Evidence for Genetic Factors Underlying the Insulin Resistance Syndrome in American Indians

Previous analyses of American Indians of the Strong Heart Study have demonstrated that various insulin‐resistance variables cluster, although knowledge about the genetic determination of these clusters is unknown. In an effort to explore the influences on the aggregation of insulin‐resistance phenotypes, we used principal component factor analysis to examine the clustering of these phenotypes in participants of the Strong Heart Family Study and evaluated the genetic and environmental contributions of such factors. Nine traits were chosen for principal component factor analysis: BMI, diastolic blood pressure, fasting glucose, high‐density lipoprotein‐cholesterol, natural log‐transformed insulin, natural log‐transformed triglycerides, percentage of body fat, systolic blood pressure, and waist‐to‐hip ratio. Analyses revealed three clusters: glucose/insulin/obesity, blood pressure, and dyslipidemia factors. Using a variance component approach and accounting for the effects of age, sex, center, and medication, we detected significant heritabilities (h²) for the three factors: h² = 0.67, h² = 0.33, and h² = 0.61, respectively. In multivariate analysis, no significant genetic correlations among factors were found. These results suggest that heredity explains a substantial proportion of the variability of the factors that underlie the insulin resistance syndrome in American Indians and that these factors are genetically independent.     

Leptin Predicts a Worsening of the Features of the Metabolic Syndrome Independently of Obesity

Objective: The term metabolic syndrome (MS) describes a cluster of cardiovascular risk factors including dyslipidemia, glucose intolerance, insulin resistance, and hypertension. Obesity increases the risk of MS, but as obesity is neither necessary nor sufficient to cause the syndrome, there is considerable interest in identifying obesity‐independent pathways. One such pathway may involve the actions of the adipokine leptin, which is associated cross‐sectionally with MS and prospectively with coronary heart disease and stroke, independently of obesity. Our goal was to test the hypothesis that leptin predicts the development of the features of MS independently of obesity. Research Methods and Procedures: This study used a prospective population‐based cohort of 748 middle‐aged whites in whom baseline measures of leptin and repeated measurement of the subcomponents of the MS at 5 and 10 years were available. The features of the MS were characterized as five factors (obesity, dyslipidemia, elevated blood pressure, glucose intolerance, and insulin resistance), which were combined to create an MS summary score. Results: Baseline leptin significantly predicted the development of obesity (p = 0.001) and, after adjustment for BMI, development of glucose intolerance (p = 0.016) and insulin resistance (p < 0.0001). Leptin levels did not independently predict a change in lipids or blood pressure. Leptin levels significantly predicted the development of the MS (p = 0.036), independently of baseline BMI. Discussion: Leptin predicts the development of the MS independently of baseline obesity. This association is specifically related to the development of glucose intolerance and insulin resistance. The extent to which these relationships are explained through residual confounding by obesity remains to be determined.     

Increased Levels of Plasma Acylcarnitines in Obesity and Type 2 Diabetes and Identification of a Marker of Glucolipotoxicity

Dysregulation of fatty acid oxidation (FAO) is recognized as important in the pathophysiology of obesity and insulin resistance (IR). However, demonstrating FAO defects in vivo in humans has entailed complex and invasive methodologies. Recently, the identification of genetic blocks in FAO has been vastly simplified by using tandem mass spectrometry (MS/MS) of dried bloodspots to specify acylcarnitine (AcylCN) alterations characteristic for each disorder. This technology has recently been applied to examine FAO alterations in human and animal models of obesity and type 2 diabetes mellitus (T2DM). This study focused on characterizing AcylCN profiles in human plasma from individuals with obesity and T2DM during fasting and insulin‐stimulated conditions. Following an overnight fast, plasma was obtained from lean (n = 12), obese nondiabetic (n = 14), and T2DM (n = 10) participants and analyzed for AcylCN using MS/MS. Plasma samples were also obtained at the end of a 4‐h insulin‐stimulated euglycemic clamp. In obesity and T2DM, long‐chain AcylCNs were similarly significantly increased in the fasted state; free‐CN levels were also elevated. Additionally, T2DM subjects of comparable BMI had increased short‐ and medium‐chain AcylCNs, both saturated and hydroxy, as well as increased C₄‐dicarboxylcarnitine (C₄DC–CN) that correlated with an index of poor glycemic control (HbA_1c; r = 0.74; P < 0.0001). Insulin infusion reduced all species of plasma AcylCN but this reduction was blunted in T2DM. Plasma long‐chain AcylCN species are increased in obesity and T2DM, suggesting that more fatty acids can enter mitochondria. In T2DM, many shorter species accumulate, suggesting that they have a generalized complex oxidation defect.     

