The antianginal ranolazine does not confer beneficial actions against hepatic steatosis in male mice subjected to high-fat diet and streptozotocin induced type 2 diabetes

2021 ◽  
Author(s):  
Christina T Saed ◽  
Amanda A Greenwell ◽  
Seyed Amirhossein Tabatabaei Dakhili ◽  
Keshav Gopal ◽  
Farah Eaton ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Low Fat Diet ◽  
Insulin Tolerance ◽  
Triacylglycerol Content ◽  
Hepatic Triacylglycerol

Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess fat in the liver in the absence of alcohol and increases one’s risk for both diabetes and cardiovascular disease (e.g. angina). We have shown that the second-line anti-anginal therapy, ranolazine, mitigates obesity-induced NAFLD, and our aim was to determine whether these actions of ranolazine also extend to NAFLD associated with type 2 diabetes (T2D). 8-week-old male C57BL/6J mice were fed either a low-fat diet or a high-fat diet for 15-weeks, with a single dose of streptozotocin (STZ; 75 mg/kg) administered in the high-fat diet fed mice at 4-weeks to induce experimental T2D. Mice were treated with either vehicle control or ranolazine during the final 7-weeks (50 mg/kg once daily). We assessed glycemia via monitoring glucose tolerance, insulin tolerance, and pyruvate tolerance, whereas hepatic steatosis was assessed via quantifying triacylglycerol content. We observed that ranolazine did not improve glycemia in mice with experimental T2D, while also having no impact on hepatic triacylglycerol content. Therefore, the salutary actions of ranolazine against NAFLD may be limited to obese individuals but not those who are obese with T2D.

scholarly journals Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels

2020 ◽  
Vol 295 (31) ◽  
pp. 10842-10856 ◽  
Author(s):  
Wen Liu ◽  
Ye Yin ◽  
Meijing Wang ◽  
Ting Fan ◽  
Yuyu Zhu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Low Grade ◽  
High Fat ◽  
Caspase 1

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro. Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.

scholarly journals Lipoic Acid Prevents High-Fat Diet-Induced Hepatic Steatosis in Goto Kakizaki Rats by Reducing Oxidative Stress Through Nrf2 Activation

2018 ◽  
Vol 19 (9) ◽  
pp. 2706 ◽  
Author(s):  
Cristina Sena ◽  
Maria Cipriano ◽  
Maria Botelho ◽  
Raquel Seiça
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Liver Function ◽  
Hepatic Steatosis ◽  
Lipoic Acid ◽  
High Fat Diet ◽  
Control Group ◽  
High Fat ◽  
Tnf Α

Prevention of hepatic fat accumulation may be an important approach for liver diseases due to the increased relevance of hepatic steatosis in this field. This study was conducted to investigate the effects of the antioxidant α-lipoic acid (α-LA) on hepatic steatosis, hepatocellular function, and oxidative stress in a model of type 2 diabetes fed with a high fat diet (HFD). Goto-Kakizaki rats were randomly divided into four groups. The first group received only a standard rat diet (control GK) including groups 2 (HFD), 3 (vehicle group), and 4 (α-LA group), which were given HFD, ad libitum during three months. Wistar rats are the non-diabetic control group. Carbohydrate and lipid metabolism, liver function, plasma and liver tissue malondialdehyde (MDA), liver GSH, tumor necrosis factor-α (TNF-α) and nuclear factor E2 (erythroid-derived 2)-related factor-2 (Nrf2) levels were assessed in the different groups. Liver function was assessed using quantitative hepatobiliary scintigraphy, serum aspartate, and alanine aminotransferases (AST, ALT), alkaline phosphatase, gamma-glutamyltranspeptidase, and bilirubin levels. Histopathologically steatosis and fibrosis were evaluated. Type 2 diabetic animals fed with HFD showed a marked hepatic steatosis and a diminished hepatic extraction fraction and both were fully prevented with α-LA. Plasma and liver tissue MDA and hepatic TNF-α levels were significantly higher in the HFD group when compared with the control group and significantly lower in the α-LA group. Systemic and hepatic cholesterol, triglycerides, and serum uric acid levels were higher in hyperlipidemic GK rats and fully prevented with α-LA. In addition, nuclear Nrf2 activity was significantly diminished in GK rats and significantly augmented after α-LA treatment. In conclusion, α-LA strikingly ameliorates steatosis in this animal model of diabetes fed with HFD by decrementing the inflammatory marker TNF-α and reducing oxidative stress. α-LA might be considered a useful therapeutic tool to prevent hepatic steatosis by incrementing antioxidant defense systems through Nrf2 and consequently decreasing oxidative stress and inflammation in type 2 diabetes.

