Increasing endogenous PPARγ ligands improves insulin sensitivity and protects against diet-induced obesity without side effects of thiazolidinediones

2021 ◽  
Author(s):  
Yu-Hua Tseng ◽  
Lee-Ming Chuang ◽  
Yi-Cheng Chang ◽  
Meng-Lun Hsieh ◽  
Lun Tsou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Side Effects ◽  
Knockout Mice ◽  
Fasting Glucose ◽  
Binding Mode ◽  
Fluid Retention ◽  
Diet Induced Obesity

Abstract Insulin resistance and obesity are pivotal features of type 2 diabetes mellitus. Peroxisome proliferator-activated receptor γ (PPARγ) is a master transcriptional regulator of systemic insulin sensitivity and energy balance. The anti-diabetic drug thiazolidinediones are potent synthetic PPARγ ligands and insulin sensitizers with undesirable side effects including increased adiposity, fluid retention, and osteoporosis, which limit their clinical use. We and others have proved that 15-keto-PGE2 is an endogenous natural PPARγ ligand. 15-keto-PGE2 is catalyzed by prostaglandin reductase 2 (PTGR2) to become inactive metabolites. We found that 15-keto-PGE2 level is increased in Ptgr2 knockout mice. Ptgr2 knockout mice were protected from diet-induced obesity, insulin resistance, and hepatic steatosis without fluid retention nor reduced bone mineral density. Diet-induced obese mice have drastically reduced 15-keto-PGE2 levels compared to lean mice. Administration of 15-keto-PGE2 markedly improved insulin sensitivity and prevented diet-induced obesity in mice. We demonstrated that 15-keto-PGE2 activates PPARγ through covalent binding to its cysteine 285 residue at helix 3, which restrained its binding pocket between helix 3 and β-sheets of the PPARγ ligand binding domain. This binding mode differs from the helix12-dependent binding mode of thiazolidinediones. We further identified a small-molecule PTGR2 inhibitor BPRPT245, which interferes the interaction between the substrate-binding sites of PTGR2 and 15-keto-PGE2. BPRPT245 increased 15-keto-PGE2 concentration, activated PPARγ, and promoted glucose uptake in adipocytes. BPRPT245 also prevented diet-induced obesity, improved insulin sensitivity and glucose tolerance, lowers fasting glucose without fluid retention and osteoporosis. In humans, reduced serum 15-keto-PGE2 levels were observed in patients with type 2 diabetes compared with controls. Furthermore, serum 15-keto-PGE2 levels correlate inversely with insulin resistance and fasting glucose in non-diabetic humans. In conclusion, we identified a new therapeutic approach to improve insulin sensitivity and protect diet-induced obesity through increasing endogenous natural PPARγ ligands without side effects of thiazolidinediones.

scholarly journals Effect of Salivary Exosomal miR-25-3p on Periodontitis With Insulin Resistance

2022 ◽  
Vol 12 ◽  
Author(s):  
Jin-Seok Byun ◽  
Ho Yeop Lee ◽  
Jingwen Tian ◽  
Ji Sun Moon ◽  
Jaejin Choi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
T Cells ◽  
Immune Cells ◽  
Γδ T Cells ◽  
Healthy Individuals ◽  
Local Inflammation ◽  
Diet Induced Obesity ◽  
Exosomal Mirna

Periodontitis is caused by an oral microbial dysbiosis-mediated imbalance of the local immune microenvironment, which is promoted by insulin resistance and obesity. The prevalence and severity of periodontitis is higher in patients with type 2 diabetes than in healthy individuals, possibly because of differences in immune responses. The level of glycemic control also affects the saliva profile, which may further promote periodontal disease in diabetes patients. Therefore, we compared the salivary exosomal miRNA profiles of patients with type 2 diabetes with those of healthy individuals, and we found that exosomal miR-25-3p in saliva is significantly enriched (by approximately 2-fold, p < 0.01) in obese patients with type 2 diabetes. We also identified CD69 mRNA as a miR-25-3p target that regulates both activation of γδ T cells and the inflammatory response. Knockdown of CD69 increased (by approximately 2-fold) interleukin-17A production of γδ T cells in vitro. To evaluate the role of exosomal miRNA on progression of periodontitis, we analyzed regional immune cells in both periodontal tissues and lymph nodes from mice with periodontitis. We found that diet-induced obesity increased the population of infiltrating pro-inflammatory immune cells in the gingiva and regional lymph nodes of these mice. Treatment with miR-25-3p inhibitors prevented the local in vivo inflammatory response in mice with periodontitis and diet-induced obesity. Finally, we showed that suppression of interleukin 17-mediated local inflammation by a miR-25-3p inhibitor alleviated (by approximately 34%) ligature-induced periodontal alveolar bone loss in mice. Taken together, these data suggest that exosomal miR-25-3p in saliva contributes to development and progression of diabetes-associated periodontitis. Discovery of additional miR-25-3p targets may provide critical insights into developing drugs to treat periodontitis by regulating γδ T cell-mediated local inflammation.

