Differential effect of weight loss on insulin resistance in surgically treated obese patients

PURPOSE: To compare the effects of equivalent weight loss induced by two bariatric surgical techniques on insulin action in severely obese patients. METHODS: Eighteen nondiabetic patients with severe obesity (mean [+/- SD] body mass index: 53.5 +/- 9.0 kg/m(2)) and 20 sex- and age-matched lean subjects (body mass index: 23.8 +/- 3.0 kg/m(2)) underwent metabolic studies, including measurement of insulin sensitivity by the insulin clamp technique. Patients then underwent either vertical banded gastroplasty with Roux-en-Y gastric bypass, or biliopancreatic diversion, and were restudied at 5 to 6 months and again at 16 to 24 months postsurgery. RESULTS: At baseline, patients were hyperinsulinemic (194 +/- 47 pmol/L vs. 55 +/- 25 pmol/L, P < 0.0001), hypertriglyceridemic (1.56 +/- 0.30 mmol/L vs. 0.78 +/- 0.32 mmol/L, P < 0.0001), and profoundly insulin resistant (insulin-mediated glucose disposal: 20.8 +/- 4.4 micromol/min/kg fat-free mass vs. 52.0 +/- 10.1 micromol/min/kg, P < 0.0001) as compared with controls. Weight loss by the two procedures was equivalent in both amount (averaging -53 kg) and time course. In the gastric bypass group, insulin sensitivity improved (23.8 +/- 6.0 micromol/min/kg at 5 months and 33.7 +/- 11.3 micromol/min/kg at 16 months, P < 0.01 vs. baseline and controls). In contrast, in the biliopancreatic diversion group, insulin sensitivity was normalized already at 6 months (52.5 +/- 12.4 micromol/min/kg, P = 0.72 vs. controls) and increased further at 24 months (68.7 +/- 9.5 micromol/min/kg, P < 0.01 vs. controls) despite a persistent obese phenotype (body mass index: 33.2 +/- 8.0 kg/m(2)). CONCLUSION: In surgically treated obese patients, insulin sensitivity improves in proportion to weight loss with use of predominantly restrictive procedures (gastric bypass), but is reversed completely by predominantly malabsorptive approaches (biliopancreatic diversion) long before normalization of body weight. Selective nutrient absorption and gut hormones may interact with one another in the genesis of the metabolic abnormalities of obesity.     

Chronic insulin resistance

Summary Chronic insulin resistance has been defined and its clinical characteristics summarized. Although increased insulin antibodies can be demonstrated in most patients with chronic insulin resistance, there is not always a good correlation between the severity of the insulin resistance and the titer of insulin antibodies. Several insulin resistant patients have been described who appear to represent examples of peripheral tissue unresponsiveness to insulin. Various forms of treatment of chronic insulin resistance have been reviewed.This work was supported by the United States Public Health Service Grant AM 06865 from the National Institutes of Health.     

简易胰岛素抵抗指数对类风湿关节炎患者胰岛素抵抗的评估价值

目的利用空腹甘油三酯及葡萄糖简易指数(TyG)评估类风湿关节炎(RA)患者中的胰岛素抵抗(IR),并探讨RA患者IR的相关因素。方法选取2019年1月至12月新疆维吾尔自治区人民医院风湿免疫科未使用激素的RA患者177例,根据病程长短分为极早期RA(病程<6月)共45例,早期RA(病程6个月至2年)共64例,非早期RA(病程>2年)共68例,并收集对照组68例。详细记录患者一般资料、实验室检查结果,计算胰岛素抵抗的稳态模型评估(HOMA-IR)指数和TyG指数,用基于红细胞沉降率的28个关节疾病活动评分(DAS28-ESR)评估RA患者疾病活动度。观察比较极早期RA组、早期RA组、非早期RA组和对照组受试者的一般资料和实验室检查指标,并观察RA患者与非RA患者的IR情况。RA患者根据不同TyG指数水平,分为TyG≥1.15组和TyG<1.15组,观察一般资料及实验室指标的情况。采用受试者工作特征(ROC)曲线分析TyG指数诊断RA患者IR的灵敏度及特异度,采用logistic回归分析RA组中IR的影响因素。结果TyG指数在RA组水平高于正常对照组(P<0.05),在早期RA组中水平最高。RA组患者类风湿因子(RF)(r=0.215)、红细胞沉降率(ESR)(r=0.216)、C反应蛋白(CRP)(r=0.219)、超敏C反应蛋白(r=0.235)、低密度脂蛋白胆固醇(LDL-C)(r=0.240)、DAS28-ESR(r=0.393)与TyG指数呈正相关(P<0.05)。TyG指数判断RA患者IR的最佳切值为1.15,灵敏度为76.4%,特异度为84.8%,约登指数为0.612,曲线下面积为0.823(95%可信区间0.755~0.892)。TyG≥1.15组患者的类风湿因子、hsCRP、DAS28-ESR水平高于TyG<1.15组,HDL-C水平低于TyG<1.15组,差异有统计学意义(P<0.05)。低水平HDL-C、RF阳性与TyG≥1.15独立相关(P<0.05)。结论TyG指数是一种初步筛选RA患者IR的可行方法。RA患者IR增加与疾病活动、炎症因子有关,低HDL-C、RF阳性是RA患者IR独立危险因素。     

