| 1. |
- Drott, Carl Johan, et al.
(författare)
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Sustained Beta-Cell Dysfunction but Normalized Islet Mass in Aged Thrombospondin-1 Deficient Mice
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:10, s. e47451-
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic islet endothelial cells have in recent years been shown to support beta-cell mass and function by paracrine interactions. Recently, we identified an islets endothelial-specific glycoprotein, thrombospondin-1 (TSP-1), that showed to be of importance for islet angiogenesis and beta-cell function in young mice. The present study aimed to investigate long-term consequences for islet morphology and beta-cell function of TSP-1 deficiency. Islet and beta-cell mass were observed increased at 10-12 weeks of age in TSP-1 deficient mice, but were normalized before 16 weeks of age when compared to wild-type controls. Islet vascularity was normal in 10-12 and 16-week-old TSP-1 deficient animals, whereas islets of one-year-old animals lacking TSP-1 were hypervascular. Beta-cell dysfunction in TSP-1 deficient animals was present at similar magnitudes between 10-12 and 52 weeks of age, as evaluated by glucose tolerance tests. The insulin secretion capacity in vivo of islets in one-year-old TSP-1 deficient animals was only similar to 15% of that in wild-type animals. Using a transplantation model, we reconstituted TSP-1 in adult TSP-deficient islets. In contrast to neonatal TSP-1 deficient islets that we previously reported to regain function after TSP-1 reconstitution, adult islets failed to recover. We conclude that TSP-1 deficiency in islets causes changing vascular and endocrine morphological alterations postnatally, but is coupled to a chronic beta-cell dysfunction. The beta-cell dysfunction induced by TSP-1 deficiency is irreversible if not substituted early in life.
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| 2. |
- Drott, Carl Johan, 1984-, et al.
(författare)
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CART decreases islet blood flow, but has no effect on total pancreatic blood flow and glucose tolerance in anesthetized rats
- 2021
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 135
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Tidskriftsartikel (refereegranskat)abstract
- Cocaine- and amphetamine-regulated transcript (CART) is a neurotransmitter and hormone, involved in the regulation of e.g. food intake, body weight, reward and addiction, and stress response. CART has also been found to affect insulin secretion and beta cell morphology, both in vivo and in vitro. Furthermore, CART affects regulation of the cardiovascular system and helps to modulate vascular tone. The present study evaluated the local effect of CART on the pancreatic and islet circulation and function. CART (25 µg/h) or saline, combinations of CART and endothelin-A receptor antagonist (BQ123; 100 µg/kg), and glucose (2 g/kg) were intravenously infused in Sprague Dawley rats followed by blood flow measurements using a microsphere technique. Separately, CART-infused animals underwent an intravenous glucose tolerance test (ivGTT). The direct effect of CART on insulin release was investigated using isolated islets from Sprague Dawley rats. CART reduced islet blood flow, without reduction in total pancreatic blood flow. The normal glucose-induced islet blood flow increase was diminished by CART, albeit still present. Simultaneously, CART had no effect on systemic-, intestinal- or renal blood flow. The endothelin-A receptor antagonist BQ123 together with CART had no pancreatic vascular effects. We found that CART has pronounced vascular constrictive actions restricted to the pancreatic islet circulation but had no effect on insulin release neither in vivo nor in vitro. The mechanisms behind the vascular effects are still unknown, but may reflect a direct action on pancreatic blood vessels.
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| 3. |
- Drott, Carl Johan, et al.
(författare)
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Ghrelin in rat pancreatic islets decreases islet blood flow
- 2019
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 317:1, s. E139-E146
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
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| 5. |
- Drott, Carl Johan, 1984-
(författare)
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Influence of Islet-derived Factors in Islet Microcirculation and Endocrine Function
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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| 6. |
- Drott, Carl Johan, 1984-, et al.
(författare)
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Irisin is present in α cells and decreases islet blood flow
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Irisin is a myokine involved in glucose homeostasis, and is primarily expressed in skeletal muscle and adipose tissue but also in multiple tissues, among them, the pancreas. We aimed to elucidate the cell-specific expression and secretion of irisin, as well as the effect of irisin, in the pancreas. Irisin was observed to be expressed predominantly in α cells, and perifusion of human islets with glucose demonstrated that irisin was secreted in a glucose-dependent manner. Intravenous infusion of irisin in Sprague-Dawley rats resulted in a nearly 50% reduction of islet blood flow compared to control. However, neither irisin nor an irisin neutralizing antibody affected insulin secretion from rat or human islets in vitro. We conclude that irisin has a novel role in pancreatic islet physiology, being secreted by α cells in response to glucose, i.e. in an inverse manner to glucagon, and exerting local vascular effects diminishing islet blood flow while not affecting insulin secretion per se.
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| 7. |
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| 8. |
- Jansson, Leif, et al.
(författare)
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Pancreatic islet blood flow and its measurement
- 2016
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 121:2, s. 81-95
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Forskningsöversikt (refereegranskat)abstract
- Pancreatic islets are richly vascularized, and islet blood vessels are uniquely adapted to maintain and support the internal milieu of the islets favoring normal endocrine function. Islet blood flow is normally very high compared with that to the exocrine pancreas and is autonomously regulated through complex interactions between the nervous system, metabolites from insulin secreting beta-cells, endothelium derived mediators, and hormones. The islet blood flow is normally coupled to the needs for insulin release and is usually disturbed during glucose intolerance and overt diabetes. The present review provides a brief background on islet vascular function and especially focuses on available techniques to measure islet blood perfusion. The gold standard for islet blood flow measurements in experimental animals is the microsphere technique, and its advantages and disadvantages will be discussed. In humans there are still no methods to measure islet blood flow selectively, but new developments in radiological techniques hold great hopes for the future.
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| 9. |
- Johan Drott, Carl, et al.
(författare)
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Fler akuta gallstensoperationer och färre elektiva under pandemin : [Swedish gallstone surgery during the covid-19 pandemic]
- 2022
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Ingår i: Läkartidningen. - : Läkartidningen. - 0023-7205 .- 1652-7518. ; 119
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Tidskriftsartikel (refereegranskat)abstract
- The covid-19 pandemic has necessitated reallocation of health care resources. This has raised concerns about the risks associated with postponing surgery for benign conditions that are given low priority. Data from the population-based Swedish National Register for Gallstone Surgery (GallRiks) show that the total number of procedures carried out during the initial months of each wave of the pandemic decreased. This was followed by a moderate increase in the number of procedures performed for acute cholecystitis, biliary pancreatitis, and obstructive jaundice. The consequences of the delayed surgery in the community at large and how this has affected health-related quality of life for patients having their procedure postponed remain to be evaluated, but so far it does not seem to have caused a major impact on public health.
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| 10. |
- Johan Drott, Carl, et al.
(författare)
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Fler akuta gallstensoperationer och färre elektiva under pandemin
- 2022
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Ingår i: Lakartidningen. - 0023-7205. ; 119
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Tidskriftsartikel (refereegranskat)abstract
- The covid-19 pandemic has necessitated reallocation of health care resources. This has raised concerns about the risks associated with postponing surgery for benign conditions that are given low priority. Data from the population-based Swedish National Register for Gallstone Surgery (GallRiks) show that the total number of procedures carried out during the initial months of each wave of the pandemic decreased. This was followed by a moderate increase in the number of procedures performed for acute cholecystitis, biliary pancreatitis, and obstructive jaundice. The consequences of the delayed surgery in the community at large and how this has affected health-related quality of life for patients having their procedure postponed remain to be evaluated, but so far it does not seem to have caused a major impact on public health.
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