Insulin Regulation of β-Cell Function Involves a Feedback Loop on SERCA Gene Expression, Ca2+Homeostasis, and Insulin Expression and Secretion†

Abstractβ-Cells depend on the islet basement membrane (BM). While some islet BM components are produced by endothelial cells (ECs), the source of others remains unknown. Pancreatic pericytes directly support β-cells through mostly unidentified secreted factors. Thus, we hypothesized that pericytes regulate β-cells through the production of BM components. Here, we show that pericytes produce multiple components of the mouse pancreatic and islet interstitial and BM matrices. Several of the pericyte-produced ECM components were previously implicated in β-cell physiology, including collagen IV, laminins, proteoglycans, fibronectin, nidogen, and hyaluronan. Compared to ECs, pancreatic pericytes produce significantly higher levels of α2 and α4 laminin chains, which constitute the peri-islet and vascular BM. We further found that the pericytic laminin isoforms differentially regulate mouse β-cells. Whereas α2 laminins promoted islet cell clustering, they did not affect gene expression. In contrast, culturing on Laminin-421 induced the expression of β-cell genes, including Ins1, MafA, and Glut2, and significantly improved glucose-stimulated insulin secretion. Thus, alongside ECs, pericytes are a significant source of the islet BM, which is essential for proper β-cell function.

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Effect of sitagliptin plus metformin on β-cell function, islet integrity and islet gene expression in Zucker diabetic fatty rats

Diabetes Research and Clinical Practice ◽

10.1016/j.diabres.2011.01.016 ◽

2011 ◽

Vol 92 (2) ◽

pp. 213-222 ◽

Cited By ~ 17

Author(s):

Seung Jin Han ◽

Sung-E. Choi ◽

Yup Kang ◽

Jong Gab Jung ◽

Sang-A. Yi ◽

...

Keyword(s):

Gene Expression ◽

Cell Function ◽

Β Cell ◽

Zucker Diabetic Fatty Rats ◽

Β Cell Function

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STAT3 Regulates Mitochondrial Gene Expression in Pancreatic β-Cells and its Deficiency Induces Glucose Intolerance in Obesity

10.2337/figshare.14831049.v1 ◽

2021 ◽

Author(s):

Anaïs Schaschkow ◽

Lokman Pang ◽

Valerie Vandenbempt ◽

Bernat Elvira ◽

Sara A. Litwak ◽

...

Keyword(s):

Gene Expression ◽

Glucose Intolerance ◽

High Fat Diet ◽

Cell Function ◽

Mitochondrial Gene ◽

High Fat ◽

Β Cells ◽

Β Cell ◽

Β Cell Function ◽

Deficient Mice

Most obese and insulin-resistant individuals do not develop diabetes. This is the result of the capacity of β-cells to adapt and produce enough insulin to cover the needs of the organism. The underlying mechanism of β-cell adaptation in obesity, however, remains unclear. Previous studies have suggested a role for STAT3 in mediating β-cell development and human glucose homeostasis, but little is known about STAT3 in β-cells in obesity. We observed enhanced cytoplasmic expression of STAT3 in severely obese and diabetic subjects. To address the functional role of STAT3 in adult β-cells, we generated mice with tamoxifen-inducible partial or full deletion of STAT3 in β-cells and fed them a high-fat diet before analysis. Interestingly, β-cell heterozygous and homozygous STAT3-deficient mice showed glucose intolerance when fed a high-fat diet. Gene expression analysis by RNA-Seq showed reduced expression of mitochondrial genes in STAT3 knocked down human EndoC-βH1 cells and was confirmed in FACS-purified β-cells from obese STAT3-deficient mice. Moreover, silencing of STAT3 impaired mitochondria activity in EndoC-βH1 cells and human islets, suggesting a mechanism for STAT3-modulated β-cell function. We propose STAT3 as a regulator of β-cell function, improving glucose-induced insulin secretion in obesity.

