| 1. |
- Briant, L. J. B., et al.
(författare)
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Delta-cells and beta-cells are electrically coupled and regulate alpha-cell activity via somatostatin
- 2018
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Ingår i: Journal of Physiology-London. - 0022-3751. ; 596:2, s. 197-215
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon, the body's principal hyperglycaemic hormone, is released from alpha-cells of the pancreatic islet. Secretion of this hormone is dysregulated in type 2 diabetes mellitus but the mechanisms controlling secretion are not well understood. Regulation of glucagon secretion by factors secreted by neighbouring beta- and delta-cells (paracrine regulation) have been proposed to be important. In this study, we explored the importance of paracrine regulation by using an optogenetic strategy. Specific light-induced activation of beta-cells in mouse islets expressing the light-gated channelrhodopsin-2 resulted in stimulation of electrical activity in delta-cells but suppression of alpha-cell activity. Activation of the delta-cells was rapid and sensitive to the gap junction inhibitor carbenoxolone, whereas the effect on electrical activity in alpha-cells was blocked by CYN 154806, an antagonist of the somatostatin-2 receptor. These observations indicate that optogenetic activation of the beta-cells propagates to the delta-cells via gap junctions, and the consequential stimulation of somatostatin secretion inhibits alpha-cell electrical activity by a paracrine mechanism. To explore whether this pathway is important for regulating alpha-cell activity and glucagon secretion in human islets, we constructed computational models of human islets. These models had detailed architectures based on human islets and consisted of a collection of >500 alpha-, beta- and delta-cells. Simulations of these models revealed that this gap junctional/paracrine mechanism accounts for up to 23% of the suppression of glucagon secretion by high glucose.
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| 2. |
- Buda, Pawel, et al.
(författare)
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Eukaryotic translation initiation factor 3 subunit e controls intracellular calcium homeostasis by regulation of cav1.2 surface expression.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- Inappropriate surface expression of voltage-gated Ca(2+)channels (CaV) in pancreatic ß-cells may contribute to the development of type 2 diabetes. First, failure to increase intracellular Ca(2+) concentrations at the sites of exocytosis impedes insulin release. Furthermore, excessive Ca(2+) influx may trigger cytotoxic effects. The regulation of surface expression of CaV channels in the pancreatic β-cells remains unknown. Here, we used real-time 3D confocal and TIRFM imaging, immunocytochemistry, cellular fractionation, immunoprecipitation and electrophysiology to study trafficking of L-type CaV1.2 channels upon β-cell stimulation. We found decreased surface expression of CaV1.2 and a corresponding reduction in L-type whole-cell Ca(2+) currents in insulin-secreting INS-1 832/13 cells upon protracted (15-30 min) stimulation. This internalization occurs by clathrin-dependent endocytosis and could be prevented by microtubule or dynamin inhibitors. eIF3e (Eukaryotic translation initiation factor 3 subunit E) is part of the protein translation initiation complex, but its effect on translation are modest and effects in ion channel trafficking have been suggested. The factor interacted with CaV1.2 and regulated CaV1.2 traffic bidirectionally. eIF3e silencing impaired CaV1.2 internalization, which resulted in an increased intracellular Ca(2+) load upon stimulation. These findings provide a mechanism for regulation of L-type CaV channel surface expression with consequences for β-cell calcium homeostasis, which will affect pancreatic β-cell function and insulin production.
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| 3. |
- Eerola, Kim, 1982, et al.
