scholarly journals Novel insights into pancreatic β-cell glucolipotoxicity from real-time functional analysis of mitochondrial energy metabolism in INS-1E insulinoma cells

2013 ◽  
Vol 456 (3) ◽  
pp. 417-426 ◽  
Author(s):  
Jonathan Barlow ◽  
Charles Affourtit
Keyword(s):  
Type 2 Diabetes ◽  
Functional Analysis ◽  
Insulin Secretion ◽  
Pancreatic Β Cell ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Β Cell ◽  
Mitochondrial Energy Metabolism ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulinoma Cells

Obesity-related pancreatic β-cell failure contributes to development of Type 2 diabetes. We show that defects in mitochondrial oxidative phosphorylation largely account for fatty-acid-induced impairment of glucose-stimulated insulin secretion, but not for the lipotoxicity-related loss of β-cell viability.

scholarly journals Differential gene expression between Zucker Fatty rats and Zucker Diabetic Fatty rats: a potential role for the immediate-early gene Egr-1 in regulation of beta cell proliferation

2005 ◽  
Vol 35 (1) ◽  
pp. 13-25 ◽  
Author(s):  
Kay E Garnett ◽  
Philip Chapman ◽  
Julie A Chambers ◽  
Ian D Waddell ◽  
David S W Boam
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Cell Proliferation ◽  
Transcription Factors ◽  
Insulin Secretion ◽  
Early Gene ◽  
Β Cell ◽  
Zucker Diabetic Fatty Rats ◽  
Glucose Stimulated Insulin Secretion

The β-cell failure that characterises type 2 diabetes is likely to involve altered expression of many genes. We aimed to identify global changes in gene expression underlying β-cell dysfunction in pre-diabetic Zucker Diabetic Fatty rat islets, followed by functional studies to verify our findings. Gene expression profiles in islets from 6-week-old Zucker Diabetic Fatty rats and Zucker Fatty rat controls were analysed using Affymetrix microarrays. Totally 977 genes were found to be differentially regulated, comprising large groups of membrane and structural proteins, kinases, channels, receptors, transporters, growth factors and transcription factors. We are particularly interested in transcription factors, which can have profound effects on cellular function. Thus a subset of those with no role yet defined in the β-cell was selected for further study namely the immediate-early gene Egr-1, PAG608, rCGR19 and mSin3b. Tissue specificity of these factors varied but interestingly Egr-1 expression was highly enriched in the pancreatic islet. To determine a possible role of Egr-1 in the β-cell, Egr-1 expression in INS-1 cells was silenced using RNA interference (RNAi). Glucose-stimulated insulin secretion in these cells was then measured using ELISA and cell proliferation was measured by [3H]thymidine incorporation. Small interfering RNA (siRNA)-mediated silencing of the Egr-1 gene inhibited its induction by glucose but had no observable effect on glucose-stimulated insulin secretion. However, Egr-1 gene silencing did inhibit proliferation of INS-1 cells in a glucose-independent manner. Our studies have revealed a role for Egr-1 and suggest that reduced Egr-1 gene expression may contribute to decreased β-cell proliferation and the consequent β-cell failure observed in the later stages of type 2 diabetes.

scholarly journals Determining pancreatic β-cell compensation for changing insulin sensitivity using an oral glucose tolerance test

2014 ◽  
Vol 307 (9) ◽  
pp. E822-E829 ◽  
Author(s):  
Thomas P. J. Solomon ◽  
Steven K. Malin ◽  
Kristian Karstoft ◽  
Sine H. Knudsen ◽  
Jacob M. Haus ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Oral Glucose ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
C Peptide ◽  
Normal Glucose

