Hypoglycemic effects and mechanisms of electroacupuncture on insulin resistance

The aim of this study was to investigate effects and mechanisms of electroacupuncture (EA) on blood glucose and insulin sensitivity in mice fed a high-fat diet. Both wild-type (WT) and adipose ectonucleotide pyrophosphate phosphodiesterase (ENPP1) transgenic (TG) mice were fed a high-fat diet for 12 wk; for each mouse, an intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) were performed with or without EA at abdomen or auricular areas. A high-fat diet-induced insulin resistance in both WT and TG mice. In the WT mice, EA at 3 Hz and 15 Hz, but not at 1 Hz or 100 Hz, via CV4+CV12 significantly reduced postprandial glucose levels; EA at 3 Hz was most potent. The glucose level was reduced by 61.7% at 60 min and 74.5% at 120 min with EA at 3 Hz (all P < 0.001 vs. control). Similar hypoglycemic effect was noted in the TG mice. On the contrary, EA at auricular points increased postprandial glucose level ( P < 0.03). 4). EA at 3 Hz via CV4+CV12 significantly enhanced the decrease of blood glucose after insulin injection, suggesting improvement of insulin sensitivity. Plasma free fatty acid was significantly suppressed by 42.5% at 15 min and 50.8% at 30 min with EA ( P < 0.01) in both WT and TG mice. EA improves glucose tolerance in both WT and TG mice fed a high-fat diet, and the effect is associated with stimulation parameters and acupoints and is probably attributed to the reduction of free fatty acid.

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MiR-425-5p Regulates Glucagon-like Peptide-1 Production and Affects Blood Glucose Levels in High-fat Diet-fed Mice

10.21203/rs.3.rs-948391/v1 ◽

2021 ◽

Author(s):

Lirui Wei ◽

Xuenan Zhao ◽

Feng Guo ◽

Fengjiao Huang ◽

Yanyan Zhao ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Protein Level ◽

High Fat Diet ◽

Molecular Mechanisms ◽

Tolerance Test ◽

Control Group ◽

High Fat ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Abstract BackgroundIn modern society, obesity has become a global problem with resulting in metabolic disorders and poses high risk for type 2 diabetes mellitus (T2DM). The glucagon-like peptide-1 (GLP-1) has been taken as an effective drug for the therapy of T2DM and obesity. In the present study, the regulatory roles and molecular mechanisms of miR-425-5p in GLP-1 secretion in high-fat diet (HFD)-induced diabetic mice were explored. MethodsOral glucose tolerance test and insulin tolerance test were performed to assess glucose metabolism and GLP-1 and LPS levels. Quantitative real time polymerase chain reaction (qRT-PCR) was employed to detect the expression of LPS, GLP-1, GLP-1 receptors, miR-425-5p, phosphatase and tensin homology (PTEN), proglucagon, p65 and β-catenin. Western blot was performed to determine the expression of proglucagon, p65, β-catenin and PTEN. ResultsThe results showed that plasma GLP-1 level was negatively correlated with plasma LPS level in HFD-fed mice, and miR-425-5p expression and LPS level were up-regulated in the ileal fluid compared with control groups. LPS injection boosted miR-425-5p expression in ileum. MiR-425-5p ameliorated glucose intolerance and insulin resistance in HFD-fed mice by increasing GLP-1 secretion. Furthermore, p65 protein level in the cytoplasmic and nuclear in the ileum of HFD-fed mice was increased compared with the control group. MiR-425-5p agomir elevated nuclear β-catenin protein level, but reduced PTEN protein level in HFD-fed mice compared with HFD-fed mice treated with the miR-425-5p antagomir. ConclusionsOur results suggest that miR-425-5p promotes GLP-1 secretion and improves glucose tolerance and insulin resistance in high-fat diet-fed mice.

