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

Endocrinology ◽  
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.

Determinants of reversibility of β-cell dysfunction in response to short-term intensive insulin therapy in patients with early type 2 diabetes

2013 ◽  
Vol 305 (11) ◽  
pp. E1398-E1407 ◽  
Author(s):  
Caroline Kaercher Kramer ◽  
Haysook Choi ◽  
Bernard Zinman ◽  
Ravi Retnakaran
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Therapy ◽  
Intensive Insulin Therapy ◽  
Cell Function ◽  
Sensitivity Index ◽  
Β Cell ◽  
Short Term ◽  
Cell Dysfunction ◽  
Β Cell Function

Short-term intensive insulin therapy (IIT) can improve pancreatic β-cell function when administered early in the course of type 2 diabetes mellitus (T2DM). However, the degree of improvement in response to this therapy varies between patients. Thus, we sought to characterize the determinants of improvement in β-cell function in response to short-term IIT in early T2DM. Sixty-three patients with mean 3.0 ± 2.1 yr duration of T2DM and Hb A1c of 6.8 ± 0.8% underwent 4 wk of IIT consisting of basal insulin detemir and premeal insulin aspart, with oral glucose tolerance test administered at baseline and 1 day post-IIT. β-Cell function before and after IIT was assessed by Insulin Secretion Sensitivity Index-2 (ISSI-2). Reversibility of β-cell dysfunction was defined as percentage change in ISSI-2 of ≥25%. Overall, the study population experienced an increase in ISSI-2 from baseline to post-IIT ( P = 0.01), with one-third of participants achieving ≥25% improvement in ISSI-2. Compared with their peers, those with increases in ISSI-2 of ≥25% had greater decrements in fasting glucose ( P < 0.0001), Hb A1c ( P = 0.001), ALT ( P = 0.04), AST ( P = 0.02), and HOMA-IR ( P < 0.0001). On logistical regression analysis, baseline Hb A1c (OR = 2.83, 95% CI 1.16–6.88, P = 0.02) and change in HOMA-IR (OR = 0.008, 95%CI 0.0004–0.16, P = 0.001) emerged as independent predictors of reversibility of β-cell dysfunction. Indeed, reversibility of β-cell dysfunction was achieved in only those participants in whom IIT yielded an improvement in HOMA-IR. In conclusion, decline in HOMA-IR may be a key determinant of improvement of β-cell function in response to short-term IIT, suggesting a fundamental contribution of insulin resistance to the reversible component of β-cell dysfunction in early T2DM.

scholarly journals Impact of Magnesium Deficiency on Pancreatic β-Cell Function in Type 2 Diabetic Nigerians

2020 ◽  
Author(s):  
Abdullahi Mohammed ◽  
Ibrahim M. Bello
Keyword(s):  
Cell Function ◽  
Magnesium Deficiency ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Mg Deficiency ◽  
Cell Dysfunction ◽  
North Eastern ◽  
Β Cell Function ◽  
Type 2 Diabetic

Objective: Pancreatic β-cell dysfunction is described to be present at the diagnosis of type 2 diabetes mellitus (T2DM) and progressively deteriorated with disease duration. However, its progression is variable and potentially influenced by several factors. The Magnesium (Mg) deficiency mediates insulin resistance but reports regarding its role in pancreatic β-cell dysfunction are scarce and conflicting. The aim of this study was to evaluate Mg deficiency effect on pancreatic β-cell function in T2DM patients at a specialist hospital in north eastern Nigeria. Materials and Methods: Study subjects were categorized in to two groups according to plasma Mg levels; 34 subjects with hypomagnesemia and 45 subjects with normal magnesium levels. Fasting blood samples were analyzed for Mg, glucose and insulin. Pancreatic β-cell function was estimated as HOMA-β. Results: Degree of pancreatic β-cell function, as measured by HOMA-β, was significantly lower among T2DM subjects with hypomagnesemia compared to the subjects with normal magnesium levels (38.1± 5.5 vs. 41.2± 6.2, Pvalue< 0.05). Lower plasma Mg was associated with decreased pancreatic β-cell function among the study subjects independent of age, BMI and duration of diabetes. Conclusion: We concluded that among subjects with T2DM in this study, Mg deficiency might be linked with worsening of pancreatic β-cell function.

scholarly journals Transcription factors regulating β-cell function

2006 ◽  
Vol 155 (5) ◽  
pp. 671-679 ◽  
Author(s):  
Marlon E Cerf
Keyword(s):  
Transcription Factors ◽  
Cell Function ◽  
Regulation Of Transcription ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Development ◽  
Cell Dysfunction ◽  
Β Cell Function ◽  
Insight Into

Type 2 diabetes is primarily associated with insulin resistance and β-cell dysfunction. Maintenance of functional mature β-cells is imperative for ensuring glucose homeostasis. This can be achieved by optimal expression of key transcription factors that are required for normal pancreatic development and maintaining β-cell function. Defining the regulation of transcription factors as well as their regulation of important β-cell genes like insulin will provide further insight into elucidating the mechanisms leading to β-cell dysfunction.

Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies

2011 ◽  
Vol 300 (2) ◽  
pp. E255-E262 ◽  
Author(s):  
Adria Giacca ◽  
Changting Xiao ◽  
Andrei I. Oprescu ◽  
Andre C. Carpentier ◽  
Gary F. Lewis
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Β Cell Function

The phenomenon of lipid-induced pancreatic β-cell dysfunction (“lipotoxicity”) has been very well documented in numerous in vitro experimental systems and has become widely accepted. In vivo demonstration of β-cell lipotoxicity, on the other hand, has not been consistently demonstrated, and there remains a lack of consensus regarding the in vivo effects of chronically elevated free fatty acids (FFA) on β-cell function. Much of the disagreement relates to how insulin secretion is quantified in vivo and in particular whether insulin secretion is assessed in relation to whole body insulin sensitivity, which is clearly reduced by elevated FFA. By correcting for changes in in vivo insulin sensitivity, we and others have shown that prolonged elevation of FFA impairs β-cell secretory function. Prediabetic animal models and humans with a positive family history of type 2 diabetes are more susceptible to this impairment, whereas those with severe impairment of β-cell function (such as individuals with type 2 diabetes) demonstrate no additional impairment of β-cell function when FFA are experimentally raised. Glucolipotoxicity (i.e., the combined β-cell toxicity of elevated glucose and FFA) has been amply demonstrated in vitro and in some animal studies but not in humans, perhaps because there are limitations in experimentally raising plasma glucose to sufficiently high levels for prolonged periods of time. We and others have shown that therapies directed toward diminishing oxidative stress and ER stress have the potential to reduce lipid-induced β-cell dysfunction in animals and humans. In conclusion, lipid-induced pancreatic β-cell dysfunction is likely to be one contributor to the complex array of genetic and metabolic insults that result in the relentless decline in pancreatic β-cell function in those destined to develop type 2 diabetes, and mechanisms involved in this lipotoxicity are promising therapeutic targets.

scholarly journals Retinol-Binding Protein 4 Activates STRA6 Provoking Pancreatic β Cell Dysfunction in Type 2 Diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Rong Huang ◽  
Xinxiu Bai ◽  
Xueyan Li ◽  
Xiaohui Wang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Retinol Binding Protein 4 ◽  
Cell Dysfunction ◽  
Β Cell Function

Pancreatic β cell dysfunction plays a decisive role in progression of type 2 diabetes. Retinol binding protein 4 (RBP4) is a prominent adipokine in type 2 diabetes while its effect on β cell function remains elusive and the underlying mechanisms are unknown. Here, we found that elevated circulating RBP4 levels were inversely correlated with pancreatic β cell function in db/db mice across different glycemic stages. RBP4 directly suppressed glucose stimulated insulin secretion (GSIS) in primary isolated islets and INS-1E cells in a dose- and time-dependent manner. RBP4-transgenic overexpressing mice (RBP4-Tg) showed a dynamic decrease of GSIS which appeared as early as 8-week-old preceding the impairment of insulin sensitivity and glucose tolerance. Islets isolated from RBP4-Tg mice showed a significant decrease of GSIS. Mechanistically, we demonstrated that the stimulated by retinoic acid 6(STRA6), RBP4’s only known specific membrane receptor, is expressed in β cells and mediates the inhibitory effect of RBP4 on insulin synthesis via JAK2/STAT1/ISL-1 pathway. Moreover, decreasing circulating RBP4 level could effectively restore β cell dysfunction and ameliorate hyperglycemia in db/db mice. These observations revealed a role of RBP4 in pancreatic β cell dysfunction which provided new insight into the diabetogenic effect of RBP4.

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

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.

scholarly journals A missense KCNQ1 Mutation Impairs Insulin Secretion in Neonatal Diabetes

2021 ◽  
Author(s):  
Zhimin Zhou ◽  
Maolian Gong ◽  
Amit Pande ◽  
Ulrike Lisewski ◽  
Torsten Röpke ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Embryonic Stem ◽  
Heart Rhythm ◽  
Neonatal Diabetes ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Metabolic Genes ◽  
Β Cell Function

AbstractKCNQ1/Kv7 is a voltage-gated K+ channel that regulates heart rhythm, glucose and salt homeostasis. Mutations of KCNQ1 are primarily associated with long-QT syndrome and type 2 diabetes; however, thus far KCNQ1 mutations have not been associated with monogenetic diabetes. Here, we identified a homozygous KCNQ1 missense mutation (R397W) in an individual with permanent neonatal diabetes (PND). To identify the mechanisms that link the mutation to the disease, we introduced the mutation into human embryonic stem cells (hESCs), and used them to derived pancreatic β-like cells (hESC-β cell). In early β-like cells, we observed atypical membrane electrical activity, increased levels of cytoplasmic Ca2+, and a hypersecretion of insulin. Upon extended culture, their insulin secretion decreased and the number of apoptotic cells increased, resulting in a reduction in the numbers of β-like cells. Late-stage β-like cells exhibited a decrease in the expression of metabolic genes, e.g. HNF4α, PDX1 and GLUT1, providing a possible mechanism for β-cell dysfunction. Our study identifies KCNQ1 as a novel candidate gene of monogenetic diabetes and shows that KCNQ1 regulates β-cell function and survival.

