scholarly journals Disruption of GIP/GIPR Axis in Human Adipose Tissue Is Linked to Obesity and Insulin Resistance

2014 ◽  
Vol 99 (5) ◽  
pp. E908-E919 ◽  
Author(s):  
Victòria Ceperuelo-Mallafré ◽  
Xavier Duran ◽  
Gisela Pachón ◽  
Kelly Roche ◽  
Lourdes Garrido-Sánchez ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Stem Cells ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Human Adipose Tissue ◽  
Fat Cells ◽  
Model Assessment ◽  
Adipose Derived Stem Cells ◽  
Obese Patients ◽  
Insulin Sensitizer

Context: Glucose-dependent insulinotropic peptide (GIP) has a central role in glucose homeostasis through its amplification of insulin secretion; however, its physiological role in adipose tissue is unclear. Objective: Our objective was to define the function of GIP in human adipose tissue in relation to obesity and insulin resistance. Design: GIP receptor (GIPR) expression was analyzed in human sc adipose tissue (SAT) and visceral adipose (VAT) from lean and obese subjects in 3 independent cohorts. GIPR expression was associated with anthropometric and biochemical variables. GIP responsiveness on insulin sensitivity was analyzed in human adipocyte cell lines in normoxic and hypoxic environments as well as in adipose-derived stem cells obtained from lean and obese patients. Results: GIPR expression was downregulated in SAT from obese patients and correlated negatively with body mass index, waist circumference, systolic blood pressure, and glucose and triglyceride levels. Furthermore, homeostasis model assessment of insulin resistance, glucose, and G protein-coupled receptor kinase 2 (GRK2) emerged as variables strongly associated with GIPR expression in SAT. Glucose uptake studies and insulin signaling in human adipocytes revealed GIP as an insulin-sensitizer incretin. Immunoprecipitation experiments suggested that GIP promotes the interaction of GRK2 with GIPR and decreases the association of GRK2 to insulin receptor substrate 1. These effects of GIP observed under normoxia were lost in human fat cells cultured in hypoxia. In support of this, GIP increased insulin sensitivity in human adipose-derived stem cells from lean patients. GIP also induced GIPR expression, which was concomitant with a downregulation of the incretin-degrading enzyme dipeptidyl peptidase 4. None of the physiological effects of GIP were detected in human fat cells obtained from an obese environment with reduced levels of GIPR. Conclusions: GIP/GIPR signaling is disrupted in insulin-resistant states, such as obesity, and normalizing this function might represent a potential therapy in the treatment of obesity-associated metabolic disorders.

scholarly journals The Relationship between Insulin Resistance and the Cardiovascular Biomarker Growth Differentiation Factor-15 in Obese Patients

2011 ◽  
Vol 57 (2) ◽  
pp. 309-316 ◽  
Author(s):  
Greisa Vila ◽  
Michaela Riedl ◽  
Christian Anderwald ◽  
Michael Resl ◽  
Ammon Handisurya ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Gastric Bypass ◽  
Insulin Sensitivity ◽  
Oral Glucose ◽  
Model Assessment ◽  
Obese Patients ◽  
Growth Differentiation Factor 15 ◽  
Homeostatic Model Assessment ◽  
Homeostatic Model ◽  
The Relationship

