scholarly journals Protective effects of calorie restriction on insulin resistance and islets function in STZ-induced type 2 diabetes rats

2021 ◽  
Author(s):  
Li Zhang ◽  
Ying-juan Huang ◽  
Jia-pan Sun ◽  
Ting-ying Zhang ◽  
Tao-li Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Chow Diet ◽  
Islet Function ◽  
Model Assessment ◽  
Protective Effects ◽  
Sprague Dawley

Abstract Background Caloric restriction (CR) has become increasingly attractive in the treatment of type 2 diabetes mellitus (T2DM) because of the increasingly common high-calorie diet and sedentary lifestyle. This study aimed to evaluate the role of CR in T2DM treatment and further explore its potential molecular mechanisms.Methods Sixty male Sprague-Dawley rats were used in this study. The diabetes model was induced by 8 weeks of high-fat diet (HFD) followed by a single dose of streptozotocin injection (30 mg/kg). Subsequently, the diabetic rats were fed HFD at 28 g/day (diabetic control) or 20 g/day (30% CR regimen) for 20 weeks. Meanwhile, normal rats fed a free standard chow diet served as the vehicle control. Body mass, plasma glucose levels, and lipid profiles were monitored. After diabetes-related functional tests were performed, the rats were sacrificed at 10 and 20 weeks, and glucose uptake in fresh muscle was determined. In addition, western blotting and immunofluorescence were used to detect alterations in AKT/AS160/GLUT4 signaling. Results We found that 30% CR significantly attenuated hyperglycemia and dyslipidemia, leading to alleviation of glucolipotoxicity and thus protection of islet function. Insulin resistance was also markedly ameliorated, as indicated by notably improved insulin tolerance and homeostatic model assessment for insulin resistance (HOMA-IR). However, the improvement in glucose uptake in skeletal muscle was not significant. The upregulation of AKT/AS160/GLUT4 signaling in muscle induced by 30% CR also attenuated gradually over time. Interestingly, the consecutive decrease in AKT/AS160/GLUT4 signaling in white adipose tissue was significantly reversed by 30% CR. Conclusion CR (30%) could protect islet function from hyperglycemia and dyslipidemia, and improve insulin resistance. The mechanism by which these effects occurred is likely related to the upregulation of AKT/AS160/GLUT4 signaling.

scholarly journals Protective effects of calorie restriction on insulin resistance and islets function in STZ-induced type 2 diabetes rats

2020 ◽  
Author(s):  
Li Zhang ◽  
Ying-juan Huang ◽  
Jia-pan Sun ◽  
Ting-ying Zhang ◽  
Tao-li Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Glucose Uptake ◽  
Diabetic Control ◽  
Diabetic Rats ◽  
Chow Diet ◽  
Protective Effects ◽  
Insulin Tolerance ◽  
Calorie Diet

Abstract Background Caloric restriction (CR), as the only approved scientific method that can retard aging, has become more and more attractive in the treatment of type 2 diabetes mellitus (T2DM) due to increasingly common high calorie diet and sedentary lifestyle. This study aimed to evaluate its role in T2DM treatment and further explored the potential molecular mechanism.Methods A total of 60 male SD rats were used in this study. Diabetes model was induced by 8 weeks of high-fat diet (HFD) followed by a single dose of streptozotocin injection (30mg/kg). Subsequently, the diabetic rats were fed ab libitum of 28g/day (diabetic control) or 20g/day (30% CR regimen) with HFD for 20 weeks. Meanwhile, normal rats had free standard chow diet served as vehicle control. Body mass, plasma glucose, and lipid profile were monitored. After diabetes-related functional tests being done, rats were sacrificed at 10 and 20 weeks, and glucose uptake in fresh muscle were determined. Liver and pancreas were prepared for histopathology and histochemical evaluations, and western blotting and immunofluorescence were applied to detect alterations in AKT/AS160/GLUT4 signaling. Results 30% CR significantly attenuated hyperglycemia and dyslipidemia, leading to alleviation of glucolipotoxicity, thus protected islets secretion, retarding the exhaustion of islets function. Insulin resistance was also markedly ameliorated, as indicated by notably improved insulin tolerance and HOMA-IR. However, glucose uptake in skeletal muscle was not significantly improved, and the up-regulation of AKT/AS160/GLUT4 signaling in muscle induced by 30% CR attenuated gradually over time. However, the consecutive decrease in AKT/AS160/GLUT4 signaling in white adipose tissue was significantly reversed by 30% CR. Conclusion 30% CR could protect islets function from hyperglycemia and dyslipidemia, and improve insulin resistance with probable mechanism related to the up-regulation of AKT/AS160/GLUT4 signaling.

