OR28-6 Short-Term Mifepristone Treatment Improves Hepatic and Adipose Tissue Insulin Sensitivity in Overweight and Obese Subjects with Glucose Intolerance

To compare the effect of short- vs long-term amylin infusion on insulin sensitivity, glucose tolerance and serum calcemia, euglycemic-hyperinsulinemic clamp (26 pmol·kg−1·min−1) and glucose tolerance tests (2.4 mmol/kg over 30 min) were performed in lean Zucker rats. Three infusion protocols were employed: control group: 24 h of iv saline; short-term amylin exposure: 22 h of iv saline followed by 2 h of iv amylin (20 μg/h); long-term amylin exposure: 24 h of iv amylin (20 μg/h). Insulin resistance was induced by short-term amylin infusion during euglycemic clamping, as shown by a 41% decrease in space-corrected glucose infusion rates (μmol·kg−1·min−1; control group, 106.0±15.0; short-term iv amylin, 62.7±15.0; p<0.00 5). After long-term amylin exposure, insulin sensitivity was identical to control values (109.9±6.7). This fading action of amylin was confirmed by data from the glucose tolerance test, demonstrating glucose intolerance after short- but not after long-term amylin exposure. Serum calcium concentration decreased during short-term (2 h) amylin infusion (from 2.52±0.15 to 2.09±0.12 mmol/l; p<0.01) and hypocalcemia of a similar extent also was present after 22 h and 24 h of amylin exposure (2.10±0.09 and 2.04±0.14 mmol/l, respectively). The data demonstrate that short-term amylin infusion induces insulin resistance and glucose intolerance, both of which vanish during long-term (>22 h) amylin exposure, being apparently independent of induced hypocalcemia.

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Epigenetic Downregulation of FASN in Visceral Adipose Tissue of Insulin Resistant Subjects

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1150-7446 ◽

2020 ◽

Author(s):

Helen Sievert ◽

Christin Krause ◽

Cathleen Geißler ◽

Martina Grohs ◽

Alexander T. El-Gammal ◽

...

Keyword(s):

Type 2 Diabetes ◽

Dna Methylation ◽

Fatty Acids ◽

Adipose Tissue ◽

Glucose Intolerance ◽

Visceral Adipose Tissue ◽

High Hba1c ◽

Obese Subjects ◽

Visceral Adipose

Abstract Objective The risk to develop type 2 diabetes increases with the amount of visceral adiposity presumably due to increased lipolysis and subsequent lipid accumulation in visceral organs. However, data describing the molecular regulation of these pathways in humans are rare. We tested if genes of the lipogenic and lipolytic pathways are associated with glucose intolerance independently of obesity in visceral adipose tissue (VAT) of obese subjects. Moreover, we studied DNA methylation of FASN (fatty acid synthase), that catalyses the synthesis of long-chain fatty acids, in VAT of the same subjects and whether it is associated with metabolic traits. Subjects and methods Visceral adipose tissue biopsies and blood samples were taken from 93 severely obese subjects undergoing bariatric surgery. Subjects were grouped in low HbA1c (L-HbA1c, HbA1c<6.5 %) and high HbA1c (H-HbA1c, HbA1c≥6.5 %) groups and expression of genes from the lipogenic and lipolytic pathways was analysed by TaqMan qPCR. DNA methylation of FASN was quantified by bisulfite-pyrosequencing. Results FASN expression was downregulated in visceral fat from subjects with high HbA1c (p = 0.00009). Expression of other lipogenetic (SCD, ELOVL6) or lipolytic genes (ADRB3, PNPLA2) and FABP4 was not changed. DNA methylation of FASN was increased at a regulatory ChoRE recognition site in the H-HbA1c-subgroup and correlated negatively with FASN mRNA (r = − 0.302, p = 0.0034) and positively with HbA1c (r = 0.296, p = 0.0040) and blood glucose (r = 0.363, p = 0.0005). Conclusions Epigenetic downregulation of FASN in visceral adipose tissue of obese subjects might contribute to limited de novo lipogenesis of important insulin sensitizing fatty acids and could thereby contribute to glucose intolerance and the development of type 2 diabetes independently of obesity.

