scholarly journals Sorcin stimulates Activation Transcription Factor 6α (ATF6) transcriptional activity

2020 ◽  
Author(s):  
Steven Parks ◽  
Tian Gao ◽  
Natalia Jimenez Awuapura ◽  
Joseph Ayathamattam ◽  
Pauline L. Chabosseau ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Beta Cell ◽  
Er Stress ◽  
Transcriptional Activity ◽  
Pancreatic Beta Cell ◽  
Mrna Levels ◽  
High Fat ◽  
Insulin Promoter

ABSTRACTLevels of the transcription factor ATF6α, a key mediator of the unfolded protein response, that provides cellular protection during the progression endoplasmic reticulum (ER) stress, are markedly reduced in the pancreatic islet of patients with type 2 diabetes and in rodent models of the disease, including ob/ob and high fat-fed mice. Sorcin (gene name SRI) is a calcium (Ca2+) binding protein involved in maintaining ER Ca2+ homeostasis.We have previously shown that overexpressing sorcin under the rat insulin promoter in transgenic mice was protective against high fat diet-induced pancreatic beta cell dysfunction, namely preserving intracellular Ca2+ homeostasis and glucose-stimulated insulin secretion during lipotoxic stress. Additionally, sorcin overexpression was apparently activating ATF6 signalling in MIN6 cells despite lowering ER stress.Here, in order to investigate further the relationship between sorcin and ATF6, we describe changes in sorcin expression during ER and lipotoxic stress and changes in ATF6 signalling after sorcin overexpression or inactivation, both in excitable and non-excitable cells.Sorcin mRNA levels were significantly increased in response to the ER stress-inducing agents thapsigargin and tunicamycin, but not by palmitate. On the contrary, palmitate caused a significant decrease in sorcin expression as assessed by both qRT-PCR and Western blotting despite inducing ER stress. Moreover, palmitate prevented the increase in sorcin expression induced by thapsigargin. In addition, sorcin overexpression significantly increased ATF6 transcriptional activity, whereas sorcin inactivation decreased ATF6 signalling. Finally, sorcin overexpression increased levels of ATF6 immunoreactivity and FRET imaging experiments following ER stress induction by thapsigargin showed a direct sorcin-ATF6 interaction.Altogether, our data suggest that sorcin down-regulation during lipotoxicity may prevent full ATF6 activation and a normal UPR during the progression of obesity and insulin resistance, contributing to beta cell failure and type 2 diabetes.

scholarly journals Time-of-Day-Dependent Effects of Bromocriptine to Ameliorate Vascular Pathology and Metabolic Syndrome in SHR Rats Held on High Fat Diet

2021 ◽  
Vol 22 (11) ◽  
pp. 6142
Author(s):  
Michael Ezrokhi ◽  
Yahong Zhang ◽  
Shuqin Luo ◽  
Anthony H. Cincotta
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
High Fat Diet ◽  
Nitrosative Stress ◽  
Time Of Day ◽  
Vascular Pathology ◽  
Mrna Levels ◽  
High Fat ◽  
Nadph Oxidase 4