Polymorphisms in VKORC1 have more impact than CYP2C9 polymorphisms on early warfarin International Normalized Ratio control and bleeding rates

Poor warfarin control with resultant high International Normalized Ratios (INRs) and bleeding events is most common during the first months of treatment. The effects of genetic polymorphisms at the vitamin K epoxide reductase [VKORC1] and cytochrome P450 2C9 [CYP2C9] loci have been increasingly acknowledged as contributory factors of enhanced warfarin sensitivity. In our prospective, blinded study, 557 patients (49·1% male, mean age 65·4 years, range 18-91 years) commencing warfarin (target INR 2·5) were genotyped and monitored through the first 3 months of anticoagulation. Homozygosity for the -1639 G>A single nucleotide functional promoter polymorphism of the VKORC1 gene (genotype AA; 14·5% of cases) was associated with a significantly shortened time to therapeutic INR ≥ 2 (P < 0·01), reduced stable warfarin dose (P < 0·01), and an increased number of INRs > 5 (P < 0·001) and occurrence of bleeding events (P < 0·01) during the first month, as compared to the GG genotype. CYP2C9 genetic variations *2 and *3 were not associated with significant effect on these factors. Neither VKORC1 nor CYP2C9 polymorphisms influenced these parameters beyond the first month of treatment. These findings imply possible benefits of assessing VKORC1 polymorphisms prior to anticoagulation, particularly as a low dose induction regime in VKORC1 AA individuals appears to reduce the incidence of high INRs.     

Pathophysiology of insulin resistance

Insulin resistance is a feature of a number of clinical disorders, including type 2 diabetes/glucose intolerance, obesity, dyslipidaemia and hypertension clustering in the so-called metabolic syndrome. Insulin resistance in skeletal muscle manifests itself primarily as a reduction in insulin-stimulated glycogen synthesis due to reduced glucose transport. Ectopic lipid accumulation plays an important role in inducing insulin resistance. Multiple defects in insulin signalling are responsible for impaired glucose metabolism in target tissues of subjects with features of insulin resistance. Inflammatory molecules and lipid metabolites inhibit insulin signalling by stimulating a number of different serine kinases which are responsible for serine phosphorylation of Insulin Receptor Substrate-1 (IRS-1).     

Pathogenesis of insulin resistance

Insulin resistance characterized by a decreased biological response to insulin is caused by genetic and exogenous factors influencing the target tissues for insulin, like the muscle, adipose tissue and the liver. A hyperbolic relationship was found between insulin secretion and insulin action. The insulin hypersecretion caused by short-time B-cell stimulation with free fatty acids is associated with hyperinsulinemia and worsening of insulin resistance. On the contrary, longtime exposure of B-cells by free fatty acids is followed by a decreased secretion and thus by hypoinsulinemia. Triglyceride infiltration of the muscle tissue and B-cells further worsens the insulin resistance and impairs the insulin secretion. Lipotoxicity worsens the whole metabolic disorder including the glucose tolerance and causes apoptosis of the islet cells. Free fatty acids are causative factor in the pathogenesis of insulin resistance as well as of Type 2 diabetes.     

Neuroendocrine mechanisms in insulin resistance

Dysregulated hormonal, metabolic and neural signalling within and between organs can contribute to development of metabolic diseases including type 2 diabetes. Insulin-antagonistic effects of hormones, cytokines and excess metabolic substrates such as glucose and fatty acids may be exerted via common mechanisms involving for example reactive oxygen species (ROS) accumulation and associated inflammatory responses. Visceral adiposity is a central component of the metabolic syndrome and it is also strongly associated with insulin resistance. Both visceral obesity and insulin resistance are important risk factors for the development of type 2 diabetes. In the development of insulin resistance, it is likely that intra-abdominal adipose tissue plays a critical role in a complex endocrine and neural network involving several tissues. This review paper focuses on neuroendocrine 'stress' factors that target insulin-responsive tissues, in particular adipose tissue. We propose that there are common pathways by which dysregulation in different endocrine systems may contribute to the development of type 2 diabetes.     