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Interleukin-18 in plasma and adipose tissue: effects of obesity, insulin resistance, and weight loss

Acta Endocrinologica ◽

10.1530/eje-07-0206 ◽

2007 ◽

Vol 157 (4) ◽

pp. 465-471 ◽

Cited By ~ 93

Author(s):

Jens M Bruun ◽

Bente Stallknecht ◽

Jørn W Helge ◽

Bjørn Richelsen

Keyword(s):

Insulin Resistance ◽

Weight Loss ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Rt Pcr ◽

Reduced Body ◽

Daily Exercise ◽

Life Style Intervention ◽

Obese Subjects ◽

Isolated Adipocytes

Objective: Interleukin (IL)-18 is associated with obesity, insulin resistance, and cardiovascular disease. The present study compared 1) IL-18 in adipocytes versus stromal vascular (SV) cells, 2) IL-18 in plasma and adipose tissue (AT) in obese versus lean subjects, and 3) IL-18 in plasma, AT, and skeletal muscle (SM) in obese subjects after weight loss. Subjects and methods: At baseline, plasma and AT IL-18 in 23 obese subjects were compared with that in 12 lean subjects. The obese subjects were submitted to a 15-week life-style intervention (hypocaloric diet and daily exercise) after which plasma samples, AT, and SM biopsies were obtained. Analyses were performed by ELISA and RT-PCR respectively. Results: IL-18 expression in isolated adipocytes was ~2% of that in SV cells. Plasma IL-18 was higher in obese subjects (P < 0.001) and associated with insulin resistance (HOMA; P < 0.001). AT expression of IL-18, CD14, and CD68 was higher in obese (P < 0.01). The intervention reduced body weight (P < 0.001), plasma IL-18 (P < 0.001), and increased insulin sensitivity (HOMA; P < 0.05). AT and SM expression of IL-18 remained unchanged after the intervention. Changes in plasma IL-18 were associated with changes in insulin sensitivity (P < 0.05) but not with BMI or AT expression of IL-18. Conclusion: Plasma IL-18 is associated with changes in insulin resistance and reduced after weight loss. AT expression of IL-18 is increased in obesity but not affected by weight loss, indicating that changes in plasma IL-18 are related to insulin resistance rather than changes in obesity per se.

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Markers of Adipogenesis, but Not Inflammation, in Adipose Tissue Are Independently Related to Insulin Sensitivity

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-00597 ◽

2017 ◽

Vol 102 (8) ◽

pp. 3040-3049 ◽

Cited By ~ 13

Author(s):

Natalia Matulewicz ◽

Magdalena Stefanowicz ◽

Agnieszka Nikołajuk ◽

Monika Karczewska-Kupczewska

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Immune Cells ◽

Insulin Signaling ◽

Transcriptional Level ◽

Altered Expression ◽

Ecm Remodeling ◽

Expression Of Genes ◽

Obese Subjects

Abstract Context In obesity, adipose tissue (AT) undergoes dynamic remodeling, including an alternation in adipogenesis, AT-resident cell content, angiogenesis, and turnover of extracellular matrix (ECM) components. Studies of AT in humans have been carried out mostly in people with severe metabolic abnormalities, like type 2 diabetes or morbid obesity. Objective The purpose of this study was to investigate subcutaneous AT gene expression of markers of adipogenesis, ECM remodeling, and inflammation in young, healthy, overweight or obese subjects. Design The study group comprised 83 normal-weight, 48 overweight, and 19 obese subjects. Euglycemic hyperinsulinemic clamp, biopsy of subcutaneous AT, and isolation of peripheral blood mononuclear cells (PBMCs) were performed. Gene expression was measured with real-time polymerase chain reaction. Results Overweight/obese subjects had lower AT expression of markers of adipogenesis, insulin signaling, and angiogenesis; higher expression of markers of ECM remodeling; altered expression of genes of the nuclear factor-κ-B (NFκB), but not c-Jun NH2-terminal kinase, pathway; and higher expression of macrophage markers but not markers of other immune cells. In multiple regression analysis, the expression of CEBPA, ADIPOQ, IRS1, IRS2, SLC2A4, and MMP9 was associated with insulin sensitivity independently of body mass index. No differences were found in inflammatory-gene PBMC expression. Conclusion Overweight/obesity is associated with altered expression of genes of adipogenesis, insulin signaling, ECM remodeling, and inflammation. NFκB seems to be the earliest inflammatory pathway altered at the transcriptional level in AT. Macrophages seem to be the first immune cells to infiltrate AT. Adipogenesis and ECM remodeling are the initial processes in AT that are independently associated with insulin sensitivity.