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L-Alanine induces changes in metabolic and signal transduction gene expression in a clonal rat pancreatic β-cell line and protects from pro-inflammatory cytokine-induced apoptosis

Clinical Science ◽

10.1042/cs20050149 ◽

2005 ◽

Vol 109 (5) ◽

pp. 447-455 ◽

Cited By ~ 43

Author(s):

Grainne A. Cunningham ◽

Neville H. Mcclenaghan ◽

Peter R. Flatt ◽

Philip Newsholme

Keyword(s):

Gene Expression ◽

Amino Acids ◽

Inflammatory Cytokine ◽

Cell Function ◽

Pancreatic Β Cell ◽

Secretory Function ◽

Β Cell ◽

Diphenylene Iodonium ◽

Β Cell Function ◽

Induced Apoptosis

Acute effects of nutrient stimuli on pancreatic β-cell function are widely reported; however, the chronic effects of insulinotropic amino acids, such as L-alanine, on pancreatic β-cell function and integrity are unknown. In the present study, the effects of prolonged exposure (24 h) to the amino acid L-alanine on insulin secretory function, gene expression and pro-inflammatory cytokine-induced apoptosis were studied using clonal BRIN-BD11 cells. Expression profiling of BRIN-BD11 cells chronically exposed to L-alanine was performed using oligonucleotide microarray analysis. The effect of alanine, the iNOS (inducible nitric oxide synthase) inhibitor NMA (NG-methyl-L-arginine acetate) or the iNOS and NADPH oxidase inhibitor DPI (diphenylene iodonium) on apoptosis induced by a pro-inflammatory cytokine mix [IL-1β (interleukin-1β), TNF-α (tumour necrosis factor-α) and IFN-γ (interferon-γ)] was additionally assessed by flow cytometry. Culture for 24 h with 10 mM L-alanine resulted in desensitization to the subsequent acute insulin stimulatory effects of L-alanine. This was accompanied by substantial changes in gene expression of BRIN-BD11 cells. Sixty-six genes were up-regulated >1.8-fold, including many involved in cellular signalling, metabolism, gene regulation, protein synthesis, apoptosis and the cellular stress response. Subsequent functional experiments confirmed that L-alanine provided protection of BRIN-BD11 cells from pro-inflammatory cytokine-induced apoptosis. Protection from apoptosis was mimicked by NMA or DPI suggesting L-alanine enhances intracellular antioxidant generation. These observations indicate important long-term effects of L-alanine in regulating gene expression, secretory function and the integrity of insulin-secreting cells. Specific amino acids may therefore play a key role in β-cell function in vivo.

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STAT3 Regulates Mitochondrial Gene Expression in Pancreatic β-Cells and its Deficiency Induces Glucose Intolerance in Obesity

10.2337/figshare.14831049 ◽

2021 ◽

Author(s):

Anaïs Schaschkow ◽

Lokman Pang ◽

Valerie Vandenbempt ◽

Bernat Elvira ◽

Sara A. Litwak ◽

...

Keyword(s):

Gene Expression ◽

Glucose Intolerance ◽

High Fat Diet ◽

Cell Function ◽

Mitochondrial Gene ◽

High Fat ◽

Β Cells ◽

Β Cell ◽

Β Cell Function ◽

Deficient Mice

Most obese and insulin-resistant individuals do not develop diabetes. This is the result of the capacity of β-cells to adapt and produce enough insulin to cover the needs of the organism. The underlying mechanism of β-cell adaptation in obesity, however, remains unclear. Previous studies have suggested a role for STAT3 in mediating β-cell development and human glucose homeostasis, but little is known about STAT3 in β-cells in obesity. We observed enhanced cytoplasmic expression of STAT3 in severely obese and diabetic subjects. To address the functional role of STAT3 in adult β-cells, we generated mice with tamoxifen-inducible partial or full deletion of STAT3 in β-cells and fed them a high-fat diet before analysis. Interestingly, β-cell heterozygous and homozygous STAT3-deficient mice showed glucose intolerance when fed a high-fat diet. Gene expression analysis by RNA-Seq showed reduced expression of mitochondrial genes in STAT3 knocked down human EndoC-βH1 cells and was confirmed in FACS-purified β-cells from obese STAT3-deficient mice. Moreover, silencing of STAT3 impaired mitochondria activity in EndoC-βH1 cells and human islets, suggesting a mechanism for STAT3-modulated β-cell function. We propose STAT3 as a regulator of β-cell function, improving glucose-induced insulin secretion in obesity.