scholarly journals Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng

2009 ◽  
Vol 203 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Yun Wang ◽  
Patsy M Nishina ◽  
Jürgen K Naggert
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Insulin Resistant

The TALLYHO/Jng (TH) mouse strain is a polygenic model for type 2 diabetes (T2D) characterized by moderate obesity, impaired glucose tolerance and uptake, insulin resistance, and hyperinsulinemia. The goal of this study was to elucidate the molecular mechanisms responsible for the reduced glucose uptake and insulin resistance in the adipose tissue of this model. The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. IRS1 protein but not mRNA levels was found to be lower in TH mice than controls. Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. Immunohistochemistry showed that IRS1 colocalized with the 20S proteasome in proteasomal structures in TH adipocytes, supporting the notion that IRS1 is actively degraded. Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. Since low-IRS1 levels are often observed in human T2D, the TH mouse is an attractive model to investigate mechanisms of insulin resistance and explore new treatments.

Echinops Spp. Polysaccharide B Ameliorates Metabolic Abnormalities in a Rat Model of Type 2 Diabetes Mellitus

2020 ◽  
Vol 19 (1) ◽  
pp. 106-114
Author(s):  
Guang Hao ◽  
Xiaoyu Ma ◽  
Mengru Jiang ◽  
Zhenzhen Gao ◽  
Ying Yang
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Insulin Receptor ◽  
Skeletal Muscles ◽  
Insulin Receptor Substrate ◽  
Sprague Dawley

This study examined the in vivo effects of Echinops spp. polysaccharide B on type 2 diabetes mellitus in Sprague-Dawley rats. We constructed a type 2 diabetes mellitus Sprague-Dawley rat models by feeding a high-fat and high-sugar diet plus intraperitoneal injection of a small dose of streptozotocin. Using this diabetic rat model, different doses of Echinops polysaccharide B were administered orally for seven weeks. Groups receiving Xiaoke pill and metformin served as positive controls. The results showed that Echinops polysaccharide B treatment normalized the weight and blood sugar levels in the type 2 diabetes mellitus rats, increased muscle and liver glycogen content, improved glucose tolerance, increased insulin secretion, and reduced glucagon and insulin resistance indices. More importantly, Echinops polysaccharide B treatment upregulated the expression of insulin receptor in the liver, skeletal muscles, and pancreas, and significantly improved the expression levels of insulin receptor substrate-2 protein in the liver and pancreas, as well as it increased insulin receptor substrate-1 expression in skeletal muscles. These two proteins play crucial roles in increasing insulin secretion and in controlling type 2 diabetes mellitus. The findings of the present study suggest that Echinops polysaccharide B could improve the status of diabetes in type 2 diabetes mellitus rats, which may be achieved by improving insulin resistance. Our study provides a new insight into the development of a natural drug for the control of type 2 diabetes mellitus.

scholarly journals Modelling ethnic differences in the distribution of insulin resistance via Bayesian nonparametric processes: an application to the SABRE cohort study

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Marco Molinari ◽  
Maria de Iorio ◽  
Nishi Chaturvedi ◽  
Alun Hughes ◽  
Therese Tillin
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mcmc Methods ◽  
Model Assessment ◽  
Bayesian Nonparametric ◽  
Nonparametric Prior ◽  
Posterior Inference ◽  
Regression Framework ◽  
Analyse Data

AbstractWe analyse data from the Southall And Brent REvisited (SABRE) tri-ethnic study, where measurements of metabolic and anthropometric variables have been recorded. In particular, we focus on modelling the distribution of insulin resistance which is strongly associated with the development of type 2 diabetes. We propose the use of a Bayesian nonparametric prior to model the distribution of Homeostasis Model Assessment insulin resistance, as it allows for data-driven clustering of the observations. Anthropometric variables and metabolites concentrations are included as covariates in a regression framework. This strategy highlights the presence of sub-populations in the data, characterised by different levels of risk of developing type 2 diabetes across ethnicities. Posterior inference is performed through Markov Chains Monte Carlo (MCMC) methods.

scholarly journals Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1236
Author(s):  
Jesús Burillo ◽  
Patricia Marqués ◽  
Beatriz Jiménez ◽  
Carlos González-Blanco ◽  
Manuel Benito ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Progressive Disease

Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer’s disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction.

scholarly journals Docking protein 1 and free fatty acids are associated with insulin resistance in patients with type 2 diabetes mellitus

2021 ◽  
Vol 49 (11) ◽  
pp. 030006052110482
Author(s):  
Xiaoqin Ha ◽  
Xiaoling Cai ◽  
Huizhe Cao ◽  
Jie Li ◽  
Bo Yang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Effective Means ◽  
Model Assessment ◽  
High Concentration ◽  
Obesity And Diabetes ◽  
Docking Protein

Objective Insulin resistance (IR) is a key defect in type 2 diabetes mellitus (T2DM); therefore, effective means of ameliorating IR are sought. Methods We performed a retrospective cohort study of 154 patients with T2DM and 39 with pre-diabetes (pre-DM). The effects of IR and a high concentration of FFA on gene expression were determined using microarray analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR) in patients with T2DM or pre-DM. Results Serum FFA concentration and homeostasis model assessment of IR (HOMA-IR) were significantly higher in patients with T2DM but no obesity and in those with pre-DM than in controls. HOMA-IR was significantly associated with T2DM. RT-qPCR showed that the expression of FBJ murine osteosarcoma viral oncogene homolog ( FOS) and AE binding protein 1 ( AEBP1) was much lower in the circulation of participants with obesity and diabetes. RT-qPCR showed that the expression of docking protein 1 ( DOK1) was significantly lower in the blood of participants with diabetes but no obesity and in those with pre-DM than in controls. Conclusions FFA and DOK1 are associated with IR in patients with T2DM but no obesity or pre-DM. The downregulation of DOK1 might inhibit lipid synthesis and induce lipolysis, inducing or worsening IR.

scholarly journals Phenylalanine Impairs Insulin Signaling and Inhibits Glucose Uptake by Modifying IRβ

2021 ◽  
Author(s):  
Qian Zhou ◽  
Wan-Wan Sun ◽  
Jia-Cong Chen ◽  
Huilu Zhang ◽  
Jie Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Trna Synthetase ◽  
Blood Samples ◽  
Receptor Beta

Abstract Although elevated circulating amino acids are associated with the onset of type 2 diabetes (T2D), how amino acids act on cell insulin signaling and glucose uptake remains unclear. Herein, we report that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or overexpressing human phenylalanyl-tRNA synthetase (hFARS) developed insulin resistance and symptoms of T2D. Mechanistically, FARS phenylalanylated lysine 1057/1079 of IRβ (F-K1057/1079) inactivated IRβ and prevented insulin from generating insulin signaling to promote glucose uptake by cells. SIRT1 reversed F-K1057/1079 and counteracted the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels of white cells of T2D patients’ blood samples were positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitized insulin signaling and relieved T2D symptoms in hFARS-transgenic and db/db mice. We revealed mechanisms of how phenylalanylation inactivates insulin signaling that may be employed to control T2D.

scholarly journals Serum and urinary concentrations of calprotectin as markers of insulin resistance and type 2 diabetes

2012 ◽  
Vol 167 (4) ◽  
pp. 569-578 ◽  
Author(s):  
Francisco J Ortega ◽  
Mónica Sabater ◽  
José M Moreno-Navarrete ◽  
Neus Pueyo ◽  
Patricia Botas ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Weight Loss ◽  
Lipid Metabolism ◽  
Inflammatory Markers ◽  
Low Grade ◽  
Model Assessment ◽  
Glucose And Lipid Metabolism ◽  
Obese Subjects

ObjectiveIncreased circulating calprotectin has been reported in obese subjects but not in association with measures of insulin resistance and type 2 diabetes (T2D). The main aim of this study was to determine whether calprotectins in plasma and urine are associated with insulin resistance.DesignWe performed both cross-sectional and longitudinal (diet-induced weight loss) studies.MethodsCirculating calprotectin concentrations (ELISA), other inflammatory markers, homeostasis model assessment of insulin resistance (HOMA-IR), and parameters of glucose and lipid metabolism were evaluated in 298 subjects (185 with normal (NGT) and 62 with impaired (IGT) glucose tolerance and 51 T2D subjects). Calprotectin was also evaluated in urine samples from 71 participants (50 NGT and 21 subjects with IGT). Insulin sensitivity (SI, Minimal Model) was determined in a subset of 156 subjects, and the effects of weight loss were investigated in an independent cohort of obese subjects (n=19).ResultsCirculating calprotectin was significantly increased in IGT–T2D (independently of BMI) and positively associated with HOMA-IR, obesity measures, inflammatory markers, and parameters of glucose and lipid metabolism. Similar findings were reported for calprotectin concentrations in urine. In the subset of subjects, the association of calprotectin withSIwas independent of BMI and age. In fact,SItogether with C-reactive protein contributed to 27.4% of calprotectin variance after controlling for age and blood neutrophils count. Otherwise, weight loss led to decreased circulating calprotectin in parallel to fasting glucose and HOMA-IR.ConclusionThese findings suggest that circulating and urinary concentrations of calprotectin are linked to chronic low-grade inflammation and insulin resistance beyond obesity.

