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Ghrelin in rat pancreatic islets decreases islet blood flow
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
2019 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 317, no 1, p. E139-E146Article in journal (Refereed) Published
Abstract [en]

The peptide ghrelin is mainly produced in some of the epithelial cells in the stomach, but also, during starvation, by the epsilon-cells in the endocrine pancreas. Ghrelin, as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1 alpha). exerts a variety of metabolic functions including stimulation of appetite and weight gain. Its complete role is not yet fully understood, including whether it has any vascular functions. The present study evaluated if ghrelin affects pancreatic and islet blood flow. Ghrelin and the GHS-R1 alpha receptor antagonist GHRP-6 were injected intravenously in rats followed by blood flow measurements using a microsphere technique. Ghrelin decreased, while GHRP-6 in fasted, but not fed, rats selectively increased islet blood flow fourfold. GHS-R1 alpha was identified not only on glucagon-producing cells but also seemed to be present in the islet arterioles. GHRP-6 in fasted rats. only, also improved the peak insulin response to glucose in vivo. thereby substantially blunting the hyperglycemia. GHRP-6 doubled glucose-stimulated insulin release in vitro of both islets obtained from fed and fasted rats. Our results indicate a novel role for endogenous ghrelin acting directly or indirectly as a local vasoconstrictor in the islets during fasting, thereby restricting the insulin response to hyperglycemia. This is to the best of our knowledge the first report that shows this physiological mechanism to restrict insulin delivery from the islets by acting on the vasculature; a mode of action that can be envisaged to complement the previously well-described mechanisms of ghrelin acting directly on the islet endocrine cells.

Place, publisher, year, edition, pages
2019. Vol. 317, no 1, p. E139-E146
Keywords [en]
blood flow, ghrelin, pancreatic islets, vascular
National Category
Endocrinology and Diabetes Physiology
Identifiers
URN: urn:nbn:se:uu:diva-390975DOI: 10.1152/ajpendo.00004.2019ISI: 000475371500005PubMedID: 31063397OAI: oai:DiVA.org:uu-390975DiVA, id: diva2:1343483
Funder
Swedish Research CouncilEXODIAB - Excellence of Diabetes Research in SwedenSwedish Child Diabetes FoundationSwedish Diabetes AssociationNovo NordiskAvailable from: 2019-08-16 Created: 2019-08-16 Last updated: 2020-10-09Bibliographically approved
In thesis
1. Influence of Islet-derived Factors in Islet Microcirculation and Endocrine Function
Open this publication in new window or tab >>Influence of Islet-derived Factors in Islet Microcirculation and Endocrine Function
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 76
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1691
Keywords
diabetes mellitus, pancreas, blood flow, islet vascularity, islet-derived, TSP-1, ghrelin, CART, irisin
National Category
Physiology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-421465 (URN)978-91-513-1033-6 (ISBN)
Public defence
2020-11-27, B21: BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Funder
Swedish Research CouncilEXODIAB - Excellence of Diabetes Research in SwedenSwedish Child Diabetes FoundationSwedish Diabetes AssociationErnfors FoundationNovo Nordisk
Available from: 2020-11-06 Created: 2020-10-09 Last updated: 2021-01-22

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Drott, Carl JohanFranzén, PetraCarlsson, Per-Ola

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