Plasma glucose, insulin, and C-peptide responses during an OGTT are informative for both research and clinical practice in type 2 diabetes. The aim of this study was to use such information to determine insulin sensitivity and insulin secretion so as to calculate an oral glucose disposition index (DIOGTT) that is a measure of pancreatic β-cell insulin secretory compensation for changing insulin sensitivity. We conducted an observational study of n = 187 subjects, representing the entire glucose tolerance continuum from normal glucose tolerance to type 2 diabetes. OGTT-derived insulin sensitivity (SI OGTT) was calculated using a novel multiple-regression model derived from insulin sensitivity measured by hyperinsulinemic euglycemic clamp as the independent variable. We also validated the novel SI OGTT in n = 40 subjects from an independent data set. Plasma C-peptide responses during OGTT were used to determine oral glucose-stimulated insulin secretion (GSISOGTT), and DIOGTT was calculated as the product of SI OGTT and GSISOGTT. Our novel SI OGTT showed high agreement with clamp-derived insulin sensitivity (typical error = +3.6%; r = 0.69, P < 0.0001) and that insulin sensitivity was lowest in subjects with impaired glucose tolerance and type 2 diabetes. GSISOGTT demonstrated a significant inverse relationship with SI OGTT. GSISOGTT was lowest in normal glucose-tolerant subjects and greatest in those with impaired glucose tolerance. DIOGTT was sequentially lower with advancing glucose intolerance. We hereby derive and validate a novel OGTT-derived measurement of insulin sensitivity across the entire glucose tolerance continuum and demonstrate that β-cell compensation for changing insulin sensitivity can be readily calculated from clinical variables collected during OGTT.

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.

Elevated Circulating LINC-P21 Serves as a Diagnostic Biomarker of Type 2 Diabetes Mellitus and Regulates Pancreatic β-cell Function by Sponging miR-766-3p to Upregulate NR3C2

2020 ◽  
Author(s):  
Zhibin Cao ◽  
Fuwang Yao ◽  
Yuqin Lang ◽  
Xueqiang Feng
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Cell Proliferation ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Cell Function ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

Abstract Objective The purpose of this study was to evaluate the clinical value and biological function of long non-coding RNA (lncRNA) LINC-P21 in type 2 diabetes mellitus (T2DM), and explore the underlying mechanisms. Methods The expression of LINC-P21 was estimated using quantitative real-time PCR. The functional role of LINC-P21 was explored by gain- and loss-of-function experiments. INS-1 cell proliferation was analyzed using a cell counting kit-8 (CCK-8)assay, and the glucose-stimulated insulin secretion was measured using an ELISA kit. The miRNAs that might be sponged by LINC-P21 were analyzed, and the subsequent target genes were predicted and assessed in INS-1 cells. Results Serum expression of LINC-P21 was elevated in T2DM patients, which was correlated with fasting blood glucose levels and disease diagnosis. The glucose-stimulated insulin secretion and the proliferation of INS-1 cells were enhanced by LINC-P21 knockdown, but the overexpression of LINC-P21 led to opposite effects. miR-766-3p could be directly inhibited by LINC-P21 in INS-1 cells and reverse the effects of LINC-P21 on β-cell function. Additionally, NR3C2 was determined as a target of miR-766-3p, which could be positively regulated by LINC-P21 and had same effects with LINC-P21 on INS-1 cell proliferation and insulin secretion. Conclusion All the data demonstrated that serum elevated LINC-P21 and decreased miR-766-3p serve as candidate diagnostic biomarkers in T2DM patients. LINC-P21 acts as a potential regulator in insulin secretion and proliferation of pancreatic β-cells through targeting miR-766-3p to upregulate NR3C2.

The presence of the 1068 G>A variant of P2X7 receptors is associated to an increase in IL-1Ra levels, insulin secretion and pancreatic β-cell function but not with glycemic control in type 2 diabetes patients

Gene ◽  
2018 ◽  
Vol 652 ◽  
pp. 1-6 ◽  
Author(s):  
Edith Elena Uresti-Rivera ◽  
Rocío Edith García-Jacobo ◽  
José Alfredo Méndez-Cabañas ◽  
Laura Elizabeth Gaytan-Medina ◽  
Nancy Cortez-Espinosa ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glycemic Control ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
P2x7 Receptors ◽  
Β Cell Function ◽  
Diabetes Patients

scholarly journals Glutamate dehydrogenase, insulin secretion, and type 2 diabetes: a new means to protect the pancreatic β-cell?

