scholarly journals OGT regulates mitochondrial biogenesis and function via diabetes susceptibility gene Pdx1

2021 ◽  
Author(s):  
Ramkumar Mohan ◽  
Seokwon Jo ◽  
Amber Lockridge ◽  
Deborah A. Ferrington ◽  
Kevin Murray ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Susceptibility Gene ◽  
Mitochondrial Morphology ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell ◽  
Atp Production ◽  
Glcnac Transferase ◽  
And Function

O-GlcNAc transferase (OGT), a nutrient-sensor sensitive to glucose flux, is highly expressed in the pancreas. However, the role of OGT in the mitochondria of β-cells is unexplored. Here, we identified the role of OGT in mitochondrial function in β-cells. Constitutive deletion of OGT (βOGTKO) or inducible ablation in mature β-cells (iβOGTKO) causes distinct effects on mitochondrial morphology and function. Islets from βOGTKO, but not iβOGTKO, mice display swollen mitochondria, reduced glucose-stimulated oxygen consumption rate, ATP production and glycolysis. Alleviating ER stress by genetic deletion of Chop did not rescue the mitochondrial dysfunction in βOGTKO mice. We identified altered islet proteome between βOGTKO and iβOGTKO mice. Pancreatic and duodenal homeobox 1 (Pdx1) was reduced in in βOGTKO islets. Pdx1 over-expression increased insulin content and improved mitochondrial morphology and function in βOGTKO islets. These data underscore the essential role of OGT in regulating β-cell mitochondrial morphology and bioenergetics. In conclusion, OGT couples nutrient signal and mitochondrial function to promote normal β-cell physiology. <br>

scholarly journals OGT regulates mitochondrial biogenesis and function via diabetes susceptibility gene Pdx1

2021 ◽  
Author(s):  
Ramkumar Mohan ◽  
Seokwon Jo ◽  
Amber Lockridge ◽  
Deborah A. Ferrington ◽  
Kevin Murray ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Susceptibility Gene ◽  
Mitochondrial Morphology ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell ◽  
Atp Production ◽  
Glcnac Transferase ◽  
And Function

O-GlcNAc transferase (OGT), a nutrient-sensor sensitive to glucose flux, is highly expressed in the pancreas. However, the role of OGT in the mitochondria of β-cells is unexplored. Here, we identified the role of OGT in mitochondrial function in β-cells. Constitutive deletion of OGT (βOGTKO) or inducible ablation in mature β-cells (iβOGTKO) causes distinct effects on mitochondrial morphology and function. Islets from βOGTKO, but not iβOGTKO, mice display swollen mitochondria, reduced glucose-stimulated oxygen consumption rate, ATP production and glycolysis. Alleviating ER stress by genetic deletion of Chop did not rescue the mitochondrial dysfunction in βOGTKO mice. We identified altered islet proteome between βOGTKO and iβOGTKO mice. Pancreatic and duodenal homeobox 1 (Pdx1) was reduced in in βOGTKO islets. Pdx1 over-expression increased insulin content and improved mitochondrial morphology and function in βOGTKO islets. These data underscore the essential role of OGT in regulating β-cell mitochondrial morphology and bioenergetics. In conclusion, OGT couples nutrient signal and mitochondrial function to promote normal β-cell physiology. <br>

scholarly journals Diabetic Kinome Inhibitors—A New Opportunity for β-Cells Restoration

2021 ◽  
Vol 22 (16) ◽  
pp. 9083
Author(s):  
Barbara Pucelik ◽  
Agata Barzowska ◽  
Janusz M. Dąbrowski ◽  
Anna Czarna
Keyword(s):  
High Throughput Screening ◽  
Human Life ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Binding Modes ◽  
Β Cells ◽  
Β Cell ◽  
And Function