Genetics of insulin resistance

Insulin resistance, defined as the decreased ability of insulin to perform its biological functions, is likely to represent the primary physiologic defect underlying the insulin resistance syndrome (IRS), which includes insulin resistance/hyper-insulinemia, glucose intolerance and/or type 2 diabetes mellitus, visceral obesity, hypertension, and dyslipidemia. This constellation of traits is a leading cause of cardiovascular mortality and morbidity. Insulin sensitivity varies widely among individuals. Although environmental provocations including physical inactivity and caloric excess play an important role in the development of obesity and thus insulin resistance, epidemiologic and family studies show that there are also moderate genetic influences on the development of insulin resistance. Extreme forms of insulin resistance may be caused rarely by mutations in the genes for the insulin receptor and peroxisome proliferator-activated receptor γ. However, the genetic basis for common more moderate forms of insulin resistance is likely to be polygenic and heterogeneous. Evidence further suggests that gene variants may have phenotypic influences on more than one IRS trait (so-called pleiotrophy), which may explain, in part, the clustering of these traits. This article reviews the evidence that insulin resistance has a genetic basis. Progress to date toward identifying specific gene variants are reviewed. Ultimately, the identification of specific gene variants that influence insulin resistance and other IRS traits will have profound influences on our understanding of the molecular and pathophysiologic basis of these disorders, from which new and more effective preventive and therapeutic interventions will be possible.     

胰岛素抵抗细胞模型的胰岛素降解酶表达

目的 了解胰岛素降解酶（ＩＤＥ）基因、酶蛋白表达水平与胰岛素敏感性的关系,并初步探讨胰岛素降解抑制剂氯喹改善胰岛素敏感性的分子机制。方法 以的代大鼠肝细胞胰岛抵抗（ＩＲ）模型为研究对象,分别采用免疫印迹技术和逆转录－聚合酶链反应（ＲＴ－ＰＣＲ）技术检测ＩＲ细胞模型的ＩＤＥ酶蛋白表达（ＥＩＰ）及基因表达水平（ＥＩＧ）,同时检测ＩＤＥ活性和反映细胞胰岛素敏感性的＾１４Ｃ－２－脱氧葡萄糖掺入率及＾１４Ｃ     

Mechanisms of insulin resistance in pregnancy

The causes of insulin resistance were studied in rats at late terms of pregnancy. A decrease in the sensitivity to insulin dependent incorporation of glucose in total lipids and CO2 of isolated fatty tissue of pregnant rats was shown. The maximum tissue reaction to insulin (reactivity) did not lessen indicating together with hyperinsulinemia after a glucose tolerance test and a rise of the activity of blood serum insulin-like growth factors the absence of postreceptor defects. An increase in the pregnant rats blood levels of cholesterol, triglycerides and lipoprotein atherogenic fractions was revealed. The latter in physiological concentrations made an inhibitory effect on respiration of liver and thyroid sections of intact rats. Together with the action of hormones of the fetoplacental system it was considered as one of the mechanisms of development of insulin resistance at late terms of pregnancy.     

Role of zinc in insulin resistance

This review reports the etiological aspects of insulin resistance as well as the participation of zinc in this process. Zinc participates in the metabolic pathways involving protein synthesis, and the metabolism of carbohydrate, lipid and nucleic acid. This element has been associated with the interaction between hormones and their receptors and to the improvement in the post-receptor stimulus. In vitro studies show that insulin may form a complex with zinc improving the solubility of this hormone in the pancreatic beta cells and also increasing the binding ability of insulin to its receptor. Regarding obesity and insulin resistance, alterations in zinc concentration and distribution in tissues, as well as improvement in sensitivity to insulin after supplementation with this element, have been detected. Thus, the metabolic role of zinc in the insulin resistance syndrome should be further investigated having in mind that this element may contribute to the control of the usual metabolic alterations present in obese patients.     

Modulators of insulin action and their role in insulin resistance

Insulin is a key anabolic hormone that plays a crucial role in growth, differentiation and metabolism. Insulin action is initiated by the binding of the hormone to its tyrosine kinase cell surface receptor, leading to the multisite autophosphorylation of the receptor. This results in the activation of the receptor kinase and subsequent tyrosine phosphorylation of insulin receptor substrates, most of which are docking proteins for signaling molecules. For the last several years, our laboratory has been interested in the mechanisms that lead to the modulation of insulin signal transduction, and hence might be involved in insulin resistance found in obesity and type II diabetes. For this review, we have focused on three 'modulators' of insulin action: hyperinsulinemia, suppressor of cytokine signaling proteins and advanced glycation end products.