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The Contribution of Transcriptional Coregulators in the Maintenance of β-cell Function and Identity

Endocrinology ◽

10.1210/endocr/bqaa213 ◽

2020 ◽

Vol 162 (2) ◽

Author(s):

Rebecca K Davidson ◽

Sukrati Kanojia ◽

Jason M Spaeth

Keyword(s):

Gene Expression ◽

Cell Function ◽

Β Cell ◽

Cell Dysfunction ◽

Impaired Insulin ◽

Principal Source ◽

Supporting Layer ◽

Β Cell Function ◽

Transcriptional Coregulators

Abstract Islet β-cell dysfunction that leads to impaired insulin secretion is a principal source of pathology of diabetes. In type 2 diabetes, this breakdown in β-cell health is associated with compromised islet-enriched transcription factor (TF) activity that disrupts gene expression programs essential for cell function and identity. TF activity is modulated by recruited coregulators that govern activation and/or repression of target gene expression, thereby providing a supporting layer of control. To date, more than 350 coregulators have been discovered that coordinate nucleosome rearrangements, modify histones, and physically bridge general transcriptional machinery to recruited TFs; however, relatively few have been attributed to β-cell function. Here, we will describe recent findings on those coregulators with direct roles in maintaining islet β-cell health and identity and discuss how disruption of coregulator activity is associated with diabetes pathogenesis.

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Influence of chronic hyperglycemia on the loss of the unfolded protein response in transplanted islets

Journal of Molecular Endocrinology ◽

10.1530/jme-13-0016 ◽

2013 ◽

Vol 51 (2) ◽

pp. 225-232 ◽

Cited By ~ 8

Author(s):

Stacey N Walters ◽

Jude Luzuriaga ◽

Jeng Yie Chan ◽

Shane T Grey ◽

D Ross Laybutt

Keyword(s):

Gene Expression ◽

Cell Function ◽

Mrna Levels ◽

Diabetic Mice ◽

Β Cell ◽

Unfolded Protein ◽

Chronic Hyperglycemia ◽

Β Cell Function ◽

The Unfolded Protein Response ◽

Protein Response

Chronic hyperglycemia contributes to β-cell dysfunction in diabetes and with islet transplantation, but the mechanisms remain unclear. Recent studies demonstrate that the unfolded protein response (UPR) is critical for β-cell function. Here, we assessed the influence of hyperglycemia on UPR gene expression in transplanted islets. Streptozotocin-induced diabetic or control nondiabetic mice were transplanted under the kidney capsule with syngeneic islets either sufficient or not to normalize hyperglycemia. Twenty-one days after transplantation, islet grafts were excised and RT-PCR was used to assess gene expression. In islet grafts from diabetic mice, expression levels of many UPR genes of the IRE1/ATF6 pathways, which are important for adaptation to endoplasmic reticulum stress, were markedly reduced compared with that in islet grafts from control mice. UPR genes of the PERK pathway were also downregulated. The normalization of glycemia restored the changes in mRNA expression, suggesting that chronic hyperglycemia contributes to the downregulation of multiple arms of UPR gene expression. Similar correlations were observed between blood glucose and mRNA levels of transcription factors involved in the maintenance of β-cell phenotype and genes implicated in β-cell function, suggesting convergent regulation of UPR gene expression and β-cell differentiation by hyperglycemia. However, the normalization of glycemia was not accompanied by restoration of antioxidant or pro-inflammatory cytokine mRNA levels, which were increased in islet grafts from diabetic mice. These studies demonstrate that chronic hyperglycemia contributes to the downregulation of multiple arms of UPR gene expression in transplanted mouse islets. Failure of the adaptive UPR may contribute to β-cell dedifferentiation and dysfunction in diabetes.