scholarly journals Common Risk Factors in Relatives and Spouses of Patients with Type 2 Diabetes in Developing Prediabetes

Healthcare ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1010
Author(s):  
Wei-Hao Hsu ◽  
Chin-Wei Tseng ◽  
Yu-Ting Huang ◽  
Ching-Chao Liang ◽  
Mei-Yueh Lee ◽  
...  
Keyword(s):  
Risk Factors ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Cell Function ◽  
Diabetic Patients ◽  
Β Cell ◽  
Tyg Index ◽  
Β Cell Function

Prediabetes should be viewed as an increased risk for diabetes and cardiovascular disease. In this study, we investigated its prevalence among the relatives and spouses of patients with type 2 diabetes or risk factors for prediabetes, insulin resistance, and β-cell function. A total of 175 individuals were included and stratified into three groups: controls, and relatives and spouses of type 2 diabetic patients. We compared clinical characteristics consisting of a homeostatic model assessment for insulin resistance (HOMA-IR) and beta cell function (HOMA-β), a quantitative insulin sensitivity check index (QUICKI), and triglyceride glucose (TyG) index. After a multivariable linear regression analysis, the relative group was independently correlated with high fasting glucose, a high TyG index, and low β-cell function; the relatives and spouses were independently associated with a low QUICKI. The relatives and spouses equally had a higher prevalence of prediabetes. These study also indicated that the relatives had multiple factors predicting the development of diabetes mellitus, and that the spouses may share a number of common environmental factors associated with low insulin sensitivity.

Vascular dysfunction and insulin stimulated blood flow : impact of physical inactivity and type 2 diabetes

2014 ◽  
Author(s):  
◽  
Leryn J. Boyle
Keyword(s):  
Physical Activity ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Blood Flow ◽  
Insulin Sensitivity ◽  
Endothelial Function ◽  
Physical Inactivity ◽  
Vascular Dysfunction ◽  
Insulin Stimulation

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Individuals with type 2 diabetes (T2D) have blunted femoral artery insulin mediated blood flow which is critical for the delivery and uptake of glucose into skeletal muscle. However, it is unclear in humans the precise mechanisms by which insulin resistance impairs insulin stimulated blood flow. Further, chronic physical inactivity is a powerful stimulus for reduced insulin sensitivity and vascular dysfunction; however, the effects of short term, modest reductions in physical activity are limited. Thus, we examined 1) if inactivity for 5 days would impair endothelial function in healthy individuals (study one) 2) if reducing whole body insulin sensitivity, via 5 days of inactivity, would impair the blood flow response to insulin stimulation in parallel with glycemic control (study two) and 3) phosphorylation of endothelial nitric oxide (eNOS) and endothelin-1 (ET-1) production to insulin stimulation would be decreased and increased, respectively, in insulin resistant individuals (study three). We demonstrated significant reductions in endothelial function with only 5 days of reduced daily steps while blood flow to glucose ingestion was unaltered. Further, in obese humans with type 2 diabetes it does not appear that that the reduction in blood flow to 1 hr of insulin stimulation is due to altered peNOS or ET-1. Collectively, these data suggest that reduced daily physical activity and chronic insulin resistance mediate negative impacts on vascular function and insulin stimulated blood flow and signaling.