Diabetes, and several diseases related to diabetes, including cancer, cardiovascular diseases and neurological disorders, represent one of the major ongoing threats to human life, becoming a true pandemic of the 21st century. Current treatment strategies for diabetes mainly involve promoting β-cell differentiation, and one of the most widely studied targets for β-cell regeneration is DYRK1A kinase, a member of the DYRK family. DYRK1A has been characterized as a key regulator of cell growth, differentiation, and signal transduction in various organisms, while further roles and substrates are the subjects of extensive investigation. The targets of interest in this review are implicated in the regulation of β-cells through DYRK1A inhibition—through driving their transition from highly inefficient and death-prone populations into efficient and sufficient precursors of islet regeneration. Increasing evidence for the role of DYRK1A in diabetes progression and β-cell proliferation expands the potential for pharmaceutical applications of DYRK1A inhibitors. The variety of new compounds and binding modes, determined by crystal structure and in vitro studies, may lead to new strategies for diabetes treatment. This review provides recent insights into the initial self-activation of DYRK1A by tyrosine autophosphorylation. Moreover, the importance of developing novel DYRK1A inhibitors and their implications for the treatment of diabetes are thoroughly discussed. The evolving understanding of DYRK kinase structure and function and emerging high-throughput screening technologies have been described. As a final point of this work, we intend to promote the term “diabetic kinome” as part of scientific terminology to emphasize the role of the synergistic action of multiple kinases in governing the molecular processes that underlie this particular group of diseases.

scholarly journals Chronic activation of GPR40 does not negatively impact upon BRIN-BD11 pancreatic β-cell physiology and function

2020 ◽  
Vol 72 (6) ◽  
pp. 1725-1737
Author(s):  
Eloisa Aparecida Vilas-Boas ◽  
Noémie Karabacz ◽  
Gabriela Nunes Marsiglio-Librais ◽  
Maíra Melo Rezende Valle ◽  
Lisa Nalbach ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Er Stress ◽  
Cell Physiology ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Chronic Activation ◽  
And Function

Abstract Background Free fatty acids (FFAs) are known for their dual effects on insulin secretion and pancreatic β-cell survival. Short-term exposure to FFAs, such as palmitate, increases insulin secretion. On the contrary, long-term exposure to saturated FFAs results in decreased insulin secretion, as well as triggering oxidative stress and endoplasmic reticulum (ER) stress, culminating in cell death. The effects of FFAs can be mediated either via their intracellular oxidation and consequent effects on cellular metabolism or via activation of the membrane receptor GPR40. Both pathways are likely to be activated upon both short- and long-term exposure to FFAs. However, the precise role of GPR40 in β-cell physiology, especially upon chronic exposure to FFAs, remains unclear. Methods We used the GPR40 agonist (GW9508) and antagonist (GW1100) to investigate the impact of chronically modulating GPR40 activity on BRIN-BD11 pancreatic β-cells physiology and function. Results We observed that chronic activation of GPR40 did not lead to increased apoptosis, and both proliferation and glucose-induced calcium entry were unchanged compared to control conditions. We also observed no increase in H2O2 or superoxide levels and no increase in the ER stress markers p-eIF2α, CHOP and BIP. As expected, palmitate led to increased H2O2 levels, decreased cell viability and proliferation, as well as decreased metabolism and calcium entry. These changes were not counteracted by the co-treatment of palmitate-exposed cells with the GPR40 antagonist GW1100. Conclusions Chronic activation of GPR40 using GW9508 does not negatively impact upon BRIN-BD11 pancreatic β-cells physiology and function. The GPR40 antagonist GW1100 does not protect against the deleterious effects of chronic palmitate exposure. We conclude that GPR40 is probably not involved in mediating the toxicity associated with chronic palmitate exposure.

scholarly journals Calcium Signaling in ß-cell Physiology and Pathology: A Revisit

2019 ◽  
Vol 20 (24) ◽  
pp. 6110 ◽  
Author(s):  
Christiane Klec ◽  
Gabriela Ziomek ◽  
Martin Pichler ◽  
Roland Malli ◽  
Wolfgang F. Graier
Keyword(s):  
Calcium Signaling ◽  
Adult Population ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Cell Dysfunction ◽  
Health And Disease