Longitudinal Analyses among Overweight,Insulin Resistance,and Cardiovascular Risk Factors in Children

Objective: It has been questioned whether insulin resistance or obesity is the central abnormality contributing to the cardiovascular risk factors dyslipidemia and hypertension in obesity. Research Methods and Procedures: We studied weight status [SD score (SDS)‐BMI], lipids (triglycerides, low‐density lipoprotein‐ and high‐density lipoprotein‐cholesterol), blood pressure, and insulin resistance index [as homeostasis model assessment (HOMA) model] over a 1‐year period in 229 obese white children (median age 12 years). Results: Any degree of decrease in HOMA was associated with significant decreases in triglycerides (p < 0.001), systolic blood pressure (p < 0.001), and diastolic blood pressure (p < 0.001), whereas the children with different changes in HOMA did not differ significantly in their weight changes. Only the children in the highest quartile of weight reduction (decrease in SDS‐BMI > 0.5) demonstrated a significant decrease in systolic blood pressure (p < 0.001), diastolic blood pressure (p < 0.001), and triglycerides (p = 0.012), and an increase in high‐density lipoprotein‐cholesterol (p = 0.023), whereas with a lower degree of weight loss, there were no significant changes in cardiovascular risk factors. In contrast with a lower degree of weight loss, a reduction of >0.5 SDS‐BMI was associated with a significant decrease in HOMA (p < 0.001). Discussion: Because blood pressure and triglycerides decreased with any degree of decrease in HOMA, independently of changes in weight status, these findings support the hypothesis that insulin resistance is the central abnormality contributing to these cardiovascular risk factors. Therefore, improving insulin resistance seems more important than reducing overweight to prevent or treat hypertension and dyslipidemia in obese children.     

Role of inflammatory mechanisms in pathogenesis of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is characterized by progressive β‐cell dysfunctioning and insulin resistance. This article reviews recent literature with special focus on inflammatory mechanisms that provoke the pathogenesis of T2DM. We have focused on the recent advances in progression of T2DM including various inflammatory mechanisms that might induce inflammation, insulin resistance, decrease insulin secretion from pancreatic islets and dysfunctioning of β‐cells. Here we have also summarized the role of various pro‐inflammatory mediators involved in inflammatory mechanisms, which may further alter the normal structure of β‐cells by inducing pancreatic islet's apoptosis. In conclusion, it is suggested that the role of inflammation in pathogenesis of T2DM is crucial and cannot be neglected. Moreover, the insight of inflammatory responses in T2DM may provide a new gateway for the better treatment of diabetes mellitus. J. Cell. Biochem. 114: 525–531, 2013. © 2012 Wiley Periodicals, Inc.     

Rosiglitazone Improves Glucose Metabolism in Obese Adolescents With Impaired Glucose Tolerance: A Pilot Study

