scholarly journals Coordinated regulation of gene expression and microRNA changes in adipose tissue and circulating extracellular vesicles in response to pioglitazone treatment in humans with type 2 diabetes

2021 ◽  
Author(s):  
Yury Orlando Nunez Lopez ◽  
Anna Casu ◽  
Zuzana Kovacova ◽  
Alejandra M Petrilli ◽  
Olga Sideleva ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Extracellular Vesicles ◽  
Regulation Of Gene Expression ◽  
Mirna Regulation ◽  
Pparγ Agonist ◽  
Exosomal Mirna ◽  
Pioglitazone Treatment

Pioglitazone, a PPARγ agonist, is used to treat type 2 diabetes (T2D). PPARγ is highly expressed in adipose tissue (AT), however the effects of pioglitazone to improve insulin sensitivity are also evident in other tissues. We hypothesized that pioglitazone modifies the cargo of circulating AT-derived extracellular vesicles (EVs) to alter interorgan crosstalk. We tested this in a 3-month trial in which 24 subjects with T2D who were well-controlled with diet/exercise or metformin were randomized to treatment with either pioglitazone 45 mg/day or placebo (NCT00656864). Levels of 42 adipocyte-derived EV-miRNAs were measured in plasma EVs. Levels of 5 miRNAs (i.e., miR-7-5p, miR-20a-5p, miR-92a-3p, miR-195-5p, and miR-374b-5p) were significantly downregulated in EVs in response to pioglitazone treatment relative to placebo. However, the opposite occurred for miR-195-5p in subcutaneous AT from the same participants. Changes in miRNA expression in EVs and AT correlated with changes in suppression of lipolysis and improved insulin sensitivity, among others. DICER was downregulated and exosomal miRNA sorting-related genes YBX1 and hnRNPA2B1 displayed a trend toward downregulation in AT. Furthermore, analysis of EV-miRNA targeted genes identified a network of overtargeted transcripts that changed in a coordinated manner in AT. Collectively, our results suggest that some beneficial pharmacologic effects of PIO are mediated by adipose-specific miRNA regulation and exosomal/EV trafficking.

scholarly journals Improved Insulin Sensitivity during Pioglitazone Treatment Is Associated with Changes in IGF-I and Cortisol Secretion in Type 2 Diabetes and Impaired Glucose Tolerance

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Lisa Arnetz ◽  
Neda Rajamand Ekberg ◽  
Charlotte Höybye ◽  
Kerstin Brismar ◽  
Michael Alvarsson
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Acth Stimulation Test ◽  
Acth Stimulation ◽  
Igf I ◽  
Before And After ◽  
Subcutaneous Adipose ◽  
Pioglitazone Treatment

Background. Hypercortisolism and type 2 diabetes (T2D) share clinical characteristics. We examined pioglitazone's effects on the GH-IGF-I and HPA axes in men with varying glucose intolerance. Methods. 10 men with T2D and 10 with IGT received pioglitazone 30–45 mg for 12 weeks. OGTT with microdialysis in subcutaneous adipose tissue and 1 μg ACTH-stimulation test were performed before and after. Glucose, insulin, IGF-I, IGFBP1, and interstitial measurements were analyzed during the OGTT. Insulin sensitivity was estimated using HOMA-IR. Results. HOMA-IR improved in both groups. IGF-I was initially lower in T2D subjects () and increased during treatment ( to SD; ); no change was seen in IGT ( SD before and during treatment). Fasting glycerol decreased in T2D (), indicating reduced lipolysis. Fasting cortisol decreased in T2D ( to  nmol/L; ) but increased in IGT ( to  nmol/L; ). Peak cortisol was lower in T2D during treatment ( to , versus to  nmol/L in IGT; ). Conclusions. Pioglitazone improved adipose tissue and liver insulin sensitivity in both groups. This may explain increased IGF-I in T2D. Pioglitazone affected cortisol levels in both groups but differently, suggesting different mechanisms for improving insulin sensitivity between T2D and IGT.

scholarly journals Adipose Tissue-Derived Signatures for Obesity and Type 2 Diabetes: Adipokines, Batokines and MicroRNAs

2019 ◽  
Vol 8 (6) ◽  
pp. 854 ◽  
Author(s):  
Min-Woo Lee ◽  
Mihye Lee ◽  
Kyoung-Jin Oh
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Metabolic Disturbances ◽  
Endocrine Organ ◽  
Brown Adipose ◽  
Exosomal Mirnas ◽  
Exosomal Mirna

