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'Fat's chances': Loci for phenotypic dispersion in plasma leptin in mouse models of diabetes mellitus.

ABSTRACT: BACKGROUND:Leptin, a critical mediator of feeding, metabolism and diabetes, is expressed on an incidental basis according to satiety. The genetic regulation of leptin should similarly be episodic. METHODOLOGY:Data from three mouse cohorts hosted by the Jackson Laboratory- 402 (174F, 228M) F2 Dilute Brown non-Agouti (DBA/2)×DU6i intercrosses, 142 Non Obese Diabetic (NOD/ShiLtJ×(NOD/ShiLtJ×129S1/SvImJ.H2g7) N2 backcross females, and 204 male Nonobese Nondiabetic (NON)×New Zealand Obese (NZO/HlLtJ) reciprocal backcrosses-were used to test for loci associated with absolute residuals in plasma leptin and arcsin-transformed percent fat ('phenotypic dispersion'; PDpLep and PDAFP). Individual data from 1,780 mice from 43 inbred strains was also used to estimate genetic variances and covariances for dispersion in each trait. PRINCIPAL FINDINGS:Several loci for PDpLep were detected, including possibly syntenic Chr 17 loci, but there was only a single position on Chr 6 for PDAFP. Coding SNP in genes linked to the consensus Chr 17 PDpLep locus occurred in immunological and cancer genes, genes linked to diabetes and energy regulation, post-transcriptional processors and vomeronasal variants. There was evidence of intersexual differences in the genetic architecture of PDpLep. PDpLep had moderate heritability [Formula: see text] and PDAFP low heritability [Formula: see text]; dispersion in these traits was highly genetically correlated r = 0.8). CONCLUSIONS:Greater genetic variance for dispersion in plasma leptin, a physiological trait, may reflect its more ephemeral nature compared to body fat, an accrued progressive character. Genetic effects on incidental phenotypes such as leptin might be effectively characterized with randomization-detection methodologies in addition to classical approaches, helping identify incipient or borderline cases or providing new therapeutic targets.

SUBMITTER: Perry GML

PROVIDER: S-EPMC6818960 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aims/hypothesisLow physical fitness (PF) is a risk factor for type 2 diabetes mellitus (T2D). Women with a history of gestational diabetes (GDM) are at risk for T2D at a young age, but the role of PF in this population is not clear. PF has also been found to correlate inversely with plasma leptin in previous studies. Here, we examine whether women who had GDM have lower PF than women after a normoglycemic pregnancy and, second, whether PF is associated with plasma leptin, independently of body fat mass.MethodsCross-sectional analysis of 236 participants in the PPSDiab Study (cohort study of women 3-16 months after delivery, 152 after gestational diabetes (pGDM), 84 after normoglycemic pregnancy (control subjects); consecutively recruited 2011-16); medical history, physical examination with bioelectrical impedance analysis (BIA), whole body magnetic resonance imaging (MRI) (n = 154), 5-point oral glucose tolerance test, cardiopulmonary exercise testing, clinical chemistry including fasting plasma leptin; statistical analysis with Mann-Whitney U and t -test, Spearman correlation coefficient, multiple linear regression.ResultsWomen pGDM had lower maximally achieved oxygen uptake (VO2peak/kg: 25.7(21.3-29.9) vs. 30.0(26.6-34.1)ml/min/kg; total VO2peak: 1733(1552-2005) vs. 1970(1767-2238)ml/min; p<0.0001 for both), and maximum workload (122.5(105.5-136.5) vs. 141.0(128.5-159.5)W; p<0.0001). Fasting plasma leptin correlated inversely with PF (VO2peak/kg ? = -0.72 p<0.0001; VO2peak ? = -0.16 p = 0.015; max. load ? = -0.35 p<0.0001). These associations remained significant with adjustment for body mass index, or for body fat mass (BIA and MRI).Conclusions/interpretationWomen with a recent history of GDM were less fit than control subjects. Low PF may therefore contribute to the risk for T2D after GDM. This should be tested in intervention studies. Low PF also associated with increased leptin levels-independently of body fat. PF may therefore influence leptin levels and signaling. This hypothesis requires further investigation.

Project description:BACKGROUND:Diabetes Mellitus is an increasingly prevalent chronic disease characterized by the body's inability to metabolize glucose. The objective of this study was to build an effective predictive model with high sensitivity and selectivity to better identify Canadian patients at risk of having Diabetes Mellitus based on patient demographic data and the laboratory results during their visits to medical facilities. METHODS:Using the most recent records of 13,309 Canadian patients aged between 18 and 90 years, along with their laboratory information (age, sex, fasting blood glucose, body mass index, high-density lipoprotein, triglycerides, blood pressure, and low-density lipoprotein), we built predictive models using Logistic Regression and Gradient Boosting Machine (GBM) techniques. The area under the receiver operating characteristic curve (AROC) was used to evaluate the discriminatory capability of these models. We used the adjusted threshold method and the class weight method to improve sensitivity - the proportion of Diabetes Mellitus patients correctly predicted by the model. We also compared these models to other learning machine techniques such as Decision Tree and Random Forest. RESULTS:The AROC for the proposed GBM model is 84.7% with a sensitivity of 71.6% and the AROC for the proposed Logistic Regression model is 84.0% with a sensitivity of 73.4%. The GBM and Logistic Regression models perform better than the Random Forest and Decision Tree models. CONCLUSIONS:The ability of our model to predict patients with Diabetes using some commonly used lab results is high with satisfactory sensitivity. These models can be built into an online computer program to help physicians in predicting patients with future occurrence of diabetes and providing necessary preventive interventions. The model is developed and validated on the Canadian population which is more specific and powerful to apply on Canadian patients than existing models developed from US or other populations. Fasting blood glucose, body mass index, high-density lipoprotein, and triglycerides were the most important predictors in these models.

