Exendin-4 improves glucose metabolism in insulin-resistant cells by upregulating the phosphorylative AMPK

AbstractIn this study, we aimed to evaluate the presence of glucose metabolism abnormalities and their impact on IGF-1 levels in patients with acromegaly. Ninety-three patients with acromegaly (n=93; 52 males/41 females) were included in this study. Patients were separated into three groups such as; normal glucose tolerance (n=23, 25%), prediabetes (n=38, 41%), and diabetes mellitus (n=32, 34%). Insulin resistance was calculated with homeostasis model assessment (HOMA). HOMA-IR > 2.5 or ≤2.5 were defined as insulin resistant or noninsulin resistant groups, respectively. Groups were compared in terms of factors that may be associated with glucose metabolism abnormalities. IGF-1% ULN (upper limit of normal)/GH ratios were used to evaluate the impact of glucose metabolism abnormalities on IGF-1 levels. Patients with diabetes mellitus were significantly older with an increased frequency of hypertension (p<0.001, p=0.01, respectively). IGF-1% ULN/GH ratio was significantly lower in prediabetes group than in normal glucose tolerance group (p=0.04). Similarly IGF-1% ULN/GH ratio was significantly lower in insulin resistant group than in noninsulin resistant group (p=0.04). Baseline and suppressed GH levels were significantly higher in insulin resistant group than in noninsulin resistant group (p=0.024, p<0.001, respectively). IGF-1% ULN/GH ratio is a useful marker indicating glucose metabolism disorders and IGF-1 levels might be inappropriately lower in acromegalic patients with insulin resistance or prediabetes. We suggest that IGF-1 levels should be re-evaluated after the improvement of insulin resistance or glycemic regulation for the successful management of patients with acromegaly.

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Effect of IGF-I on FFA and glucose metabolism in control and type 2 diabetic subjects

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00335.2001 ◽

2002 ◽

Vol 282 (6) ◽

pp. E1360-E1368 ◽

Cited By ~ 35

Author(s):

Thongchai Pratipanawatr ◽

Wilailak Pratipanawatr ◽

Clifford Rosen ◽

Rachele Berria ◽

Mandeep Bajaj ◽

...

Keyword(s):

Glucose Metabolism ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Glucose Disposal ◽

Insulin Resistant ◽

Control Subjects ◽

Igf I ◽

Plasma Ffa ◽

Type 2 Diabetic

The effects of insulin-like growth factor I (IGF-I) and insulin on free fatty acid (FFA) and glucose metabolism were compared in eight control and eight type 2 diabetic subjects, who received a two-step euglycemic hyperinsulinemic (0.25 and 0.5 mU · kg−1 · min−1) clamp and a two-step euglycemic IGF-I (26 and 52 pmol · kg−1 · min−1) clamp with [3-3H]glucose, [1-14C]palmitate, and indirect calorimetry. The insulin and IGF-I infusion rates were chosen to augment glucose disposal (Rd) to a similar extent in control subjects. In type 2 diabetic subjects, stimulation of Rd (second clamp step) in response to both insulin and IGF-I was reduced by ∼40–50% compared with control subjects. In control subjects, insulin was more effective than IGF-I in suppressing endogenous glucose production (EGP) during both clamp steps. In type 2 diabetic subjects, insulin-mediated suppression of EGP was impaired, whereas EGP suppression by IGF-I was similar to that of controls. In both control and diabetic subjects, IGF-I-mediated suppression of plasma FFA concentration and inhibition of FFA turnover were markedly impaired compared with insulin ( P < 0.01–0.001). During the second IGF-I clamp step, suppression of plasma FFA concentration and FFA turnover was impaired in diabetic vs. control subjects ( P < 0.05–0.01). Conclusions: 1) IGF-I is less effective than insulin in suppressing EGP and FFA turnover; 2) insulin-resistant type 2 diabetic subjects also exhibit IGF-I resistance in skeletal muscle. However, suppression of EGP by IGF-I is not impaired in diabetic individuals, indicating normal hepatic sensitivity to IGF-I.

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Gliclazide increases insulin receptor tyrosine phosphorylation but not p38 phosphorylation in insulin-resistant skeletal muscle cells

Journal of Experimental Biology ◽

10.1242/jeb.205.23.3739 ◽

2002 ◽

Vol 205 (23) ◽

pp. 3739-3746 ◽

Cited By ~ 1

Author(s):

Naresh Kumar ◽

Chinmoy S. Dey

Keyword(s):

Skeletal Muscle ◽

Insulin Receptor ◽

Glucose Uptake ◽

Tyrosine Phosphorylation ◽

Insulin Signaling ◽

Mapk Pathway ◽

Muscle Cells ◽

Skeletal Muscle Cells ◽

Insulin Resistant ◽

Resistant Cells

SUMMARY Sulfonylurea drugs are used in the treatment of type 2 diabetes. The mechanism of action of sulfonylureas is to release insulin from pancreatic cells and they have been proposed to act on insulin-sensitive tissues to enhance glucose uptake. The goal of the present study was to test the hypothesis that gliclazide, a second-generation sulfonylurea, could enhance insulin signaling in insulin-resistant skeletal muscle cells. We demonstrated that gliclazide enhanced insulin-stimulated insulin receptor tyrosine phosphorylation in insulin-resistant skeletal muscle cells. Although insulin receptor substrate-1 tyrosine phosphorylation was unaffected by gliclazide treatment, phosphatidylinositol 3-kinase activity was partially restored by treatment with gliclazide. No increase in 2-deoxyglucose uptake in insulin-resistant cells by treatment with gliclazide was observed. Further investigations into the mitogen-activated protein kinase (MAPK) pathway revealed that insulin-stimulated p38 phosphorylation was impaired, as compared with extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase(JNK), which were phosphorylated normally in insulin-resistant cells. Treatment with gliclazide could not restore p38 phosphorylation in insulin-resistant cells. We propose that gliclazide can regulate part of the insulin signaling in insulin-resistant skeletal muscle, and p38 could be a potential therapeutic target for glucose uptake to treat insulin resistance.