(författare)
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Hindbrain insulin controls feeding behavior
- 2022
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Ingår i: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 66
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Pancreatic insulin was discovered a century ago, and this discovery led to the first lifesaving treatment for diabetes. While still controversial, nearly one hundred published reports suggest that insulin is also produced in the brain, with most focusing on hypothalamic or cortical insulin-producing cells. However, specific function for insulin produced within the brain remains poorly understood. Here we identify insulin expression in the hindbrain's dorsal vagal complex (DVC), and determine the role of this source of insulin in feeding and metabolism, as well as its response to diet-induced obesity in mice. Methods: To determine the contribution of Ins2-producing neurons to feeding behavior in mice, we used the cross of transgenic RipHER-cre mouse and channelrhodopsin-2 expressing animals, which allowed us to optogenetically stimulate neurons expressing Ins2 in vivo. To confirm the presence of insulin expression in Rip-labeled DVC cells, in situ hybridization was used. To ascertain the specific role of insulin in effects discovered via optogenetic stimulation a selective, CNS applied, insulin receptor antagonist was used. To understand the physiological contribution of insulin made in the hindbrain a virogenetic knockdown strategy was used. Results: Insulin gene expression and presence of insulin-promoter driven fluorescence in rat insulin promoter (Rip)-transgenic mice were detected in the hypothalamus, but also in the DVC. Insulin mRNA was present in nearly all fluorescently labeled cells in DVC. Diet-induced obesity in mice altered brain insulin gene expression, in a neuroanatomically divergent manner; while in the hypothalamus the expected obesity-induced reduction was found, in the DVC diet-induced obesity resulted in increased expression of the insulin gene. This led us to hypothesize a potentially divergent energy balance role of insulin in these two brain areas. To determine the acute impact of activating insulin-producing neurons in the DVC, optic stimulation of light-sensitive channelrhodopsin 2 in Rip-transgenic mice was utilized. Optogenetic photoactivation induced hyperphagia after acute activation of the DVC insulin neurons. This hyperphagia was blocked by central application of the insulin receptor antagonist S961, suggesting the feeding response was driven by insulin. To determine whether DVC insulin has a necessary contribution to feeding and meta-bolism, virogenetic insulin gene knockdown (KD) strategy, which allows for site-specific reduction of insulin gene expression in adult mice, was used. While chow-fed mice failed to reveal any changes of feeding or thermogenesis in response to the KD, mice challenged with a high-fat diet consumed less food. No changes in body weight were identified, possibly resulting from compensatory reduction in thermogenesis. Conclusions: Together, our data suggest an important role for hindbrain insulin and insulin-producing cells in energy homeostasis. (c) 2022 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 4. |
- Mahdi, Taman, et al.
(författare)
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Secreted frizzled-related protein 4 reduces insulin secretion and is overexpressed in type 2 diabetes.
- 2012
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131. ; 16:5, s. 625-633
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Tidskriftsartikel (refereegranskat)abstract
- A plethora of candidate genes have been identified for complex polygenic disorders, but the underlying disease mechanisms remain largely unknown. We explored the pathophysiology of type 2 diabetes (T2D) by analyzing global gene expression in human pancreatic islets. A group of coexpressed genes (module), enriched for interleukin-1-related genes, was associated with T2D and reduced insulin secretion. One of the module genes that was highly overexpressed in islets from T2D patients is SFRP4, which encodes secreted frizzled-related protein 4. SFRP4 expression correlated with inflammatory markers, and its release from islets was stimulated by interleukin-1β. Elevated systemic SFRP4 caused reduced glucose tolerance through decreased islet expression of Ca(2+) channels and suppressed insulin exocytosis. SFRP4 thus provides a link between islet inflammation and impaired insulin secretion. Moreover, the protein was increased in serum from T2D patients several years before the diagnosis, suggesting that SFRP4 could be a potential biomarker for islet dysfunction in T2D.
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| 5. |
- Nagaraj, Vini, et al.
(författare)
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Elevated basal insulin secretion in type 2 diabetes caused by reduced plasma membrane cholesterol
- 2016
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Ingår i: Molecular Endocrinology. - : Endocrine Society. - 0888-8809 .- 1944-9917. ; 30:10, s. 1059-1069
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Tidskriftsartikel (refereegranskat)abstract
- Elevated basal insulin secretion under fasting conditions together with insufficient stimulated insulin release is an important hallmark of type 2 diabetes, but the mechanisms controlling basal insulin secretion remain unclear. Membrane rafts exist in pancreatic islet cells and spatially organize membrane ion channels and proteins controlling exocytosis, which may contribute to the regulation of insulin secretion. Membrane rafts (cholesterol and sphingolipid containing microdomains) were dramatically reduced in human type 2 diabetic and diabetic Goto-Kakizaki (GK) rat islets when compared with healthy islets. Oxidation of membrane cholesterol markedly reduced microdomain staining intensity in healthy human islets, but was without effect in type 2 diabetic islets. Intriguingly, oxidation of cholesterol affected glucose-stimulated insulin secretion only modestly, whereas basal insulin release was elevated. This was accompanied by increased intracellular Ca2+ spike frequency and Ca2+ influx and explained by enhanced single Ca2+ channel activity. These results suggest that the reduced presence of membrane rafts could contribute to the elevated basal insulin secretion seen in type 2 diabetes.