Abstract 209: Dimethylarginine Dimethylaminohydrolase 1 and Insulin Resistance

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Sophie E Piper ◽  
James M Leiper
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Plasma Glucose ◽  
Knockout Mice ◽  
Physiological Role ◽  
Causal Link ◽  
Chow Diet ◽  
Dimethylarginine Dimethylaminohydrolase

Type 2 diabetes is a prevalent metabolic condition and is the result of an impaired response to insulin. Insulin resistance and type 2 diabetes are clearly associated with obesity and the secondary cardiovascular complications of this condition are serious and life threatening. Asymemetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases and increased levels are seen in multiple pathologies. Increased plasma levels of ADMA have been associated with patients with type 2 diabetes, insulin resistance and obesity, although a causal link between ADMA and diabetes has not been established. Dimethylarginine dimethylaminohydrolase (DDAH) is the enzyme that catalyses the metabolism of ADMA. There are two isoforms of the enzyme which are both involved in the control of ADMA and NO. The interplay of insulin with NO release is well established but the initial causes for the onset of insulin resistance are not well defined. Elevated levels of ADMA are linked to insulin resistance and transgenic mice that over-express ddah1 show increased insulin sensitivity. Of note is that metformin, an insulin sensitising drug that is widely used in the treatment of insulin resistance, reduces plasma glucose and ADMA concentrations. In order to elucidate the physiological role of DDAH1 in glucose homeostasis we investigated the glucose handling in a ddah1 global knockout model. Intra-peritoneal glucose tolerance tests in ddah1 global knockout mice demonstrate insulin resistance. Baseline plasma glucose levels were 25% higher in ddah1 knockouts and peak levels were 53% higher in ddah1 knockouts. The kinetics of plasma glucose accumulation and clearance in ddah1 knockout mice suggests dysfunction in both the liver and skeletal muscle. On a normal chow diet, hepatocyte specific ddah1 knockout mice and skeletal muscle specific ddah1 knockout mice show no insulin resistance. On a high fat diet however the hepatocyte specific ddah1 knockout mice show significant insulin resistance and lower metabolic rate than their fat fed wild-type counterparts. These studies demonstrate for the first time a causal link between ADMA accumulation and insulin resistance. Furthermore these data establish DDAH1 activity is a significant regulator of insulin resistance.

scholarly journals Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Denise E. Lackey ◽  
Felipe C. G. Reis ◽  
Roi Isaac ◽  
Rizaldy C. Zapata ◽  
Dalila El Ouarrat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Target Genes ◽  
Obese Mice ◽  
Tissue Macrophage

Abstract Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity.

scholarly journals Effect of folate supplementation on insulin sensitivity and type 2 diabetes: a meta-analysis of randomized controlled trials

2019 ◽  
Vol 109 (1) ◽  
pp. 29-42 ◽  
Author(s):  
Mads Vendelbo Lind ◽  
Lotte Lauritzen ◽  
Mette Kristensen ◽  
Alastair B Ross ◽  
Jane Nygaard Eriksen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Randomized Controlled Trials ◽  
Fasting Glucose ◽  
Meta Analysis ◽  
Controlled Trials ◽  
Folate Supplementation ◽  
Randomized Controlled ◽  
Meta Analyses

ABSTRACT Background Various mechanisms link higher total homocysteine to higher insulin resistance (IR) and risk of type 2 diabetes (T2D). Folate supplementation is recognized as a way to lower homocysteine. However, randomized controlled trials (RCTs) show inconsistent results on IR and T2D outcomes. Objective The aim of this study was to examine the effect of folate supplementation on IR and T2D outcomes. Design We conducted a systematic literature search in PubMed, Web of Science, and EMBASE and prior systematic reviews and meta-analyses and identified 29 RCTs (22,250 participants) that assessed the effect of placebo-controlled folate supplementation alone or in combination with other B vitamins on fasting glucose, insulin, homeostasis model assessment for insulin resistance (HOMA-IR), glycated hemoglobin (HbA1c), or risk of T2D. The meta-analysis was conducted using both random- and fixed-effects models to calculate weighted mean differences (WMDs) or risk ratios with 95% CIs. Subgroup analyses were conducted based on intervention type (folate alone or in combination with other B vitamins), as well as analysis based on population characteristics, duration, dose, and change in homocysteine. Results When compared with placebo, folate supplementation lowered fasting insulin (WMD: −13.47 pmol/L; 95% CI: −21.41, −5.53 pmol/L; P < 0.001) and HOMA-IR (WMD: −0.57 units; 95% CI: −0.76, −0.37 units; P < 0.0001), but no overall effects were observed for fasting glucose or HbA1c. Heterogeneity was low in all meta-analyses, and subgroup analysis showed no signs of effect modification except for change in homocysteine, with the most pronounced effects in trials with a change of >2.5 µmol/L. Changes in homocysteine after folate supplementation correlated with changes in fasting glucose (β = 0.07; 95% CI: 0.01, 0.14; P = 0.025) and HbA1c (β = 0.46; 95% CI: 0.06, 0.85; P = 0.02). Only 2 studies examined folate supplementation on risk of T2D, and they found no change in RR (pooled RR: 0.91; 95% CI: 0.80, 1.04; P = 0.16). Conclusion Folate supplementation might be beneficial for glucose homeostasis and lowering IR, but at present there are insufficient data to conclusively determine the effect on development of T2D. This trial was registered on the Prospero database as CRD42016048254.