Pancreatic beta (β) cell dysfunction results in compromised insulin release and, thus, failed regulation of blood glucose levels. This forms the backbone of the development of diabetes mellitus (DM), a disease that affects a significant portion of the global adult population. Physiological calcium (Ca2+) signaling has been found to be vital for the proper insulin-releasing function of β-cells. Calcium dysregulation events can have a dramatic effect on the proper functioning of the pancreatic β-cells. The current review discusses the role of calcium signaling in health and disease in pancreatic β-cells and provides an in-depth look into the potential role of alterations in β-cell Ca2+ homeostasis and signaling in the development of diabetes and highlights recent work that introduced the current theories on the connection between calcium and the onset of diabetes.

scholarly journals β-Hydroxybutyrate improves β-cell mitochondrial function and survival

2017 ◽  
Vol 1 (1) ◽  
Author(s):  
MaryJane Sampson ◽  
Daniel R. Lathen ◽  
Blake W. Dallon ◽  
Carrie Draney ◽  
Jason D. Ray ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mitochondrial Function ◽  
Cellular Proliferation ◽  
Cell Function ◽  
Cell Physiology ◽  
Β Cell ◽  
Atp Production ◽  
Improve Insulin Resistance ◽  
Β Cell Function

Pharmacological interventions aimed at improving outcomes in type 2 diabetes and achieving normoglycaemia, including insulin therapy, are increasingly common, despite the potential for substantial side effects. Carbohydrate-restricted diets that result in increased ketogenesis have effectively been used to improve insulin resistance, a fundamental feature of type 2 diabetes. In addition, limited evidence suggests that states of ketogenesis may also improve β-cell function in type 2 diabetics. Considering how little is known regarding the effects of ketones on β-cell function, we sought to determine the specific effects of β-Hydroxybutyrate (βHB) on pancreatic β-cell physiology and mitochondrial function. βHB treatment increased β-cell survival and proliferation, while also increasing mitochondrial mass, respiration and adenosine triphosphate (ATP) production. Despite these improvements, were unable to detect an increase in β-cell or islet insulin production and secretion. Collectively, these findings have two implications. Firstly, they indicate that β-cells have improved survival and proliferation in the midst of βHB, the circulating form of ketones. Secondly, insulin secretion does not appear to be directly related to apparent improvements in mitochondrial function and cellular proliferation.

scholarly journals 14-3-3ζ constrains insulin secretion in pancreatic β-cells by regulating mitochondrial function

2021 ◽  
Author(s):  
Yves Mugabo ◽  
Cheng Zhao ◽  
Ju Jing Tan ◽  
Anindya Ghosh ◽  
Scott A Campbell ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Mitochondrial Function ◽  
Cell Function ◽  
Cell Mass ◽  
Atp Synthesis ◽  
Whole Body ◽  
Β Cells ◽  
Β Cell ◽  
Insulinoma Cells

While critical for neurotransmitter synthesis in the brain, members of the 14-3-3 protein family are often assumed to have redundant, over-lapping roles due to their high sequence homology and ubiquitous expression. Despite this assumption, various mammalian 14-3-3 isoforms have now been implicated in regulating cellular and organismal metabolism; however, these functions were primarily observed in cell lines or from systemic knockout mouse models. To date, we have begun to define the contributions of 14-3-3ζ in adipocytes, but whether 14-3-3ζ has additional metabolic roles in other cell types, such as the pancreatic β-cell, is unclear. We previously documented a pro-survival role of 14-3-3ζ in MIN6 insulinoma cells, as depletion of 14-3-3ζ induced cell death, but paradoxically, whole-body deletion of 14-3-3ζ knockout in mice resulted in significantly enlarged β-cell area with no effects on insulin secretion. To better understand the role of 14-3-3ζ in β-cells, we generated β-cell-specific 14-3-3ζ knockout (β14-3-3ζKO) mice, and while no differences in β-cell mass were observed, β14-3-3ζKO mice displayed potentiated insulin secretion due to enhanced mitochondrial function and ATP synthesis. Deletion of 14-3-3ζ led to profound changes to the β-cell transcriptome, where pathways associated with mitochondrial respiration and oxidative phosphorylation were upregulated. Acute treatment of mouse islets and human islets with pan-14-3-3 inhibitors recapitulated the potentiation in glucose-stimulated insulin secretion (GSIS) and mitochondrial function, suggesting that 14-3-3ζ is a critical isoform inβ-cells that regulates GSIS. In dysfunctional db/db islets and islets from type 2 diabetic donors, expression of Ywhaz/YWHAZ, the gene encoding 14-3-3ζ, was inversely associated with insulin secretory capacity, and pan-14-3-3 protein inhibition was capable of enhancing GSIS and mitochondrial function. Taken together, this study demonstrates important regulatory functions of 14-3-3ζ and its related isoforms in insulin secretion and mitochondrial function in β-cells. A deeper understanding of how 14-3-3ζ influences β-cell function will further advance our knowledge of how insulin secretion from β-cells is regulated.

