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Essential role of glucokinase in the protection of pancreatic ? cells to the glucose energetic status.

ABSTRACT: Energy sensing is indispensable to balance anabolic and catabolic processes for the maintenance of cell viability. Pancreatic ? cells are especially relevant because of their involvement in the coordination of insulin secretion when glucose concentration arises in the local milieu. In this work, we uncover the increased susceptibility of pancreatic ? cells to cell death in response to different energy stressors. Upon glucose decline, from 25 to 5?mM, caused by stimulation with either 2-deoxyglucose or metformin, only pancreatic ? cells showed an increase in cell death. Very interestingly, when we transfected either mouse insulinoma cell or human embryo kidney cells with a phospho-mutant form of B cell lymphoma 2 associated agonist of cell death at serine 155 (BAD S155D), an increase in the pro-survival factor B cell lymphoma 2 was detected in pancreatic ? cells and not in human embryonic kidney cells in the presence of the energetic stressors. This data suggests that the protective capacity of this mutant form is only present in cells that present glucokinase. In contrast, upon hyperactivation of mechanistic target of rapamycin complex 1 signaling by knocking-down tuberous sclerosis complex protein, we observed increased susceptibility to cell death in response to energy stress in both pancreatic and non-pancreatic ? cells. Therefore, mechanistic target of rapamycin complex 1 signaling presents a dual effect on cell viability. On the one hand, a chronic inhibition of mechanistic target of rapamycin complex 1 activity in response to the energy status is deleterious for pancreatic ? cells, being attenuated by the overexpression of B cell lymphoma 2 associated agonist of cell death S155D. On the other hand, mechanistic target of rapamycin complex 1 hyperactivity provokes a susceptibility to energetic stress-induced cell death. Taken together, these results may open potential implications for the use of glucokinase activators or mechanistic target of rapamycin complex 1 modulators for the maintenance of pancreatic ? cells for longer periods of time avoiding its loss in different pathologies such as type 2 diabetes mellitus.

SUBMITTER: Marques P

PROVIDER: S-EPMC6769003 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Essential role of glucokinase in the protection of pancreatic β cells to the glucose energetic status.

Marqués Patricia P Kamitz Anne A Bartolomé Alberto A Burillo Jesús J Martínez Helena H Jiménez Beatriz B Fernández-Rhodes María M Guillén Carlos C Guillén Carlos C Benito Manuel M

Cell death discovery 20190930

Energy sensing is indispensable to balance anabolic and catabolic processes for the maintenance of cell viability. Pancreatic β cells are especially relevant because of their involvement in the coordination of insulin secretion when glucose concentration arises in the local milieu. In this work, we uncover the increased susceptibility of pancreatic β cells to cell death in response to different energy stressors. Upon glucose decline, from 25 to 5 mM, caused by stimulation with either 2-deoxygluc ...[more]

PMID: 31583121

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Project description:Aims/introductionSrc, a non-receptor tyrosine kinase, regulates a wide range of cellular functions, and hyperactivity of Src is involved in impaired glucose metabolism in pancreatic ?-cells. However, the physiological role of Src in glucose metabolism in normal, unstressed ?-cells remains unclear. In the present study, we investigated the role of Src in insulin secretion and glucose metabolism.Materials and methodsSrc was downregulated using small interfering ribonucleic acid in INS-1 cells, and glucose-induced insulin secretion, adenosine triphosphate content, intracellular calcium concentration, glucose utilization and glucokinase activity were measured. Expression levels of messenger ribonucleic acid and protein of glucokinase were examined by semiquantitative real-time polymerase chain reaction and immunoblotting, respectively. Cells were fractionated by digitonin treatment, and subcellular localization of glucokinase was examined by immunoblotting. Interaction between glucokinase and neuronal nitric oxide synthase was estimated by immunoprecipitation.ResultsIn Src downregulated INS-1 cells, glucose-induced insulin secretion was impaired, whereas insulin secretion induced by high K(+) was not affected. Intracellular adenosine triphosphate content and elevation of intracellular calcium concentration by glucose stimulation were suppressed by Src downregulation. Src downregulation reduced glucose utilization in the presence of high glucose, which was accompanied by a reduction in glucokinase activity without affecting its expression. However, Src downregulation reduced glucokinase in soluble, cytoplasmic fraction, and increased it in pellet containing intaracellular organelles. In addition, interaction between glucokinase and neuronal nitric oxide synthase was facilitated by Src downregulation.ConclusionsSrc plays an important role in glucose-induced insulin secretion in pancreatic ?-cells through maintaining subcellular localization and activity of glucokinase.

Dataset Information

Essential role of glucokinase in the protection of pancreatic ? cells to the glucose energetic status.

Publications

Essential role of glucokinase in the protection of pancreatic β cells to the glucose energetic status.

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