BACKGROUND Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine linked to obesity comorbidities such as cardiovascular disease, inflammation, and cancer. GDF-15 also has adipokine properties and recently emerged as a prognostic biomarker for cardiovascular events. METHODS We evaluated the relationship of plasma GDF-15 concentrations with parameters of obesity, inflammation, and glucose and lipid metabolism in a cohort of 118 morbidly obese patients [mean (SD) age 37.2 (12) years, 89 females, 29 males] and 30 age- and sex-matched healthy lean individuals. All study participants underwent a 75-g oral glucose tolerance test; 28 patients were studied before and 1 year after Roux-en-Y gastric bypass surgery. RESULTS Obese individuals displayed increased plasma GDF-15 concentrations (P < 0.001), with highest concentrations observed in patients with type 2 diabetes. GDF-15 was positively correlated with age, waist-to-height ratio, mean arterial blood pressure, triglycerides, creatinine, glucose, insulin, C-peptide, hemoglobin A1c, and homeostatic model assessment insulin resistance index and negatively correlated with oral glucose insulin sensitivity. Age, homeostatic model assessment index, oral glucose insulin sensitivity, and creatinine were independent predictors of GDF-15 concentrations. Roux-en-Y gastric bypass led to a significant reduction in weight, leptin, insulin, and insulin resistance, but further increased GDF-15 concentrations (P < 0.001). CONCLUSIONS The associations between circulating GDF-15 concentrations and age, insulin resistance, and creatinine might account for the additional cardiovascular predictive information of GDF-15 compared to traditional risk factors. Nevertheless, GDF-15 changes following bariatric surgery suggest an indirect relationship between GDF-15 and insulin resistance. The clinical utility of GDF-15 as a biomarker might be limited until the pathways directly controlling GDF-15 concentrations are better understood.

scholarly journals Melatonin Treatment Improves Insulin Resistance and Pigmentation in Obese Patients with Acanthosis Nigricans

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Hang Sun ◽  
Xingchun Wang ◽  
Jiaqi Chen ◽  
Aaron M. Gusdon ◽  
Kexiu Song ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Acanthosis Nigricans ◽  
Resistance Index ◽  
Inflammatory Factors ◽  
Model Assessment ◽  
Obese Patients ◽  
Inflammatory Status ◽  
Before And After ◽  
Matsuda Index

Objective. This study aimed to determine the effects of melatonin on insulin resistance in obese patients with acanthosis nigricans (AN). Methods. A total of 17 obese patients with acanthosis nigricans were recruited in a 12-week pilot open trial. Insulin sensitivity, glucose metabolism, inflammatory factors, and other biochemical parameters before and after the administration of melatonin were measured. Results. After 12 weeks of treatment with melatonin (3 mg/day), homeostasis model assessment insulin resistance index (HOMA-IR) (8.99 ± 5.10 versus 7.77 ± 5.21, p<0.05) and fasting insulin (37.09 5 ± 20.26 μU/ml versus 32.10 ± 20.29 μU/ml, p<0.05) were significantly decreased. Matsuda index (2.82 ± 1.54 versus 3.74 ± 2.02, p<0.05) was significantly increased. There were also statistically significant declines in the AN scores of the neck and axilla, body weight, body mass index, body fat, visceral index, neck circumference, waist circumference, and inflammatory markers. Conclusions. It was concluded that melatonin could improve cutaneous symptoms in obese patients with acanthosis nigricans by improving insulin sensitivity and inflammatory status. This trial is registered with ClinicalTrials.gov NCT02604095.

Abstract 402: Human CD271-positive Adipose Derived Stem Cells are the Angiogenic Subset Decreased by Donor Insulin Resistance

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Oto Inoue ◽  
Soichiro Usui ◽  
Kosei Yamaguchi ◽  
Yusuke Takeda ◽  
Chiaki Goten ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Stem Cells ◽  
Adipose Tissue ◽  
Cell Therapy ◽  
Capillary Density ◽  
Adipose Derived Stem Cells ◽  
Knock Out ◽  
Healthy Donors ◽  
Knock Out Mice

