Protection of pancreatic β-cells against glucotoxicity by short-term treatment with GLP-1

Park, Sun-Hyun; Park, Jae-Hyung; Shim, Hye-Min; Na, Ann-Yae; Bae, Ki-Churl; Lim, Jeung-Geun; Song, Dae‐Kyu

doi:10.1016/j.bbrc.2015.02.139

Cited by 12 publications

(9 citation statements)

References 36 publications

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“…Type II diabetes is characterized through decreased insulin secretion, long-term high blood glucose and increased glucagon release [ 17 , 18 ]. Long-term exposure to high glucose, known as glucotoxicity, typically leads to the dysfunction of a wide range of organs, including pancreatic α and β cells [ 19 – 22 ]. In previous studies, miRNAs have been implicated in decreased insulin secretion resulting from pro-longed high glucose [ 14 ].…”

Section: Resultsmentioning

confidence: 99%

The microRNA-124-iGluR2/3 pathway regulates glucagon release from alpha cells

Zhang

Deng

et al. 2016

Oncotarget

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Glucagon, secreted from islet alpha cells, plays an important role in regulating glucose homeostasis; however, the molecular mechanism underlying this process is not fully understood. Previous studies have demonstrated that miRNAs are involved in the function of alpha cells. Glutamate promotes glucagon secretion by mediating the opening of Ca2+ channels. In this present, iGluR2 and iGluR3 levels were significantly increased in fasting-treated mouse islets. Additional studies showed that miR-124-3p simultaneously regulates the expression of iGluR2 and iGluR3 through the direct targeting of mRNA 3’UTR of these two genes. The miR-124-iGluRs pathway also contributed to the high level of glucagon secretion through long-term high glucose levels. Thus, a novel pathway comprising miRNA, glutamate and iGluRs has been demonstrated to regulate the biological process of glucagon release.

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Section: Resultsmentioning

confidence: 99%

The microRNA-124-iGluR2/3 pathway regulates glucagon release from alpha cells

Zhang

Deng

et al. 2016

Oncotarget

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“…Gluco-toxicity is a major cause of β-cell dysfunction in type 2 diabetes (20). The current study demonstrates that high glucose concentration inhibited the expression and secretion of both insulin and hepcidin.…”

Section: Discussionmentioning

confidence: 99%

Hepcidin links gluco-toxicity to pancreatic beta cell dysfunction by inhibiting Pdx-1 expression

Mao

Chen

Tang

et al. 2017

Endocrine Connections

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ObjectiveGluco-toxicity is a term used to convey the detrimental effect of hyperglycemia on β-cell function through impaired insulin synthesis. Although it is known that the expression and activity of several key insulin transcription regulators is inhibited, other molecular mechanisms that mediate gluco-toxicity are poorly defined. Our objective was to explore the role of hepcidin in β-cell gluco-toxicity.DesignWe first confirmed that high glucose levels inhibited hepcidin expression in the mouse insulinoma cell line, MIN6. The downregulation of hepcidin decreased Pdx-1 expression, which reduced insulin synthesis.MethodsMIN6 cells were exposed to high glucose concentrations (33.3 mmol/L). Glucose-stimulated insulin secretion (GSIS) and serum hepcidin levels were measured by ELISA. The mRNA levels of insulin1, insulin2, Pdx-1 and hepcidin were measured by real-time polymerase chain reaction. Western blot analysis was used to detect the changes in PDX-1 expression. Transient overexpression with hepcidin was used to reverse the downregulation of Pdx-1 and insulin synthesis induced by gluco-toxicity.ResultsExposure of MIN6 cells to high glucose significantly decreased GSIS and inhibited insulin synthesis as well as Pdx-1 transcriptional activity and expression at both the mRNA and protein levels. High glucose also decreased hepcidin expression and secretion. Hepcidin overexpression in MIN6 cells partially reversed the gluco-toxicity-induced downregulation of Pdx-1 and insulin expression and improved GSIS. The restoration of insulin synthesis by transfection of a hepcidin overexpression plasmid confirmed the role of hepcidin in mediating the gluco-toxic inhibition of insulin synthesis.ConclusionsOur observations suggest that hepcidin is associated with gluco-toxicity-reduced pancreatic β-cell insulin synthesis in type 2 diabetes by inhibiting Pdx-1 expression.

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“…For instance, the glucagon hormone that is produced by pancreatic α cells, which increases liver glucose production, is essential for maintaining the glucose level within healthy limits. It has been reported that the manipulation of glucagon by receptor agonists, such as glucagon-like peptide-1 (GLP-1), or by dipeptidyl peptidase-4 (DPP-4) inhibitors can decrease glucagon levels and eventually reduce the degree of hyperglycemia and its associated risks (D'Alessio, 2011 ; Park et al, 2015 ). Incretin, or hormone glucose-dependent insulinotropic peptide (GIP), is yet another critical hormone in glucose homeostasis and stimulates glucagon secretion and the eventual state of hyperglycemia.…”

Section: Sophisticated Cell Death Caused By a Simple Sugarmentioning

confidence: 99%

Pancreatic β Cell Mass Death

Marrif

Alsunousi

2016

Front. Pharmacol.

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Type two diabetes (T2D) is a challenging metabolic disorder for which a cure has not yet been found. Its etiology is associated with several phenomena, including significant loss of insulin-producing, beta cell (β cell) mass via progressive programmed cell death and disrupted cellular autophagy. In diabetes, the etiology of β cell death and the role of mitochondria are complex and involve several layers of mechanisms. Understanding the dynamics of those mechanisms could permit researchers to develop an intervention for the progressive loss of β cells. Currently, diabetes research has shifted toward rejuvenation and plasticity technology and away from the simplified approach of hormonal compensation. Diabetes research is currently challenged by questions such as how to enhance cell survival, decrease apoptosis and replenish β cell mass in diabetic patients. In this review, we discuss evidence that β cell development and mass formation are guided by specific signaling systems, particularly hormones, transcription factors, and growth factors, all of which could be manipulated to enhance mass growth. There is also strong evidence that β cells are dynamically active cells, which, under specific conditions such as obesity, can increase in size and subsequently increase insulin secretion. In certain cases of aggressive or advanced forms of T2D, β cells become markedly impaired, and the only alternatives for maintaining glucose homeostasis are through partial or complete cell grafting (the Edmonton protocol). In these cases, the harvesting of an enriched population of viable β cells is required for transplantation. This task necessitates a deep understanding of the pharmacological agents that affect β cell survival, mass, and function. The aim of this review is to initiate discussion about the important signals in pancreatic β cell development and mass formation and to highlight the process by which cell death occurs in diabetes. This review also examines the attempts that have been made to recover or increase cell mass in diabetic patients by using various pharmacological agents.

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Protection of pancreatic β-cells against glucotoxicity by short-term treatment with GLP-1

Cited by 12 publications

References 36 publications

The microRNA-124-iGluR2/3 pathway regulates glucagon release from alpha cells

The microRNA-124-iGluR2/3 pathway regulates glucagon release from alpha cells

Hepcidin links gluco-toxicity to pancreatic beta cell dysfunction by inhibiting Pdx-1 expression

Pancreatic β Cell Mass Death

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