| 1. |
- Amisten, Stefan, et al.
(författare)
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An atlas and functional analysis of G-protein coupled receptors in human islets of Langerhans
- 2013
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Ingår i: Pharmacology and Therapeutics. - : Elsevier BV. - 0163-7258. ; 139:3, s. 359-391
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Forskningsöversikt (refereegranskat)abstract
- G-protein coupled receptors (GPCRs) regulate hormone secretion from islets of Langerhans, and recently developed therapies for type-2 diabetes target islet GLP-1 receptors. However, the total number of GPCRs expressed by human islets, as well as their function and interactions with drugs, is poorly understood. In this review we have constructed an atlas of all GPCRs expressed by human islets: the 'islet GPCRome'. We have used this atlas to describe how islet GPCRs interact with their endogenous ligands, regulate islet hormone secretion, and interact with drugs known to target GPCRs, with a focus on drug/receptor interactions that may affect insulin secretion. The islet GPCRome consists of 293 GPCRs, a majority of which have unknown effects on insulin, glucagon and somatostatin secretion. The islet GPCRs are activated by 271 different endogenous ligands, at least 131 of which are present in islet cells. A large signalling redundancy was also found, with 119 ligands activating more than one islet receptor. Islet GPCRs are also the targets of a large number of clinically used drugs, and based on their coupling characteristics and effects on receptor signalling we identified 107 drugs predicted to stimulate and 184 drugs predicted to inhibit insulin secretion. The islet GPCRome highlights knowledge gaps in the current understanding of islet GPCR function, and identifies GPCR/ligand/drug interactions that might affect insulin secretion, which are important for understanding the metabolic side effects of drugs. This approach may aid in the design of new safer therapeutic agents with fewer detrimental effects on islet hormone secretion. (C) 2013 Elsevier Inc. All rights reserved.
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| 2. |
- Eliasson, Lena, et al.
(författare)
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Novel aspects of the molecular mechanisms controlling insulin secretion
- 2008
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Ingår i: Journal of Physiology. - : Wiley. - 1469-7793 .- 0022-3751. ; 586:14, s. 3313-3324
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Forskningsöversikt (refereegranskat)abstract
- Pancreatic beta-cells secrete insulin by Ca2+-dependent exocytosis of secretory granules. beta-cell exocytosis involves SNARE (soluble NSF-attachment protein receptor) proteins similar to those controlling neurotransmitter release and depends on the close association of L-type Ca2+ channels and granules. In most cases, the secretory granules fuse individually but there is ultrastructural and biophysical evidence of multivesicular exocytosis. Estimates of the secretory rate in beta-cells in intact islets indicate a release rate of similar to 15 granules per beta-cell per second, 100-fold higher than that observed in biochemical assays. Single-vesicle capacitance measurements reveal that the diameter of the fusion pore connecting the granule lumen with the exterior is similar to 1.4 nm. This is considerably smaller than the size of insulin and membrane fusion is therefore not obligatorily associated with release of the cargo, a feature that may contribute to the different rates of secretion detected by the biochemical and biophysical measurements. However, small molecules like ATP and GABA, which are stored together with insulin in the granules, are small enough to be released via the narrow fusion pore, which accordingly functions as a molecular sieve. We finally consider the possibility that defective fusion pore expansion accounts for the decrease in insulin secretion observed in pathophysiological states including long-term exposure to lipids.
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| 3. |
- Hastoy, B., et al.
(författare)
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Fusion pore in exocytosis: More than an exit gate? A beta-cell perspective
- 2017
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Ingår i: Cell Calcium. - : Elsevier BV. - 0143-4160. ; 68, s. 45-61
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Forskningsöversikt (refereegranskat)abstract
- Secretory vesicle exocytosis is a fundamental biological event and the process by which hormones (like insulin) are released into the blood. Considerable progress has been made in understanding this precisely orchestrated sequence of events from secretory vesicle docked at the cell membrane, hemifusion, to the opening of a membrane fusion pore. The exact biophysical and physiological regulation of these events implies a close interaction between membrane proteins and lipids in a confined space and constrained geometry to ensure appropriate delivery of cargo. We consider some of the still open questions such as the nature of the initiation of the fusion pore, the structure and the role of the Soluble N-ethylmaleimide-sensitive-factor Attachment protein REceptor (SNARE) transmembrane domains and their influence on the dynamics and regulation of exocytosis. We discuss how the membrane composition and protein-lipid interactions influence the likelihood of the nascent fusion pore forming. We relate these factors to the hypothesis that fusion pore expansion could be affected in type-2 diabetes via changes in disease-related gene transcription and alterations in the circulating lipid profile. Detailed characterisation of the dynamics of the fusion pore in vitro will contribute to understanding the larger issue of insulin secretory defects in diabetes.
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| 4. |
- Kanno, T, et al.