scholarly journals SAT-293 Osteocalcin and Exercise Improve Mood and Cognition in Female Mice with High-Fat Diet Induced Type 2 Diabetes

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jesse Rentz ◽  
Jordan Winberg ◽  
Walter Swardfager ◽  
Jane Mitchell
Keyword(s):  
Type 2 Diabetes ◽  
High Fat Diet ◽  
Treadmill Running ◽  
Control Group ◽  
High Fat ◽  
Low Fat ◽  
Female Mice ◽  
Low Fat Diet ◽  
Metabolic Conditions

Abstract The skeleton has been characterized as an endocrine organ, demonstrating a capacity to modulate cognition, mood and energy homeostasis (1,2). These endocrine actions of the skeleton have been attributed to the osteoblast-derived peptide osteocalcin. In mice, uncarboxylated osteocalcin (ucOCN) decreased the acquisition of type 2 diabetes mellitus (T2DM) and ameliorated depressive- and anxiety-like behaviours (1,2). Clinically, T2DM patients present with reduced serum osteocalcin levels and approximately 1 in 4 also suffer from co-morbid depression (3,4). The cognitive and metabolic benefits of ucOCN are similar to the beneficial effects of exercise that is recommended in treatment of both depression and T2DM. Here we compared the effects of ucOCN or exercise in female C57-BL/6J mice under two different metabolic conditions. Mice were fed either a high-fat diet (60% calories from fat) to induce T2DM or a control diet (10% calories from fat). Groups of mice were either sedentary or exercised daily by 30 min treadmill running for two months, with or without daily administration of ucOCN (30 ng/g/day). Mice with T2DM displayed depressive behaviours marked by a higher immobile time in tail suspension tests compared to control mice (97±25 n=11 vs 207±9.0 s n=12; t21=4.21, P=0.0004). Exercise and osteocalcin both improved depressive behaviour (137±8 n=12; t22=5.85, P<0.0001 & 127±15 s n=12; t22=4.46, P=0.0002). Anxiety, measured by the elevated-plus maze revealed the mice with T2DM displayed increased anxiety spending less time in the open arms and had a lower ratio of open to closed arm entries than the control group (0.37±0.03 n=10 vs 0.21±0.032 n=11; t19=3.56, P=0.0021). Neither exercise nor osteocalcin improved anxiety in the T2DM mice. The puzzle box test revealed the negative effects of the high-fat diet in problem solving and memory, where the sedentary mice displayed greater latencies to solve each task compared to control mice. Exercised and mice receiving osteocalcin displayed performances comparable to that of the control group. Under normal metabolic conditions (low fat diet), neither osteocalcin nor exercise altered responses in any of the behavioural tests. Together, these results: 1. The effects of osteocalcin on behaviour and cognition are comparable to that of the effects of exercise in female mice with T2DM; 2. Behaviour and cognition did not improve from exercise or osteocalcin in female mice on a low-fat diet. References: (1) Ferron et al., Bone. 2012 Feb;50(2):568–575. (2) Oury et al., Cell. 2013 Sep 26:155(1):228–241. (3) Liu et al., Horm Metab Res. 2015 Oct;47(11):813–9. (4) Khaledi et al., Acta Diabetol. 2019 June;56(6):631–650.

scholarly journals Modulatory Effect of Polyphenolic Compounds from the Mangrove Tree Rhizophora mangle L. on Non-Alcoholic Fatty Liver Disease and Insulin Resistance in High-Fat Diet Obese Mice