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Adipose Triglyceride Lipase-Null Mice Are Resistant to High-Fat Diet–Induced Insulin Resistance Despite Reduced Energy Expenditure and Ectopic Lipid Accumulation

Endocrinology ◽

10.1210/en.2010-0661 ◽

2011 ◽

Vol 152 (1) ◽

pp. 48-58 ◽

Cited By ~ 74

Author(s):

Andrew J. Hoy ◽

Clinton R. Bruce ◽

Sarah M. Turpin ◽

Alexander J. Morris ◽

Mark A. Febbraio ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Insulin Sensitivity ◽

Energy Expenditure ◽

Glucose Tolerance ◽

Lipid Accumulation ◽

High Fat Diet ◽

Adipose Triglyceride Lipase ◽

Wild Type ◽

High Fat

Abstract Adipose triglyceride lipase (ATGL) null (−/−) mice store vast amounts of triacylglycerol in key glucoregulatory tissues yet exhibit enhanced insulin sensitivity and glucose tolerance. The mechanisms underpinning these divergent observations are unknown but may relate to the reduced availability of circulating fatty acids. The aim of this study was to determine whether the enhancements in insulin stimulated glucose metabolism in ATGL−/− mice persist when challenged with a high-fat diet. ATGL−/− mice fed a low-fat diet exhibit improved whole-body insulin sensitivity and glucose tolerance compared with wild-type mice. Wild-type mice became hyperlipidemic and insulin-resistant when challenged with a high-fat diet (HFD, 60% fat) for 4 wk. ATGL−/− mice fed a HFD had elevated circulating fatty acids but had reduced fasting glycemia compared to pre–high-fat diet levels and were refractory to glucose intolerance and insulin resistance. This protection from high-fat diet–induced metabolic perturbations was associated with a preference for fatty acid utilization but reduced energy expenditure and no change in markers of mitochondrial capacity or density. The protection from high-fat diet–induced insulin resistance in ATGL−/− mice was due to increased cardiac and liver insulin-stimulated glucose clearance despite increased lipid content in these tissues. Additionally, there was no difference in skeletal muscle insulin-stimulated glucose disposal, but there was a reduction observed in brown adipose tissue. Overall, these results show that ATGL−/− mice are protected from HFD-induced insulin resistance and reveal a tissue specific disparity between lipid accumulation and insulin sensitivity.

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Combined deletion of free fatty-acid receptors 1 and 4 minimally impacts glucose homeostasis in mice

10.1101/2020.08.04.236471 ◽

2020 ◽

Cited By ~ 1

Author(s):

Marine L. Croze ◽

Arthur Guillaume ◽

Mélanie Ethier ◽

Grace Fergusson ◽

Caroline Tremblay ◽

...

Keyword(s):

Insulin Secretion ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Free Fatty Acid ◽

Glucose Tolerance ◽

Glucose Homeostasis ◽

Dependent Manner ◽

High Fat ◽

Normal Chow ◽

Free Fatty Acid Receptors

ABSTRACTThe free fatty-acid receptors FFAR1 (GPR40) and FFAR4 (GPR120) are implicated in the regulation of insulin secretion and insulin sensitivity, respectively. Although GPR120 and GPR40 share similar ligands, few studies have addressed possible interactions between these two receptors in the control of glucose homeostasis. Here we generated mice deficient in gpr120 (Gpr120KO) or gpr40 (Gpr40KO), alone or in combination (Gpr120/40KO), and metabolically phenotyped male and female mice fed a normal chow or high-fat diet. We assessed insulin secretion in isolated mouse islets exposed to selective GPR120 and GPR40 agonists singly or in combination. Following normal chow feeding, body weight and energy intake were unaffected by deletion of either receptor, although fat mass increased in Gpr120KO females. Fasting blood glucose levels were mildly increased in Gpr120/40KO mice, and in a sex-dependent manner in Gpr120KO and Gpr40KO animals. Oral glucose tolerance was slightly reduced in male Gpr120/40KO mice and in Gpr120KO females, whereas insulin secretion and insulin sensitivity were unaffected. In hyperglycemic clamps, the glucose infusion rate was lower in male Gpr120/40KO mice but insulin and c-peptide levels were unaffected. No changes in glucose tolerance were observed in either single or double KO animals under high-fat feeding. In isolated islets from wild-type mice, the combination of selective GPR120 and GPR40 agonists additively increased insulin secretion. We conclude that while simultaneous activation of GPR120 and GPR40 enhances insulin secretion ex vivo, combined deletion of these two receptors only minimally affects glucose homeostasis in vivo in mice.