Obesity is one of the main risk factors for type 2 diabetes mellitus (T2DM). It is closely related to metabolic disturbances in the adipose tissue that primarily functions as a fat reservoir. For this reason, adipose tissue is considered as the primary site for initiation and aggravation of obesity and T2DM. As a key endocrine organ, the adipose tissue communicates with other organs, such as the brain, liver, muscle, and pancreas, for the maintenance of energy homeostasis. Two different types of adipose tissues—the white adipose tissue (WAT) and brown adipose tissue (BAT)—secrete bioactive peptides and proteins, known as “adipokines” and “batokines,” respectively. Some of them have beneficial anti-inflammatory effects, while others have harmful inflammatory effects. Recently, “exosomal microRNAs (miRNAs)” were identified as novel adipokines, as adipose tissue-derived exosomal miRNAs can affect other organs. In the present review, we discuss the role of adipose-derived secretory factors—adipokines, batokines, and exosomal miRNA—in obesity and T2DM. It will provide new insights into the pathophysiological mechanisms involved in disturbances of adipose-derived factors and will support the development of adipose-derived factors as potential therapeutic targets for obesity and T2DM.

scholarly journals Effects of Exenatide and Humalog Mix25 on Fat Distribution, Insulin Sensitivity, and β-Cell Function in Normal BMI Patients with Type 2 Diabetes and Visceral Adiposity

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Xinlei Wang ◽  
Xiaoqin Zhao ◽  
Yunjuan Gu ◽  
Xiaohui Zhu ◽  
Tong Yin ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Magnetic Resonance ◽  
Cell Function ◽  
Visceral Adiposity ◽  
Fibroblast Growth Factor 21 ◽  
Resonance Spectroscopy

In China, most normal BMI (body mass index of ≥18.5 to <25 kg/m2) adults with type 2 diabetes (T2DM) exhibit visceral adiposity. This study compared the effects of exenatide and humalog Mix25 on normal BMI patients with T2DM and visceral adiposity. A total of 95 patients were randomized to receive either exenatide or humalog Mix25 treatment for 24 weeks. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were quantified by magnetic resonance imaging (MRI) and liver fat content (LFC) by liver proton magnetic resonance spectroscopy (1H MRS). Each patient’s weight, waist circumference, BMI, blood glucose, insulin sensitivity, pancreatic β-cell function, and fibroblast growth factor 21 (FGF-21) levels were measured. Data from 81 patients who completed the study (40 and 41 in the exenatide and humalog Mix25 groups, respectively) were analysed. The change in 2 h plasma blood glucose was greater in the exenatide group (P=0.039). HOMA-IR and MBCI improved significantly after exenatide therapy (P<0.01, P=0.045). VAT and LFC decreased in both groups (P<0.01 for all) but to a greater extent in the exenatide group, while SAT only decreased with exenatide therapy (P<0.01). FGF-21 levels declined more in the exenatide group (P<0.01), but were positively correlated with VAT in the entire cohort before (r=0.244, P=0.043) and after (r=0.290, P=0.016) the intervention. The effects of exenatide on glycaemic metabolism, insulin resistance, pancreatic β-cell function, and fat deposition support its administration to normal BMI patients with T2DM and visceral adiposity.

scholarly journals Inhibition of Protein Tyrosine Phosphatase-1B with Antisense Oligonucleotides Improves Insulin Sensitivity and Increases Adiponectin Concentrations in Monkeys

Endocrinology ◽  
2009 ◽  
Vol 150 (4) ◽  
pp. 1670-1679 ◽  
Author(s):  
Michael M. Swarbrick ◽  
Peter J. Havel ◽  
Arthur A. Levin ◽  
Andrew A. Bremer ◽  
Kimber L. Stanhope ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Protein Tyrosine Phosphatase ◽  
Antisense Oligonucleotides ◽  
Tyrosine Phosphatase ◽  
Ptp 1B ◽  
Insulin Responses