(författare)
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Cellular function in multicellular system for hormone-secretion: electrophysiological aspect of studies on alpha-, beta- and delta-cells of the pancreatic islet
- 2002
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Ingår i: Neuroscience Research. - 0168-0102. ; 42:2, s. 79-90
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Forskningsöversikt (refereegranskat)abstract
- We review a neck method to explore the cellular functions in multicellular system by application of the perforated patch-clamp technique to intact pancreatic islet of Langerhans. Using this approach, the integrity of the islet is preserved and intercellular communication via gap junctions and paracrine processes are maintained. 13 using low-resistance patch electrodes, rapid current responses can be monitored wider voltage-clamp control. We have applied this methodology to answer questions not resolved by patch-clamp experiments on isolated single insulin-secreting, beta-cells. First, the role of a K+-current dependent on Ca2+-influx for the termination of burst of action potentials in beta-cells could be documented. Neither the current, nor the bursting pattern of electrical activity is preserved in isolated beta-cells. Second. the conductance of gap junctions (similar to1 nS) between beta-cells was determined. Third, electrical properties of glucagon-producing alpha- and somatostatin-secreting delta-cells and the different mechanisms for glucose-sensing in these cells could be explored. The findings emanating from these experiments may hake implications for neuroscience research such as the mechanism of oscillatory electrical activity in general anti processes involved in the glucose-sensing in some neurons, which response to changes of blood glucose concentration. (C) 2002 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
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| 5. |
- Rorsman, Patrik, et al.
(författare)
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Electrophysiology of pancreatic beta-cells in intact mouse islets of Langerhans
- 2011
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Ingår i: Progress in Biophysics and Molecular Biology. - : Elsevier BV. - 1873-1732 .- 0079-6107. ; 107:2, s. 224-235
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Forskningsöversikt (refereegranskat)abstract
- When exposed to intermediate glucose concentrations (6-16 mol/l), pancreatic beta-cells in intact islets generate bursts of action potentials (superimposed on depolarised plateaux) separated by repolarised electrically silent intervals. First described more than 40 years ago, these oscillations have continued to intrigue beta-cell electrophysiologists. To date, most studies of beta-cell ion channels have been performed on isolated cells maintained in tissue culture (that do not burst). Here we will review the electrophysiological properties of beta-cells in intact, freshly isolated, mouse pancreatic islets. We will consider the role of ATP-regulated K+-channels (K-ATP-channels), small-conductance Ca2+-activated K+-channels and voltage-gated Ca2+-channels in the generation of the bursts. Our data indicate that K-ATP-channels not only constitute the glucose-regulated resting conductance in the beta-cell but also provide a variable K+- conductance that influence the duration of the bursts of action potentials and the silent intervals. We show that inactivation of the voltage-gated Ca2+-current is negligible at voltages corresponding to the plateau potential and consequently unlikely to play a major role in the termination of the burst. Finally, we propose a model for glucose-induced beta-cell electrical activity based on observations made in intact pancreatic islets. Crown Copyright (C) 2011 Published by Elsevier Ltd. All rights reserved.
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| 6. |
- Rorsman, Patrik, et al.
(författare)
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Insulin granule dynamics in pancreatic beta cells
- 2003
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 46:8, s. 1029-1045
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Forskningsöversikt (refereegranskat)abstract
- Glucose-induced insulin secretion in response to a step increase in blood glucose concentrations follows a biphasic time course consisting of a rapid and transient first phase followed by a slowly developing and sustained second phase. Because Type 2 diabetes involves defects of insulin secretion, manifested as a loss of first phase and a reduction of second phase, it is important to understand the cellular mechanisms underlying biphasic insulin secretion. Insulin release involves the packaging of insulin in small (diameter approximate to0.3 mum) secretory granules, the trafficking of these granules to the plasma membrane, the exocytotic fusion of the granules with the plasma membrane and eventually the retrieval of the secreted membranes by endocytosis. Until recently, studies on insulin secretion have been confined to the appearance of insulin in the extracellular space and the cellular events preceding exocytosis have been inaccessible to more detailed analysis. Evidence from a variety of secretory tissues, including pancreatic islet cells suggests, however, that the secretory granules can be functionally divided into distinct pools that are distinguished by their release competence and/or proximity to the plasma membrane. The introduction of fluorescent proteins that can be targeted to the secretory granules, in combination with the advent of new techniques that allow real-time imaging of granule trafficking in living cells (granule dynamics), has led to an explosion of our knowledge of the pre-exocytotic and post-exocytotic processes in the beta cell. Here we discuss these observations in relation to previous functional and ultra-structural data as well as the secretory defects of Type 2 diabetes.
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| 7. |
- Rorsman, Patrik, et al.
(författare)
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K-ATP-channels and glucagon secretion glucose-regulated
- 2008
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Ingår i: Trends in Endocrinology and Metabolism. - : Elsevier BV. - 1879-3061 .- 1043-2760. ; 19:8, s. 277-284
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Forskningsöversikt (refereegranskat)abstract
- Glucagon, secreted by the a-cells of the pancreatic islets, is the most important glucose-increasing hormone of the body. The precise regulation of glucagon release remains incompletely defined but has been proposed to involve release of inhibitory factors from neighbouring P-cells (paracrine control). However, the observation that glucose can regulate glucagon secretion under conditions when insulin secretion does not occur argues that the a-cell is also equipped with its own intrinsic (exerted within the a-cell itself) glucose sensing. Here we consider the possible mechanisms involved with a focus on ATP-regulated K+-channels and changes in a-cell membrane potential.
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