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Abnormalities in myo-inositol metabolism associated with type 2 diabetes in mice fed a high-fat diet: benefits of a dietary myo-inositol supplementation

British Journal Of Nutrition ◽

10.1017/s000711451500121x ◽

2015 ◽

Vol 113 (12) ◽

pp. 1862-1875 ◽

Cited By ~ 27

Author(s):

Marine L. Croze ◽

Alain Géloën ◽

Christophe O. Soulage

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Mouse Model ◽

High Fat Diet ◽

Fatty Acid Synthase ◽

Dietary Intervention ◽

Tolerance Test ◽

High Fat ◽

Fasting Hyperglycaemia ◽

Inositol Metabolism

We previously reported that a chronic supplementation with myo-inositol (MI) improved insulin sensitivity and reduced fat accretion in mice. We then tested the potency of such dietary intervention in the prevention of insulin resistance in C57BL/6 male mouse fed a high-fat diet (HFD). In addition, some abnormalities in inositol metabolism were reported to be associated with insulin resistance in several animal and human studies. We then investigated the presence of such anomalies (i.e. inosituria and an inositol intra-tissue depletion) in this diet-induced obesity (DIO) mouse model, as well as the potential benefit of a MI supplementation for inositol intra-tissue deficiency correction. HFD (60 % energy from fat) feeding was associated with inosituria and inositol intra-tissue depletion in the liver and kidneys. MI supplementation (0·58 mg/g per d) restored inositol pools in kidneys (partially) and liver (fully). HFD feeding for 4 months induced ectopic lipid redistribution to liver and muscles, fasting hyperglycaemia and hyperinsulinaemia, insulin resistance and obesity that were not prevented by MI supplementation, despite a significant improvement in insulin sensitivity parameter Kinsulin tolerance test and a reduction in white adipose tissue (WAT) mass ( − 17 %, P< 0·05). MI supplementation significantly reduced fatty acid synthase activity in epididymal WAT, which might explain its beneficial, but modest, effect on WAT accretion in HFD-fed mice. Finally, we found some abnormalities in inositol metabolism in association with a diabetic phenotype (i.e. insulin resistance and fasting hyperglycaemia) in a DIO mouse model. Dietary MI supplementation was efficient in the prevention of inositol intra-tissue depletion, but did not prevent insulin resistance or obesity efficiently in this mouse model.

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Kun-Dan Decoction Ameliorates Insulin Resistance by Activating AMPK/mTOR-Mediated Autophagy in High-Fat Diet-Fed Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2021.670151 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zuqing Su ◽

