| 1. |
- Acreman, Samuel
(författare)
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Physiology and Pathophysiology of Hormone Secretion from lslets of Langerhans
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diabetes is a metabolic disorder stemming from the improper regulation of blood glucose levels by hormones secreted by pancreatic islets of Langerhans. Paper I describes the mechanism by which glucose can regulate glucagon secretion, independent of membrane potential, from pancreatic α-cells, via modulation of endoplasmic reticulum Ca2+ handling. Paper II shows that the GLP-1 metabolite GLP-1(9-36) acts directly on α-cells to inhibit glucagon secretion, via activation of Gi-coupled glucagon receptors. Paper III, shows that the islet autoantigen tetraspanin-7 regulates β-cell transmembrane Ca2+ influx and the Ca2+ sensitivity of exocytosis. Paper IV demonstrates that α-cells and their neighbouring δ-cells exhibit a novel paracrine signalling loop. δ-cells react to the activity of adjacent α-cells, secreting somatostatin, to prevent glucagon hypersecretion. This mechanism becomes sensitised following exposure to hypoglycaemia, leading to excessive intra-islet somatostatin secretion, impairing glucose counter-regulation. Together, these papers reveal novel mechanisms governing the regulation of islet hormone secretion, which may lead to improvements in therapies for diabetes.
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| 2. |
- Acreman, Samuel, et al.
(författare)
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Regulation of α-cell glucagon secretion: The role of second messengers
- 2022
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Ingår i: Chronic Diseases and Translational Medicine. - : Wiley. - 2095-882X .- 2589-0514. ; 8:1, s. 7-18
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon is a potent glucose-elevating hormone that is secreted by pancreatic α-cells. While well-controlled glucagon secretion plays an important role in maintaining systemic glucose homeostasis and preventing hypoglycaemia, it is increasingly apparent that defects in the regulation of glucagon secretion contribute to impaired counter-regulation and hyperglycaemia in diabetes. It has therefore been proposed that pharmacological interventions targeting glucagon secretion/signalling can have great potential in improving glycaemic control of patients with diabetes. However, despite decades of research, a consensus on the precise mechanisms of glucose regulation of glucagon secretion is yet to be reached. Second messengers are a group of small intracellular molecules that relay extracellular signals to the intracellular signalling cascade, modulating cellular functions. There is a growing body of evidence that second messengers, such as cAMP and Ca2+, play critical roles in α-cell glucose-sensing and glucagon secretion. In this review, we discuss the impact of second messengers on α-cell electrical activity, intracellular Ca2+ dynamics and cell exocytosis. We highlight the possibility that the interaction between different second messengers may play a key role in the glucose-regulation of glucagon secretion. © 2021 Chinese Medical Association
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| 3. |
- Gandasi, Nikhil, et al.
(författare)
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GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion
- 2024
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Ingår i: DIABETOLOGIA. - 0012-186X .- 1432-0428. ; 67:3, s. 528-546
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Diabetes mellitus is associated with impaired insulin secretion, often aggravated by oversecretion of glucagon. Therapeutic interventions should ideally correct both defects. Glucagon-like peptide 1 (GLP-1) has this capability but exactly how it exerts its glucagonostatic effect remains obscure. Following its release GLP-1 is rapidly degraded from GLP-1(7-36) to GLP-1(9-36). We hypothesised that the metabolite GLP-1(9-36) (previously believed to be biologically inactive) exerts a direct inhibitory effect on glucagon secretion and that this mechanism becomes impaired in diabetes.Methods We used a combination of glucagon secretion measurements in mouse and human islets (including islets from donors with type 2 diabetes), total internal reflection fluorescence microscopy imaging of secretory granule dynamics, recordings of cytoplasmic Ca2+ and measurements of protein kinase A activity, immunocytochemistry, in vivo physiology and GTP-binding protein dissociation studies to explore how GLP-1 exerts its inhibitory effect on glucagon secretion and the role of the metabolite GLP-1(9-36).Results GLP-1(7-36) inhibited glucagon secretion in isolated islets with an IC50 of 2.5 pmol/l. The effect was particularly strong at low glucose concentrations. The degradation product GLP-1(9-36) shared this capacity. GLP-1(9-36) retained its glucagonostatic effects after genetic/pharmacological inactivation of the GLP-1 receptor. GLP-1(9-36) also potently inhibited glucagon secretion evoked by beta-adrenergic stimulation, amino acids and membrane depolarisation. In islet alpha cells, GLP-1(9-36) led to inhibition of Ca2+ entry via voltage-gated Ca2+ channels sensitive to omega-agatoxin, with consequential pertussis-toxin-sensitive depletion of the docked pool of secretory granules, effects that were prevented by the glucagon receptor antagonists REMD2.59 and L-168049. The capacity of GLP-1(9-36) to inhibit glucagon secretion and reduce the number of docked granules was lost in alpha cells from human donors with type 2 diabetes. In vivo, high exogenous concentrations of GLP-1(9-36) (>100 pmol/l) resulted in a small (30%) lowering of circulating glucagon during insulin-induced hypoglycaemia. This effect was abolished by REMD2.59, which promptly increased circulating glucagon by >225% (adjusted for the change in plasma glucose) without affecting pancreatic glucagon content.Conclusions/interpretation We conclude that the GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of glucagon secretion. We propose that the increase in circulating glucagon observed following genetic/pharmacological inactivation of glucagon signalling in mice and in people with type 2 diabetes reflects the removal of GLP-1(9-36)'s glucagonostatic action.