Introduction: Type 2 diabetes mellitus (T2DM) is an important risk factor for cardiovascular diseases (CVDs). Recently, cell therapy using adipose-derived stem cells (ADSCs) has emerged as an attractive therapy for severe CVDs because of their angiogenic potentials. However, whether and how T2DM would impair human ADSC angiogenic capacity is still uncertain. We previously reported that CD31 - CD34 + CD271 + ADSCs (CD271 + ADSCs) were specifically decreased in adipose tissue of T2DM patients. Therefore, we aimed to investigate the angiogenic capacity of CD271 + ADSCs. Furthermore, we evaluate which patients’ parameters regard as T2DM would decrease the amount of CD271 + ADSCs. Methods and Results: Human CD45 - CD34 + CD31 - ADSCs were obtained from subcutaneous adipose tissue of healthy donors, separated into CD271 + and CD271 - subsets by FACS, and cultured. Both subsets of ADSCs were assessed gene expression profile by microarray. Microarray analysis and validation PCR elucidated that PI3K/Akt/mTOR pathway was significantly up-regulated in CD271 + ADSCs compared to in CD271 - ADSCs. ( p < 0.05). Then, we compared in vivo angiogenic capacity in xenograft experiments of nude mice subjected to hindlimb ischemia. Angiogenesis was evaluated histologically using perfused lectin (capillary density) at day 14. Cell therapy using CD271 + ADSCs demonstrated about 3-fold more lectin + capillaries compared to CD271 - ADSCs or PBS injection ( p < 0.005, n = 5 / group). Next, we established cultured ADSCs obtained from CD271 knock-out mice (KO-ADSCs) and compared their angiogenic capacity with those from WT mice. Consistently, KO-ADSCs demonstrated impaired in vivo angiogenic capacity ( p < 0.005, n = 5 / group). Finally, we collected 23 samples of adipose tissue obtained from CVD patients and evaluated the frequency of CD271 + ADSCs in CD45 - CD34 + CD31 - ADSCs. Among studied parameters, HOMA-IR, an index of insulin resistance, was negatively correlated with the frequency of CD271+ ADSCs ( r = -0.64, p < 0.005). Conclusions: Human CD271 + ADSCs demonstrated enhanced in vivo angiogenic capacity with higher mTOR expression. Donor insulin resistance might decrease this regenerative subset of ADSCs. These findings would be critical for development and improvement of ADSC therapy.

scholarly journals Lower Zinc-α2-Glycoprotein Production by Adipose Tissue and Liver in Obese Patients Unrelated to Insulin Resistance

2009 ◽  
Vol 94 (11) ◽  
pp. 4499-4507 ◽  
Author(s):  
David M. Selva ◽  
Albert Lecube ◽  
Cristina Hernández ◽  
Juan A. Baena ◽  
José M. Fort ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Mass Index ◽  
Adipose Tissue ◽  
Body Mass ◽  
Control Group ◽  
Mrna Levels ◽  
Model Assessment ◽  
Obese Patients ◽  
Obese Subjects

Context: Zinc-α2 glycoprotein (ZAG) has been proposed as a new candidate in the pathogenesis of obesity, but most of the information stems from studies performed in rodents and in vitro assays. Objective: The main aim of the study was to compare serum levels of ZAG and its expression (mRNA levels and protein) in adipose tissue and the liver between obese and nonobese subjects. The relationship between ZAG and insulin resistance was also explored. Design: This was a case-control study. Setting: The study was conducted at a university referral center. Patients and Methods: Samples of serum, sc adipose tissue (SAT), visceral adipose tissue (VAT), and liver were obtained from 20 obese subjects during bariatric surgery. Samples from 10 nonobese patients matched by age and gender were used as a control group. Serum ZAG levels were determined by ELISA. ZAG mRNA levels were measured by real-time PCR and protein content by Western blot. The effect of insulin on liver production of ZAG was assessed using HepG2 cultures. Results: Serum concentration of ZAG (micrograms per milliliter) was significantly lower in obese subjects (40.87 ± 10.45 vs. 63.26 ± 16.40; P = 0.002). ZAG expression was significantly lower in the adipose tissue (SAT and VAT) and liver of obese patients than in control subjects. Significant negative correlations between body mass index and circulating ZAG (r = −0.65, P &lt; 0.001) as well as between body mass index and mRNA ZAG levels in SAT (r = −0.68, P &lt; 0.001) and VAT were detected (r = −0.64, P &lt; 0.001). No relationship was found between ZAG and homeostasis model assessment for insulin resistance and insulin had no effect on ZAG production in vitro. Conclusion: A down-regulation of ZAG in SAT, VAT, and liver exists in obese patients but seems unrelated to insulin resistance. A downregulation of zinc-α2 glycoprotein in adipose tissue and liver exists in obese patients, and it is unrelated to insulin resistance.