Kexue Zeng ◽

Bing Feng ◽

Lipeng Tang ◽

Chaoyue Sun ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Oleic Acid ◽

Insulin Sensitivity ◽

High Fat Diet ◽

Density Lipoprotein ◽

Tolerance Test ◽

Network Pharmacology ◽

High Fat ◽

Interfering Rna

Background: Metabolic syndrome is characterized by central obesity, hyperglycemia and hyperlipidemia. Insulin resistance is the leading risk factor for metabolic syndrome. Kun-Dan decoction (KD), a traditional Chinese medicine, has been applied to treat patients with metabolic syndrome for over ten years. It is increasingly recognized that autophagy deficiency is the key cause of metabolic syndrome. Therefore, we aimed to explore whether KD can activate autophagy to improve metabolic syndrome.Methods: Network pharmacology was used to explore the underlying mechanism of KD in the treatment of metabolic syndrome. The high-fat diet-fed rats and oleic acid-induced LO2 cells were employed in our study. Oral glucose tolerance test and insulin tolerance test, obesity and histological examination, serum cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity in high-fat diet-fed rats were analyzed. Furthermore, the protein expressions of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), phospho-AMPK, mammalian target of rapamycin (mTOR), phospho-mTOR, p62, autophagy related protein (Atg) 5, Atg7, Atg12, Atg13, Atg16L1 and microtubule-associated protein 1A/1B-light chain 3 (LC3)-Ⅱ/Ⅰ were examined in rats and LO2 cells. Moreover, autophagy activator rapamycin and inhibitor 3-methyladenine, and small interfering RNA against Atg7 were utilized to verify the role of autophagy in the treatment of metabolic syndrome by KD in oleic acid-induced LO2 cells.Results: Results from network pharmacology indicated that targeted insulin resistance might be the critical mechanism of KD in the treatment of metabolic syndrome. We found that KD significantly suppressed obesity, serum cholesterol, triglyceride and LDL-C levels and increased serum HDL-C level in high-fat diet-fed rats. Furthermore, KD enhanced insulin sensitivity and attenuated HOMA-IR in high-fat diet-fed rats. Western blot showed that KD could enhance autophagy to increase the insulin sensitivity of high-fat diet-fed rats and oleic acid-induced LO2 cells. Furthermore, 3-methyladenine and small interfering RNA against Atg7 could reverse the protective effect of KD on LO2 cells. However, rapamycin could cooperate with KD to enhance autophagic activation to increase insulin sensitivity in LO2 cells.Conclusion: The induction of autophagy may be the major mechanism for KD to improve insulin resistance and metabolic syndrome.

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Consumption of a Mango Fruit Powder Protects Mice from High-Fat Induced Insulin Resistance and Hepatic Fat Accumulation

Cellular Physiology and Biochemistry ◽

10.1159/000477606 ◽

2017 ◽

Vol 42 (2) ◽

pp. 564-578 ◽

Cited By ~ 7

Author(s):

Agustín G. Sabater ◽

Joan Ribot ◽

Teresa Priego ◽

Itxaso Vazquez ◽

Sonja Frank ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Fatty Acid Oxidation ◽

High Fat Diet ◽

Acid Oxidation ◽

High Fat ◽

Food Ingredient ◽

Mango Fruit ◽

Fruit Powder

Background/Aims: The aim of this study was to gain more insight into the beneficial effects of mango fruit powder on the early metabolic adverse effects of a high-fat diet. Methods: The progressive dose-response effects of mango fruit powder on body composition, circulating parameters, and the expression of genes related to fatty acid oxidation and insulin sensitivity in key tissues were studied in mice fed a moderate (45%) high-fat diet. Results: Findings suggest that mango fruit powder exerts physiological protective effects in the initial steps of insulin resistance and hepatic lipid accumulation induced by a high-fat diet in mice. Moreover, AMPK and SIRT1 appear as key regulators of the observed improvement in fatty acid oxidation capacity, as well as of the improved insulin sensitivity and the increased glucose uptake and metabolism through the glycolytic pathway capacity in liver and skeletal muscle. Conclusion: In summary, this study provides evidence that the functional food ingredient (CarelessTM) from mango fruit prevents early metabolic alterations caused by a high-fat diet in the initial stages of the metabolic syndrome.

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Adipose tissue inflammation contributes to short-term high-fat diet-induced hepatic insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00179.2013 ◽

2013 ◽

Vol 305 (3) ◽

pp. E388-E395 ◽

Cited By ~ 41

Author(s):

