scholarly journals Overexpression of miR-297b-5p protects against stearic acid-induced pancreatic β-cell apoptosis by targeting LATS2

2020 ◽  
Vol 318 (3) ◽  
pp. E430-E439 ◽  
Author(s):  
Rui Guo ◽  
Yue Yu ◽  
Yunjin Zhang ◽  
Yinling Li ◽  
Xia Chu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Stearic Acid ◽  
Palmitic Acid ◽  
Cell Apoptosis ◽  
Control Group ◽  
Β Cell ◽  
Cell Dysfunction ◽  
High Stearic Acid ◽  
Mouse Islets

Chronic exposure to high concentrations of stearic acid (C18:0) can result in β -cell dysfunction, leading to development of type 2 diabetes. However, the molecular mechanisms underlying the destructive effects of stearic acid on β-cells remain largely unknown. In this study, we aimed to investigate the role of miR-297b-5p on stearic acid-induced β-cell apoptosis. Differential expression of microRNAs (miRNAs) was assessed in a β-TC6 cell line exposed to stearic acid, palmitic acid, or a normal culture medium by high-throughput sequencing. The apoptosis rate was measured by flow cytometry after miR-297b-5p mimic/inhibitor transfection, and large-tumor suppressor kinase 2 (LATS2) was identified as a target of miR-297b-5p using a luciferase activity assay. In vivo, C57BL/6 mice were fed with normal and high-stearic-acid diet, respectively. Mouse islets were used for similar identification of miR-297b-5p and Lats2 in β-TC6 cell. We selected two differentially expressed miRNAs in stearic acid compared with those in the palmitic acid and control groups. miR-297b-5p expression was significantly lower in β-TC6 cells and mouse islets in stearic acid than in control group. Upregulation of miR-297b-5p alleviated the stearic acid-induced cell apoptosis and reduction in insulin secretion by inhibiting Lats2 expression in vitro. Meanwhile, silencing Lats2 significantly reversed the stearic acid-stimulated β-cell dysfunction in both β-TC6 cells and islets. Our findings indicate a suppressive role for miR-297b-5p in stearic acid-induced β-cell apoptosis, which may reveal a potential target for the treatment of β-cell dysfunction in the pathogenesis of type 2 diabetes.

Fatty acids and glucolipotoxicity in the pathogenesis of Type 2 diabetes

2008 ◽  
Vol 36 (3) ◽  
pp. 348-352 ◽  
Author(s):  
Miriam Cnop
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cell Loss ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Dysfunction

The prevalence of Type 2 diabetes is increasing dramatically as a result of the obesity epidemic, and poses a major health and socio-economic burden. Type 2 diabetes develops in individuals who fail to compensate for insulin resistance by increasing pancreatic insulin secretion. This insulin deficiency results from pancreatic β-cell dysfunction and death. Western diets rich in saturated fats cause obesity and insulin resistance, and increase levels of circulating NEFAs [non-esterified (‘free’) fatty acids]. In addition, they contribute to β-cell failure in genetically predisposed individuals. NEFAs cause β-cell apoptosis and may thus contribute to progressive β-cell loss in Type 2 diabetes. The molecular pathways and regulators involved in NEFA-mediated β-cell dysfunction and apoptosis are beginning to be understood. We have identified ER (endoplasmic reticulum) stress as one of the molecular mechanisms implicated in NEFA-induced β-cell apoptosis. ER stress was also proposed as a mechanism linking high-fat-diet-induced obesity with insulin resistance. This cellular stress response may thus be a common molecular pathway for the two main causes of Type 2 diabetes, namely insulin resistance and β-cell loss. A better understanding of the molecular mechanisms contributing to pancreatic β-cell loss will pave the way for the development of novel and targeted approaches to prevent Type 2 diabetes.

scholarly journals TCONS_00230836 silencing restores stearic acid-induced β cell dysfunction through alleviating endoplasmic reticulum stress rather than apoptosis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Rui Guo ◽  
Yunjin Zhang ◽  
Yue Yu ◽  
Shenghan Su ◽  
Qingrui Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Endoplasmic Reticulum Stress ◽  
Stearic Acid ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Acid Diet ◽  
High Stearic Acid ◽  
Mouse Islets

