Dapagliflozin not only improves hepatic injury and pancreatic endoplasmic reticulum stress, but also induces hepatic gluconeogenic enzymes expression in obese rats

2019 ◽  
Vol 133 (23) ◽  
pp. 2415-2430 ◽  
Author(s):  
Myat Theingi Swe ◽  
Laongdao Thongnak ◽  
Krit Jaikumkao ◽  
Anchalee Pongchaidecha ◽  
Varanuj Chatsudthipong ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Er Stress ◽  
Plasma Glucose ◽  
Fasting Plasma Glucose ◽  
High Fat Diet ◽  
Plasma Glucose Level ◽  
Hepatic Injury ◽  
High Fat ◽  
Gluconeogenic Enzymes ◽  
Obese Rats

Abstract Background: With an increasing prevalence of obesity and metabolic syndrome, exploring the effects and delineating the mechanisms of possible therapeutic agents are of critical importance. We examined the effects of SGLT2 inhibitor-dapagliflozin on insulin resistance, hepatic gluconeogenesis, hepatic injury and pancreatic ER stress in high-fat diet-induced obese rats. Materials and methods: Male Wistar rats were fed with normal diet (ND) or high-fat diet for 16 weeks. Then high-fat rats were given vehicle (HF) or dapagliflozin (1 mg/kg/day; HFDapa) or metformin (30 mg/kg/day; HFMet) for another 4 weeks. Results: We found that dapagliflozin ameliorated high-fat diet-induced insulin resistance. The fasting plasma glucose level was comparable among groups, although dapagliflozin treatment led to substantial glycosuria. Hepatic gluconeogenic enzymes, PEPCK, G6Pase and FBPase, expression was not different in HF rats compared with ND rats. Meanwhile, dapagliflozin-treated group exhibited the elevation of these enzymes in parallel with the rise of transcription factor CREB, co-factor PGC1α and upstream regulator SIRT1. Hepatic oxidative stress, inflammation and NAFLD activity score as well as hepatic and pancreatic ER stress and apoptosis in obese rats were attenuated by dapagliflozin. Conclusion: We conclude that dapagliflozin improved obesity-related insulin resistance, hepatic and pancreatic injury independent of fasting plasma glucose level. Of note, dapagliflozin-induced glycosuria apparently triggered the up-regulation of hepatic gluconeogenic enzymes to prevent hypoglycemia.

scholarly journals 12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response

2012 ◽  
Vol 302 (6) ◽  
pp. E654-E665 ◽  
Author(s):  
Banumathi K. Cole ◽  
Norine S. Kuhn ◽  
Shamina M. Green-Mitchell ◽  
Kendall A. Leone ◽  
Rebekah M. Raab ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Pancreatic Islets ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Stress Markers ◽  
Deficient Mice

Central obesity is associated with chronic inflammation, insulin resistance, β-cell dysfunction, and endoplasmic reticulum (ER) stress. The 12/15-lipoxygenase enzyme (12/15-LO) promotes inflammation and insulin resistance in adipose and peripheral tissues. Given that obesity is associated with ER stress and 12/15-LO is expressed in adipose tissue, we determined whether 12/15-LO could mediate ER stress signals. Addition of 12/15-LO lipid products 12(S)-HETE and 12(S)-HPETE to differentiated 3T3-L1 adipocytes induced expression and activation of ER stress markers, including BiP, XBP-1, p-PERK, and p-IRE1α. The ER stress inducer, tunicamycin, upregulated ER stress markers in adipocytes with concomitant 12/15-LO activation. Addition of a 12/15-LO inhibitor, CDC, to tunicamycin-treated adipocytes attenuated the ER stress response. Furthermore, 12/15-LO-deficient adipocytes exhibited significantly decreased tunicamycin-induced ER stress. 12/15-LO action involves upregulation of interleukin-12 (IL-12) expression. Tunicamycin significantly upregulated IL-12p40 expression in adipocytes, and IL-12 addition increased ER stress gene expression; conversely, LSF, an IL-12 signaling inhibitor, and an IL-12p40-neutralizing antibody attenuated tunicamycin-induced ER stress. Isolated adipocytes and liver from 12/15-LO-deficient mice fed a high-fat diet revealed a decrease in spliced XBP-1 expression compared with wild-type C57BL/6 mice on a high-fat diet. Furthermore, pancreatic islets from 12/15-LO-deficient mice showed reduced high-fat diet-induced ER stress genes compared with wild-type mice. These data suggest that 12/15-LO activity participates in ER stress in adipocytes, pancreatic islets, and liver. Therefore, reduction of 12/15-LO activity or expression could provide a new therapeutic target to reduce ER stress and downstream inflammation linked to obesity.