Impaired glucose tolerance (IGT) is a prediabetic state fueling the rising prevalence of type 2 diabetes mellitus (T2DM) in adolescents with marked obesity. Given the importance of insulin resistance, the poor β‐cell compensation and the altered fat partitioning as underlying defects associated with this condition, it is crucial to determine the extent to which these underlying abnormalities can be reversed in obese adolescents. We tested, in a pilot study, whether rosiglitazone (ROSI) restores normal glucose tolerance (NGT) in obese adolescents with IGT by improving insulin sensitivity and β‐cell function. In a small randomized, double‐blind, placebo (PLA)‐controlled study, lasting 4 months, 21 obese adolescents with IGT received either ROSI (8 mg daily) (n = 12, 5M/7F, BMI z‐score 2.44 ± 0.11) or PLA (n = 9, 4M/5F, BMI z‐score 2.41 ± 0.09). Before and after treatment, all subjects underwent oral glucose tolerance test (OGTT), hyperinsulinemic‐euglycemic clamp, magnetic resonance imaging, and ¹H NMR assessment. After ROSI treatment, 58% of the subjects converted to NGT compared to 44% in the PLA group (P = 0.528). Restoration of NGT was associated with a significant increase in insulin sensitivity (P < 0.04) and a doubling in the disposition index (DI) (P < 0.04), whereas in the PLA group, these changes were not significant. The short‐term use of ROSI appears to be safe in obese adolescents with IGT. ROSI restores NGT by increasing peripheral insulin sensitivity and β‐cell function, two principal pathophysiological abnormalities of IGT.     

Baseline Correlates of Insulin Resistance in Inner City High‐BMI African‐American Children

To characterize the influence of diet‐, physical activity–, and self‐esteem‐related factors on insulin resistance in 8–10‐year‐old African‐American (AA) children with BMI greater than the 85th percentile who were screened to participate in a community‐based type 2 diabetes mellitus (T2DM) prevention trial. In 165 subjects, fasting glucose‐ and insulin‐derived values for homeostasis model assessment of insulin resistance (HOMA‐IR) assessed insulin resistance. Body fatness was calculated following bioelectrical impedance analysis, and fitness was measured using laps from a 20‐m shuttle run. Child questionnaires assessed physical activity, dietary habits, and self‐esteem. Pubertal staging was assessed using serum levels of sex hormones. Parent questionnaires assessed family demographics, family health, and family food and physical activity habits. Girls had significantly higher percent body fat but similar anthropometric measures compared with boys, whereas boys spent more time in high‐intensity activities than girls. Scores for self‐perceived behavior were higher for girls than for boys; and girls desired a more slender body. Girls had significantly higher insulin resistance (HOMA‐IR), compared with boys (P < 0.01). Adjusting for age, sex, pubertal stage, socioeconomic index (SE index), and family history of diabetes, multivariate regression analysis showed that children with higher waist circumference (WC) (P < 0.001) and lower Harter's scholastic competence (SC) scale (P = 0.044) had higher insulin resistance. WC and selected self‐esteem parameters predicted insulin resistance in high‐BMI AA children. The risk of T2DM may be reduced in these children by targeting these factors.     

Retinol‐binding Protein 4 (RBP4) Protein Expression Is Increased in Omental Adipose Tissue of Severely Obese Patients

Visceral fat has been linked to insulin resistance and type 2 diabetes mellitus (T2DM); and emerging data links RBP4 gene expression in adipose tissue with insulin resistance. In this study, we examined RBP4 protein expression in omental adipose tissue obtained from 24 severely obese patients undergoing bariatric surgery, and 10 lean controls (4 males/6 females, BMI = 23.2 ± 1.5 kg/m²) undergoing elective abdominal surgeries. Twelve of the obese patients had T2DM (2 males/10 females, BMI: 44.7 ± 1.5 kg/m²) and 12 had normal glucose tolerance (NGT: 4 males/8 females, BMI: 47.6 ± 1.9 kg/m²). Adipose RBP4, glucose transport protein‐4 (GLUT4), and p85 protein expression were determined by western blot. Blood samples from the bariatric patients were analyzed for serum RBP4, total cholesterol, triglycerides, and glucose. Adipose RBP4 protein expression (NGT: 11.0 ± 0.6; T2DM: 11.8 ± 0.7; lean: 8.7 ± 0.8 arbitrary units) was significantly increased in both NGT (P = 0.03) and T2DM (P = 0.005), compared to lean controls. GLUT4 protein was decreased in both NGT (P = 0.02) and T2DM (P = 0.03), and p85 expression was increased in T2DM subjects, compared to NGT (P = 0.03) and lean controls (P = 0.003). Regression analysis showed a strong correlation between adipose RBP4 protein and BMI for all subjects, as well as between adipose RBP4 and fasting glucose levels in T2DM subjects (r = 0.76, P = 0.004). Further, in T2DM, serum RBP4 was correlated with p85 expression (r = 0.68, P = 0.01), and adipose RBP4 protein trended toward an association with p85 protein (r = 0.55, P = 0.06). These data suggest that RBP4 may regulate adiposity, and p85 expression in obese‐T2DM, thus providing a link to impaired insulin signaling and diabetes in severely obese patients.     