Abstract 209: Dimethylarginine Dimethylaminohydrolase 1 and Insulin Resistance

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Sophie E Piper ◽  
James M Leiper
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Plasma Glucose ◽  
Knockout Mice ◽  
Physiological Role ◽  
Causal Link ◽  
Chow Diet ◽  
Dimethylarginine Dimethylaminohydrolase

Type 2 diabetes is a prevalent metabolic condition and is the result of an impaired response to insulin. Insulin resistance and type 2 diabetes are clearly associated with obesity and the secondary cardiovascular complications of this condition are serious and life threatening. Asymemetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases and increased levels are seen in multiple pathologies. Increased plasma levels of ADMA have been associated with patients with type 2 diabetes, insulin resistance and obesity, although a causal link between ADMA and diabetes has not been established. Dimethylarginine dimethylaminohydrolase (DDAH) is the enzyme that catalyses the metabolism of ADMA. There are two isoforms of the enzyme which are both involved in the control of ADMA and NO. The interplay of insulin with NO release is well established but the initial causes for the onset of insulin resistance are not well defined. Elevated levels of ADMA are linked to insulin resistance and transgenic mice that over-express ddah1 show increased insulin sensitivity. Of note is that metformin, an insulin sensitising drug that is widely used in the treatment of insulin resistance, reduces plasma glucose and ADMA concentrations. In order to elucidate the physiological role of DDAH1 in glucose homeostasis we investigated the glucose handling in a ddah1 global knockout model. Intra-peritoneal glucose tolerance tests in ddah1 global knockout mice demonstrate insulin resistance. Baseline plasma glucose levels were 25% higher in ddah1 knockouts and peak levels were 53% higher in ddah1 knockouts. The kinetics of plasma glucose accumulation and clearance in ddah1 knockout mice suggests dysfunction in both the liver and skeletal muscle. On a normal chow diet, hepatocyte specific ddah1 knockout mice and skeletal muscle specific ddah1 knockout mice show no insulin resistance. On a high fat diet however the hepatocyte specific ddah1 knockout mice show significant insulin resistance and lower metabolic rate than their fat fed wild-type counterparts. These studies demonstrate for the first time a causal link between ADMA accumulation and insulin resistance. Furthermore these data establish DDAH1 activity is a significant regulator of insulin resistance.

Lipid-Induced Insulin Resistance Mechanisms: The Link to Inflammation and Type 2 Diabetes.

2021 ◽  
pp. 1-9
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Molecular Mechanisms ◽  
Laboratory Data ◽  
Phosphatidyl Inositol ◽  
Resistance Mechanisms ◽  
Cellular Mechanisms ◽  
Insulin Resistant

1. Abstract Insulin Resistance is the leading cause of Type 2 diabetes mellitus [T2DM] onset. It occurs as a result of disturbances in lipid metabolism and increased levels of circulating free fatty acids [FFAs]. FFAs accumulate within the insulin sensitive tissues such as muscle, liver and adipose tissues exacerbating different molecular mechanisms. Increased fatty acid flux has been documented to be strongly associated with insulin resistant states and obesity causing inflammation that eventually causes type 2-diabetes development. FFAs appear to cause this defect in glucose transport by inhibiting insulin –stimulated tyrosine phosphorylation of insulin receptor substrate-1 [IRS-1] and IRS-1 associated phosphatidyl-inositol 3-kinase activity. A number of different metabolic abnormalities may increase intramyocellular or intrahepatic fatty acid metabolites that induce insulin resistance through different cellular mechanisms. The current review point out the link between enhanced FFAs flux and activation of PKC and how it impacts on both the insulin signaling in muscle and liver as shown from our laboratory data and highlighting the involvement of the inflammatory pathways importance. This embarks the importance of measuring the inflammatory biomarkers in clinical settings.

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