Abstract 686: Intervention with Naringenin Enhances Weight Loss, Potentiates Improvements in Metabolic Dysregulation and Halts Progression of Atherosclerosis Induced by a High-Fat Diet in LDLr-/- Mice.

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Amy C Burke ◽  
Brian G Sutherland ◽  
Julia M Assini ◽  
Murray W Huff
Keyword(s):  
Insulin Resistance ◽  
Weight Loss ◽  
Plasma Glucose ◽  
High Fat Diet ◽  
Lesion Size ◽  
Chow Diet ◽  
High Fat ◽  
Metabolic Dysregulation ◽  
The Metabolic Syndrome ◽  
Progression Of Atherosclerosis

Previous studies demonstrate that the addition of naringenin, a grapefruit flavonoid, to a high-fat diet prevents the development of many disorders of the metabolic syndrome and atherosclerosis in Ldlr-/- mice. Furthermore, in intervention studies, the addition of naringenin to a high-fat, high cholesterol (HFHC) diet reversed pre-established obesity, hyperlipidemia, hepatic steatosis, insulin resistance and improved atherosclerotic lesion pathology, but not lesion size. In the present intervention study, we tested the hypothesis that addition of naringenin to a chow diet would further improve pre-established metabolic dysregulation and attenuate lesion development, compared to chow alone. Ldlr-/- mice were fed a HFHC diet for 12 weeks to induce metabolic dysregulation. Subsequently, mice received one of 3 diets for another 12 weeks: 1) continuation of the HFHC diet, 2) an isoflavone-free chow diet or 3) isoflavone-free chow with 3% naringenin. At 12 weeks, the HFHC diet induced significant weight gain and increased adiposity. Intervention with chow alone reduced the weight gained during induction by 22%, whereas the addition of naringenin to chow induced a weight loss of 71%. Specifically, the reduction in adiposity was 2.75-times greater in naringenin-treated mice, compared to chow alone. The HFHC diet increased VLDL cholesterol 20-fold and LDL cholesterol 5-fold, which were reduced by intervention with both chow (>60%) and chow supplemented with naringenin (>80%). The HFHC diet induced insulin resistance and glucose intolerance. Naringenin improved insulin tolerance (plasma glucose AUC -38%) and glucose tolerance (plasma glucose AUC -58%), which was accompanied by normalization of plasma insulin and glucose. HFHC-induction promoted the development of intermediate atherosclerotic lesions. Continuation of the HFHC diet doubled lesion size. Intervention with chow alone attenuated lesion size progression by 65%. The addition of naringenin to chow slowed lesion progression by 90%, resulting in smaller lesions compared to chow intervention alone (P=0.042). We conclude that intervention with naringenin-supplemented chow enhances weight loss, improves metabolic dysregulation and halts the progression of atherosclerosis.

scholarly journals Effect of resveratrol on diabetic neuropathy in wistar albino rats

2019 ◽  
Vol 9 (1) ◽  
pp. 16
Author(s):  
Smita Das ◽  
Jayanti Prava Behera ◽  
Y. Rojaramani ◽  
Rashmi Ranjan Mohanty
Keyword(s):  
Diabetic Neuropathy ◽  
Lipid Profile ◽  
Plasma Glucose ◽  
Fasting Plasma Glucose ◽  
High Fat Diet ◽  
Albino Rats ◽  
High Fat ◽  
Multiple Comparison Test ◽  
Wistar Albino Rats

