity restricted to their ␤ cells were generated by overexpressing the glucocorticoid receptor (GR) under the control of the insulin promoter. Intravenous glucose tolerance tests showed that the GR transgenic mice had normal fasting and postabsorptive blood glucose levels but exhibited a reduced glucose tolerance compared with their control littermates. Measurement of plasma insulin levels 5 min after intravenous glucose load demonstrated a dramatic decrease in acute insulin response in the GR transgenic mice. These results show that glucocorticoids directly inhibit insulin release in vivo and identify the pancreatic ␤ cell as an important target for the diabetogenic action of glucocorticoids. (

Type 2 diabetes mellitus is affecting more than 382 million people worldwide. Although much progress has been made, a comprehensive understanding of the underlying disease mechanism is still lacking. Here we report a role for the b-cell primary cilium in type 2 diabetes susceptibility. We find impaired glucose handling in young Bbs4 À / À mice before the onset of obesity. Basal body/ciliary perturbation in murine pancreatic islets leads to impaired first phase insulin release ex and in vivo. Insulin receptor is recruited to the cilium of stimulated b-cells and ciliary/basal body integrity is required for activation of downstream targets of insulin signalling. We also observe a reduction in the number of ciliated b-cells along with misregulated ciliary/basal body gene expression in pancreatic islets in a diabetic rat model. We suggest that ciliary function is implicated in insulin secretion and insulin signalling in the b-cell and that ciliary dysfunction could contribute to type 2 diabetes susceptibility.