α-cell glucokinase suppresses glucose-regulated glucagon secretion

Basco, Davide; Zhang, Quan; Salehi, Albert; Tarasov, Andrei I.; Dolci, Wanda; Herrera, Pedro Luis; Spiliotis, Ioannis; Berney, Xavier; Tarussio, David; Rorsman, Patrik; Thorens, Bernard

doi:10.1038/s41467-018-03034-0

Cited by 81 publications

(87 citation statements)

References 28 publications

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“…81 Therefore, studies of α-cell physiology, regulation of glucagon secretion and most importantly molecular and functional interactions between αand β-cells have increasingly caught attention, in particular with respect to the development and management of diabetes mellitus. [82][83][84][85][86][87][88] Although fundamental aspects concerning the circadian control of transcription and functional regulation in the context of the intact pancreatic islet have been largely explored (as highlighted in the previous chapter), studies aiming to zoom into pancreatic islet cells in order to decipher circadian clock function in different islet cell types have only recently emerged. Our own recent study focuses on the molecular characterization of the αand β-cellular clocks, their interactions, impact on gene transcription and islet hormone secretion.…”

Section: Body Metabolism Is Orchestrated By Circadian Clocks In Rodmentioning

confidence: 99%

Time zones of pancreatic islet metabolism

Petrenko

Philippe

Dibner

2018

Diabetes Obesity Metabolism

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Most living beings possess an intrinsic system of circadian oscillators, allowing anticipation of the Earth's rotation around its own axis. The mammalian circadian timing system orchestrates nearly all aspects of physiology and behaviour. Together with systemic signals originating from the central clock that resides in the hypothalamic suprachiasmatic nucleus, peripheral oscillators orchestrate tissue-specific fluctuations in gene transcription and translation, and posttranslational modifications, driving overt rhythms in physiology and behaviour. There is accumulating evidence of a reciprocal connection between the circadian oscillator and most aspects of physiology and metabolism, in particular as the circadian system plays a critical role in orchestrating body glucose homeostasis. Recent reports imply that circadian clocks operative in the endocrine pancreas regulate insulin secretion, and that islet clock perturbation in rodents leads to the development of overt type 2 diabetes. While whole islet clocks have been extensively studied during the last years, the heterogeneity of islet cell oscillators and the interplay between α- and β-cellular clocks for orchestrating glucagon and insulin secretion have only recently gained attention. Here, we review recent findings on the molecular makeup of the circadian clocks operative in pancreatic islet cells in rodents and in humans, and focus on the physiologically relevant synchronizers that are resetting these time-keepers. Moreover, the implication of islet clock functional outputs in the temporal coordination of metabolism in health and disease will be highlighted.

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Section: Body Metabolism Is Orchestrated By Circadian Clocks In Rodmentioning

confidence: 99%

Time zones of pancreatic islet metabolism

Petrenko

Philippe

Dibner

2018

Diabetes Obesity Metabolism

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“…As a systemic modulator, GLP-1 inhibits glucagon secretion; however, there are controversies as to whether GLP-1 directly inhibits glucagon secretion from α cells by signaling through the alpha cell GLP-1R (13)(14)(15), or indirectly by increasing inter-islet somatostatin or insulin secretion (13,16). Glucagon secretion is also suppressed by paracrine signaling through the insulin, somatostatin and GABA A receptors on the α cell (16)(17)(18) At an intrinsic level, glucose directly or indirectly inhibits glucagon secretion from the α cell (19)(20)(21)(22) by altering downstream activities of Ca 2+ channels, K ATP channels (23), and trafficking of secretory granules (24).…”

Section: Introductionmentioning

confidence: 99%

Stathmin-2 Mediates Glucagon Secretion From Pancreatic α-Cells

Asadi

Dhanvantari

2020

Front. Endocrinol.