Abstract Background Chronic exposure of pancreatic β cells to high levels of stearic acid (C18:0) leads to impaired insulin secretion, which accelerates the progression of type 2 diabetes mellitus (T2DM). Recently, long noncoding RNAs (lncRNAs) were found to participate in saturated fatty acid-induced metabolism dysfunction. However, their contribution to stearic acid-induced β-cell dysfunction remains largely unknown. This study evaluated the possible role of the lncRNA TCONS_00230836 in stearic acid-stimulated lipotoxicity to β cells. Method Using high-throughput RNA-sequencing, TCONS_00230836 was screened out as being exclusively differentially expressed in stearic acid-treated mouse β-TC6 cells. Co-expression network was constructed to reveal the potential mRNAs targeted for lncRNA TCONS_00230836. Changes in this lncRNA’s and candidate mRNAs’ levels were further assessed by real-time PCR in stearic acid-treated β-TC6 cells and islets of mice fed a high-stearic-acid diet (HSD). The localization of TCONS_00230836 was detected by fluorescent in situ hybridization. The endogenous lncRNA TCONS_00230836 in β-TC6 cells was abrogated by its Smart Silencer. Results TCONS_00230836 was enriched in mouse islets and mainly localized in the cytoplasm. Its expression was significantly increased in stearic acid-treated β-TC6 cells and HSD-fed mouse islets. Knockdown of TCONS_00230836 significantly restored stearic acid-impaired glucose-stimulated insulin secretion through alleviating endoplasmic reticulum stress. However, stearic acid-induced β cell apoptosis was not obviously recovered. Conclusion Our findings suggest the involvement of TCONS_00230836 in stearic acid-induced β-cell dysfunction, which provides novel insight into stearic acid-induced lipotoxicity to β cells. Anti-lncRNA TCONS_00230836 might be a new therapeutic strategy for alleviating stearic acid-induced β-cell dysfunction in the progression of T2DM.

scholarly journals TCONS_00230836 silencing restores stearic acid-induced β-cell dysfunction through alleviating endoplasmic reticulum stress via a PERK/eIF2α-dependent pathway rather than apoptosis

2020 ◽  
Author(s):  
Rui Guo ◽  
Yunjin Zhang ◽  
Yue Yu ◽  
Shenghan Su ◽  
Qingrui Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Stearic Acid ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Acid Diet ◽  
High Stearic Acid ◽  
Mouse Islets ◽  
Dependent Pathway

Abstract Background: Chronic exposure of pancreatic β cells to high levels of stearic acid (C18:0) leads to impaired insulin secretion, which accelerates the progression of type 2 diabetes mellitus (T2DM). Recently, long noncoding RNAs (lncRNAs) were found to participate in saturated fatty acid-induced metabolism dysfunction. However, their contribution to stearic acid-induced β-cell dysfunction remains largely unknown. This study evaluated the possible role of the lncRNA TCONS_00230836 in stearic acid-stimulated lipotoxicity to β cells. Method: Using high-throughput RNA-sequencing, TCONS_00230836 was screened out as being exclusively differentially expressed in stearic acid-treated mouse β-TC6 cells. Co-expression network was constructed to reveal the potential mRNAs targeted for lncRNA TCONS_00230836. Changes in this lncRNA’s and candidate mRNAs’levels were further assessed by real-time PCR in stearic acid-treated β-TC6 cells and islets of mice fed a high-stearic-acid diet (HSD). The localization of TCONS_00230836 was detected by fluorescent in situ hybridization. The endogenous lncRNA TCONS_00230836 in β-TC6 cells was abrogated by its Smart Silencer. Results: The lncRNA TCONS_00230836 was enriched in mouse islets and mainly localized in the cytoplasm. Its expression was significantly increased in stearic acid-treated β-TC6 cells and HSD-fed mouse islets. Knockdown of TCONS_00230836 apparently restored stearic acid-impaired GSIS through alleviating endoplasmic reticulum stress via a PERK/eIF2α-dependent pathway. However, stearic acid-induced β-cell apoptosis was not obviously recovered. Conclusion: Our findings suggest the involvement of the lncRNA TCONS_00230836 in stearic acid-induced β-cell dysfunction, which provides novel insight into stearic acid-induced lipotoxicity to β cells. Anti-lncRNA TCONS_00230836 might be a new therapeutic strategy for alleviating stearic acid-induced β-cell dysfunction in the progression of T2DM.

Comparison of Sleeve Gastrectomy and Conservatory Treatment Effect on Biochemical and Hormonal Profile of Obese Type 2 Diabetes Subjects: CREDOR Randomized Controlled Study Results

2017 ◽  
Vol 68 (7) ◽  
pp. 1622-1627 ◽  
Author(s):  
Diana Simona Stefan ◽  
Andrada Mihai ◽  
Daiana Bajko ◽  
Daniela Lixandru ◽  
Laura Petcu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Weight Loss ◽  
Sleeve Gastrectomy ◽  
Beta Cell ◽  
Beta Cell Dysfunction ◽  
Control Group ◽  
Cell Dysfunction ◽  
Randomized Controlled