Michael S. F. Wiedemann ◽

Stephan Wueest ◽

Flurin Item ◽

Eugen J. Schoenle ◽

Daniel Konrad

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

High Fat Diet ◽

Hepatic Insulin Resistance ◽

Adipose Tissue Inflammation ◽

High Fat ◽

Hepatic Insulin Sensitivity ◽

Tissue Inflammation

High-fat feeding for 3–4 days impairs glucose tolerance and hepatic insulin sensitivity. However, it remains unclear whether the evolving hepatic insulin resistance is due to acute lipid overload or the result of induced adipose tissue inflammation and consequent dysfunctional adipose tissue-liver cross-talk. In the present study, feeding C57Bl6/J mice a fat-enriched diet [high-fat diet (HFD)] for 4 days induced glucose intolerance, hepatic insulin resistance (as assessed by hyperinsulinemic euglycemic clamp studies), and hepatic steatosis as well as adipose tissue inflammation (i.e., TNFα expression) compared with standard chow-fed mice. Adipocyte-specific depletion of the antiapoptotic/anti-inflammatory factor Fas (CD95) attenuated adipose tissue inflammation and improved glucose tolerance as well as hepatic insulin sensitivity without altering the level of hepatic steatosis induced by HFD. In summary, our results identify adipose tissue inflammation and resulting dysfunctional adipose tissue-liver cross-talk as an early event in the development of HFD-induced hepatic insulin resistance.

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Resveratrol reduces the inflammatory response in adipose tissue and improves adipose insulin signaling in high-fat diet-fed mice

PeerJ ◽

10.7717/peerj.5173 ◽

2018 ◽

Vol 6 ◽

pp. e5173 ◽

Cited By ~ 15

Author(s):

Shibin Ding ◽

Jinjin Jiang ◽

Zhe Wang ◽

Guofu Zhang ◽

Jianli Yin ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Inflammatory Response ◽

Glucose Tolerance ◽

Insulin Signaling ◽

High Fat Diet ◽

Density Lipoprotein ◽

High Fat

Background Obesity-induced glucose metabolism disorder is associated with chronic, low-grade, systemic inflammation and is considered a risk factor for diabetes and metabolic syndrome. Resveratrol (RES), a natural anti-inflammatory compound, is observed to improve glucose tolerance and insulin sensitivity in obese rodents and humans. This study aimed to test the effects of RES administration on insulin signaling and the inflammatory response in visceral white adipose tissue (WAT) caused by a high-fat diet (HFD) in mice. Methods A total of 40 wild-type C57BL/6 male mice were divided into four groups (10 in each group): the standard chow diet (STD) group was fed a STD; the HFD group was fed a HFD; and the HFD-RES/L and HFD-RES/H groups were fed a HFD plus RES (200 and 400 mg/kg/day, respectively). The L and H in RES/L and RES/H stand for low and high, respectively. Glucose tolerance, insulin sensitivity, circulating inflammatory biomarkers and lipid profile were determined. Quantitative PCR and Western blot were used to determine the expression of CC-chemokine receptor 2 (CCR2), other inflammation markers, glucose transporter 4 (GLUT4), insulin receptor substrate 1 (IRS-1) and pAkt/Akt and to assess targets of interest involving glucose metabolism and inflammation in visceral WAT. Results HFD increased the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol and proinflammatory cytokines in serum, decreased the high-density lipoprotein cholesterol level in serum, and induced insulin resistance and WAT inflammation in mice. However, RES treatment alleviated insulin resistance, increased the expressions of pAkt, GLUT4 and IRS-1 in WAT, and decreased serum proinflammatory cytokine levels, macrophage infiltration and CCR2 expression in WAT. Conclusion Our results indicated that WAT CCR2 may play a vital role in macrophage infiltration and the inflammatory response during the development of insulin resistance in HFD-induced obesity. These data suggested that administration of RES offers protection against abnormal glucose metabolism and inflammatory adaptations in visceral WAT in mice with HFD-induced obesity.