The treatment of type 2 diabetes patients with bromocriptine-QR, a unique, quick release micronized formulation of bromocriptine, improves glycemic control and reduces adverse cardiovascular events. While the improvement of glycemic control is largely the result of improved postprandial hepatic glucose metabolism and insulin action, the mechanisms underlying the drug’s cardioprotective effects are less well defined. Bromocriptine is a sympatholytic dopamine agonist and reduces the elevated sympathetic tone, characteristic of metabolic syndrome and type 2 diabetes, which potentiates elevations of vascular oxidative/nitrosative stress, known to precipitate cardiovascular disease. Therefore, this study investigated the impact of bromocriptine treatment upon biomarkers of vascular oxidative/nitrosative stress (including the pro-oxidative/nitrosative stress enzymes of NADPH oxidase 4, inducible nitric oxide (iNOS), uncoupled endothelial nitric oxide synthase (eNOS), the pro-inflammatory/pro-oxidative marker GTP cyclohydrolase 1 (GTPCH 1), and the pro-vascular health enzyme, soluble guanylate cyclase (sGC) as well as the plasma level of thiobarbituric acid reactive substances (TBARS), a circulating marker of systemic oxidative stress), in hypertensive SHR rats held on a high fat diet to induce metabolic syndrome. Inasmuch as the central nervous system (CNS) dopaminergic activities both regulate and are regulated by CNS circadian pacemaker circuitry, this study also investigated the time-of-day-dependent effects of bromocriptine treatment (10 mg/kg/day at either 13 or 19 h after the onset of light (at the natural waking time or late during the activity period, respectively) among animals held on 14 h daily photoperiods for 16 days upon such vascular biomarkers of vascular redox state, several metabolic syndrome parameters, and mediobasal hypothalamic (MBH) mRNA expression levels of neuropeptides neuropeptide Y (NPY) and agouti-related protein (AgRP) which regulate the peripheral fuel metabolism and of mRNA expression of other MBH glial and neuronal cell genes that support such metabolism regulating neurons in this model system. Such bromocriptine treatment at ZT 13 improved (reduced) biomarkers of vascular oxidative/nitrosative stress including plasma TBARS level, aortic NADPH oxidase 4, iNOS and GTPCH 1 levels, and improved other markers of coupled eNOS function, including increased sGC protein level, relative to controls. However, bromocriptine treatment at ZT 19 produced no improvement in either coupled eNOS function or sGC protein level. Moreover, such ZT 13 bromocriptine treatment reduced several metabolic syndrome parameters including fasting insulin and leptin levels, as well as elevated systolic and diastolic blood pressure, insulin resistance, body fat store levels and liver fat content, however, such effects of ZT 19 bromocriptine treatment were largely absent versus control. Finally, ZT 13 bromocriptine treatment reduced MBH NPY and AgRP mRNA levels and mRNA levels of several MBH glial cell/neuronal genes that code for neuronal support/plasticity proteins (suggesting a shift in neuronal structure/function to a new metabolic control state) while ZT 19 treatment reduced only AgRP, not NPY, and was with very little effect on such MBH glial cell genes expression. These findings indicate that circadian-timed bromocriptine administration at the natural circadian peak of CNS dopaminergic activity (that is diminished in insulin resistant states), but not outside this daily time window when such CNS dopaminergic activity is naturally low, produces widespread improvements in biomarkers of vascular oxidative stress that are associated with the amelioration of metabolic syndrome and reductions in MBH neuropeptides and gene expressions known to facilitate metabolic syndrome. These results of such circadian-timed bromocriptine treatment upon vascular pathology provide potential mechanisms for the observed marked reductions in adverse cardiovascular events with circadian-timed bromocriptine-QR therapy (similarly timed to the onset of daily waking as in this study) of type 2 diabetes subjects and warrant further investigations into related mechanisms and the potential application of such intervention to prediabetes and metabolic syndrome patients as well.

scholarly journals A Common Functional Regulatory Variant at a Type 2 Diabetes Locus Upregulates ARAP1 Expression in the Pancreatic Beta Cell

2014 ◽  
Vol 94 (2) ◽  
pp. 186-197 ◽  
Author(s):  
Jennifer R. Kulzer ◽  
Michael L. Stitzel ◽  
Mario A. Morken ◽  
Jeroen R. Huyghe ◽  
Christian Fuchsberger ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
Regulatory Variant

scholarly journals A role for pancreatic beta-cell secretory hyperresponsiveness in catch-up growth hyperinsulinemia: Relevance to thrifty catch-up fat phenotype and risks for type 2 diabetes

2011 ◽  
Vol 8 (1) ◽  
pp. 2 ◽  
Author(s):  
Marina Casimir ◽  
Paula B de Andrade ◽  
Asllan Gjinovci ◽  
Jean-Pierre Montani ◽  
Pierre Maechler ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
Catch Up

scholarly journals Transcription factor 7-like 2 (TCF7L2): a culprit gene in Type 2 Diabetes Mellitus

2021 ◽  
Vol 24 (4) ◽  
pp. 371-376
Author(s):  
A. Jan ◽  
H. Jan ◽  
Z. Ullah
Keyword(s):  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Insulin Secretion ◽  
Blood Glucose ◽  
Pancreatic Beta Cell ◽  
Genetic Research ◽  
Wnt Signaling Pathway ◽  
Diabetes Type 2 ◽  
Ethnic Population

The genetics of Type 2 diabetes a complex metabolic disorder, characterized by decreased insulin secretion and insulin resistance resulting in impaired blood glucose homeostasis remains enigma for geneticists. In 2006 an important step while finding genetic causes of diabetes type 2 was identification of transcription factor 7-like 2 (TCF7L2) gene an important marker in predisposition of type 2 diabetes in almost all ethnic population. Recent genetic research identifies numerous novel type 2 diabetes susceptible genes among these genes TCF7L2 is considered as gang head and emerged as the most promising types 2 diabetes causing gene. Risk variants in TCF7L2 effects pancreatic beta cell development and insulin secretion by influencing Wnt Signaling pathway. Genetic variants in TCF7L2 confer risk for type 2 diabetes by altering expression of transcription factor (which has key role in blood glucose regulation) in pancreas. The purpose of this paper is to evaluate type 2 diabetes susceptible gene the TCF7L2 and to present a comprehensive review of studies carried out worldwide in different ethnic population on association of TCF7L2 polymorphism with type 2 diabetes.