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| 6. |
- Paul-Visse, Gesine, et al.
(författare)
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The adult human brain harbors multipotent perivascular mesenchymal stem cells.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- Blood vessels and adjacent cells form perivascular stem cell niches in adult tissues. In this perivascular niche, a stem cell with mesenchymal characteristics was recently identified in some adult somatic tissues. These cells are pericytes that line the microvasculature, express mesenchymal markers and differentiate into mesodermal lineages but might even have the capacity to generate tissue-specific cell types. Here, we isolated, purified and characterized a previously unrecognized progenitor population from two different regions in the adult human brain, the ventricular wall and the neocortex. We show that these cells co-express markers for mesenchymal stem cells and pericytes in vivo and in vitro, but do not express glial, neuronal progenitor, hematopoietic, endothelial or microglial markers in their native state. Furthermore, we demonstrate at a clonal level that these progenitors have true multilineage potential towards both, the mesodermal and neuroectodermal phenotype. They can be epigenetically induced in vitro into adipocytes, chondroblasts and osteoblasts but also into glial cells and immature neurons. This progenitor population exhibits long-term proliferation, karyotype stability and retention of phenotype and multipotency following extensive propagation. Thus, we provide evidence that the vascular niche in the adult human brain harbors a novel progenitor with multilineage capacity that appears to represent mesenchymal stem cells and is different from any previously described human neural stem cell. Future studies will elucidate whether these cells may play a role for disease or may represent a reservoir that can be exploited in efforts to repair the diseased human brain.
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| 7. |
- Reinbothe, Thomas, 1981, et al.
(författare)
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Glutaredoxin-1 mediates NADPH-dependent stimulation of calcium-dependent insulin secretion
- 2009
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Ingår i: Mol Endocrinol. - : The Endocrine Society. - 1944-9917 .- 0888-8809. ; 23:6, s. 893-900
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Tidskriftsartikel (refereegranskat)abstract
- Nicotinamide adenine dinucleotide phosphate (NADPH) enhances Ca(2+)-induced exocytosis in pancreatic beta-cells, an effect suggested to involve the cytosolic redox protein glutaredoxin-1 (GRX-1). We here detail the role of GRX-1 in NADPH-stimulated beta-cell exocytosis and glucose-stimulated insulin secretion. Silencing of GRX-1 by RNA interference reduced glucose-stimulated insulin secretion in both clonal INS-1 832/13 cells and primary rat islets. GRX-1 silencing did not affect cell viability or the intracellular redox environment, suggesting that GRX-1 regulates the exocytotic machinery by a local action. By contrast, knockdown of the related protein thioredoxin-1 (TRX-1) was ineffective. Confocal immunocytochemistry revealed that GRX-1 locates to the cell periphery, whereas TRX-1 expression is uniform. These data suggest that the distinct subcellular localizations of TRX-1 and GRX-1 result in differences in substrate specificities and actions on insulin secretion. Single-cell exocytosis was likewise suppressed by GRX-1 knockdown in both rat beta-cells and clonal 832/13 cells, whereas after overexpression exocytosis increased by approximately 40%. Intracellular addition of NADPH (0.1 mm) stimulated Ca(2+)-evoked exocytosis in both cell types. Interestingly, the stimulatory action of NADPH on the exocytotic machinery coincided with an approximately 30% inhibition in whole-cell Ca(2+) currents. After GRX-1 silencing, NADPH failed to amplify insulin release but still inhibited Ca(2+) currents in 832/13 cells. In conclusion, NADPH stimulates the exocytotic machinery in pancreatic beta-cells. This effect is mediated by the NADPH acceptor protein GRX-1 by a local redox reaction that accelerates beta-cell exocytosis and, in turn, insulin secretion.
