Glucagon-like peptide 1 receptor agonist ameliorates the insulin resistance function of islet β cells via the activation of PDX-1/JAK signaling transduction in C57/BL6 mice with high-fat diet-induced diabetes

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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Brain Glucagon-Like Peptide 1 Signaling Controls the Onset of High-Fat Diet-Induced Insulin Resistance and Reduces Energy Expenditure

Endocrinology ◽

10.1210/en.2008-0180 ◽

2008 ◽

Vol 149 (10) ◽

pp. 4768-4777 ◽

Cited By ~ 68

Author(s):

Claude Knauf ◽

Patrice D. Cani ◽

Afifa Ait-Belgnaoui ◽

Alexandre Benani ◽

Cédric Dray ◽

...

Keyword(s):

Insulin Resistance ◽

Energy Expenditure ◽

High Fat Diet ◽

Body Weight Gain ◽

Carbon Dioxide Production ◽

High Fat ◽

Ambulatory Activity ◽

Ucp2 Expression ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is a peptide released by the intestine and the brain. We previously demonstrated that brain GLP-1 increases glucose-dependent hyperinsulinemia and insulin resistance. These two features are major characteristics of the onset of type 2 diabetes. Therefore, we investigated whether blocking brain GLP-1 signaling would prevent high-fat diet (HFD)-induced diabetes in the mouse. Our data show that a 1-month chronic blockage of brain GLP-1 signaling by exendin-9 (Ex9), totally prevented hyperinsulinemia and insulin resistance in HFD mice. Furthermore, food intake was dramatically increased, but body weight gain was unchanged, showing that brain GLP-1 controlled energy expenditure. Thermogenesis, glucose utilization, oxygen consumption, carbon dioxide production, muscle glycolytic respiratory index, UCP2 expression in muscle, and basal ambulatory activity were all increased by the exendin-9 treatment. Thus, we have demonstrated that in response to a HFD, brain GLP-1 signaling induces hyperinsulinemia and insulin resistance and decreases energy expenditure by reducing metabolic thermogenesis and ambulatory activity.

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Glucagon-like peptide-1 analog prevents obesity-related glomerulopathy by inhibiting excessive autophagy in podocytes

AJP Renal Physiology ◽

10.1152/ajprenal.00302.2017 ◽

2018 ◽

Vol 314 (2) ◽

pp. F181-F189 ◽

Cited By ~ 11

Author(s):

Honglei Guo ◽

Bin Wang ◽

Hongmei Li ◽

Lilu Ling ◽

Jianying Niu ◽

...

Keyword(s):

Insulin Resistance ◽

Plasma Membrane ◽

High Fat Diet ◽

Glucose Transporter ◽

Periodic Acid ◽

Fasting Blood Glucose ◽

High Fat ◽

Periodic Acid Schiff ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

To investigate the role of glucagon-like peptide-1 analog (GLP-1) in high-fat diet-induced obesity-related glomerulopathy (ORG). Male C57BL/6 mice fed a high-fat diet for 12 wk were treated with GLP-1 (200 μg/kg) or 0.9% saline for 4 wk. Fasting blood glucose and insulin and the expression of podocin, nephrin, phosphoinositide 3-kinase (PI3K), glucose transporter type (Glut4), and microtubule-associated protein 1A/1B-light chain 3 (LC3) were assayed. Glomerular morphology and podocyte foot structure were evaluated by periodic acid-Schiff staining and electron microscopy. Podocytes were treated with 150 nM GLP-1 and incubated with 400 μM palmitic acid (PA) for 12 h. The effect on autophagy was assessed by podocyte-specific Glut4 siRNA. Insulin resistance and autophagy were assayed by immunofluorescence and Western blotting. The high-fat diet resulted in weight gain, ectopic glomerular lipid accumulation, increased insulin resistance, and fusion of podophyte foot processes. The decreased translocation of Glut4 to the plasma membrane and excess autophagy seen in mice fed a high-fat diet and in PA-treated cultured podocytes were attenuated by GLP-1. Podocyte-specific Glut4 siRNA promoted autophagy, and rapamycin-enhanced autophagy worsened the podocyte injury caused by PA. Excess autophagy in podocytes was induced by inhibition of Glut4 translocation to the plasma membrane and was involved in the pathology of ORG. GLP-1 restored insulin sensitivity and ameliorated renal injury by decreasing the level of autophagy.

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