Influence of Islet-derived Factors in Islet Microcirculation and Endocrine Function

Abstract: Diabetes mellitus is a disorder with complex pathology and is frequently associated with vascular complications. In the islet micro milieu locally generated factors may affect both the physiology and the morphology of the tissue. This thesis examines the impact of four different islet-derived factors; thrombospondin-1 (TSP-1), ghrelin, Cocaine and amphetamine regulated transcript (CART) and irisin, and how they influence the endocrine pancreas.TSP-1 is an angiogenesis inhibitor. Islets from TSP-1 deficient mice were hypervascular, but with normal endocrine mass. Beta-cell dysfunction was present in islets of TSP-1 deficient mice, both in vivo and in vitro. When trying to reconstitute TSP-1 in islets of TSP-1 deficient animals through a transplantation model, adult islets failed to recover, showing the importance of TSP-1 for glucose stimulated insulin secretion and thereby glucose homeostasis.Ghrelin inhibited glucose stimulated insulin secretion and decreased the islet blood flow, while the ghrelin receptor antagonist GHRP-6 in fasted, but not fed, rats increased the islet blood flow fourfold and improved the peak insulin response to glucose. The ghrelin receptor GHS-R1α was identified in the alpha cells and the islet arterioles.CART selectively reduced the islet blood flow in the pancreas, and this effect was unaltered by simultaneous administration of an endothelin-A receptor antagonist. CART administration did not affect insulin release, neither in insulin release from isolated islets or in an intravenous glucose tolerance test. Irisin was confirmed located within the pancreatic islets predominately in the alpha-cells. Irisin reduced islet and white adipose tissue blood flow. Irisin was secreted as a response to increased glucose concentrations in vivo.  Irisin had no direct effect on insulin secretion.In conclusion, all factors investigated proved to have roles locally in the endocrine pancreas. TSP-1 deficiency caused vascular morphological alterations, and chronic β-cell dysfunction. Ghrelin, CART and irisin all decreased islet blood flow. Ghrelin acted directly through its receptor GHS-R1α in islet arterioles, thereby restricting the insulin response to hyperglycemia, whereas for CART and irisin the specific mechanism continues to be unknown, without identification of a receptor. In order to reach full physiological understanding, the receptors for CART and irisin need to be identified. All four islet-derived factors hold potential for the treatment of type 2 diabetes.