scholarly journals Elevated circulating microRNA-122 is associated with obesity and insulin resistance in young adults

2015 ◽  
Vol 172 (3) ◽  
pp. 291-300 ◽  
Author(s):  
Rui Wang ◽  
Jie Hong ◽  
Yanan Cao ◽  
Juan Shi ◽  
Weiqiong Gu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Young Adults ◽  
Insulin Sensitivity ◽  
Hdl Cholesterol ◽  
Circulating Microrna ◽  
Model Assessment ◽  
Obese Patients ◽  
Serum Samples ◽  
Functional Studies ◽  
Control Subjects

ObjectiveMicroRNAs (miRNAs) are involved in the regulation of adiposity, but functional studies have yielded inconclusive results. Examining the associations of circulating miRNAs levels with obesity and insulin sensitivity in humans may lead to improved insights.Design and methodsSerum samples collected from 112 obese and control subjects (50.0% men) were randomly divided and combined into four pools (28 samples in each obese or control pool). The genome-wide circulating miRNA profiles were detected via microarray. Elevated miR-122 was selected and validated in individual serum samples from 123 obese (46.7% men) and 107 control (50.0% men) young adults. Associations between circulating miR-122 levels and parameters related to adiposity, insulin resistance, lipid profiles and hepatic enzymes were further assessed.ResultsThirty-four miRNAs were found to be expressed differently in the sera of obese patients compared with control subjects (P<0.001). Further analyses confirmed that obese patients had 3.07-fold higher circulating miR-122 levels than controls (P<0.001). Serum miR-122 levels were correlated with BMI (r=0.469), alanine aminotransferase (r=0.634), triglycerides (r=0.448), HDL-cholesterol (r=−0.351) and homeostasis model assessment of insulin resistance (r=0.401, allP<0.01). After controlling for confounding factors, miR-122 remained as an independent risk factor for insulin resistance (OR=3.379, 95% CI=1.141–10.007,P=0.028).ConclusionsElevated circulating miR-122 is positively associated with obesity and insulin resistance in young adults. These findings provide a better understanding regarding the role of miRNAs in adiposity and insulin sensitivity.

scholarly journals Serum Resistin (FIZZ3) Protein Is Increased in Obese Humans

2003 ◽  
Vol 88 (11) ◽  
pp. 5452-5455 ◽  
Author(s):  
Mikako Degawa-Yamauchi ◽  
Jason E. Bovenkerk ◽  
Beth Elisa Juliar ◽  
William Watson ◽  
Kimberly Kerr ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Significant Positive Correlation ◽  
Human Adipose Tissue ◽  
Model Assessment ◽  
Homeostasis Model Assessment ◽  
Obese Subjects ◽  
Isolated Adipocytes ◽  
Resistance Score

Abstract The role of resistin in obesity and insulin resistance in humans is controversial. Therefore, resistin protein was quantitated by ELISA in serum of 27 lean [13 women/14 men, body mass index (BMI) 21.7 ± 0.4 kg/m2, age 33 ± 2 yr] and 50 obese (37 women/13 men, BMI 49.8 ± 1.5 kg/m2, age 47 ± 1 yr) subjects. There was more serum resistin protein in the obese (mean ± sem: 5.3 ± 0.4 ng/ml; range 1.8–17.9) than lean subjects (3.6 ± 0.4 ng/ml; range 1.5–9.9; P = 0.001). The elevation of serum resistin in obese humans was confirmed by Western blot as was expression of resistin protein in human adipose tissue and isolated adipocytes. There was a significant positive correlation between resistin and BMI (r = 0.37; P = 0.002). Multiple regression analysis with predictors BMI and resistin explained 25% of the variance in homeostasis model assessment of insulin resistance score. BMI was a significant predictor of insulin resistance (P = 0.0002), but resistin adjusted for BMI was not (P = 0.11). The data demonstrate that resistin protein is present in human adipose tissue and blood, and that there is significantly more resistin in the serum of obese subjects. Serum resistin is not a significant predictor of insulin resistance in humans.

