non-IR Subjects Research Articles

1730-P: Thromboxane Signaling and Obesity-Related Insulin Resistance

Background: Thromboxane A2 (TxA2), a lipid mediator plays a critical role in cardiovascular disease and chronic inflammatory disorders. TxA2 signaling is regulated by TxA2 synthase (Tbxas1), an enzyme that produces TxA2, and TxA2 receptor (Tbxa2r). Objective: To determine if Tbxa2r gene expression in adipose tissue (AT) is higher in obese insulin resistant (IR) subjects compared to overweight non-IR subjects. Methods: Insulin resistance was measured via a homeostatic model assessment of insulin resistance (HOMA-IR). Subcutaneous AT biopsies were obtained from overweight (BMI between ≥25 to <30) no IR and obese (BMI ≥30) IR (HOMA-IR>2.5) subjects. Gene expression of Tbxa2r and Tbxas1 were analyzed in tissue samples and compared between groups. Results: The mRNA levels of Tbxa2r and Tbxas1 were significantly higher in obese IR subjects compared to overweight subjects (P<0.05). A positive correlation was observed between AT expression of Tbxa2r and Tbxas1 (Spearman’s r=0.49, n=35, P<0.01). We noted a weak positive correlation between AT Tbxa2r and HOMA-IR (Spearman’s r=0.31, n=35, P<0.07). A positive correlation was also noted between AT Tbxas1 and HOMA-IR (Spearman’s r=0.42, n=37, P<0.05). Conclusion: Our data suggest that TxA2 signaling is activated in AT in obesity and is associated with the development of insulin resistance in obesity. Tbxas1 and/or Tbxa2r may be a potential therapeutic target for obesity-linked metabolic diseases. Disclosure D. Alcaraz Alvarez: None. S. Viswanathan: None. T. Thangavelu: None. N. Kumar: None. K. Kelley: None. C. Desouza: Consultant; Self; AstraZeneca, Bayer AG, Novo Nordisk A/S.

Relationship between insulin resistance, metabolic syndrome components and serum uric acid

BackgroundMetabolic syndrome is cluster of abnormality related with increasing cardiovascular events. Hyperuricemia is level of uric acid more than 7 mg/dL for men. Some research have reported relation between metabolic syndrome mediated by insulin resistance with increasing of serum uric acid level. ObjectiveAssess relationship between insulin resistance and metabolic syndrome components with the level of serum uric acid. MethodObservational study with cross sectional approach conducted on 102 outpatient subjects at Dr. RSUP Wahidin Sudirohusodo (RSWS) hospital and Hasanuddin University Hospital in the period of July–September 2018. ResultsSubjects with IR were found to be significantly higher for having MetS (88.23% vs. 11.77% p = 0,000). In subjects with IR, the average serum uric acid level was higher compared to non-IR subjects, but this difference was not significant (6.63 vs 6.42 mg/dL; P = 0.325). In subjects with MetS, the average serum uric acid level was higher compared to subjects with non-MetS but this difference was not significant (6.62 vs. 6.28 mg/dL; P = 0.556). No significant relationship was found between IR and MetS with serum uric acid level. ConclusionInsulin resistance is related to the incidence of MetS and in both of these circumstances an independent tendency is found to increase uric acid levels. The role of insulin resistance in the relationship between metabolic syndrome and uric acid levels was not proven in this study.

Influence of Insulin Resistance Status on the Development of Gallstones Following Roux-En-Y Gastric Bypass: a Prospective Cohort Study.

The occurrence of gallstones following Roux-en-Y gastric bypass (RYGB) has been extensively reported. As RYGB promotes improvement in insulin resistance (IR), which is one of the factors enrolled in the pathophysiology of gallstones, this study aims to determine the influence of IR and its post-RYGB course on the development of gallstones. This is a prospective cohort study that enrolled 108 morbidly obese subjects free of gallstones which underwent RYGB and were followed up for 24 months, through clinical, laboratory, and ultrasound examinations. IR was assessed through the surrogate marker homeostasis model assessment (HOMA). Of the individuals evaluated, 29 (26.8%) developed gallstones following RYGB. In the univariate analysis, postsurgical gallstones were associated with preoperative HOMA (p < 0.0001), preoperative fasting glucose (p = 0.0019), preoperative fasting insulin (p = 0.0001), and preoperative triglycerides (p = 0.0001). Multivariate analysis revealed that preoperative HOMA was the only factor independently associated with gallstones (p < 0.0001). The incidence of gallstones among individuals with IR was 46.8%; in the non-IR subjects, the incidence was 7.4% (p < 0.0001). Preoperative IR led to a relative risk of 6.02 (95% CI = 2.1-17.3; p = 0.0009) of gallstones. As gallstones often occur following RYGB, there is controversy regarding their management. Some authors propose systematic cholecystectomy along with RYGB, while others suggest that the aggregate risk of the concomitant approach is significantly higher. As IR was a significant risk factor in this study, an individualized approach for this population may be proposed. Further research is needed to confirm these findings.

