The overall aim is to advance understanding of the function of the endocrine pancreas in health and in diabetes. Insulin, glucagon and somatostatin are each capable of modifying each other's secretion. It is not clear if these capabilities are actually operative endogenously or, if they are, whether they operate via the islet interstitial, via the intra-islet microvasculature and/or via the systemic circulation. We have indirect evidence that islet hormones secreted into the circulation normally are excluded from the interstitial compartment of the islets in which receptors to those hormones are located, which permits the relatively very low systemic concentrations of islet hormones to influence the secretion of islet hormones. We wish to document directly the existence of this putative hormone-poor compartment, elucidate the roles of islet hormones in islet cell function, and determine if aberrations in the foregoing contribute to the dysfunction of islet cells in diabetes. For example, loss of the intra-islet insulin inhibition of glucagon after destruction of the beta cells may cause hyperglucagonemia; loss of sensitivity to islet hormones because of breakdown of the putative interstitial compartmentalization could explain aberrations of hormones in various diabetic syndromes. These studies also extend work on the nature of adrenergic control over the islets which has suggested the existence of a self-contained intrapancreatic sympathetic system and will probe the cause of loss of the glucagon response to glucopenia after beta cell destruction. Finally, the role of hyperglycemia in producing reversible functional islet cell derangements and ultimately irreversible destruction of beta cells, the so-called """"""""hyperglycemic hypothesis"""""""", will be carefully examined. If correct, it would vastly change our understanding and method of treating and perhaps preventing Type 2 diabetes.
| Unger, R H (1991) Diabetic hyperglycemia: link to impaired glucose transport in pancreatic beta cells. Science 251:1200-5 |
