| 1. |
- De Marinis, Yang, et al.
(författare)
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GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis.
- 2010
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131. ; 11:6, s. 543-553
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon secretion is inhibited by glucagon-like peptide-1 (GLP-1) and stimulated by adrenaline. These opposing effects on glucagon secretion are mimicked by low (1-10 nM) and high (10 muM) concentrations of forskolin, respectively. The expression of GLP-1 receptors in alpha cells is <0.2% of that in beta cells. The GLP-1-induced suppression of glucagon secretion is PKA dependent, is glucose independent, and does not involve paracrine effects mediated by insulin or somatostatin. GLP-1 is without much effect on alpha cell electrical activity but selectively inhibits N-type Ca(2+) channels and exocytosis. Adrenaline stimulates alpha cell electrical activity, increases [Ca(2+)](i), enhances L-type Ca(2+) channel activity, and accelerates exocytosis. The stimulatory effect is partially PKA independent and reduced in Epac2-deficient islets. We propose that GLP-1 inhibits glucagon secretion by PKA-dependent inhibition of the N-type Ca(2+) channels via a small increase in intracellular cAMP ([cAMP](i)). Adrenaline stimulates L-type Ca(2+) channel-dependent exocytosis by activation of the low-affinity cAMP sensor Epac2 via a large increase in [cAMP](i).
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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. |
- Gao, Rui, et al.
(författare)
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α-cell electrophysiology and the regulation of glucagon secretion
- 2023
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Ingår i: The Journal of endocrinology. - 1479-6805. ; 258:2
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Forskningsöversikt (refereegranskat)abstract
- Glucagon is the principal glucose-elevating hormone that forms the first-line defence against hypoglycaemia. Along with insulin, glucagon also plays a key role in maintaining systemic glucose homeostasis. The cells that secrete glucagon, pancreatic α-cells, are electrically excitable cells and use electrical activity to couple its hormone secretion to changes in ambient glucose levels. Exactly how glucose regulates α-cells has been a topic of debate for decades but it is clear that electrical signals generated by the cells play an important role in glucagon secretory response. Decades of studies have already revealed the key players involved in the generation of these electrical signals and possible mechanisms controlling them to tune glucagon release. This has offered the opportunity to fully understand the enigmatic α-cell physiology. In this review, we describe the current knowledge on cellular electrophysiology and factors regulating excitability, glucose sensing, and glucagon secretion. We also discuss α-cell pathophysiology and the perspective of addressing glucagon secretory defects in diabetes for developing better diabetes treatment, which bears the hope of eliminating hypoglycaemia as a clinical problem in diabetes care.
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| 4. |
- 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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| 5. |
- Stanaway, Jeffrey D., et al.
(författare)
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Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017
- 2018
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Ingår i: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1923-1994
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Tidskriftsartikel (refereegranskat)abstract
- Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk- outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.
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| 6. |
- Zhang, Quan, et al.
(författare)
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Cell coupling in mouse pancreatic beta-cells measured in intact islets of Langerhans
- 2008
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Ingår i: Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Science. - : The Royal Society. - 1364-503X .- 1471-2962. ; 366:1880, s. 3503-3523
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Tidskriftsartikel (refereegranskat)abstract
- The perforated whole-cell configuration of the patch-clamp technique was applied to functionally identified beta-cells in intact mouse pancreatic islets to study the extent of cell coupling between adjacent beta-cells. Using a combination of current- and voltage-clamp recordings, the total gap junctional conductance between beta-cells in an islet was estimated to be 1.22 nS. The analysis of the current waveforms in a voltage-clamped cell ( due to the. ring of an action potential in a neighbouring cell) suggested that the gap junctional conductance between a pair of beta-cells was 0.17 nS. Subthreshold voltage-clamp depolarization (to -55 mV) gave rise to a slow capacitive current indicative of coupling between beta-cells, but not in non-beta-cells, with a time constant of 13.5 ms and a total charge movement of 0.2 pC. Our data suggest that a superficial beta-cell in an islet is in electrical contact with six to seven other beta-cells. No evidence for dye coupling was obtained when cells were dialysed with Lucifer yellow even when electrical coupling was apparent. The correction of the measured resting conductance for the contribution of the gap junctional conductance indicated that the whole-cell K-ATP channel conductance (G(K,ATP)) falls from approximately 2.5 nS in the absence of glucose to 0.1 nS at 15 mM glucose with an estimated IC50 of approximately 4 mM. Theoretical considerations indicate that the coupling between beta-cells within the islet is sufficient to allow propagation of [Ca2+](i) waves to spread with a speed of approximately 80 mu m s(-1), similar to that observed experimentally in confocal [Ca2+](i) imaging.
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