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Donor metabolic characteristics drive effects of faecal microbiota transplantation on recipient insulin sensitivity, energy expenditure and intestinal transit time

Gut ◽

10.1136/gutjnl-2019-318320 ◽

2019 ◽

Vol 69 (3) ◽

pp. 502-512 ◽

Cited By ~ 34

Author(s):

Pieter de Groot ◽

Torsten Scheithauer ◽

Guido J Bakker ◽

Andrei Prodan ◽

Evgeni Levin ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Bile Acids ◽

Transit Time ◽

Intestinal Transit ◽

Faecal Microbiota ◽

Intestinal Transit Time ◽

Insulin Resistant

ObjectiveBariatric surgery improves glucose metabolism. Recent data suggest that faecal microbiota transplantation (FMT) using faeces from postbariatric surgery diet-induced obese mice in germ-free mice improves glucose metabolism and intestinal homeostasis. We here investigated whether allogenic FMT using faeces from post-Roux-en-Y gastric bypass donors (RYGB-D) compared with using faeces from metabolic syndrome donors (METS-D) has short-term effects on glucose metabolism, intestinal transit time and adipose tissue inflammation in treatment-naïve, obese, insulin-resistant male subjects.DesignSubjects with metabolic syndrome (n=22) received allogenic FMT either from RYGB-D or METS-D. Hepatic and peripheral insulin sensitivity as well as lipolysis were measured at baseline and 2 weeks after FMT by hyperinsulinaemic euglycaemic stable isotope (2H2-glucose and 2H5-glycerol) clamp. Secondary outcome parameters were changes in resting energy expenditure, intestinal transit time, faecal short-chain fatty acids (SCFA) and bile acids, and inflammatory markers in subcutaneous adipose tissue related to intestinal microbiota composition. Faecal SCFA, bile acids, glycaemic control and inflammatory parameters were also evaluated at 8 weeks.ResultsWe observed a significant decrease in insulin sensitivity 2 weeks after allogenic METS-D FMT (median rate of glucose disappearance: from 40.6 to 34.0 µmol/kg/min; p<0.01). Moreover, a trend (p=0.052) towards faster intestinal transit time following RYGB-D FMT was seen. Finally, we observed changes in faecal bile acids (increased lithocholic, deoxycholic and (iso)lithocholic acid after METS-D FMT), inflammatory markers (decreased adipose tissue chemokine ligand 2 (CCL2) gene expression and plasma CCL2 after RYGB-D FMT) and changes in several intestinal microbiota taxa.ConclusionAllogenic FMT using METS-D decreases insulin sensitivity in metabolic syndrome recipients when compared with using post-RYGB-D. Further research is needed to delineate the role of donor characteristics in FMT efficacy in human insulin-resistant subjects.Trial registration numberNTR4327.

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Changes in glucose metabolism and reversion of genes expression in the liver of insulin-resistant rats exposed to malathion. The protective effects of N-acetylcysteine

General and Comparative Endocrinology ◽

10.1016/j.ygcen.2014.10.002 ◽

2015 ◽

Vol 215 ◽

pp. 88-97 ◽

Cited By ~ 13

Author(s):

Mohamed Montassar Lasram ◽

Narjes El-Golli ◽

Aicha Jrad Lamine ◽

Ines Bini Douib ◽

Kahena Bouzid ◽

...

Keyword(s):

Glucose Metabolism ◽

Protective Effects ◽

Insulin Resistant ◽

Genes Expression

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Astaxanthin prevents loss of insulin signaling and improves glucose metabolism in liver of insulin resistant mice

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y2012-119 ◽

2012 ◽

Vol 90 (11) ◽

pp. 1544-1552 ◽

Cited By ~ 51

Author(s):

Saravanan Bhuvaneswari ◽

Carani Venkatraman Anuradha

Keyword(s):

Glucose Metabolism ◽

Body Mass ◽

Insulin Signaling ◽

Serine Phosphorylation ◽

Insulin Resistant ◽

Extracellular Signal ◽

High Fructose ◽

Normal Chow ◽

Serine Kinases ◽

Irs Proteins

This study investigates the effects of astaxanthin (ASX) on insulin signaling and glucose metabolism in the liver of mice fed a high fat and high fructose diet (HFFD). Adult male Mus musculus mice of body mass 25–30 g were fed either normal chow or the HFFD. After 15 days, mice in each group were subdivided among 2 smaller groups and treated with ASX (2 mg·(kg body mass)–1) in olive oil for 45 days. At the end of 60 days, HFFD-fed mice displayed insulin resistance while ASX-treated HFFD animals showed marked improvement in insulin sensitivity parameters. ASX treatment normalized the activities of hexokinase, pyruvate kinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glycogen phosphorylase, and increased glycogen reserves in the liver. Liver tissue from ASX-treated HFFD-fed animals showed increased tyrosine phosphorylation and decreased serine phosphorylation of insulin receptor substrates (IRS)-1 and -2. ASX increased IRS 1/2 and phosphatidylinositol 3-kinase (PI3K) association and serine phosphorylation of Akt. In addition, ASX decreased HFFD-induced serine kinases (c-jun N-terminal kinase-1 and extracellular signal-regulated kinase-1). The results suggest that ASX treatment promotes the IRS–PI3K–Akt pathway of insulin signaling by decreasing serine phosphorylation of IRS proteins, and improves glucose metabolism by modulating metabolic enzymes.

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