Protein tyrosine phosphatase (PTP)-1B antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To date, studies of PTP-1B have been limited by the availability of specific antagonists; however, treatment of rodents with antisense oligonucleotides (ASOs) directed against PTP-1B improves insulin sensitivity, inhibits lipogenic gene expression, and reduces triglyceride accumulation in liver and adipose tissue. Here we investigated ASO-mediated PTP-1B inhibition in primates. First, PTP-1B ASO (ISIS 113715) dose-dependently inhibited PTP-1B mRNA and protein expression in cultured monkey hepatocytes. Subcutaneous administration of ISIS 113715 reduced PTP-1B mRNA expression in liver and adipose tissue of normal-weight monkeys by 40–50% and improved insulin sensitivity during an iv glucose tolerance test (IVGTT). In obese, insulin-resistant rhesus monkeys, treatment with 20 mg/kg ISIS 113715 for 4 wk reduced fasting concentrations of insulin and glucose and reduced insulin responses during an IVGTT. In these animals, adiponectin concentrations were also increased by 70%, most of which was an increase of high-molecular-weight oligomers. These effects were not observed in monkeys on a lower, dose-escalation regimen (1–10 mg/kg over 9 wk). Overall, the increase of adiponectin concentrations during ISIS 113715 treatment was correlated with the lowering of insulin responses during IVGTT (r = −0.47, P = 0.042). These results indicate that inhibition of PTP-1B with ASOs such as ISIS 113715 may be a viable approach for the treatment and prevention of obesity-associated insulin resistance and type 2 diabetes because they potently increase adiponectin concentrations in addition to improving insulin sensitivity.

Gender differences in non-glycemic responses to improved insulin sensitivity by pioglitazone treatment in patients with type 2 diabetes

2013 ◽  
Vol 51 (2) ◽  
pp. 185-192 ◽  
Author(s):  
Lisa Arnetz ◽  
Mozhgan Dorkhan ◽  
Michael Alvarsson ◽  
Kerstin Brismar ◽  
Neda Rajamand Ekberg
Keyword(s):  
Type 2 Diabetes ◽  
Gender Differences ◽  
Insulin Sensitivity ◽  
Pioglitazone Treatment

scholarly journals Inflammation during obesity is not all bad: evidence from animal and human studies

2013 ◽  
Vol 304 (5) ◽  
pp. E466-E477 ◽  
Author(s):  
Jianping Ye ◽  
Owen P. McGuinness
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Energy Expenditure ◽  
Proinflammatory Cytokines ◽  
Beneficial Effects ◽  
Positive Effects ◽  
Anti Inflammatory ◽  
The Impact

Chronic inflammation is a characteristic of obesity and is associated with accompanying insulin resistance, a hallmark of type 2 diabetes mellitus (T2DM). Although proinflammatory cytokines are known for their detrimental effects on adipose tissue function and insulin sensitivity, their beneficial effects in the regulation of metabolism have not drawn sufficient attention. In obesity, inflammation is initiated by a local hypoxia to augment angiogenesis and improve adipose tissue blood supply. A growing body of evidence suggests that macrophages and proinflammatory cytokines are essential for adipose remodeling and adipocyte differentiation. Phenotypes of multiple lines of transgenic mice consistently suggest that proinflammatory cytokines increase energy expenditure and act to prevent obesity. Removal of proinflammatory cytokines by gene knockout decreases energy expenditure and induces adult-onset obesity. In contrast, elevation of proinflammatory cytokines augments energy expenditure and decreases the risk for obesity. Anti-inflammatory therapies have been tested in more than a dozen clinical trials to improve insulin sensitivity and glucose homeostasis in patients with T2DM, and the results are not encouraging. One possible explanation is that anti-inflammatory therapies also attenuate the beneficial effects of inflammation in stimulating energy expenditure, which may have limited the efficacy of the treatment by promoting energy accumulation. Thus, the positive effects of proinflammatory events should be considered in evaluating the impact of inflammation in obesity and type 2 diabetes.

scholarly journals Quantification of adipose tissue insulin sensitivity

2016 ◽  
Vol 64 (5) ◽  
pp. 989-991 ◽  
Author(s):  
Esben Søndergaard ◽  
Michael D Jensen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Resistant ◽  
Healthy Humans ◽  
Metabolic Defects ◽  
Tissue Resistance

In metabolically healthy humans, adipose tissue is exquisitely sensitive to insulin. Similar to muscle and liver, adipose tissue lipolysis is insulin resistant in adults with central obesity and type 2 diabetes. Perhaps uniquely, however, insulin resistance in adipose tissue may directly contribute to development of insulin resistance in muscle and liver because of the increased delivery of free fatty acids to those tissues. It has been hypothesized that insulin adipose tissue resistance may precede other metabolic defects in obesity and type 2 diabetes. Therefore, precise and reproducible quantification of adipose tissue insulin sensitivity, in vivo, in humans, is an important measure. Unfortunately, no consensus exists on how to determine adipose tissue insulin sensitivity. We review the methods available to quantitate adipose tissue insulin sensitivity and will discuss their strengths and weaknesses.

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