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Inhibition of glucagon hypersecretion from pancreatic α-cells is an appealing strategy for the treatment of diabetes. Our hypothesis is that proteins that associate with glucagon within alpha cell secretory granules will regulate glucagon secretion, and may provide druggable targets for controlling abnormal glucagon secretion in diabetes. Recently, we identified a dynamic glucagon interactome within the secretory granules of the α cell line, αTC1-6, and showed that select proteins within the interactome could modulate glucagon secretion. In the present study, we show that one of these interactome proteins, the neuronal protein stathmin-2, is expressed in αTC1-6 cells and in mouse pancreatic alpha cells, and is a novel regulator of glucagon secretion. The secretion of both glucagon and Stmn2 was significantly enhanced in response to 55 mM K + , and immunofluorescence confocal microscopy showed co-localization of stathmin-2 with glucagon and the secretory granule markers chromogranin A and VAMP-2 in αTC1-6 cells. In mouse pancreatic islets, Stathmin-2 co-localized with glucagon, but not with insulin, and co-localized with secretory pathway markers. To show a function for stathmin-2 in regulating glucagon secretion, we showed that siRNA-mediated depletion of stathmin-2 in αTC1-6 cells caused glucagon secretion to become constitutive without any effect on proglucagon mRNA levels, while overexpression of stathmin-2 completely abolished both basal and K + -stimulated glucagon secretion. Overexpression of stathmin-2 increased the localization of glucagon into the endosomal-lysosomal compartment, while depletion of stathmin-2 reduced the endosomal localization of glucagon. Therefore, we describe stathmin-2 as having a novel role as an alpha cell secretory granule protein that modulates glucagon secretion via trafficking through the endosomal-lysosomal system. These findings describe a potential new pathway for the regulation of glucagon secretion, and may have implications for controlling glucagon hypersecretion in diabetes.

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“…The mechanism(s) by which glucagon secretion is controlled is a contentious topic (Gylfe, 2013;Lai et al, 2018). Based on observations in isolated (ex vivo) islets, islets have been shown to respond to hypoglycaemia (and adjust glucagon secretion accordingly) via intrinsic (Rorsman et al, 2014;Basco et al, 2018;Yu et al, 2019) and paracrine mechanisms (Briant et al, 2018;Vergari et al, 2019). While it is indisputable that the islet is a critical component of the body's glucostat (Rodriguez-Diaz et al, 2018) and has the ability to intrinsically modulate glucagon output, it is clear that such an 'islet-centric' viewpoint is overly simplistic (Schwartz et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes

Kim

Knudsen

Madara

et al. 2020

Preprint

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Hypoglycaemia is a major barrier to the treatment of diabetes. Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon -the body's principle blood glucose-elevating hormone which is secreted from alpha-cells of the pancreatic islets. In isolated islets, varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (from 8 to 4 mM) has no significant effect on glucagon secretion and yet associates with dramatic changes in plasma glucagon in vivo. The identity of the systemic factor that stimulates glucagon secretion in vivo remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Glucagon-secreting alpha-cells express high levels of the vasopressin 1b receptor (V1bR). Activation of AVP neurons in vivo increased circulating AVP, stimulated glucagon release and evoked hyperglycaemia; effects blocked by pharmacological antagonism of either the glucagon receptor or vasopressin 1b receptor. AVP also mediates the stimulatory effects of dehydration and hypoglycaemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata, which are known to be activated by hypoglycaemia, drive AVP neuron activation in response to insulin-induced hypoglycaemia.Hypoglycaemia also increases circulating levels of copeptin (derived from the same pre-pro hormone as AVP) levels in humans and this hormone stimulates glucagon secretion from isolated human islets. In patients with type 1 diabetes, hypoglycaemia failed to increase both plasma copeptin and glucagon. These findings provide a new mechanism for the central regulation of glucagon secretion in both health and disease.

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α-cell glucokinase suppresses glucose-regulated glucagon secretion

Cited by 81 publications

References 28 publications

Time zones of pancreatic islet metabolism

Time zones of pancreatic islet metabolism

Stathmin-2 Mediates Glucagon Secretion From Pancreatic α-Cells

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes

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