scholarly journals Legume consumption and its association with fasting glucose, insulin resistance and type 2 diabetes in the Indian Migration Study

2016 ◽  
Vol 19 (16) ◽  
pp. 3017-3026 ◽  
Author(s):  
Preet K Dhillon ◽  
Liza Bowen ◽  
Sanjay Kinra ◽  
Ankalmadugu Venkatsubbareddy Bharathi ◽  
Sutapa Agrawal ◽  
...  
Keyword(s):  
Physical Activity ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Large Scale ◽  
Fasting Glucose ◽  
Epidemiological Studies ◽  
Model Assessment ◽  
Dietary Intakes ◽  
Migration Status

AbstractObjectiveLegume consumption is associated with lower fasting glucose (FG) and insulin levels in nutrition trials and lower CVD mortality in large-scale epidemiological studies. In India, legumes are widely consumed in various preparations, yet no epidemiological study has evaluated the association of legumes with FG levels, insulin resistance and diabetes risk. The present study aimed to fill this gap.DesignFasting blood samples, in-person interviews to obtain information on demographic/socio-economic factors, physical activity, alcohol and tobacco use, and anthropometric measurements were collected. Dietary intakes were assessed by an interviewer-administered, validated, semi-quantitative FFQ.SettingLucknow, Nagpur, Hyderabad and Bangalore, India.SubjectsMen and women (n 6367) aged 15–76 years – urban residents, urban migrants and their rural siblings.ResultsIn multivariate random-effects models adjusted for age, BMI, total energy intake, macronutrients, physical activity and rural/migration status, daily legume consumption was not associated with FG (P-for-trend=0·78), insulin resistance (homeostasis model assessment score; P-for-trend=0·73) or the prevalence of type 2 diabetes mellitus (P-for-trend=0·41). Stratified analyses by vegetarian diet and migration status did not change the findings. Inverse associations between legumes and FG emerged for participants with lower BMI and higher carbohydrate, protein, fat and sugar intakes.ConclusionsAlthough legumes are essential in traditional Indian diets, as well as in prudent and Mediterranean diets in the West, we did not find an association between legumes and markers of glycaemic control, insulin resistance or diabetes, except for subgroups based on BMI and macronutrient intake. The ubiquitous presence and complexity of legume preparations in Indian diets may contribute to these findings.

Coffee consumption and type 2 diabetes — An extensive review

Open Medicine ◽  
2008 ◽  
Vol 3 (1) ◽  
pp. 9-19 ◽  
Author(s):  
Siamak Bidel ◽  
Gang Hu ◽  
Jaakko Tuomilehto
Keyword(s):  
Type 2 Diabetes ◽  
Clinical Trials ◽  
Insulin Sensitivity ◽  
Fasting Glucose ◽  
Complex Mixture ◽  
Coffee Consumption ◽  
Epidemiological Studies ◽  
Extensive Review

AbstractCoffee is a complex mixture of potentially active chemicals. It contains significant amounts of phenolic polymers, chlorogenic acid and also caffeine. Agricultural factors, roasting, blending, and brewing determine coffee’s chemical composition. Recent epidemiological studies suggest that habitual coffee consumption may help to prevent some chronic diseases including type 2 diabetes. Despite reports from the clinical trials of the effect of caffeine on decreasing insulin sensitivity, long-term prospective studies revealed that coffee may improve fasting glucose, glucose tolerance and insulin sensitivity as well. In the most recent publication habitual coffee drinkers have a lower total and cardiovascular mortality rate among diabetic subjects.