Relationships of Obesity and Fat Distribution With Atherothrombotic Risk Factors: Baseline Results From the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial

The impact of obesity on cardiovascular disease (CVD) outcomes in patients with type 2 diabetes mellitus (T2DM) and established coronary artery disease (CAD) is controversial; whether BMI and/or waist circumference correlate with atherothrombotic risk factors in such patients is uncertain. We sought to evaluate whether higher BMI or waist circumference are associated with specific risk factors among 2,273 Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study participants with T2DM and documented CAD (baseline data, mean age 62 years, 66% non‐Hispanic white, 71% men). Multiple linear regression models were constructed after adjusting for sex, age, race/ethnicity, US vs. non‐US site, diabetes duration, exercise, smoking, alcohol, and relevant medication use. First‐order partial correlations of BMI with risk factors after controlling for waist circumference and of waist circumference with risk factors after controlling for BMI were also evaluated. Ninety percent of the patients were overweight (BMI ≥25 kg/m²); 68% of men and 89% of women had high‐risk waist circumference measures (≥102 and ≥88 cm, respectively). BMI and waist circumference, in separate models, explained significant variation in metabolic (insulin, lipids, blood pressure (BP)) and inflammatory/procoagulation (C‐reactive protein, PAI‐1 activity and antigen, and fibrinogen) risk factors. In partial correlation analyses BMI was independently associated with BP and inflammatory/procoagulation factors, waist circumference with lipids, and both BMI and waist circumference with insulin. We conclude that, in cross‐sectional analyses, both BMI and waist circumference, independently, are associated with increased atherothrombotic risk in centrally obese cohorts such as the BARI 2D patients with T2DM and CAD.     

Work stress, obesity and the risk of type 2 diabetes: gender-specific bidirectional effect in the Whitehall II study

Psychosocial work stress has been linked to higher risk of type 2 diabetes (T2DM), with the effect being consistently higher among women than men. Also, work stress has been linked to prospective weight gain among obese men but weight loss among lean men. Here, we aimed to examine the interaction between work stress and obesity in relation to T2DM risk in a gender‐specific manner. We studied 5,568 white middle‐aged men and women in the Whitehall II study, who were free from diabetes at analysis baseline (1993). After 1993, diabetes was ascertained at six consecutive phases by an oral glucose tolerance test supplemented by self‐reports. Cox regression analysis was used to assess the association between job strain (high job demands/low job control) and 18‐year incident T2DM stratifying by BMI (BMI <30 kg/m² vs. BMI ≥30 kg/m²). Overall, work stress was associated with incident T2DM among women (hazard ratio (HR) 1.41: 95% confidence intervals: 1.02; 1.95) but not among men (HR 0.87: 95% confidence interval 0.69; 1.11) (P_INTERACTION = 0.017). Among men, work stress was associated with a lower risk of T2DM in nonobese (HR 0.70: 0.53; 0.93) but not in obese individuals (P_INTERACTION = 0.17). Among women, work stress was associated with higher risk of T2DM in the obese (HR 2.01: 1.06; 3.92) but not in the nonobese (P_INTERACTION = 0.005). Gender and body weight status play a critical role in determining the direction of the association between psychosocial stress and T2DM. The potential effect‐modifying role of gender and obesity should not be ignored by future studies looking at stress‐disease associations.     