scholarly journals DIMT1, a regulator of ribosomal biogenesis, controls β-cell protein synthesis, mitochondrial function and insulin secretion

2020 ◽  
Author(s):  
Gaurav Verma ◽  
Alexander Bowen ◽  
Alexander Hamilton ◽  
Jonathan Esguerra ◽  
Alexandros Karagiannopoulos ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Insulin Secretion ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Cell Protein ◽  
Ribosomal Biogenesis ◽  
Β Cells ◽  
Β Cell ◽  
Ribosomal Subunits ◽  
Atp Production

AbstractWe previously reported that transcription factor B1 mitochondrial (TFB1M) is involved in the pathogenesis of type 2 diabetes (T2D) owing to mitochondrial dysfunction. Here, we describe that dimethyladenosine transferase 1 homolog (DIMT1), a homologue of TFB1M, is expressed and active in pancreatic β-cells. Like TFB1M, it has been implicated in control of ribosomal RNA (rRNA) but its role in β-cells or T2D remains to be identified. Silencing of DIMT1 impacted mitochondrial function, leading to reduced expression of mitochondrial OXPHOS proteins, reduced oxygen consumption rate (OCR), dissipated mitochondrial membrane potential (ΔΨm) and caused a lower rate of ATP production (mATP). In addition, DIMT1 knockdown slowed the rate of protein synthesis. In accordance with these findings, DIMT1-deficiency perturbed insulin secretion in rodent and human β-cell lines. These effects are likely a result of destabilization of ribosomal assembly, involving NIN1 (RPN12) binding protein 1 homolog (NOB-1) and Pescadillo ribosomal biogenesis factor 1 (PES-1). These are two critical ribosomal subunits proteins, whose interactions were perturbed upon DIMT1-deficiency, thereby disturbing protein synthesis in β-cells. Thus, we have here highlighted a role of DIMT1 in ribosomal biogenesis that perturbs protein synthesis, resulting in mitochondrial dysfunction and disrupted insulin secretion, both being potential pathogenetic factors in T2D.

scholarly journals Reg3g ameliorates Tacrolimus-induced pancreatic β cell dysfunction by restoring mitochondrial function

2021 ◽  
Author(s):  
Ming Xiang ◽  
Senlin Li ◽  
Hong Zhou ◽  
Mengyuan Xie ◽  
Zijun Zhang ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Calcium Uptake ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Atp Production ◽  
Mitochondria Membrane Potential ◽  
Cell Dysfunction ◽  
Mitochondrial Functions ◽  
Induced Apoptosis