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| 8. |
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| 9. |
- Reinbothe, Thomas
(författare)
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New aspects of voltage-gated calcium channel regulation in pancreatic beta-cells - Relevance for insulin release and type 2 diabetes
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Voltage-gated Ca2+ channels are essential transducers of cellular signals in many electrically excitable cells. In the pancreatic beta-cell they mediate controlled Ca2+ influx, which is the final trigger for Ca2+ dependent release (exocytosis) of the blood glucose lowering hormone insulin. Several subtypes of voltage-gated Ca2+ channels are known and the L-type has been found to be the main contributor to electrical Ca2+ currents in beta-cells. However, which L-type isoform is operative in human beta-cells and how the L-type channels may be regulated in health and disease are two questions that remain unanswered and formed the basis for this thesis. The first study identified the redox protein glutaredoxin-1 to localize to rat beta-cell membranes and to be indispensable for glucose induced insulin release. In addition, its substrate NADPH reduces L-type channel activity while at the same time it is increasing the rate of insulin release. We suggest this to happen by a redox dependent mechanism that makes the exocytotic machinery more Ca2+ sensitive, thereby increasing its efficiency to release insulin. In the second study we found that glucose stimulation of an insulin secreting cell line induces the internalization of the L-type channel isoform Cav1.2. This process is dependent on the eukaryotic translation initiation factor 3 subunit e (eIF3e). Impairment of this mechanism by suppressing the expression of eIF3e in human islets results in increased intracellular Ca2+ levels and augmented rates of apoptosis, two phenomena of great importance in the pathogenesis of beta-cell destruction in diabetes. The third study revealed that the L-type Ca2+ channel isoform Cav1.3 is the major isoform in enriched human beta-cells and that islets of type 2 diabetes patients express reduced levels of Cav1.3 mRNA than controls. We also identified a single nucleotide polymorphism (SNP) that diminishes Cav1.3 expression and insulin release and 2 SNPs that increase the risk for type 2 diabetes. Investigating glucose dependent effects on Cav1.3 expression demonstrates that the beta-cell responds to increased glucose levels with a raise in Cav1.3 expression, which in turn is necessary for insulin release but also lifts the intracellular Ca2+ concentration to in the long run putatively cytotoxic levels. In the last part of this thesis we gathered genetic, molecular and functional data about the two main L-type Ca2+ channel isoforms Cav1.2 and Cav1.3 in order to identify significant differences that may allow for development of currently unavailable isoform specific drugs. A review of the literature revealed that there are indeed discrete dissimilarities that could form the basis for such venture. In conclusion this thesis not only supports the notion of L-type Ca2+ channels being essential for beta-cell function but also reveals new aspects that help to understand their regulation in health and disease with the prospect of this being of relevance for future scientific work.
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| 10. |
- Reinbothe, Thomas, et al.
(författare)
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Optogenetic control of insulin secretion in intact pancreatic islets with β-cell-specific expression of Channelrhodopsin-2.
- 2014
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Ingår i: Islets. - : Informa UK Limited. - 1938-2022 .- 1938-2014. ; 6:1, s. 28095-28095
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Tidskriftsartikel (refereegranskat)abstract
- Insulin is secreted from the pancreatic β-cells in response to elevated glucose. In intact islets the capacity for insulin release is determined by a complex interplay between different cell types. This has made it difficult to specifically assess the role of β-cell defects to the insulin secretory impairment in type 2 diabetes. Here we describe a new approach, based on optogenetics, that enables specific investigation of β-cells in intact islets. We used transgenic mice expressing the light-sensitive cation channel Channelrhodopsin-2 (ChR2) under control of the insulin promoter. Glucose tolerance in vivo was assessed using intraperitoneal glucose tolerance tests, and glucose-induced insulin release was measured from static batch incubations. ChR2 localization was determined by fluorescence confocal microscopy. The effect of ChR2 stimulation with blue LED light was assessed using Ca(2+) imaging and static islet incubations. Light stimulation of islets from transgenic ChR2 mice triggered prompt increases in intracellular Ca(2+). Moreover, light stimulation enhanced insulin secretion in batch-incubated islets at low and intermediate but not at high glucose concentrations. Glucagon release was not affected. Beta-cells from mice rendered diabetic on a high-fat diet exhibited a 3.5-fold increase in light-induced Ca(2+) influx compared with mice on a control diet. Furthermore, light enhanced insulin release also at high glucose in these mice, suggesting that high-fat feeding leads to a compensatory potentiation of the Ca(2+) response in β-cells. The results demonstrate the usefulness and versatility of optogenetics for studying mechanisms of perturbed hormone secretion in diabetes with high time-resolution and cell-specificity.