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2114 ◽  
Author(s):  
Leonardo de Souza Mesquita ◽  
Cíntia Caria ◽  
Paola Santos ◽  
Caio Ruy ◽  
Natalia da Silva Lima ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Rhizophora Mangle ◽  
Mrna Levels ◽  
Obese Mice ◽  
High Fat ◽  
Mangrove Tree

No scientific report proves the action of the phytochemicals from the mangrove tree Rhizophora mangle in the treatment of diabetes. The aim of this work is to evaluate the effects of the acetonic extract of R. mangle barks (AERM) on type 2 diabetes. The main chemical constituents of the extract were analyzed by high-performance liquid chromatography (HPLC) and flow injection analysis electrospray-iontrap mass spectrometry (FIA-ESI-IT-MS/MS). High-fat diet (HFD)-fed mice were used as model of type 2 diabetes associated with obesity. After 4 weeks of AERM 5 or 50 mg/kg/day orally, glucose homeostasis was evaluated by insulin tolerance test (kiTT). Hepatic steatosis, triglycerides and gene expression were also evaluated. AERM consists of catechin, quercetin and chlorogenic acids derivatives. These metabolites have nutritional importance, obese mice treated with AERM (50 mg/kg) presented improvements in insulin resistance resulting in hepatic steatosis reductions associated with a strong inhibition of hepatic mRNA levels of CD36. The beneficial effects of AERM in an obesity model could be associated with its inhibitory α-amylase activity detected in vitro. Rhizophora mangle partially reverses insulin resistance and hepatic steatosis associated with obesity, supporting previous claims in traditional knowledge.

scholarly journals Type 2 Diabetes Mellitus in Rats on a High-Fat Diet with Streptozotocin Induction: Evaluation of the Model

2018 ◽  
Vol 3 (1) ◽  
pp. 20
Author(s):  
Alexander A. Spasov ◽  
Denis A. Babkov ◽  
Diana R. Prilepskaya ◽  
Olga Yu. Zakharyashcheva
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Total Cholesterol ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
High Fat ◽  
Antidiabetic Agents ◽  
Insulin Tolerance

Introduction: Type 2 diabetes mellitus (T2DM) is a complex heterogeneous disease linked with genetic conditions and lifestyle, especially dietary component. Development of the accessible experimental animal model of T2DM is indispensable for elucidation of its pathogenesis and identification of novel antidiabetic agents. Methods: Modeling of experimental T2DM were performed on male Wistar rats aged 9-12 weeks with 2 weeks of dietary manipulation (58% of calories from fats) followed with 35 mg·kg-1 i.p. streptozotocin injection. To evaluate the model, we used intraperitoneal glucose and insulin tolerance test and determined fasting blood concentration of glucose, triglycerides, total cholesterol, and insulin. Additional evaluation of the model was performed by administration of pioglitazone (10 mg/kg-1 p.o.) for 7 days. Student’s t-test was used for single variable comparison between two groups. One-way ANOVA followed by Dunnett post hoc test was used for multiple comparisons versus the control group. Results: T2DM model obtained reproduced key metabolic disorders of the disease, including hyperglycemia (p<0.05), hyperinsulinemia (p<0.05), dyslipidemia (p<0.05) and impaired glucose and insulin tolerance (p<0.05). Administration of pioglitazone significantly improved these metabolic disorders. Thus, we obtained a suitable rat model of T2DM for screening of antidiabetic agents. Conclusion: In comparison of our results with other authors’ data, we have found decreased severity of plasma glucose and basal total cholesterol levels impairment, which highlights the need for careful monitoring of biochemical parameters in high-fat diet and streptozotocin-treated rats.

723-P: Effect of Low-Carbohydrate High-Fat vs. High-Carbohydrate Low-Fat Diet on HbA1c Control in Chinese Patients with Type 2 Diabetes

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 723-P
Author(s):  
LINGWANG AN ◽  
DANDAN WANG ◽  
XIAORONG SHI ◽  
CHENHUI LIU ◽  
KUEICHUN YEH ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Chinese Patients ◽  
High Fat ◽  
Low Fat ◽  
High Carbohydrate ◽  
Low Fat Diet ◽  
Low Carbohydrate ◽  
Hba1c Control

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.

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