scholarly journals Ethnic distinctions in the pathophysiology of type 2 diabetes: a focus on black African-Caribbean populations

2019 ◽  
Vol 79 (2) ◽  
pp. 184-193 ◽  
Author(s):  
Louise M. Goff ◽  
Meera Ladwa ◽  
Olah Hakim ◽  
Oluwatoyosi Bello
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Global Public Health ◽  
Black African ◽  
African Caribbean ◽  
Black Populations ◽  
The Impact ◽  
Caribbean Populations

Type 2 diabetes (T2D) is a global public health priority, particularly for populations of black African-Caribbean ethnicity, who suffer disproportionately high rates of the disease. While the mechanisms underlying the development of T2D are well documented, there is growing evidence describing distinctions among black African-Caribbean populations. In the present paper, we review the evidence describing the impact of black African-Caribbean ethnicity on T2D pathophysiology. Ethnic differences were first recognised through evidence that metabolic syndrome diagnostic criteria fail to detect T2D risk in black populations due to less central obesity and dyslipidaemia. Subsequently more detailed investigations have recognised other mechanistic differences, particularly lower visceral and hepatic fat accumulation and a distinctly hyperinsulinaemic response to glucose stimulation. While epidemiological studies have reported exaggerated insulin resistance in black populations, more detailed and direct measures of insulin sensitivity have provided evidence that insulin sensitivity is not markedly different to other ethnic groups and does not explain the hyperinsulinaemia that is exhibited. These findings lead us to hypothesise that ectopic fat does not play a pivotal role in driving insulin resistance in black populations. Furthermore, we hypothesise that hyperinsulinaemia is driven by lower rates of hepatic insulin clearance rather than heightened insulin resistance and is a primary defect rather than occurring in compensation for insulin resistance. These hypotheses are being investigated in our ongoing South London Diabetes and Ethnicity Phenotyping study, which will enable a more detailed understanding of ethnic distinctions in the pathophysiology of T2D between men of black African and white European ethnicity.

scholarly journals Association of Vitamin D with Type 2 Diabetes in Postmenopausal Females in Saudi Arabia

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Shatha Alharazy ◽  
Eman Alissa ◽  
Mohammed Ardawi ◽  
Susan Lanham-New ◽  
M. Denise Robertson
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Vitamin D ◽  
Saudi Arabia ◽  
Insulin Sensitivity ◽  
Postmenopausal Women ◽  
Cell Activity ◽  
Study Cohort ◽  
Model Assessment

AbstractVitamin D (vitD) deficiency has been suspected as a risk factor for type 2 diabetes mellitus (T2DM). It has been reported that an inverse relationship exists between vitD status and risk of T2DM. The aim of this study was to investigate whether there is an association between vitD status and glycemic profile and other metabolic parameters among postmenopausal women with T2DM (living in Saudi Arabia). A cross-sectional study was conducted at King Fahad Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia. One thirty six (n = 136) postmenopausal females (age ≥ 50 years) living in Jeddah city, Saudi Arabia, with T2DM were randomly recruited in this study. Anthropometric measures, blood pressure readings and fasting blood samples were obtained fro all study participants. Several biochemical parameters were estimated in fasting serum samples including total 25(OH)D, HbA1c, insulin, glucose, c-peptide and lipid profile. Surrogate markers for insulin resistance were calculated using Homeostasis Model Assessment for insulin resistance and beta cell activity (HOMA-IR, HOMA-β), Quantitative insulin sensitivity check index (QUICK-I) and McAuley's index. VitD deficiency was defined as serum total 25(OH)D level below 20 ng/ml.The Mean (± SD) serum levels of total 25(OH)D were 13.8 ± 8.6 ng/ml with 79% of the study cohort being vitD deficient. Furthermore, serum total 25(OH)D levels were found to be inversely correlated with fasting insulin (r = -0.24, p = 0.029), HOMA-IR (r = -0.24, p = 0.03), and positively correlated with McAuley's index (r = 0.22, p = 0.048) and QUICK-I (r = 0.25, p = 0.024). In conclusion, vitD deficiency is highly prevalent among postmenopausal women with T2DM living in Jeddah, Saudi Arabia. VitD was found to be associated with insulin resistance. Whether vitD supplements are able to improve insulin sensitivity and other parameters in T2DM postmenopausal women should be further investigated.

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