Background: Type 2 diabetes mellitus (DM) is a common chronic disease with increasing prevalence worldwide. Prolonged uncontrolled hyperglycemia, dyslipidemia are major risk factor for its complication like neuropathy. Since there is no definite treatment for diabetic neuropathy, this study aims to evaluate the effect of resveratrol on diabetic neuropathy in high fat diet with low dose streptozotocin induced type-2 DM model in wistar albino rats.Methods: First type 2 diabetic rat model was established. Wistar albino rats, fed with high-fat diet (HFD) rendered diabetic with streptozotocin, were divided into 6 groups, disease control (DC) treated with vehicle, standard control (SC) which received metformin, test groups treated with 5, 10, and 20 mg/kg b.w. of resveratrol and combination of half dose of metformin and resveratrol (10 mg/kg) (TC). A group of six normal animals served as normal control (NC), another six as HFD control. Fasting plasma glucose, lipid profile were measured one week after induction of diabetes. The animals were then treated orally for 2 weeks after which the same parameters were repeated. Behavioral biomarkers for neuropathy are measured in 4 weeks and 6 weeks of treatment. The in-vivo results were analyzed by one way ANOVA followed by Tukey’s multiple comparison test for biochemical parameters and Kruskal Wallis test followed by Dun’s multiple comparison test for behavioral biomarkers.Results: Increase in fasting plasma glucose (FPG), deranged lipid profile, increased neuropathy in DC compared to NC, HFD control while a significant decrease in FBG, improved pain behavior with SC, test groups (p<0.05) as compared to the DC group.Conclusions: Resveratrol prevents diabetic neuropathy.

Loss of ARC worsens high fat diet-induced hyperglycemia in mice

2021 ◽  
Author(s):  
Andrew T Templin ◽  
Christine Schmidt ◽  
Meghan F Hogan ◽  
Nathalie Esser ◽  
Richard N Kitsis ◽  
...  
Keyword(s):  
Cell Death ◽  
Body Weight ◽  
Plasma Glucose ◽  
Fasting Plasma Glucose ◽  
High Fat Diet ◽  
Metabolic Adaptation ◽  
High Fat ◽  
Β Cell ◽  
Fasting Plasma

Apoptosis repressor with caspase recruitment domain (ARC) is an endogenous inhibitor of cell death signaling that is expressed in insulin-producing β-cells. ARC has been shown to reduce β-cell death in response to diabetogenic stimuli in vitro, but its role in maintaining glucose homeostasis in vivo has not been fully established. Here we examined whether loss of ARC in FVB background mice exacerbates high fat diet (HFD)-induced hyperglycemia in vivo over 24 weeks. Prior to commencing 24-week HFD, ARC-/- mice had lower body weight than wild type (WT) mice. This body weight difference was maintained until the end of the study and was associated with decreased epididymal and inguinal adipose tissue mass in ARC-/- mice. Non-fasting plasma glucose was not different between ARC-/- and WT mice prior to HFD feeding, and ARC-/- mice displayed a greater increase in plasma glucose over the first 4 weeks of HFD. Plasma glucose remained elevated in ARC-/- mice after 16 weeks of HFD feeding, at which time it had returned to baseline in WT mice. Following 24 weeks of HFD, non-fasting plasma glucose in ARC-/- mice returned to baseline and was not different from WT mice. At this final time point, no differences in plasma glucose or insulin were observed under fasted conditions or following IV glucose administration between genotypes. However, HFD-fed ARC-/- mice exhibited significantly decreased β-cell area compared to WT mice. Thus, ARC deficiency delays, but does not prevent, metabolic adaptation to HFD feeding in mice, worsening transient HFD-induced hyperglycemia.

scholarly journals Heat-killed and live Lactobacillus reuteri GMNL-263 exhibit similar effects on improving metabolic functions in high-fat diet-induced obese rats

2016 ◽  
Vol 7 (5) ◽  
pp. 2374-2388 ◽  
Author(s):  
Feng-Ching Hsieh ◽  
Cheng-Che E. Lan ◽  
Tsui-Yin Huang ◽  
Kuan-Wei Chen ◽  
Chee-Yin Chai ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Lactobacillus Reuteri ◽  
High Fat ◽  
Metabolic Functions ◽  
Obese Rats

Our objective was to investigate and compare the effects of heat-killed (HK) and liveLactobacillus reuteriGMNL-263 (Lr263) on insulin resistance and its related complications in high-fat diet (HFD)-induced rats.

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