Characterization of β‐Cell Mass and Insulin Resistance in Diet‐induced Obese and Diet‐resistant Rats

The selectively bred diet‐induced obese (DIO) and diet‐resistant (DR) rats represent a polygenetic animal model mimicking most clinical variables characterizing the human metabolic syndrome. When fed a high‐energy (HE) diet DIO rats develop visceral obesity, dyslipidemia, hyperinsulinemia, and insulin resistance but never frank diabetes. To improve our understanding of the underlying cause for the deteriorating glucose and insulin parameters, we have investigated possible adaptive responses in DIO and DR rats at the level of the insulin‐producing β‐cells. At the time of weaning, DR rats were found to have a higher body weight and β‐cell mass compared to DIO rats, and elevated insulin and glucose responses to an oral glucose load. However, at 2.5 months of age, and for the remaining study period, the effect of genotype became evident: the chow‐fed DIO rats steadily increased their body weight and β‐cell mass, as well as insulin and glucose levels compared to the DR rats. HE feeding affected both DIO and DR rats leading to an increased body weight and an increased β‐cell mass. Interestingly, although the β‐cell mass in DR rats and chow‐fed DIO rats appeared to constantly increase with age, the β‐cell mass in the HE‐fed DIO rats did not continue to do so. This might constitute part of an explanation for their reduced glucose tolerance. Collectively, the data support the use of HE‐fed DIO rats as a model of human obesity and insulin resistance, and accentuate its relevance for studies examining the benefit of pharmaceutical compounds targeting this disease complex.     

Impact of Obesity and Body Fat Distribution on Cardiovascular Risk Factors in Hong Kong Chinese

Objective: Body fat distribution has been reported to differentially contribute to the development of cardiovascular risk. We report the relative associations between general and central obesity and risk factors in 2893 Chinese subjects recruited from the Hong Kong population. Research Methods and Procedures: Anthropometric parameters [waist circumference (WC) and BMI], surrogate measures of insulin resistance (fasting plasma glucose and insulin, oral glucose tolerance test, 2 hours glucose and insulin), fasting lipids (total, low‐density lipoprotein‐cholesterol, high‐density lipoprotein‐cholesterol, and triglycerides) and systolic and diastolic blood pressure were measured. General obesity was classified as BMI ≥25.0 kg/m² and central obesity as a WC ≥80 or ≥90 cm in women and men, respectively. Results: A total of 39.2% of the population was found to be obese. Obesity per se increased the levels of the risk factors, but central adiposity contributed to a greater extent to adverse high‐density lipoprotein‐cholesterol, triglyceride, and insulin resistance levels. There was a continuous relationship between increasing obesity, both general and central, and cardiovascular risk, with lowest risk associated with the lowest indices of obesity. In the 1759 nonobese subjects divided into quartiles of BMI or WC, the levels of the cardiovascular risk factors still significantly increased with increasing quartiles of adiposity. Discussion: Central adiposity appears to contribute to a greater extent than general adiposity to the development of cardiovascular risk in this population. The relationship between obesity parameters and risk is a continuum, with risk factors significantly increasing even at levels usually considered nonobese. These observations support the proposed redefinition of overweight and obesity in Asian populations using lower cut‐off points.     

Insulin Resistance is the Best Predictor of the Metabolic Syndrome in Subjects With a First‐Degree Relative With Type 2 Diabetes