Pioglitazone Enhances β-Arrestin2 Signaling and Ameliorates Insulin Resistance in Classical Insulin Target Tissues

Pharmacology ◽  
2021 ◽  
pp. 1-9
Author(s):  
Shaimaa El-Fayoumi ◽  
Rehab Mansour ◽  
Amr Mahmoud ◽  
Ahmed Fahmy ◽  
Islam Ibrahim
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Resistance Index ◽  
Chow Diet ◽  
Oral Antidiabetic Agent ◽  
Insulin Sensitizer ◽  
Standard Chow Diet ◽  
High Fructose

<b><i>Introduction:</i></b> Pioglitazone is a thiazolidinedione oral antidiabetic agent. This study aimed to investigate the effects of pioglitazone as insulin sensitizer on β-arrestin2 signaling in classical insulin target tissues. <b><i>Methods:</i></b> Experiments involved three groups of mice; the first one involved mice fed standard chow diet for 16 weeks; the second one involved mice fed high-fructose, high-fat diet (HFrHFD) for 16 weeks; and the third one involved mice fed HFrHFD for 16 weeks and received pioglitazone (30 mg/kg/day, orally) in the last four weeks of feeding HFrHFD. <b><i>Results:</i></b> The results showed significant improvement in the insulin sensitivity of pioglitazone-treated mice as manifested by significant reduction in the insulin resistance index. This improvement in insulin sensitivity was associated with significant increases in the β-arrestin2 levels in the adipose tissue, liver, and skeletal muscle. Moreover, pioglitazone significantly increased β-arrestin2 signaling in all the examined tissues as estimated from significant increases in phosphatidylinositol 4,5 bisphosphate and phosphorylation of Akt at serine 473 and significant decrease in diacylglycerol level. <b><i>Conclusion:</i></b> To the best of our knowledge, our work reports a new mechanism of action for pioglitazone through which it can enhance the insulin sensitivity. Pioglitazone increases β-arrestin2 signaling in the adipose tissue, liver, and skeletal muscle of HFrHFD-fed mice.

scholarly journals In situ transplantation of adipose-derived stem cells via photoactivation improves glucose metabolism in obese mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Luochen Zhu ◽  
Ziqian Feng ◽  
Xin Shu ◽  
Qian Gao ◽  
Jiaqi Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Stem Cells ◽  
Adipose Tissue ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Epididymal Adipose Tissue ◽  
Adipose Derived Stem Cells ◽  
Combined Application

Abstract Background Accumulating evidence suggests that enhanced adipose tissue macrophages (ATMs) are associated with metabolic disorders in obesity and type 2 diabetes. However, therapeutic persistence and reduced homing stem cell function following cell delivery remains a critical hurdle for the clinical translation of stem cells in current approaches. Methods We demonstrate that the effect of a combined application of photoactivation and adipose-derived stem cells (ASCs) using transplantation into visceral epididymal adipose tissue (EAT) in obesity. Cultured ASCs were derived from subcutaneous white adipose tissue isolated from mice fed a normal diet (ND). Results In diet-induced obesity, implantation of light-treated ASCs improved glucose tolerance and ameliorated systemic insulin resistance. Intriguingly, compared with non-light-treated ASCs, light-treated ASCs reduced monocyte infiltration and the levels of ATMs in EAT. Moreover, implantation of light-treated ASCs exerts more anti-inflammatory effects by suppressing M1 polarization and enhancing macrophage M2 polarization in EAT. Mass spectrometry revealed that light-treated human obese ASCs conditioned medium retained a more complete secretome with significant downregulation of pro-inflammatory cytokines and chemokines. Conclusions These data suggest that the combined application of photoactivation and ASCs using transplantation into dysfunctional adipose tissue contribute to selective suppression of inflammatory responses and protection from insulin resistance in obesity and type 2 diabetes.

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