Omental adipose tissue gene expression, gene variants, branched-chain amino acids, and their relationship with metabolic syndrome and insulin resistance in humans.

Obesity is a complex disorder caused by several factors. Thus, the aim of the present study was to assess whether the expression of genes in the omental white adipose tissue (AT) of subjects with insulin resistance (IR) or metabolic syndrome (MetS) is associated with an elevation in serum branched-chain amino acids (BCAAs) and whether this response depends on specific genetic variants. Serum BCAA concentration, the adipocyte area, and gene variants of PPARγ, ABCA1, FTO, TCF7L2, GFOD2, BCAT2, and BCKDH were determined in 115 Mexican subjects. The gene expression in the AT and adipocytes of BCAT, BCKDH E1α, C/EBPα, PPARγ2, SREBP-1, PPARα, UCP1, leptin receptor, leptin, adiponectin, and TNFα was measured in 51 subjects. Subjects with IR showed higher values for the BMI, HOMA-IR, and adipocyte area and higher levels of serum glucose, insulin, leptin, and C-reactive protein, as well as an elevation of the AT gene expression of SREBP-1, leptin, and TNFα and a significant reduction in the expression of adiponectin, BCAT2, and BCKDH E1α, compared with non-IR subjects. The presence of MetS was associated with higher HOMA-IR as well as higher serum BCAA concentrations. Subjects with the genetic variants for BCAT2 and BCKDH E1 α showed a lower serum BCAA concentration, and those with the ABCA1 and FTO gene variant showed higher levels of insulin and HOMA-IR than non-IR subjects. AT dysfunction is the result of a combination of the presence of some genetic variants, altered AT gene expression, the presence of MetS risk factors, IR, and serum BCAA concentrations.

Waist circumference and insulin resistance in elderly men: an analysis of Kahrizak elderly study

BackgroundDiagnosis of the metabolic syndrome (MS) is crucial for health care practitioners to identify at risk people for early treatment. Visceral obesity may make unnecessary other laborious measures of insulin resistance. The aim of this study was to see whether waist circumference (WC) can predict insulin resistance as well as MS in a group of Iranian elderly.MethodsOut of 94 nondiabetic elderly, thirty three subjects were recognized with MS. MS diagnosis was based on NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) and IDF (International Diabetes Federation) definitions. HOMA (Homeostasis Model Assessment) index was used to measure insulin sensitivity. Insulin resistance (IR) was defined as top quartile of HOMA.ResultsIn both sexes, WC and HOMA index were significantly positively correlated. The optimal waist circumference (OWC) cutoff point was 94.5 cm for men and 90.5 cm for women. The high sensitivity (0.80) and specificity (0.84) of WC in males indicates the proportion of IR which is correctly identified and recognizes all non-IR males as such. In regression model only the TG level was associated with WC. But the WC is strongly associated with HOMA-IR.ConclusionsWhile OWC is very likely a good measure to exclude non-IR subjects in our study, determination of optimal WC to identify elderly IR subjects warrants further study in a larger sample of the general population.

Misclassification of subjects with insulin resistance and associated cardiovascular risk factors by homeostasis model assessment index. Utility of a postprandial method based on oral glucose tolerance test

Different methods are available for assessing insulin sensitivity in the fasting state. However, insulin resistance (IR) is initially a postprandial disturbance; and usually, when basal (fasting) disturbance appears, the process has been in progress for some time. Our aim was to investigate if a postprandial measurement, performing an oral glucose tolerance test (OGTT), is more sensitive than fasting values. We wished to identify early IR states in healthy, nonobese individuals and ascertain if this situation was associated with other cardiovascular risk factors. A total of 90 nonobese, nondiabetic, and nonsmoker individuals were studied. They were divided into 3 groups according to IR state—group 1: non-IR—homeostasis model assessment of IR (HOMA IR) and insulin sensitivity index of Matsuda-De Fronzo (ISI-Mat) were normal (HOMA IR <3.2 and ISI-Mat >4.0); group 2: with IR post-OGTT (ISI-Mat ≤4.0 and HOMA IR <3.2); and group 3: subjects with IR in basal conditions (HOMA IR ≥3.2). An intravenous glucose tolerance test to compare both indices was also performed. In 14.4% of subjects, the fasting HOMA IR values failed to identify IR (false-negative results). The ISI-Mat values were better correlated than HOMA IR ( r = 0.875, P = .0001 and r = −0.631, P = .0001, respectively) with insulin sensitivity index obtained with intravenous glucose tolerance test. Subjects with IR had higher prevalence of a cluster of cardiovascular risk factors than non-IR subjects. These data show that that a significant percentage of subjects were misclassified with HOMA IR. Early identification of IR by OGTT was associated with other cardiovascular risk factors. The OGTT is a simple method that could be applied to accurately identify IR subjects in the general population.