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Differential effects of hypercaloric choice diets on insulin sensitivity in rats

Journal of Endocrinology ◽

10.1530/joe-16-0265 ◽

2017 ◽

Vol 232 (1) ◽

pp. 49-57 ◽

Cited By ~ 8

Author(s):

Charlene Diepenbroek ◽

Leslie Eggels ◽

Mariëtte T Ackermans ◽

Eric Fliers ◽

Andries Kalsbeek ◽

...

Keyword(s):

Insulin Sensitivity ◽

Glucose Intolerance ◽

Free Choice ◽

Saturated Fat ◽

High Fat ◽

Short Term ◽

Sugar Water ◽

Hepatic Insulin Sensitivity ◽

Peripheral Insulin Sensitivity ◽

High Sugar

We showed previously that rats on a free-choice high-fat, high-sugar (fcHFHS) diet become rapidly obese and develop glucose intolerance within a week. Interestingly, neither rats on a free-choice high-fat diet (fcHF), although equally obese and hyperphagic, nor rats on a free-choice high-sugar (fcHS) diet consuming more sugar water, develop glucose intolerance. Here, we investigate whether changes in insulin sensitivity contribute to the observed glucose intolerance and whether this is related to consumption of saturated fat and/or sugar water. Rats received either a fcHFHS, fcHF, fcHS or chow diet for one week. We performed a hyperinsulinemic–euglycemic clamp with stable isotope dilution to measure endogenous glucose production (EGP; hepatic insulin sensitivity) and glucose disappearance (Rd; peripheral insulin sensitivity). Rats on all free-choice diets were hyperphagic, but only fcHFHS-fed rats showed significantly increased adiposity. EGP suppression by hyperinsulinemia in fcHF-fed and fcHFHS-fed rats was significantly decreased compared with chow-fed rats. One week fcHFHS diet also significantly decreased Rd. Neither EGP suppression nor Rd was affected in fcHS-fed rats. Our results imply that, short-term fat feeding impaired hepatic insulin sensitivity, whereas short-term consumption of both saturated fat and sugar water impaired hepatic and peripheral insulin sensitivity. The latter likely contributed to glucose intolerance observed previously. In contrast, overconsumption of only sugar water affected insulin sensitivity slightly, but not significantly, in spite of similar adiposity as fcHF-fed rats and higher sugar intake compared with fcHFHS-fed rats. These data imply that the palatable component consumed plays a role in the development of site-specific insulin sensitivity.

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Matrix Metalloproteinase-9 Is Increased in Obese Subjects and Decreases in Response to Pioglitazone

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-2623 ◽

2010 ◽

Vol 95 (6) ◽

pp. 2993-3001 ◽

Cited By ~ 40

Author(s):

Resat Unal ◽

Aiwei Yao-Borengasser ◽

Vijayalakshmi Varma ◽

Neda Rasouli ◽

Craig Labbate ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Stromal Vascular Fraction ◽

Tolerance Test ◽

University Hospital ◽

Sensitivity Testing ◽

Protein Kinase Cα ◽

Glucose Tolerant ◽

Obese Subjects

Abstract Context: The study investigated the regulation of matrix metalloproteinases (MMP)-9 in obesity-associated insulin resistance in humans. Objectives: The objectives of the investigation were to study MMP-9 regulation by insulin resistance and pioglitazone treatment in impaired glucose tolerant subjects using adipose tissue biopsies and study the mechanism of MMP-9 regulation by pioglitazone in adipocyte cultures. Research Design: 86 nondiabetic, weight-stable subjects between 21 and 66 yr of age were recruited in a university hospital research center setting. All subjects underwent a sc adipose tissue incisional biopsy from the lower abdominal wall and insulin sensitivity testing using a frequently sampled iv glucose tolerance test. Impaired glucose-tolerant subjects were randomized to receive metformin or pioglitazone for 10 wk. To study the mechanism of MMP-9 regulation in adipocytes, cells were treated with pioglitazone or protein kinase Cα antisense oligomers, and MMP-9 levels were examined. Results: There was a positive correlation between MMP-9 and body mass index (r = 0.40, P < 0.01) and negative correlation between MMP-9 and insulin sensitivity (r = −0.46, P < 0.001). The improvement in insulin sensitivity from pioglitazone resulted in a 52 ± 0.2% reduction in MMP-9 mRNA. Fractionation of adipose tissue indicated that MMP-9 was mostly in the stromal vascular fraction. Pioglitazone also decreased MMP-9 in 3T3-F442A adipocytes and THP1 macrophages. Coculture of adipocytes with macrophages augmented MMP-9 expression in adipocytes and pioglitazone decreased MMP-9 in both adipocytes and macrophages. Conclusion: These data indicate that MMP-9 is elevated in insulin resistance and is reduced by pioglitazone.