Although obesity is associated with insulin resistance and the metabolic syndrome (MetS), some obese individuals are metabolically healthy. Conversely, some lean individuals are insulin resistant (IR) and at increased cardiometabolic risk. To determine the relative importance of insulin sensitivity, BMI and waist circumference (WC) in predicting MetS, we studied these two extreme groups in a high‐risk population. One thousand seven hundred and sixty six subjects with a first‐degree relative with type 2 diabetes were stratified by BMI and homeostasis model assessment of insulin resistance (HOMA_IR) into groups. IR groups had higher triglycerides, fasting glucose, and more diabetes than their BMI‐group insulin sensitive (IS) counterparts. Within both IS and IR groups, obesity was associated with higher HOMA_IR and diastolic blood pressure (BP), but no difference in other metabolic variables. MetS (Adult Treatment Panel III (ATPIII)) prevalence was higher in IR groups (P < 0.001) and more subjects met each MetS criterion (P < 0.001). Within each BMI category, HOMA_IR independently predicted MetS (P < 0.001) whereas WC did not. Within IS and IR groups, age and WC, but not BMI, were independent determinants of MetS (P < 0.001). WC was a less meaningful predictor of MetS at higher values of HOMA_IR. HOMA_IR was a better predictor of MetS than WC or BMI (receiver operating characteristic (ROC) area under the curve 0.76 vs. 0.65 vs. 0.59, P < 0.001). In conclusion, insulin sensitivity rather than obesity is the major predictor of MetS and is better than WC at identifying obese individuals with a healthier metabolic profile. Further, as many lean individuals with a first‐degree relative with type 2 diabetes are IR and metabolically unhealthy, they may all benefit from metabolic testing.     

Association of ADIPOR2 with liver function tests in type 2 diabetic subjects

Objective: Adiponectin protects against liver dysfunction in insulin‐resistant states such as obesity and type 2 diabetes (T2DM), but the role of adiponectin receptors in this disorder is largely unknown. We studied whether common single‐nucleotide polymorphisms (SNPs) in ADIPOR1 and ADIPOR2 are associated with liver function tests (LFTs) in human subjects with various degrees of insulin resistance. Methods and Procedures: Serum alanine (ALT) and aspartate (AST) aminotransferases, homeostasis model assessment of insulin resistance (HOMA‐IR), ?8503 G/A (rs6666089) and +5843 C/T (rs1342387) SNPs in ADIPOR1, ?64,241 T/G (rs1029629) and +33447 C/T (rs1044471) SNPs in ADIPOR2 were assessed in 700 white subjects from a population‐based study. Results: In nondiabetic subjects, the at‐risk alleles for the common ?64,241 T/G and +33447 C/T SNPs in ADIPOR2 were associated with increased circulating adiponectin (P < 0.05 to P < 0.005), but not with LFT. Conversely, in T2DM subjects (who are at risk for liver dysfunction), the same alleles were associated with increased serum ALT and AST (P < 0.05 to P < 0.0001), but not with circulating adiponectin. No significant associations with these parameters were evident for the common ?8503 G/A and +5843 C/T SNPs in ADIPOR1. In a replication study, the ?64,241 T/G and +33447 C/T SNPs in ADIPOR2 were associated with ALT and AST (P < 0.05 to P < 0.0001) in pooled obese and T2DM subjects. Discussion: Common SNPs in ADIPOR2 are associated with LFT in T2DM subjects, which suggests a possible role of this receptor in liver dysfunction associated with insulin resistance.     

Prevention and treatment of type 2 diabetes in youth

Parallel to the increase in obesity worldwide, there has been a rise in the prevalence of type 2 diabetes mellitus (T2DM) in children and adolescents. The etiology of T2DM in youth, similar to adults, is multifactorial including genetic and environmental factors, among them obesity, sedentary lifestyle, family history of the disease, high-risk ethnicity and insulin resistance phenotype playing major roles. Treatment of T2DM should not have a glucocentric approach; it should rather target improving glycemia, dyslipidemia, hypertension, weight management and the prevention of short- and long-term complications. Prevention strategies, especially in high-risk groups, should focus on environmental change involving participation of families, schools, the food and entertainment industries and governmental agencies. Presently, limited pharmacotherapeutic options need to be expanded both for childhood T2DM and obesity. The coming decades will prove very challenging for healthcare providers battling socioeconomic waves conducive to obesity and T2DM. Evidence-based research and clinical experience in pediatrics, possibly modeled after adult trials, need to be developed if this public health threat is to be contained.     