scholarly journals THE ROLE OF SURVIVIN AND RAF-1 KINASE AGAINST ENHANCEMENT OF PANCREATIC BETA-CELL APOPTOSIS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

2018 ◽  
Vol 11 (11) ◽  
pp. 344
Author(s):  
Eva Decroli ◽  
Asman Manaf ◽  
Syafril Syahbuddin ◽  
Sarwono Waspadji ◽  
Dwisari Dillasamola
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Beta Cell ◽  
Cell Apoptosis ◽  
Pancreatic Beta Cell ◽  
Enzyme Linked Immunosorbent Assay ◽  
Beta Cell Apoptosis

Objective: This study aimed to reveal differences in levels of survivin and Raf-1 kinase in prediabetes, controlled Type 2 diabetes mellitus (T2DM), uncontrolled T2DM, and their relationship with hemoglobin A1c (HbA1c) levels and serum triglyceride levels.Methods: This study was an observational study with a cross-sectional design. The study involved 60 people with T2DM who visited the endocrine and metabolic clinic and 30 prediabetes patients. The variables were survivin levels and Raf-1 kinase enzymes that examined using enzyme-linked immunosorbent assay techniques. HbA1c values are measured by high-performance liquid chromatography and triglyceride levels measured by enzymatic method.Results: Average levels of Raf-1 kinase were significantly higher in the prediabetes group, controlled T2DM, and uncontrolled T2DM (11.6±1.4 pg mL, 9.9±1.1 pg/mL, and 9.1±1.5 pg/mL). Survivin was significantly higher in the prediabetes group, controlled T2DM, and uncontrolled T2DM (5.4±0.4 pg mL, 5.0±0.2 pg/mL, and 4.7±0.1 pg/mL). There was no correlation between HbA1c with Raf-1 kinase levels (R=−0.215, p=0.250), but there was a correlation between HbA1c with serum survivin levels (R=−0.6, *p<0.05). There was a correlation between the levels of triglycerides with survivin but not with Raf-1 kinase (R=−0.267, *p=0.039).Conclusion: Survivin and Raf-1 kinase levels are lower in uncontrolled T2DM. This explained the role of survivin and Raf-1 kinase against enhancement of pancreatic beta-cell apoptosis in patients with T2DM.

Modulation of palmitate-induced endoplasmic reticulum stress and apoptosis in pancreatic β-cells by stearoyl-CoA desaturase and Elovl6

2011 ◽  
Vol 300 (4) ◽  
pp. E640-E649 ◽  
Author(s):  
Christopher D. Green ◽  
L. Karl Olson
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Neutral Lipids ◽  
Saturated Fatty Acids ◽  
Mrna Levels ◽  
Β Cells ◽  
Fatty Acid Elongase ◽  
Stearoyl Coa Desaturase

Induction of endoplasmic reticulum (ER) stress and apoptosis by elevated exogenous saturated fatty acids (FAs) plays a role in the pathogenesis of β-cell dysfunction and loss of islet mass in type 2 diabetes. Regulation of monounsaturated FA (MUFA) synthesis through FA desaturases and elongases may alter the susceptibility of β-cells to saturated FA-induced ER stress and apoptosis. Herein, stearoyl-CoA desaturase (SCD)1 and SCD2 mRNA expression were shown to be induced in islets from prediabetic hyperinsulinemic Zucker diabetic fatty (ZDF) rats, whereas SCD1, SCD2, and fatty acid elongase 6 (Elovl6) mRNA levels were markedly reduced in diabetic ZDF rat islets. Knockdown of SCD in INS-1 β-cells decreased desaturation of palmitate to MUFA, lowered FA partitioning into complex neutral lipids, and increased palmitate-induced ER stress and apoptosis. Overexpression of SCD2 increased desaturation of palmitate to MUFA and attenuated palmitate-induced ER stress and apoptosis. Knockdown of Elovl6 limited palmitate elongation to stearate, increasing palmitoleate production and attenuating palmitate-induced ER stress and apoptosis, whereas overexpression of Elovl6 increased palmitate elongation to stearate and palmitate-induced ER stress and apoptosis. Overall, these data support the hypothesis that enhanced MUFA synthesis via upregulation of SCD2 activity can protect β-cells from elevated saturated FAs, as occurs in prediabetic states. Overt type 2 diabetes is associated with diminished islet expression of SCD and Elovl6, and this can disrupt desaturation of saturated FAs to MUFAs, rendering β-cells more susceptible to saturated FA-induced ER stress and apoptosis.

scholarly journals Autophagy and the pancreatic beta-cell in human type 2 diabetes

Autophagy ◽  
2009 ◽  
Vol 5 (7) ◽  
pp. 1055-1056 ◽  
Author(s):  
Piero Marchetti ◽  
Matilde Masini
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
Human Type
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