scholarly journals Retinol-Binding Protein 4 Activates STRA6 Provoking Pancreatic β Cell Dysfunction in Type 2 Diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Rong Huang ◽  
Xinxiu Bai ◽  
Xueyan Li ◽  
Xiaohui Wang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Retinol Binding Protein 4 ◽  
Cell Dysfunction ◽  
Β Cell Function

Pancreatic β cell dysfunction plays a decisive role in progression of type 2 diabetes. Retinol binding protein 4 (RBP4) is a prominent adipokine in type 2 diabetes while its effect on β cell function remains elusive and the underlying mechanisms are unknown. Here, we found that elevated circulating RBP4 levels were inversely correlated with pancreatic β cell function in db/db mice across different glycemic stages. RBP4 directly suppressed glucose stimulated insulin secretion (GSIS) in primary isolated islets and INS-1E cells in a dose- and time-dependent manner. RBP4-transgenic overexpressing mice (RBP4-Tg) showed a dynamic decrease of GSIS which appeared as early as 8-week-old preceding the impairment of insulin sensitivity and glucose tolerance. Islets isolated from RBP4-Tg mice showed a significant decrease of GSIS. Mechanistically, we demonstrated that the stimulated by retinoic acid 6(STRA6), RBP4’s only known specific membrane receptor, is expressed in β cells and mediates the inhibitory effect of RBP4 on insulin synthesis via JAK2/STAT1/ISL-1 pathway. Moreover, decreasing circulating RBP4 level could effectively restore β cell dysfunction and ameliorate hyperglycemia in db/db mice. These observations revealed a role of RBP4 in pancreatic β cell dysfunction which provided new insight into the diabetogenic effect of RBP4.

scholarly journals Impact of triglycerides and waist circumference on insulin resistance and β-cell function in non-diabetic first-degree relatives of type 2 diabetes

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fahd Ahmed ◽  
Molham AL-Habori ◽  
Ebtesam Al-Zabedi ◽  
Riyadh Saif-Ali
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Cell Function ◽  
Β Cell ◽  
Cell Dysfunction ◽  
First Degree Relatives ◽  
Type 2 Dm ◽  
Β Cell Function ◽  
The Impact

Abstract Background Although there is abundant evidence indicating the relative contribution of insulin resistance (HOMA-IR) and β-cell dysfunction (HOMA-β) among first-degree relatives (FDRs) of Type 2 DM patients, few studies reported the association between HOMA-IR and HOMA-β with metabolic syndrome. Our objective was to evaluate the impact of metabolic syndrome factors on HOMA-IR, HOMA-β and glycoproteins in non-diabetic FDRs. Methods In this study, 103 Yemeni male subjects aged 25–42 years, with BMI < 25 kg/m2 were examined, 39 of whom were normal subjects with no family history of diabetes served as control and 64 subjects were non-diabetic FDRs of Type 2 DM patients. Results Both glycoproteins, glycated haemoglobin (HbA1c) and fructosamine as well as insulin, HOMA-IR and HOMA-β were significantly (p = 4.9 × 10−9; 6.0 × 10−8; 6.6 × 10−12; 1.3 × 10−7; 5.5 × 10−12, respectively) higher in non-diabetic FDRs as compared to control group. Fasting plasma glucose, though within normal range, were significantly (p = 0.026) higher in non-diabetic FDRs. Linear regression analysis showed that both TG and WC are the main metabolic syndrome factors that significantly increased HOMA-IR (B = 0.334, p = 1.97 × 10−6; B = 0.024, p = 1.05 × 10−5), HOMA-β (B = 16.8, p = 6.8 × 10−5; B = 0.95, p = 0.004), insulin (B = 16.5, p = 1.2 × 10−6; B = 1.19, p = 8.3 × 10−6) and HbA1c (B = 0.001, p = 0.034; B = 0.007, p = 0.037). Conclusion Triglyceride and WC are the important metabolic syndrome factors associated with insulin resistance, basal β-cell function and insulin levels in non-diabetic FDR men of Type 2 DM patients. Moreover, FDRs showed insulin resistance with compensatory β-cell function (hyperinsulinaemia) suggesting that insulin resistance precede the development of pancreatic β-cell dysfunction in individuals at risk of Type 2 DM.

scholarly journals Visceral Adiposity Index is associated with Insulin Resistance, impaired Insulin Secretion, and β-cell dysfunction in subjects at risk for Type 2 Diabetes

2021 ◽  
pp. 100013
Author(s):  
Froylan David Martínez-Sánchez ◽  
Valerie Paola Vargas-Abonce ◽  
Andrea Rocha-Haro ◽  
Romina Flores-Cardenas ◽  
Milagros Fernández-Barrio ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
At Risk ◽  
Insulin Secretion ◽  
Visceral Adiposity ◽  
Visceral Adiposity Index ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Impaired Insulin
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