Background and Purpose: Tacrolimus (Tac) induces pancreatic β cell dysfunction, causing new-onset diabetes mellitus (NODM) after transplantation. Reg3g is a member of the pancreatic regenerative gene family, as reported to improve type 1 diabetes by promoting β cell regeneration. Here, we aim to investigate the role and approach of Reg3g in reversing Tac-induced β cell dysfunction and NODM in mice. Experimental Approach: Circulating REG3A (the human homolog of mouse Reg3g) concentrations of patients treated with Tac after heart transplantation(HT) were detected. The glucose-stimulated insulin secretion (GSIS) and mitochondrial functions, including mitochondria membrane potential (MMP), mitochondria calcium uptake, ATP production, and oxygen consumption rate (OCR), were tested in β cells. Effects of Reg3g on Tac-induced NODM in mice were studied. Key Results: Circulating REG3A levels significantly decreased in NODM patients treated with Tac compared with those without diabetes. Tac down-regulated Reg3g via inhibiting STAT3-mediated transcription activation, while Reg3g protected against Tac-induced apoptosis of β cells. Besides, Reg3g restored GSIS suppressed by Tac in β cells via improving mitochondrial function, including increased MMP, mitochondria calcium uptake, ATP production, and OCR. Mechanically, Reg3g increased accumulation of pSTAT3(Ser727) in mitochondria by activating ERK1/2-STAT3 signaling pathway, leading to restoration of Tac-caused mitochondrial impairment. Moreover, Reg3g overexpression effectively ameliorated Tac-induced NODM in mice. Conclusion and Implications: Reg3g ameliorates Tac-induced pancreatic β cell dysfunction by restoring mitochondrial function via a pSTAT3(Ser727)-dependent way. Our observations identify a novel Reg3g-involved mechanism underlying the augmented incidence of Tac-induced NODM and reveal that Reg3g ameliorates Tac-induced β cell dysfunction.

ATP-sensitive K+ channels and disease: from molecule to malady

2007 ◽  
Vol 293 (4) ◽  
pp. E880-E889 ◽  
Author(s):  
Frances M. Ashcroft
Keyword(s):  
Neonatal Diabetes ◽  
Channel Structure ◽  
Congenital Hyperinsulinism ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
American Physiological Society ◽  
And Function ◽  
The Relationship

This essay is based on a lecture given to the American Physiological Society in honor of Walter B. Cannon, an advocate of homeostasis. It focuses on the role of the ATP-sensitive potassium K+ (KATP) channel in glucose homeostasis and, in particular, on its role in insulin secretion from pancreatic β-cells. The β-cell KATP channel comprises pore-forming Kir6.2 and regulatory SUR1 subunits, and mutations in either type of subunit can result in too little or too much insulin release. Here, I review the latest information on the relationship between KATP channel structure and function, and consider how mutations in the KATP channel genes lead to neonatal diabetes or congenital hyperinsulinism.

scholarly journals Autocrine IGF2 programmes β-cell plasticity under conditions of increased metabolic demand

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ionel Sandovici ◽  
Constanze M. Hammerle ◽  
Sam Virtue ◽  
Yurena Vivas-Garcia ◽  
Adriana Izquierdo-Lahuerta ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Homeostasis ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Chow Diet ◽  
Genome Wide Association Studies ◽  
Cell Plasticity ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

AbstractWhen exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive changes in order to maintain glucose homeostasis. The role that growth control genes, highly expressed in early pancreas development, might exert in programming β-cell plasticity in later life is a poorly studied area. The imprinted Igf2 (insulin-like growth factor 2) gene is highly transcribed during early life and has been identified in recent genome-wide association studies as a type 2 diabetes susceptibility gene in humans. Hence, here we investigate the long-term phenotypic metabolic consequences of conditional Igf2 deletion in pancreatic β-cells (Igf2βKO) in mice. We show that autocrine actions of IGF2 are not critical for β-cell development, or for the early post-natal wave of β-cell remodelling. Additionally, adult Igf2βKO mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2βKO females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit hyperinsulinemia and placentomegalia. Insulin resistance induced by congenital leptin deficiency also renders Igf2βKO females more hyperglycaemic compared to leptin-deficient controls. Upon high-fat diet feeding, Igf2βKO females are less susceptible to develop insulin resistance. Based on these findings, we conclude that in female mice, autocrine actions of β-cell IGF2 during early development determine their adaptive capacity in adult life.

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