Metabolic surgery is the most efficacious method for the treatment of morbid obesity and was recently included among the antidiabetes treatments recommended in obese type 2 diabetes (T2D) patients. The aim of this study was to compare in a randomized controlled trial the effect of sleeve gastrectomy (SG) to that of intensive lifestyle intervention plus pharmacologic treatment on some markers of insulin resistance and beta cell function as well as some appetite controlling hormones in a group of male obese T2D subjects. The study groups comprised 20 subjects for SG and 21 control subjects. Fasting blood glucose, insulin, proinsulin, adiponectin, leptin, ghrelin, HOMA-IR, HOMA-%B, proinsulin-to-insulin ratio and proinsulin-to-adiponectin ratio were evaluated at baseline and after one year follow-up. Overall, patients in the SG group lost 78.98% of excess weight loss (%EWL) in comparison with 9.45% in the control group. This was accompanied by a significant improvement of insulin resistance markers, including increase of adiponectin and decrease of HOMA-IR, while no changes were recorded in the control group. Weight loss was also associated with a significant improvement of proinsulin-to-insulin and proinsulin-to-adiponectin ratio, both surrogate markers of beta cell dysfunction. These also improved in the control group, but were only marginally significant. Our findings suggest that improved insulin resistance and decreased beta cell dysfunction after sleeve gastrectomy might explain diabetes remission associated with metabolic surgery.

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

scholarly journals Systemic Metabolic Alterations Correlate with Islet-Level Prostaglandin E2 Production and Signaling Mechanisms That Predict β-Cell Dysfunction in a Mouse Model of Type 2 Diabetes

Metabolites ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 58 ◽  
Author(s):  
Michael D. Schaid ◽  
Yanlong Zhu ◽  
Nicole E. Richardson ◽  
Chinmai Patibandla ◽  
Irene M. Ong ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Prostaglandin E2 ◽  
Genetic Model ◽  
Cell Mass ◽  
Arachidonic Acid Metabolite ◽  
Β Cell ◽  
Human Organ ◽  
Cell Dysfunction ◽  
Primary Mouse

The transition from β-cell compensation to β-cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional β-cell mass in Type 2 diabetes (T2D). The primary endogenous EP3 ligand is the arachidonic acid metabolite prostaglandin E2 (PGE2). Expression of the pancreatic islet EP3 and PGE2 synthetic enzymes and/or PGE2 excretion itself have all been shown to be upregulated in primary mouse and human islets isolated from animals or human organ donors with established T2D compared to nondiabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptinob/ob mutation—a strong genetic model of T2D—were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found numerous alterations in full-body metabolic parameters in T2D-protected mice (e.g., gut microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated β-cell dysfunction.

The role of vitamin D in the development of type 2 diabetes

2021 ◽  
Vol 19 (1) ◽  
pp. 44-52
Author(s):  
A.P. Shumilov ◽  
◽  
M.Yu. Semchenkova ◽  
D.S. Mikhalik ◽  
T.G. Avdeeva ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Vitamin D ◽  
Inverse Relationship ◽  
Biological Mechanisms ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Vitamin D Levels

Vitamin D plays an important role in decreasing the risk of developing type 2 diabetes by influencing calcium metabolism, thereby reducing β-cell dysfunction and preventing insulin resistance. The findings of research works are contradictory enough, although some of them demonstrated an inverse relationship between vitamin D levels and the incidence of type 2 diabetes. The article describes the biological mechanisms of relationships between vitamin D levels and type 2 diabetes, reviews the results of the studies conducted and summarizes the available data. Key words: vitamin D, type 2 diabetes mellitus, insulin resistance

scholarly journals N-acyl Taurines and Acylcarnitines Cause an Imbalance in Insulin Synthesis and Secretion Provoking β Cell Dysfunction in Type 2 Diabetes

2017 ◽  
Vol 25 (6) ◽  
pp. 1334-1347.e4 ◽  
Author(s):  
Michaela Aichler ◽  
Daniela Borgmann ◽  
Jan Krumsiek ◽  
Achim Buck ◽  
Patrick E. MacDonald ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Β Cell ◽  
Insulin Synthesis ◽  
Cell Dysfunction

Analysis of compensatory β-cell response in mice with combined mutations of Insr and Irs2

2007 ◽  
Vol 292 (6) ◽  
pp. E1694-E1701 ◽  
Author(s):  
Jane J. Kim ◽  
Yoshiaki Kido ◽  
Philipp E. Scherer ◽  
Morris F. White ◽  
Domenico Accili
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Response ◽  
Cell Mass ◽  
Comprehensive Treatment ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Impaired Insulin

Type 2 diabetes results from impaired insulin action and β-cell dysfunction. There are at least two components to β-cell dysfunction: impaired insulin secretion and decreased β-cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired β-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. As previously reported, ∼70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased β-cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as β-cell mass gradually declined, indicating that replication-defective β-cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous β-cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of β-cell dysfunction in type 2 diabetes should positively affect both aspects of β-cell physiology.

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