2012 ◽  
Vol 212 (3) ◽  
pp. 239-242 ◽  
Author(s):  
Isabel Göhring ◽  
Hindrik Mulder
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Carboxylic Acid ◽  
Glutamate Dehydrogenase ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Novel Treatment ◽  
Β Cell Function

In this issue of Journal of Endocrinology, Dr Han and colleagues report a protective effect of the glutamate dehydrogenase activator 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) under diabetes-like conditions that impair β-cell function in both a pancreatic β-cell line and db/db mice. Based on these observations, the authors suggest that BCH could serve as a novel treatment modality in type 2 diabetes. The present commentary discusses the importance of the findings. Some additional questions are raised, which may be addressed in future investigations, as there is some concern regarding the BCH treatment of β-cell failure.

scholarly journals miR-765 Impairs Pancreatic β-cell Function by Targeting PDX1 in type 2 Diabetes

2020 ◽  
Author(s):  
Li Zheng ◽  
Yalan Wang ◽  
Yanhong Li ◽  
Li Li ◽  
Xiaohong Wang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Viability ◽  
Healthy Volunteers ◽  
Peripheral Blood ◽  
Cell Apoptosis ◽  
Expression Level ◽  
Pancreatic Β Cell ◽  
Β Cell

Abstract Background: Type 2 diabetes (T2D) is highly connected with the defect in insulin secretion of pancreatic β-cells, which has been developing into a severe public health problem.Methods: Here, we first detected expression of PDX1 and miR-765 in peripheral blood from 40 patients with T2D and 40 healthy volunteers. INS-1E cells (pancreatic β-cell line) were cultured as experimental model. For glucose induction, we incubated INS-1E cells with 11 mM glucose as control group and INS-1E cells with 25 mM glucose as T2D model group. For target relationship verification, we performed Luciferase reporter assay. Generally, we utilized qRT-PCR (quantitative real-time PCR), western blotting, insulin secretion detection, CCK-8, and flow cytometry in this study.Results: The expression level of PDX1 was dramatically lower in peripheral blood from T2D patients than healthy volunteers, while miR-765 exhibited an opposite result. PDX1 expression level had an inverse correlation with blood glucose level of T2D patients whereas miR-765 exhibited a positive correlation. Furthermore, PDX1 improved insulin secretion, cell viability, and restrained cell apoptosis of INS-1E cells. PDX1 was identified as a target of miR-765 which was observed to reduce insulin secretion, cell viability, and induce cell apoptosis of INS-1E cells.Conclusions: Taken together, we confirmed that miR-765 could cause detrimental effect on pancreatic β-cell survival and function by targeting and repressing PDX1 in T2D.

scholarly journals The magnesium transporter NIPAL1 is a pancreatic islet–expressed protein that conditionally impacts insulin secretion

2020 ◽  
Vol 295 (29) ◽  
pp. 9879-9892
Author(s):  
Yousef Manialawy ◽  
Saifur R. Khan ◽  
Alpana Bhattacharjee ◽  
Michael B. Wheeler
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Line ◽  
Cell Function ◽  
Insulin Content ◽  
Pancreatic Β Cell ◽  
Sequencing Data ◽  
Β Cell

Type 2 diabetes is a chronic metabolic disease characterized by pancreatic β-cell dysfunction and peripheral insulin resistance. Among individuals with type 2 diabetes, ∼30% exhibit hypomagnesemia. Hypomagnesemia has been linked to insulin resistance through reduced tyrosine kinase activity of the insulin receptor; however, its impact on pancreatic β-cell function is unknown. In this study, through analysis of several single-cell RNA-sequencing data sets in tandem with quantitative PCR validation in both murine and human islets, we identified NIPAL1 (NIPA-like domain containing 1), encoding a magnesium influx transporter, as an islet-enriched gene. A series of immunofluorescence experiments confirmed NIPAL1's magnesium-dependent expression and that it specifically localizes to the Golgi in Min6-K8 cells, a pancreatic β-cell–like cell line (mouse insulinoma 6 clone K8). Under varying magnesium concentrations, NIPAL1 knockdown decreased both basal insulin secretion and total insulin content; in contrast, its overexpression increased total insulin content. Although the expression, distribution, and magnesium responsiveness of NIPAL1 in α-TC6 glucagonoma cells (a pancreatic α-cell line) were similar to the observations in Min6-K8 cells, no effect was observed on glucagon secretion in α-TC6 cells under the conditions studied. Overall, these results suggest that NIPAL1 expression is regulated by extracellular magnesium and that down-regulation of this transporter decreases glucose-stimulated insulin secretion and intracellular insulin content, particularly under conditions of hypomagnesemia.

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