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| 11. |
- Reinbothe, Thomas, 1981, et al.
(författare)
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Optogenetic Control of Pancreatic Islets
- 2016
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Ingår i: Methods in Molecular Biology, vol. 1408. - Heidelberg : Springer. - 1064-3745 .- 1940-6029. - 9781493935123 - 9781493935109 ; , s. 107-23
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Bokkapitel (refereegranskat)abstract
- In light of the emerging diabetes epidemic, new experimental approaches in islet research are needed to elucidate the mechanisms behind pancreatic islet dysfunction and to facilitate the development of more effective therapies. Optogenetics has created numerous new experimental tools enabling us to gain insights into processes little was known about before. The spatial and temporal precision that it can achieve is also attractive for studying the cells of the pancreatic islet and we set out to explore the possibilities of this technology for our purposes. We here describe how to use the islets of an "optogenetic beta-cell" mouse line in islet batch incubations and Ca(2+) imaging experiments. This protocol enables light-induced insulin release and provides an all-optical solution to control and measure intracellular Ca(2+) levels in pancreatic beta-cells. The technique is easy to set up and provides a useful tool for controlling the activity of distinct islet cell populations.
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| 12. |
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| 13. |
- Reinbothe, Thomas, et al.
(författare)
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The human L-type calcium channel Ca(v)1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes.
- 2013
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 56:2, s. 340-349
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Voltage-gated calcium channels of the L-type have been shown to be essential for rodent pancreatic beta cell function, but data about their presence and regulation in humans are incomplete. We therefore sought to elucidate which L-type channel isoform is functionally important and its association with inherited diabetes-related phenotypes. METHODS: Beta cells of human islets from cadaver donors were enriched using FACS to study the expression of the genes encoding voltage-gated calcium channel (Ca(v))1.2 and Ca(v)1.3 by absolute quantitative PCR in whole human and rat islets, as well as in clonal cells. Single-cell exocytosis was monitored as increases in cell capacitance after treatment with small interfering (si)RNA against CACNA1D (which encodes Ca(v)1.3). Three single nucleotide polymorphisms (SNPs) were genotyped in 8,987 non-diabetic and 2,830 type 2 diabetic individuals from Finland and Sweden and analysed for associations with type 2 diabetes and insulin phenotypes. RESULTS: In FACS-enriched human beta cells, CACNA1D mRNA expression exceeded that of CACNA1C (which encodes Ca(v)1.2) by approximately 60-fold and was decreased in islets from type 2 diabetes patients. The latter coincided with diminished secretion of insulin in vitro. CACNA1D siRNA reduced glucose-stimulated insulin release in INS-1 832/13 cells and exocytosis in human beta cells. Phenotype/genotype associations of three SNPs in the CACNA1D gene revealed an association between the C allele of the SNP rs312480 and reduced mRNA expression, as well as decreased insulin secretion in vivo, whereas both rs312486/G and rs9841978/G were associated with type 2 diabetes. CONCLUSION/INTERPRETATION: We conclude that the L-type calcium channel Ca(v)1.3 is important in human glucose-induced insulin secretion, and common variants in CACNA1D might contribute to type 2 diabetes.
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| 14. |
- Rosengren, Anders, et al.