Hepatic steatosis in overweight/obese females: Newscreening method for those at risk

To identify which parameters could help to distinguish the "metabolically benign obesity", which is not accompanied by insulin resistance (IR) and early atherosclerosis. Eighty two of 124 overweight/obese females formed the study population, which was divided into two groups (52 and 30 subjects, respectively) with and without IR according to a HO meostatic Metabolic Assessment (HOMA) cut-off of 2, and were studied in a cross-sectional manner. The main outcome measures were waist circumference, serum uric acid, high-density lipoprotein-cholesterol and triglycerides, alanine aminotransferase, blood pressure and the two imaging parameters, hepatic steatosis and longitudinal diameter of the spleen, which were measured in relation to the presence/absence of IR. A variable grade of visceral obesity was observed in all subjects with the exception of three. Obesity of a severe grade was represented more in the group of IR individuals (P = 0.01). Hepatic steatosis, revealed at ultrasound, was more pronounced in IR than in non-IR subjects (P = 0.005). The two groups also demonstrated a clear difference in longitudinal spleen diameter and blood pressure, with raised and significant values in the IR group. Metabolic syndrome was frequent in the IR group, and was not modified when adjusted for menopause (P = 0.001). At linear regression, the beta values of waist circumference and body mass index predicting HOMA were 0.295, P = 0.007 and 0.41, P = 0.0001, respectively. Measures of spleen longitudinal diameter were well predicted by body mass index (BMI) values, beta = 0.35, P = 0.01, and by HOMA, beta = 0.41, P = 0.0001. Blood pressure was predicted by HOMA values, beta = 0.39, P = 0.0001). HOMA and hepatic steatosis were highly associated (rho = 0.34, P = 0.002). Interestingly, IR patients were almost twice as likely to have hepatic steatosis as non-IR patients. Among the MS criteria, blood pressure was very accurate in identifying the presence of IR (AUROC for systolic blood pressure 0.66, cut-off 125 mm of Hg, sensibility 64%, specificity 75%; AUROC for diastolic blood pressure 0.70, cut-off 85 mm of Hg, sensibility 54.5%, specificity 75%). As health care costs are skyrocketing, reliable and mainly inexpensive tools are advisable to better define subjects who really need to lose weight.

Insulin resistance functionally limits endothelium-dependent coronary vasodilation in nondiabetic patients

Insulin resistance (IR) is now considered to be a risk factor for coronary arterial atherosclerosis and is likely to be involved in a limited endothelium-dependent vasodilatory function in peripheral circulation. We investigated whether IR impairs endothelial vasodilator function in the noninfarcted coronary artery. In 14 nondiabetic patients (10 males, 66 +/- 6 years) who were selected from 214 patients underwent IR evaluation by glucose clamp, a Doppler flow wire was used to measure coronary flow changes (percent volume flow index, %VFI) during intracoronary administration of papaverin (10 mg) and stepwise administration of acetylcholine (Ach; 1, 3, 10 microg/ml per minute) into the non-infarcted left circumflex coronary artery. Insulin resistance was comparatively evaluated by an euglycemic hyperinsulinemic glucose clamp (M value, mg/m(2) per minute) or by a 75g-oral glucose tolerance test (120-min immunoreactive insulin; 120' IRI, pmol/l). Eight patients (57%) were defined as having IR on the basis of results obtained by both the glucose clamp method (M values <167 mg/m(2) per minute) and 120' IRI (>384 pmol/l). There was no difference between papaverin-induced %VFI increases in IR and non-IR subjects (328% +/- 43% vs. 361% +/- 87%). However, IR subjects showed significantly lower Ach-induced %VFI increases in a dose-dependent manner (P < 0.05), especially when low (1 microg/ml per minute) and moderate (3 microg/ml per minute) doses of Ach were used (165% +/- 18% or 248% +/- 29% in non-IR subjects vs. 130% +/- 20% or 183% +/- 41% in IR subjects, P < 0.001, respectively). Moreover, %VFI increase at a low dose of Ach infusion significantly correlated with M values or 120' IRI ([%VFI Ach 1 microg] = 85.9 + 0.35 [M values], r = 0.58, P = 0.038; [%VFI Ach 1 microg] = 176.8 - 0.47.[120' IRI], r = -0.57, P = 0.035). Insulin resistance limits endothelium-dependent coronary vasodilation in association with the severity of IR in non-diabetic patients.