体型肥胖2型糖尿病患者血清胆红素、胆汁酸、25(OH)D3水平及与胰岛素抵抗的关系研究

摘要 目的：探讨体型肥胖2型糖尿病（T2DM）患者血清胆红素、胆汁酸（BA）、25羟维生素D3[25(OH)D₃]水平及其与胰岛素抵抗（IR）的关系。方法：选取2018年1月-2019年12月我院就诊的240例T2DM患者,根据体重指数（BMI）将患者分为T2DM-N组84例,T2DM-OW组92例,T2DM-OB组64例。分别测定总胆红素（TBIL）、间接胆红素（IBIL）、直接胆红素（DBIL）、胆汁酸（BA）、25(OH)D₃等指标。以胰岛素抵抗指数（HOMA-IR）为因变量,行多元线性回归,分析IR的危险因素。结果：T2DM-OB组BMI、BA、甘油三酯（TG）、空腹血糖（FPG）、餐后2小时血糖（2hPG）、糖化血红蛋白（HbA1c）、空腹胰岛素（FINS）、胰岛素抵抗指数（HOMA-IR）、C反应蛋白（CRP）高于T2DM-N组,DBIL、25(OH)D₃低于T2DM-N组,差异均有统计学意义（P<0.05）。Pearson相关性分析显示,HOMA-IR与BMI、BA呈正相关（P<0.05),与DBIL、25(OH)D₃呈负相关（P<0.05);多元线性回归分析显示BMI升高,25(OH)D₃、DBIL下降为IR的危险因素（P<0.05）。结论：肥胖的T2DM患者存在IR及血脂紊乱,心血管疾病患病风险增加,BA水平升高,DBIL、25(OH)D₃水平下降,机体慢性低度炎症水平升高,除了BMI,25(OH)D₃、DBIL水平下降亦有可能是体型肥胖T2DM患者IR的重要危险因素。     

The variant at TGFBRAP1 is significantly associated with type 2 diabetes mellitus and affects diabetes‐related miRNA expression

While the transforming growth factor‐β1 (TGF‐β1) regulates the growth and proliferation of pancreatic β‐cells, its receptors trigger the activation of Smad network and subsequently induce the insulin resistance. A case‐control was conducted to evaluate the associations of the polymorphisms of TGF‐β1 receptor‐associated protein 1 (TGFBRAP1) and TGF‐β1 receptor 2 (TGFBR2) with type 2 diabetes mellitus (T2DM), and its genetic effects on diabetes‐related miRNA expression. miRNA microarray chip was used to screen T2DM‐related miRNA and 15 differential expressed miRNAs were further validated in 75 T2DM and 75 normal glucose tolerance (NGT). The variation of rs2241797 (T/C) at TGFBRAP1 showed significant association with T2DM in case‐control study, and the OR (95% CI) of dominant model for cumulative effects was 1.204 (1.060‐1.370), Bonferroni corrected P < 0.05. Significant differences in the fast glucose and HOMA‐β indices were observed amongst the genotypes of rs2241797. The expression of has‐miR‐30b‐5p and has‐miR‐93‐5p was linearly increased across TT, TC, and CC genotypes of rs2241797 in NGT, P_trend values were 0.024 and 0.016, respectively. Our findings suggest that genetic polymorphisms of TGFBRAP1 may contribute to the genetic susceptibility of T2DM by mediating diabetes‐related miRNA expression.     

Macrophage Gene Expression in Adipose Tissue is Associated with Insulin Sensitivity and Serum Lipid Levels Independent of Obesity