(författare)
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Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes
- 2010
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 327:5962, s. 217-20
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Tidskriftsartikel (refereegranskat)abstract
- Several common genetic variations have been associated with type 2 diabetes, but the exact disease mechanisms are still poorly elucidated. Using congenic strains from the diabetic Goto-Kakizaki rat, we identified a 1.4-megabase genomic locus that was linked to impaired insulin granule docking at the plasma membrane and reduced beta cell exocytosis. In this locus, Adra2a, encoding the alpha2A-adrenergic receptor [alpha(2A)AR], was significantly overexpressed. Alpha(2A)AR mediates adrenergic suppression of insulin secretion. Pharmacological receptor antagonism, silencing of receptor expression, or blockade of downstream effectors rescued insulin secretion in congenic islets. Furthermore, we identified a single-nucleotide polymorphism in the human ADRA2A gene for which risk allele carriers exhibited overexpression of alpha(2A)AR, reduced insulin secretion, and increased type 2 diabetes risk. Human pancreatic islets from risk allele carriers exhibited reduced granule docking and secreted less insulin in response to glucose; both effects were counteracted by pharmacological alpha(2A)AR antagonists.
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| 15. |
- Salunkhe, Vishal A., et al.
(författare)
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Dual Effect of Rosuvastatin on Glucose Homeostasis Through Improved Insulin Sensitivity and Reduced Insulin Secretion
- 2016
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 10, s. 185-194
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Tidskriftsartikel (refereegranskat)abstract
- Statins are beneficial in the treatment of cardiovascular disease (CVD), but these lipid-lowering drugs are associated with increased incidence of new on-set diabetes. The cellular mechanisms behind the development of diabetes by statins are elusive. Here we have treated mice on normal diet (ND) and high fat diet (HFD) with rosuvastatin. Under ND rosuvastatin lowered blood glucose through improved insulin sensitivity and increased glucose uptake in adipose tissue. In vitro rosuvastatin reduced insulin secretion and insulin content in islets. In the beta cell Ca(2+) signaling was impaired and the density of granules at the plasma membrane was increased by rosuvastatin treatment. HFD mice developed insulin resistance and increased insulin secretion prior to administration of rosuvastatin. Treatment with rosuvastatin decreased the compensatory insulin secretion and increased glucose uptake. In conclusion, our data shows dual effects on glucose homeostasis by rosuvastatin where insulin sensitivity is improved, but beta cell function is impaired.
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| 16. |
- Shigeto, Makoto, et al.
(författare)
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GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation
- 2015
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Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 125:12, s. 4714-4728
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Tidskriftsartikel (refereegranskat)abstract
- Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the K-ATP channel blacker tolbutamide, and the L-type Ca2+ channel blacker isradipine; however, depolarization was abolished by lowering extracellular Na+. The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of NW-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca2+ from thapsigargin-sensitive Ca2+ stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by beta cells.
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| 17. |
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| 18. |
- Zuccotti, Annalisa, et al.
(författare)
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Structural and functional differences between L-type calcium channels: crucial issues for future selective targeting
- 2011
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Ingår i: Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 32:6, s. 366-375
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Forskningsöversikt (refereegranskat)abstract
- Within the family of voltage-gated calcium channels (VGCCs), L-type channels (L-VGCCs) represent a well-established therapeutic target for calcium channel blockers, which are widely used to treat hypertension and myocardial ischemia. L-VGCCs outside the cardiovascular system also control key physiological processes such as neuronal plasticity, sensory cell function (e.g. in the inner ear and retina) and endocrine function (e.g. in pancreatic beta cells and adrenal chromaffin cells). Research into L-VGCCs was stimulated by the discovery that the known L-VGCC isoforms (Ca(V)1.1, Ca(V)1.2, Ca(V)1.3 and Ca(V)1.4) possess different biophysical properties. However, no L-VGCC-isoform-selective drugs have yet been identified. In this review, we examine Ca(V)1.2 and Ca(V)1.3 isoforms at the level of genetic structure, splice variants, post-translational modifications and functional protein coupling. We discuss candidate Ca(V)1.2- and Ca(V)1.3-specific characteristics as future therapeutic targets in individual organs.
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