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- 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. |
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| 3. |
- Ageberg, Malin, et al.
(författare)
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Inhibition of geranylgeranylation mediates sensitivity to CHOP-induced cell death of DLBCL cell lines.
- 2011
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 317, s. 1179-1191
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Tidskriftsartikel (refereegranskat)abstract
- Prenylation is a post-translational hydrophobic modification of proteins, important for their membrane localization and biological function. The use of inhibitors of prenylation has proven to be a useful tool in the activation of apoptotic pathways in tumor cell lines. Rab geranylgeranyl transferase (Rab GGT) is responsible for the prenylation of the Rab family. Overexpression of Rab GGTbeta has been identified in CHOP refractory diffuse large B cell lymphoma (DLBCL). Using a cell line- based model for CHOP resistant DLBCL, we show that treatment with simvastatin, which inhibits protein farnesylation and geranylgeranylation, sensitises DLBCL cells to cytotoxic treatment. Treatment with the farnesyl transferase inhibitor, FTI-277, or the geranylgeranyl transferase I inhibitor, GGTI-298, indicates that the reduction in cell viability was restricted to inhibition of geranylgeranylation. In addition, treatment with BMS1, a combined inhibitor of farnesyl transferase and Rab GGT, resulted in a high cytostatic effect in WSU-NHL cells, demonstrated by reduced cell viability and decreased proliferation. Co-treatment of BMS1 or GGTI-298 with CHOP showed synergistic effects with regard to markers of apoptosis. We propose that inhibition of protein geranylgeranylation together with conventional cytostatic therapy is a potential novel strategy for treating patients with CHOP refractory DLBCL.
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| 4. |
- 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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| 5. |
- 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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| 7. |
- 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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| 8. |
- 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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| 9. |
- Drott, Johan
(författare)
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Porous Silicon -an enzyme coupling matrix for micromachined reactors
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The development of a miniaturised silicon wafer integrated enzyme reactor is described. The reactor was micromachined by anisotropic wet etching of (110) silicon. The enzyme glucose oxidase (GOx) was coupled to the reactor surface with standard methods of immobilising enzyme to silica. The glucose turn-over rate was monitored following a colourimetric assay. The advantage, in terms of high surface area per volume ratio, of utilising (110) silicon for microreactor fabrication compared to (100) silicon was demonstrated. Two reactors with different channel widths (50 and 20 µm) and channel densities (10 and 25 per millimetre) were compared, yielding a proportionally increased enzyme activity, for the reactor with the highest surface area (20 µm channels, 25 channels per millimetre). A novel method, utilising porous silicon as a coupling matrix, to increase the surface area for enzyme coupling was investigated. A porous silicon layer was fabricated on samples by anodic dissolution of silicon in hydrofluoric acid. Three different pore morphologies were generated by anodisation at (10, 50 and 100 mA cm-2). Glucose oxidase was coupled to the samples and a non porous reference sample. The sample anodised at 10 mA cm-2 displayed a 30-fold increased catalytic efficiency, compared to the non porous reference sample. The possibility of generating porous silicon on vertical channel type silicon reactors were also demonstrated. A porous silicon layer was generated on an anisotropically preetched vertical channel type microreactor. GOx was immobilised in the reactors and the glucose turn-over rate was monitored. A more than 100-fold increase in catalytic efficiency was recorded for a reactor anodised at 50 mA cm-2, compared to a non porous reference reactor. The applicability of micro enzyme reactors was demonstrated by immobilising ß-fructose onto a porous channel type reactor. Sucrose monitoring was performed utilising Fourier transform infrared (FTIR) spectroscopy system with the micro enzyme reactor as a key component, the dissociation of sucrose into glucose and fructose. The miniaturised FTIR spectroscopy system was used for sucrose analysis of crude real samples from commercial soft drinks showing results in accordance with standardised sucrose test-kits. The influence of pore morphology was investigated to further improve the catalytic efficiency of enzyme activated porous silicon carrier matrices. Porous silicon was generated on substrates of p- and n-type silicon with different dopant concentrations. For each type of substrate, the porous layer was generated at three current densities (10, 50 and 100 mA cm2). The porous samples and a non porous reference sample was enzyme activated with GOx. A 350-fold increase in glucose turn-over rate, compared to the reference, was recorded for an n-type epilayer on n+-type substrate anodised at 100mAcm-2. The influence of the porous silicon matrix depth was also investigated, for planar samples and vertical channel type reactors. In this investigation porous silicon layers were fabricated at two current densities and for three depths at each current density. A 170-fold increase in catalytic turn-over, compared to a non porous reference, was recorded for a reactor with an average porous depth of 10 µm.
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