Project description:The global incidence of diabetes mellitus (DM) is increasing. Types 1 and 2 DM are associated with declining β-cell function. Verapamil (50% S-verapamil and 50% R-verapamil) can treat DM by downregulating thioredoxin-interacting protein (TXNIP), which induces islet β-cell apoptosis. However, it may also induce cardiovascular side effects as S-verapamil is negatively inotropic. In contrast, R-verapamil only weakly induces adverse cardiac effects. In this study, we aimed to determine the antidiabetic efficacy and cardiovascular safety of R-verapamil. We examined R- and S-verapamil binding through in vitro studies. Streptozotocin-induced type 1 and db/db type 2 DM mouse models were used to assess the antidiabetic efficacy of verapamil. IL-6, blood glucose (BG), Txnip expression, and β-cells were evaluated in streptozotocin-induced diabetic mice, while body weight, BG, and serum insulin were measured in the db/db mice. In the type 1 DM study, 100 mg/kg/day R-verapamil and racemic verapamil lowered BG, downregulated Txnip expression, and reduced β-cell apoptosis. In the type 2 DM study, the optimal R-verapamil dosage was 60 mg/kg/day and it lowered BG and raised serum insulin. However, efficacy did not increase with R-verapamil dosage. R-verapamil combined with metformin/acarbose improved BG and serum insulin more effectively than metformin/acarbose alone or verapamil combined with acarbose. R-verapamil had weaker cardiovascular side effects than S-verapamil. R-verapamil was 9.0× and 3.4× less effective than S-verapamil at inhibiting atrial inotropy and ileal contractility, respectively. It was also 8.7× weaker than S-verapamil as an agonist of somatostatin receptor type 2 (SSTR2), inhibiting ileal neurogenic contraction. Hence, R-verapamil may be an optimal DM treatment as it is safe, improves glycemic control, and preserves β-cell function both as monotherapy and in combination with metformin or acarbose. R-Verapamil has potential for delaying or arresting DM progression and improving patients' quality of life.

Project description:Insulin and leptin have proliferative and anti-apoptotic effects. Ghrelin promotes gastric emptying and secretion of growth hormone and inhibits inflammation. We assessed whether diabetes mellitus and serum levels of insulin, leptin, and ghrelin are associated with gastroesophageal reflux disease (GERD) and Barrett's esophagus.We conducted a case-control study in 822 men undergoing colorectal cancer screening who were recruited to also undergo upper endoscopy. We identified 70 with Barrett's esophagus; 80 additional men with Barrett's esophagus were recruited shortly after their clinical diagnoses. Serum levels of insulin, leptin, and ghrelin were assayed in all 104 fasting men with Barrett's esophagus without diabetes and 271 without diabetes or Barrett's esophagus. Logistic regression was used to estimate the effects of diabetes and levels of insulin, leptin, and ghrelin on GERD and Barrett's esophagus.Among men with GERD, diabetes was inversely associated with Barrett's esophagus (adjusted odds ratio [OR] = 0.383; 95% confidence interval [CI]: 0.179-0.821). Among nondiabetics, hyperinsulinemia was positively associated with Barrett's esophagus, but the association was attenuated by adjustment for leptin and ghrelin. Leptin was positively associated with Barrett's esophagus, adjusting for obesity, GERD, and levels of insulin and ghrelin (OR for 3(rd) vs 1(st) tertile = 3.25; 95% CI: 1.29-8.17); this association was stronger in men with GERD (P = .01 for OR heterogeneity). Ghrelin was positively associated with Barrett's esophagus (OR for an increment of 400 pg/mL = 1.39; 95% CI: 1.09-1.76), but inversely associated with GERD (OR for 3(rd) vs 1(st) tertile = 0.364; 95% CI: 0.195-0.680).Based on a case-control study, leptin was associated with Barrett's esophagus, particularly in men with GERD. Serum insulin level was associated with Barrett's esophagus, but might be mediated by leptin. Serum ghrelin was inversely associated with GERD, as hypothesized, but positively associated with Barrett's esophagus, contrary to our hypothesis. Additional studies are needed in men and women to replicate these findings.

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'Fat's chances': Loci for phenotypic dispersion in plasma leptin in mouse models of diabetes mellitus.

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