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 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 GABA administration improves liver function and insulin resistance in offspring of type 2 diabetic rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Azadehalsadat Hosseini Dastgerdi ◽  
Mohammadreza Sharifi ◽  
Nepton Soltani
Keyword(s):  
Insulin Resistance ◽  
Lipid Profile ◽  
Liver Lipid ◽  
Liver Glycogen ◽  
Tolerance Test ◽  
Diabetic Control ◽  
Diabetic Rats ◽  
Insulin Tolerance ◽  
Liver Insulin Resistance

AbstractThis study investigated the role of GABA in attenuating liver insulin resistance (IR) in type 2 diabetes parents and reducing its risk in their descendants’ liver. Both sexes’ rats were divided into four groups of non-diabetic control, diabetic control (DC), GABA-treated (GABA), and insulin-treated (Ins). The study duration lasted for six months and the young animals followed for four months. Consequently, hyperinsulinemic-euglycemic clamp was performed for all animals. Apart from insulin tolerance test (ITT), serum and liver lipid profile were measured in all groups. Glycogen levels, expression of Foxo1, Irs2, Akt2, and Pepck genes in the liver were assessed for all groups. Overall, GABA improved ITT, increased liver glycogen levels and decreased lipid profile, blood glucose level, and HbA1c in parents and their offspring in compared to the DC group. GIR also increased in both parents and their offspring by GABA. Moreover, the expression of Foxo1, Irs2, Akt2, and Pepck genes improved in GABA-treated parents and their descendants in compared to DC group. Results indicated that GABA reduced liver IR in both parents and their offspring via affecting their liver insulin signaling and gluconeogenesis pathways.

Abstract P246: Inhibition of Endothelial Senescence Ameliorates Insulin Resistance of Obese Mice

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Masataka Yokoyama ◽  
Tohru Minamino ◽  
Sho Okada ◽  
Kaoru Tateno ◽  
Junji Moriya ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Endothelial Cell ◽  
Glucose Uptake ◽  
Cellular Senescence ◽  
P53 Expression ◽  
Calorie Diet ◽  
High Calorie Diet ◽  
High Calorie

Various stimuli can induce irreversible cell growth arrest, termed cellular senescence. This response is controlled by negative regulators of the cell cycle such as p53. Accumulating evidence suggests a potential relationship between cellular senescence and age-associated diseases including type 2 diabetes. Here we show a crucial role for endothelial p53 in the regulation of insulin resistance. We found that treatment of endothelial cells with high glucose and palmitate synergistically increased p53 expression. Consistent with the in vitro results, endothelial expression of p53 was markedly up-regulated when the mice were fed a high-calorie diet, suggesting that excessive calorie intake promotes endothelial senescence. To investigate the role of endothelial p53 in type 2 diabetes, we analyzed metabolic parameters in endothelial cell-specific p53 conditional knockout (ECp53CKO) mice on a high-calorie diet. In spite of no difference in dietary intake, ECp53CKO mice had a significantly smaller weight and less fat accumulation than control mice. Moreover, ECp53CKO mice showed better insulin sensitivity and glucose tolerance than control littermates. ECp53CKO demonstrated a significant increase in oxygen consumption and had a higher core body temperature compared with control mice. Next we considered some assumed mechanisms of relationship of endothelial cell p53 expression and metabolic disorders. As a result, we found that ECp53CKO mice had higher glucose uptake in skeletal muscles than control. These results indicate that inhibition of endothelial senescence ameliorates insulin resistance by increasing energy consumption via glucose uptake and suggest that endothelial p53 will be a novel therapeutic target for type 2 diabetes.

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.

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.

scholarly journals Eleutheroside E, An Active Component ofEleutherococcus senticosus, Ameliorates Insulin Resistance in Type 2 Diabetic db/db Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Jiyun Ahn ◽  
Min Young Um ◽  
Hyunjung Lee ◽  
Chang Hwa Jung ◽  
Seok Hyun Heo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Uptake ◽  
Serum Insulin ◽  
Principal Component ◽  
C2c12 Myotubes ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Eleutheroside E ◽  
Type 2 Diabetic