Objective: Obesity is linked to both increased metabolic disturbances and increased adipose tissue macrophage infiltration. However, whether macrophage infiltration directly influences human metabolism is unclear. The aim of this study was to investigate if there are obesity‐independent links between adipose tissue macrophages and metabolic disturbances. Design and Methods: Expression of macrophage markers in adipose tissue was analyzed by DNA microarrays in the SOS Sib Pair study and in patients with type 2 diabetes and a BMI‐matched healthy control group. Results: The expression of macrophage markers in adipose tissue was increased in obesity and associated with several metabolic and anthropometric measurements. After adjustment for BMI, the expression remained associated with insulin sensitivity, serum levels of insulin, C‐peptide, high density lipoprotein cholesterol (HDL‐cholesterol) and triglycerides. In addition, the expression of most macrophage markers was significantly increased in patients with type 2 diabetes compared to the control group. Conclusion: Our study shows that infiltration of macrophages in human adipose tissue, estimated by the expression of macrophage markers, is increased in subjects with obesity and diabetes and associated with insulin sensitivity and serum lipid levels independent of BMI. This indicates that adipose tissue macrophages may contribute to the development of insulin resistance and dyslipidemia.     

Effects of acquired obesity on endothelial function in monozygotic twins

Objective: To determine whether acquired obesity or accompanying metabolic changes such as adiponectin deficiency, insulin resistance, dyslipidemia, or visceral fat are associated, independent of genetic influences, with endothelial dysfunction by studying young adult monozygotic (MZ) twin pairs discordant for obesity. Research Methods and Procedures: Nine obesity‐discordant (intra‐pair difference in BMI, 3.8 to 10.1 kg/m²) and nine concordant (0 to 2.3 kg/m²) 24‐ to 27‐year‐old MZ twin pairs were identified from a population‐based FinnTwin16‐sample. Endothelial function was measured by blood flow responses to intrabrachial infusions of an endothelium‐dependent (acetylcholine) and an endothelium‐independent (sodium nitroprusside) vasodilator. Whole body insulin sensitivity was measured using the euglycemic insulin clamp technique, and forearm and body composition were measured with magnetic resonance imaging and DXA. In addition, serum levels of adiponectin, high‐sensitivity C‐reactive protein, and lipids were determined. Results: The heavier co‐twins of the discordant pairs had significantly lower whole body insulin sensitivity than the leaner co‐twins. Blood flows/muscle volume during infusions of acetylcholine and sodium nitroprusside were not altered by obesity. However, intra‐pair differences in serum adiponectin, intra‐abdominal fat, and C‐reactive protein were significantly correlated with those in endothelial function. Only the relationship between intra‐pair differences in adiponectin and endothelial function persisted in multiple linear regression analysis. Obesity‐concordant co‐twins had comparable insulin sensitivity and endothelial function. Discussion: In young adult MZ twins discordant for obesity, acquired adiponectin deficiency rather than obesity per se is an independent correlate of endothelial dysfunction.     

脂联素基因单核苷酸多态性与Ⅱ型糖尿病合并肥胖及胰岛素抵抗相关联

脂联素是近年新发现的脂肪组织特异性的细胞因子,其mRNA是脂肪组织中含量最丰富的基因转录产物,该因子可通过多种途径影响个体对胰岛素的敏感性。脂联素基因多态性与肥胖、胰岛素抵抗和2型糖尿病密切相关,而与冠心病相关性研究的报道较少。本研究以中国汉族人群1,098例为对象,其中304例冠心病(CHD)患者,389例糖尿病患者(T2DM),及405例性别年龄相匹配的正常对照,采用PCR-RFLP技术对脂联素基因-4522C/T进行基因分型,并分别对血脂水平、胰岛素抵抗、体重指数等临床数据进行分析比较。研究结果显示,脂联素基因-4522C/T各基因型及等位基因在CHD组与对照组、T2DM组与对照组中的分布差异无显著性;经分组分析发现,T2DM合并肥胖患者BMI≥25kg/m2TT基因型及T等位基因明显多于对照组,差异有显著性,P=0.014和P=0.034;TT基因型T2DM患者胰岛素抵抗指数(HOMA-IR)显著高于携带有C等位基因的T2DM患者,P=0.0069。本研究提示脂联素基因-4522C/T与中国汉族人群T2DM合并肥胖的发生及T2DM患者胰岛素抵抗相关,是引发糖尿病患者肥胖和胰岛素抵抗的重要候选基因,而与冠心病的发生无关联。