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Expressing the Human Cholesteryl Ester Transfer Protein Minigene Improves Diet-Induced Fatty Liver and Insulin Resistance in Female Mice

Frontiers in Physiology ◽

10.3389/fphys.2021.799096 ◽

2022 ◽

Vol 12 ◽

Author(s):

Lin Zhu ◽

Julia An ◽

Sivaprakasam Chinnarasu ◽

Thao Luu ◽

Yasminye D. Pettway ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Fatty Liver ◽

High Fat Diet ◽

Target Genes ◽

Metabolic Adaptation ◽

Liver Cholesterol ◽

Wild Type ◽

High Fat

Mounting evidence has shown that CETP has important physiological roles in adapting to chronic nutrient excess, specifically, to protect against diet-induced insulin resistance. However, the underlying mechanisms for the protective roles of CETP in metabolism are not yet clear. Mice naturally lack CETP expression. We used transgenic mice with a human CETP minigene (huCETP) controlled by its natural flanking region to further understand CETP-related physiology in response to obesity. Female huCETP mice and their wild-type littermates were fed a high-fat diet for 6 months. Blood lipid profile and liver lipid metabolism were studied. Insulin sensitivity was analyzed with euglycemic-hyperinsulinemic clamp studies combined with 3H-glucose tracer techniques. While high-fat diet feeding induced obesity for huCETP mice and their wild-type littermates lacking CETP expression, insulin sensitivity was higher for female huCETP mice than for their wild-type littermates. There was no difference in insulin sensitivity for male huCETP mice vs. littermates. The increased insulin sensitivity in females was largely caused by the better insulin-mediated suppression of hepatic glucose production. In huCETP females, CETP in the circulation decreased HDL-cholesterol content and increased liver cholesterol uptake and liver cholesterol and oxysterol contents, which was associated with the upregulation of LXR target genes in long-chain polyunsaturated fatty acid biosynthesis and PPARα target genes in fatty acid β-oxidation in the liver. The upregulated fatty acid β-oxidation may account for the improved fatty liver and liver insulin action in female huCETP mice. This study provides further evidence that CETP has beneficial physiological roles in the metabolic adaptation to nutrient excess by promoting liver fatty acid oxidation and hepatic insulin sensitivity, particularly for females.

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Combined deletion of free fatty-acid receptors 1 and 4 minimally impacts glucose homeostasis in mice

Endocrinology ◽

10.1210/endocr/bqab002 ◽

2021 ◽

Author(s):

Marine L Croze ◽

Arthur Guillaume ◽

Mélanie Ethier ◽

Grace Fergusson ◽

Caroline Tremblay ◽

...

Keyword(s):

Insulin Secretion ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Free Fatty Acid ◽

Glucose Tolerance ◽

Glucose Homeostasis ◽

Dependent Manner ◽

High Fat ◽

Normal Chow ◽

Free Fatty Acid Receptors

Abstract The free fatty-acid receptors FFAR1 (GPR40) and FFAR4 (GPR120) are implicated in the regulation of insulin secretion and insulin sensitivity, respectively. Although GPR120 and GPR40 share similar ligands, few studies have addressed possible interactions between these two receptors in the control of glucose homeostasis. Here we generated mice deficient in gpr120 (Gpr120KO) or gpr40 (Gpr40KO), alone or in combination (Gpr120/40KO), and metabolically phenotyped male and female mice fed a normal chow or high-fat diet. We assessed insulin secretion in isolated mouse islets exposed to selective GPR120 and GPR40 agonists singly or in combination. Following normal chow feeding, body weight and energy intake were unaffected by deletion of either receptor, although fat mass increased in Gpr120KO females. Fasting blood glucose levels were mildly increased in Gpr120/40KO mice, and in a sex-dependent manner in Gpr120KO and Gpr40KO animals. Oral glucose tolerance was slightly reduced in male Gpr120/40KO mice and in Gpr120KO females, whereas insulin secretion and insulin sensitivity were unaffected. In hyperglycemic clamps, the glucose infusion rate was lower in male Gpr120/40KO mice but insulin and c-peptide levels were unaffected. No changes in glucose tolerance were observed in either single or double KO animals under high-fat feeding. In isolated islets from wild-type mice, the combination of selective GPR120 and GPR40 agonists additively increased insulin secretion. We conclude that while simultaneous activation of GPR120 and GPR40 enhances insulin secretion ex vivo, combined deletion of these two receptors only minimally affects glucose homeostasis in vivo in mice.

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