Eleutheroside E (EE), a principal component ofEleutherococcus senticosus(ES), has anti-inflammatory and protective effects in ischemia heart. However, it is unknown whether it ameliorates insulin resistance and reduces hyperglycemia in diabetes. This study investigated the effect of EE-containing ES extracts, as well as EE, on hyperglycemia and insulin resistance in db/db mice. EE increased the insulin-provoked glucose uptake in C2C12 myotubes. Moreover, EE improved TNF-α-induced suppression of glucose uptake in 3T3-L1 adipocytes. Five-week-old db/db mice were fed a diet consisting of ES extract or EE for 5 weeks. Both were effective in improving serum lipid profiles and significantly decreased blood glucose and serum insulin levels. ES and EE supplementation effectively attenuated HOMA-IR. Glucose tolerance and insulin tolerance tests showed that EE increased insulin sensitivity. Immunohistochemical staining indicated that ES and EE protected pancreatic alpha and beta cells from diabetic damage. In addition, ES and EE improved hepatic glucose metabolism by upregulating glycolysis and downregulating gluconeogenesis in obese type 2 diabetic mice. These data suggest that EE mediates the hyperglycemic effects of ES by regulating insulin signaling and glucose utilization. The beneficial effects of EE may provide an effective and powerful strategy to alleviate diabetes.

scholarly journals Additive protection by LDR and FGF21 treatment against diabetic nephropathy in type 2 diabetes model

2015 ◽  
Vol 309 (1) ◽  
pp. E45-E54 ◽  
Author(s):  
Minglong Shao ◽  
Lechu Yu ◽  
Fangfang Zhang ◽  
Xuemian Lu ◽  
Xiaokun Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Combination Treatment ◽  
Combined Treatment ◽  
Protective Effects ◽  
Diabetic Mice ◽  
Renal Protection ◽  
Glucose Levels

The onset of diabetic nephropathy (DN) is associated with both systemic and renal changes. Fibroblast growth factor (FGF)-21 prevents diabetic complications mainly by improving systemic metabolism. In addition, low-dose radiation (LDR) protects mice from DN directly by preventing renal oxidative stress and inflammation. In the present study, we tried to define whether the combination of FGF21 and LDR could further prevent DN by blocking its systemic and renal pathogeneses. To this end, type 2 diabetes was induced by feeding a high-fat diet for 12 wk followed by a single dose injection of streptozotocin. Diabetic mice were exposed to 50 mGy LDR every other day for 4 wk with and without 1.5 mg/kg FGF21 daily for 8 wk. The changes in systemic parameters, including blood glucose levels, lipid profiles, and insulin resistance, as well as renal pathology, were examined. Diabetic mice exhibited renal dysfunction and pathological abnormalities, all of which were prevented significantly by LDR and/or FGF21; the best effects were observed in the group that received the combination treatment. Our studies revealed that the additive renal protection conferred by the combined treatment against diabetes-induced renal fibrosis, inflammation, and oxidative damage was associated with the systemic improvement of hyperglycemia, hyperlipidemia, and insulin resistance. These results suggest that the combination treatment with LDR and FGF21 prevented DN more efficiently than did either treatment alone. The mechanism behind these protective effects could be attributed to the suppression of both systemic and renal pathways.

scholarly journals Endothelial-protective effects of a G-protein-biased sphingosine-1 phosphate receptor-1 agonist, SAR247799, in type-2 diabetes rats and a randomized placebo-controlled patient trial.

2020 ◽  
Author(s):  
Luc Bergougnan ◽  
Grit Andersen ◽  
Leona Plum-Moerschel ◽  
Maria Francesca Evaristi ◽  
Bruno Poirier ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
G Protein ◽  
Positive Control ◽  
Diabetic Rats ◽  
Protective Effects ◽  
Protective Properties ◽  
Heart Rate Decrease ◽  
Sphingosine 1 Phosphate ◽  
Mean Differences

SAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1) agonist designed to activate endothelial S1P1 and provide endothelial-protective properties, while limiting S1P1 desensitization and consequent lymphocyte-count reduction associated with higher doses. A dose-response study in diabetic rats with 5-week SAR247799 treatment demonstrated, at sub-lymphocyte-reducing doses, renal function and endothelial biomarker improvements and was used to select doses for human investigation. Type-2 diabetes patients, enriched for endothelial dysfunction (flow-mediated dilation, FMD<7%) (n=54), were randomized, in two sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. The maximum FMD change from baseline versus placebo for all treatments was reached on day 35; mean differences versus placebo were 0.60% (95% CI -0.34%-1.53%; p=0.203) for 1 mg SAR247799, 1.07% (95% CI 0.13%-2.01%; p=0.026) for 5 mg SAR247799 and 0.88% (95% CI -0.15%-1.91%; p=0.093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal-to-no lymphocyte reduction and small-to-moderate heart rate decrease. These data provide the first human evidence for endothelial-protective properties of S1P1 activation, with SAR247799 being at least as effective as the clinical benchmark, sildenafil.