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Dynamic Strength Training Improves Insulin Sensitivity without Altering Plasma Levels and Gene Expression of Adipokines in Subcutaneous Adipose Tissue in Obese Men

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-0382 ◽

2006 ◽

Vol 91 (12) ◽

pp. 5107-5112 ◽

Cited By ~ 94

Author(s):

E. Klimcakova ◽

J. Polak ◽

C. Moro ◽

J. Hejnova ◽

M. Majercik ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Strength Training ◽

Plasma Levels ◽

Dynamic Strength ◽

Whole Body ◽

Obese Subjects ◽

Dynamic Strength Training

Abstract Context: Obesity is characterized by a low-grade inflammatory state, which could play a role in insulin resistance. Dynamic strength training improves insulin sensitivity. Objective: The objective of this study was to investigate, in obese subjects, whether the insulin sensitizing effect of dynamic strength training is associated with changes in plasma levels and gene expression of adipokines potentially involved in the development of insulin resistance. Design: Twelve obese male subjects were investigated before and at the end of 3 months of dynamic strength training. Insulin sensitivity was evaluated using euglycemic-hyperinsulinemic clamp. Blood samples and needle biopsy samples of sc abdominal adipose tissue were obtained. The plasma levels and adipose tissue mRNA levels of adiponectin, leptin, IL-1β, IL-6, and TNF-α were determined. Results: The training induced an increase in the whole-body glucose disposal rate by 24% (P = 0.04). The body weight was not altered during the training. Plasma levels of leptin decreased during the training (16.6 ± 6.3 vs. 13.1 ± 5.7 ng/ml) by 21% (P < 0.02), whereas no change in plasma levels of other adipokines and C-reactive protein was observed. Gene expression of the investigated adipokines was not changed in sc adipose tissue during the training. Conclusions: In obese subjects, the dynamic strength training resulted in an improvement of whole-body insulin sensitivity. The increase in insulin sensitivity was not associated with training-induced modifications of plasma levels or adipose tissue gene expression of adipokines supposedly involved in the development of insulin resistance.

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Secretion of adiponectin multimeric complexes from adipose tissue explants is not modified by very low calorie diet

Acta Endocrinologica ◽

10.1530/eje-08-0727 ◽

2009 ◽

Vol 160 (4) ◽

pp. 585-592 ◽

Cited By ~ 12

Author(s):

Zuzana Kovacova ◽

Michaela Vitkova ◽

Michaela Kovacikova ◽

Eva Klimcakova ◽

Magda Bajzova ◽

...

Keyword(s):

Weight Loss ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Dietary Intervention ◽

Culture Media ◽

Very Low Calorie Diet ◽

Low Calorie Diet ◽

Total Adiponectin ◽

Calorie Diet ◽

Obese Subjects

ObjectiveAdiponectin is a protein abundantly secreted by the adipose tissue (AT). Plasma adiponectin levels are decreased in obese, insulin-resistant, and type 2 diabetic patients. Various multimeric complexes, i.e. high-, middle-, and low-molecular weight isoforms (HMW, MMW and LMW), are present in plasma. Here, we investigated the effect of weight reducing diet on the distribution of adiponectin isoforms in plasma and on their secretion in AT explants from obese subjects.DesignA total of 20 obese subjects (age 37.8±7.3 years, body mass index 33.9±5.0 kg/m2) underwent eight weeks of very low-calorie diet (VLCD). A needle biopsy of subcutaneous abdominal AT and blood samples were taken before and after dietary intervention. AT explants were incubated in culture medium for 4 h. ELISA assay and western blot analyses were used to identify adiponectin complexes in culture media and in plasma.ResultsThe distribution of adiponectin polymers in plasma was different from that secreted in human AT explants. Before VLCD, the relative amount of HMW isoform was 75.5±9.1% of total adiponectin in culture media and 52.2±11.2% in plasma. Despite the diet-induced weight loss and improvement of insulin sensitivity, VLCD neither induced change in total adiponectin level nor in the ratio of HMW to total adiponectin in plasma and in culture media of AT explants.ConclusionsThe profile of adiponectin polymeric isoforms secreted by AT explants into culture media differs from the plasma profile. A dietary intervention leading to weight loss and improvement of insulin sensitivity was not associated with modifications of AT secretion of total or HMW adiponectin.

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