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H3K4 Methylation in β-cells Prevents Transcriptional Downregulation and Variance Associated with Type 2 Diabetes

10.1101/2021.01.28.428651 ◽

2021 ◽

Author(s):

Ben Vanderkruk ◽

Nina Maeshima ◽

Daniel J Pasula ◽

Meilin An ◽

Priya Suresh ◽

...

Keyword(s):

Gene Expression ◽

Type 2 Diabetes ◽

Cell Function ◽

H3k4 Methylation ◽

Β Cells ◽

Β Cell ◽

Genetic Mouse Model ◽

Expression Of Genes ◽

Β Cell Function

SummaryHistone 3 lysine 4 trimethylation (H3K4me3) is associated with promoters of actively expressed genes, with genes important for cell identity frequently having exceptionally broad H3K4me3-enriched domains at their TSS. While H3K4 methylation is implicated in contributing to transcription, maintaining transcriptional stability, facilitating enhancer-promoter interactions, and preventing irreversible silencing, some studies suggest it has little functional impact. Therefore, the function of H3K4 methylation is not resolved. Insufficient insulin release by β-cells is the primary etiology in type 2 diabetes (T2D) and is associated with the loss of expression of genes essential to normal β-cell function. We find that H3K4me3 is reduced in islets from mouse models of diabetes and from human donors with T2D. Using a genetic mouse model to impair H3K4 methyltransferase activity of TrxG complexes, we find that reduction of H3K4 methylation significantly reduces insulin production and glucose-responsiveness and increases transcriptional entropy, indicative of a loss of β-cell maturity. Genes that are downregulated by reduction to H3K4 methylation are concordantly downregulated in T2D. Loss of H3K4 methylation causes global dilution of epigenetic complexity but does not generally reduce gene expression – instead, genes related to β-cell function and/or in particular chromatin environments are specifically affected. While neither H3K4me3 nor H3K4me1 are strictly required for the expression of many genes, the expression of genes with critical roles in β-cell function becomes destabilized, with increased variance and decreased overall expression. Our data further suggests that, in absence of H3K4me3, promoter-associated H3K4me1 is sufficient to maintain expression. Together, these data implicate H3K4 methylation dysregulation as destabilizing β-cell gene expression and contributing to β-cell dysfunction in T2D.

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Pan-AMPK activator O304 prevents gene expression changes and remobilisation of histone marks in islets of diet-induced obese mice

Scientific Reports ◽

10.1038/s41598-021-03567-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ana López-Pérez ◽

Stefan Norlin ◽

Pär Steneberg ◽

Silvia Remeseiro ◽

Helena Edlund ◽

...

Keyword(s):

Gene Expression ◽

Glucose Homeostasis ◽

Energy Homeostasis ◽

Cell Function ◽

Β Cell ◽

Beneficial Effects ◽

Genome Wide ◽

Promising Target ◽

Β Cell Function ◽

Amp Activated Protein Kinase

AbstractAMP-activated protein kinase (AMPK) has an important role in cellular energy homeostasis and has emerged as a promising target for treatment of Type 2 Diabetes (T2D) due to its beneficial effects on insulin sensitivity and glucose homeostasis. O304 is a pan-AMPK activator that has been shown to improve glucose homeostasis in both mouse models of diabetes and in human T2D subjects. Here, we describe the genome-wide transcriptional profile and chromatin landscape of pancreatic islets following O304 treatment of mice fed high-fat diet (HFD). O304 largely prevented genome-wide gene expression changes associated with HFD feeding in CBA mice and these changes were associated with remodelling of active and repressive chromatin marks. In particular, the increased expression of the β-cell stress marker Aldh1a3 in islets from HFD-mice is completely abrogated following O304 treatment, which is accompanied by loss of active chromatin marks in the promoter as well as distant non-coding regions upstream of the Aldh1a3 gene. Moreover, O304 treatment restored dysfunctional glucose homeostasis as well as expression of key markers associated with β-cell function in mice with already established obesity. Our findings provide preclinical evidence that O304 is a promising therapeutic compound not only for T2D remission but also for restoration of β-cell function following remission of T2D diabetes.

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