scholarly journals Insulin Resistance Is Associated With Enhanced Brain Glucose Uptake During Euglycemic Hyperinsulinemia: A Large-Scale PET Cohort

2021 ◽  
Author(s):  
Eleni Rebelos ◽  
Marco Bucci ◽  
Tomi Karjalainen ◽  
Vesa Oikonen ◽  
Alessandra Bertoldo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
C Reactive Protein ◽  
Brain Glucose ◽  
Reactive Protein ◽  
Wide Range

<b>Objective</b> Whereas insulin resistance is expressed as reduced glucose uptake in peripheral tissues, the relationship between insulin resistance and brain glucose metabolism remains controversial. Our aim was to examine the association of insulin resistance and brain glucose uptake (BGU) during a euglycemic hyperinsulinemic clamp in a large sample of subjects across a wide range of age and insulin sensitivity. <p><b>Research Design and Methods</b> [<sup>18</sup>F]-fluorodeoxyglucose positron emission tomography (PET) data from 194 subjects scanned under clamp conditions were compiled from a single-center cohort. BGU was quantified by the fractional uptake rate. We examined the association of age, sex, M value from the clamp, steady-state insulin and free fatty acids levels, C-reactive protein, HbA<sub>1c,</sub> and presence of type 2 diabetes with BGU using Bayesian hierarchical modeling. </p> <p><b>Results</b> Insulin sensitivity, indexed by the M value, was associated negatively with BGU in all brain regions, confirming that in insulin resistant subjects BGU is enhanced during euglycemic hyperinsulinemia. In addition, the presence of type 2 diabetes was associated with a further increase in BGU. On the contrary, age was negatively related to BGU. Steady-state insulin levels, C-reactive protein, free fatty acids, sex, and HbA<sub>1c</sub> were not associated with BGU.</p> <p><b>Conclusions </b>In this large cohort of subjects of either sex across a wide range of age and insulin sensitivity,<b> </b>insulin sensitivity is the best predictor of brain glucose uptake. <b></b></p>

scholarly journals Probiotics ameliorate pioglitazone-associated bone loss in diabetic rats

2020 ◽  
Author(s):  
Ahmad Gholami ◽  
Mohammad Hossein Dabbaghmanesh ◽  
Younes Ghasemi ◽  
Pedram Talezadeh ◽  
Farhad Koohpeyma ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Bone Loss ◽  
Lactobacillus Reuteri ◽  
Diabetic Rats ◽  
Urinary Calcium ◽  
Diabetic Patients ◽  
Protective Effects

Abstract Background Pioglitazone as a PPAR-g agonist are used for management of type 2 diabetes mellitus. Nevertheless, evidence showed that the therapeutic modulation of PPARg activity using Pioglitazone may be linked with bone mass reduction and fracture risk in type 2 diabetes mellitus patients. The objective of the current research was to inspect the preventive role of some types of probiotic strains including ( Lactobacillus acidophilus , Lactobacillus reuteri , Lactobacillus casei , Bifidiobacterum longum and Bacillus coagulans ) against pioglitazone-induced bone loss. Methods Streptozotocin (60 mg/kg) was administered for diabetes induction. Diabetic rats were fed orally with pioglitazone (300 mg/kg) and probiotics (1×109 CFU/ml/day) alone and in combination of both for 4 weeks. Dual energy X-ray absorptiometry (DEXA) were used to asses BMD, BMC and area of the femur, spine and tibia at the experiment termination. Serum glucose, serum calcium, alkaline phosphatase, phosphorus, BUN, Creatinine, and urine calcium were also analyzed. Results Administration of pioglitazone and probiotics alone and in combination significantly improved elevated blood glucose. Pioglitazone treatment significantly increased urinary calcium and BUN, and decreased ALP and creatinine. Co-treatment of probiotics with pioglitazone significantly decreased urinary calcium, creatinine and ALP. Pioglitazone showed detrimental effects on femur-BMD whereas treatment with probiotics remarkably ameliorated these effects. Among the tested probiotics Bifidiobacterum longum displayed the best protective effects on pioglitazone-induced bone loss in diabetic rats. Conclusion This study suggests probiotic supplementation in diabetic patients on pioglitazone regime could be considering as a good strategy to ameliorate bone loss induced by pioglitazone.

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