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| 4. |
- Gao, R., et al.
(författare)
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a-cell electrophysiology and the regulation of glucagon secretion
- 2023
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Ingår i: Journal of Endocrinology. - 0022-0795. ; 258:2
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Tidskriftsartikel (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 a-cells, are electrically excitable cells and use electrical activity to couple its hormone secretion to changes in ambient glucose levels. Exactly how glucose regulates a-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 a-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 a-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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| 5. |
- 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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| 6. |
- McLaughlin, K., et al.
(författare)
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Loss of tetraspanin-7 expression reduces pancreatic beta-cell exocytosis Ca2+ sensitivity but has limited effect on systemic metabolism
- 2022
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Ingår i: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 39:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tetraspanin-7 (Tspan7) is an islet autoantigen involved in autoimmune type 1 diabetes and known to regulate beta-cell L-type Ca-2(+) channel activity. However, the role of Tspan7 in pancreatic beta-cell function is not yet fully understood. Methods: Histological analyses were conducted using immunostaining. Whole-body metabolism was tested using glucose tolerance test. Islet hormone secretion was quantified using static batch incubation or dynamic perifusion. beta-cell transmembrane currents, electrical activity and exocytosis were measured using whole-cell patch-clamping and capacitance measurements. Gene expression was studied using m RNA-sequencing and quantitative PCR. Results: Tspan7 is expressed in insulin-containing granules of pancreatic beta-cells and glucagon-producing alpha-cells. Tspan7 knockout mice (Tspan(gamma/-) mouse) exhibit reduced body weight and ad libitum plasma glucose but normal glucose tolerance. Tspan(gamma/- )islets have normal insulin content and glucose- or tolbutamide-stimulated insulin secretion. Depolarisation-triggered Ca2+ current was enhanced in Tspan(gamma/-) beta-cells, but beta-cell electrical activity and depolarisation-evoked exocytosis were unchanged suggesting that exocytosis was less sensitive to Ca2+. TSPAN7 knockdown (KD) in human pseudo-islets led to a significant reduction in insulin secretion stimulated by 20 mM Transcriptomic analyses show that TSPAN7 KD in human pseudo-islets correlated with changes in genes involved in hormone secretion, apoptosis and ER stress. Consistent with rodent beta-cells, exocytotic Ca2+ sensitivity was reduced in a human beta-cell line (EndoC-beta H1) following Tspan7 KD. Conclusion: Tspan7 is involved in the regulation of Ca2+-dependent exocytosis in beta-cells. Its function is more significant in human beta-cells than their rodent counterparts.
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| 7. |
- Smith, A., et al.
(författare)
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Evidence for the effectiveness of nature-based solutions to water issues in Africa
- 2021
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Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9318 .- 1748-9326. ; 16:6
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Tidskriftsartikel (refereegranskat)abstract
- There is increasing global interest in employing nature-based solutions, such as reforestation and wetland restoration, to help reduce water risks to economies and society, including water pollution, floods, droughts and water scarcity, that are likely to become worse under future climates. Africa is exposed to many such water risks. Nature-based solutions for adaptation should be designed to benefit biodiversity and can also provide multiple co-benefits, such as carbon sequestration. A systematic review of over 10 000 publications revealed 150 containing 492 quantitative case studies related to the effectiveness of nature-based solutions for downstream water quantity and water quality (including sediment load) in Africa. The solutions assessed included landscape-scale interventions and patterns (forests and natural wetlands) and site-specific interventions (constructed wetlands and urban interventions e.g. soakaways). Consistent evidence was found that nature-based solutions can improve water quality. In contrast, evidence of their effectiveness for improving downstream water resource quantity was inconsistent, with most case studies showing a decline in water yield where forests (particularly plantations of non-native species) and wetlands are present. The evidence further suggests that restoration of forests and floodplain wetlands can reduce flood risk, and their conservation can prevent future increases in risk; in contrast, this is not the case for headwater wetlands. Potential trade-offs identified include nature-based solutions reducing flood risk and pollution, whilst decreasing downstream water resource quantity. The evidence provides a scientific underpinning for policy and planning for nature-based solutions to water-related risks in Africa, though implementation will require local knowledge. © 2021 The Author(s). Published by IOP Publishing Ltd.
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