Changes In Homeostatic Model Assessment Of Insulin Resistance Research Articles

Insulin resistance reduction, intermittent fasting, and human growth hormone: secondary analysis of a randomized trial

Intense intermittent fasting regimens safely reduce weight to a similar extent as caloric restriction. A previous trial reported low-frequency 26-week intermittent fasting reduced homeostatic model assessment of insulin resistance (HOMA-IR) without significant weight loss. During fasting, human growth hormone (HGH) increases substantially, but whether basal HGH modifies the effect of fasting on outcomes of repeated fasting is unknown. In a post hoc analysis of a randomized controlled trial (registration: clinicaltrials.gov, NCT02770313, May 12, 2016), subjects (N = 68) were adults ages 21–70 years with modest cholesterol elevation, ≥1 metabolic syndrome component, available HGH measurements, no chronic disease, and no statin or anti-diabetes medication. Randomization was 1:1 to intermittent fasting (24-hour, water-only, twice-per-week for 4 weeks, then once-per-week for 22 weeks) or 26-week ad libitum control. General linear modeling evaluated the interaction of trial arm with baseline HGH for HOMA-IR changes. Subjects with lower baseline HGH had 26-week HOMA-IR changes (p = 0.003) of −1.04 ± 0.99 for fasting versus 0.60 ± 1.04 for controls. Subjects with higher baseline HGH had HOMA-IR changes (p = 0.26) of −0.69 ± 0.75 (fasting) and −0.42 ± 0.92 (controls). The interaction of fasting with lower baseline HGH was significant (p-interaction=0.004). Results were similar for insulin and glucose. Weight loss at 26 weeks was not significantly different between fasting and controls (−1.74 ± 4.81 kg vs. 0.21 ± 3.50 kg, p = 0.08) and was not correlated with changes in HOMA-IR, insulin, glucose, and HGH. In conclusion, lower baseline HGH modified the effect of low-frequency water-only 24-hour fasting in profoundly reducing HOMA-IR over 26 weeks compared both to controls and to fasting subjects with higher baseline HGH.

The effects of early time restricted eating plus daily caloric restriction compared to daily caloric restriction alone on continuous glucose levels.

The median eating duration in the U.S. is 14.75h, spread throughout the period of wakefulness and ending before sleep. Food intake at an inappropriate circadian time may lead to adverse metabolic outcomes. Emerging literature suggests that time restricted eating (TRE) may improve glucose tolerance and insulin sensitivity. The aim was to compare 24-h glucose profiles and insulin sensitivity in participants after completing 12weeks of a behavioral weight loss intervention based on early TRE plus daily caloric restriction (E-TRE+DCR) or DCR alone. Eighty-one adults with overweight or obesity (age 18-50years, BMI 25-45kg/m2) were randomized to either E-TRE+DCR or DCR alone. Each participant wore a continuous glucose monitor (CGM) for 7days and insulin sensitivity was estimated using the homeostatic model assessment of insulin resistance (HOMA-IR) at Baseline and Week 12. Changes in CGM-derived measures and HOMA-IR from Baseline to Week 12 were assessed within and between groups using random intercept mixed models. Forty-four participants had valid CGM data at both time points, while 38 had valid glucose, insulin, HOMA-IR, and hemoglobin A1c (A1c) data at both timepoints. There were no significant differences in sex, age, BMI, or the percentage of participants with prediabetes between the groups (28% female, age 39.2±6.9years, BMI 33.8±5.7kg/m2, 16% with prediabetes). After adjusting for weight, there were no between-group differences in changes in overall average sensor glucose, standard deviation of glucose levels, the coefficient of variation of glucose levels, daytime or nighttime average sensor glucose, fasting glucose, insulin, HOMA-IR, or A1c. However, mean amplitude of glycemic excursions changed differently over time between the two groups, with a greater reduction found in the DCR as compared to E-TRE+DCR (p=0.03). There were no major differences between E-TRE+DCR and DCR groups in continuous glucose profiles or insulin sensitivity 12weeks after the intervention. Because the study sample included participants with normal baseline mean glucose profiles and insulin sensitivity, the ability to detect changes in these outcomes may have been limited.

Pubertal increment in insulin resistance is negatively related to lumbar bone mineral density in 18-year-old males.

Insulin resistance (IR) might have a compromising effect on growing bone, and therefore adult bone quality might be challenged. The aim of the present study was to identify whether increases in IR during puberty contribute to bone mineral characteristics in males independently of body composition parameters. This is a retrospective cohort-based longitudinal observational study. Data from 85 subjects were included. Boys were studied annually during their pubertal years (12years at baseline) and at follow-up at the age of 18years. Anthropometry, bone age, fasting blood samples, body composition, total body, and lumbar spine bone mineral characteristics were measured. Insulin resistance was determined by homeostatic model assessment of IR (HOMA-IR). Multiple regression analysis was performed to determine the effect of changes in HOMA-IR during pubertal years as a longitudinal predictor to fixed bone mineral outcome variables at the age of 18years. All models were adjusted to potential clinically justified confounding variables. After adjustment to baseline bone indices and body composition-related predictors, the pubertal increment in the HOMA-IR was a negative independent predictor of lumbar spine bone mineral areal density (β = - 0.202, p = 0.005) and lumbar spine bone mineral apparent density (β = - 0.235, p = 0.005) in 18-year-old males. Pubertal increment in IR has a potential diminishing effect on lumbar spine bone mineral density accrual independently of body composition parameters. Further studies are needed to clarify whether monitoring HOMA-IR during puberty may identify subjects at increased risk of low peak bone mass and possible osteoporosis in the future.

Blood DNA methylation at TXNIP and glycemic changes in response to weight-loss diet interventions: the POUNDS lost trial.

Background:Thioredoxin Interacting Protein (TXNIP) functions as a master regulator for glucose homeostasis. Hypomethylation at the 5’-cytosine-phosphate-guanine-3’ (CpG) site cg19693031 of TXNIP has been consistently related to islet dysfunction, hyperglycemia, and type 2 diabetes. DNA methylation (DNAm) may reveal the missing mechanistic link between obesity and type 2 diabetes. We hypothesize that baseline DNAm level at TXNIP in blood may be associated with glycemic traits and their changes in response to weight-loss diet interventions.Methods:We included 639 adult participants with overweight or obesity, who participated in a 2-year randomized weight-loss diet intervention. Baseline blood DNAm levels were profiled by high-resolution methylC-capture sequencing. We defined the regional DNAm level of TXNIP as the average methylation level over CpGs within 500 bp of cg19693031. Generalized linear regression models were used for main analyses.Results:We found that higher regional DNAm at TXNIP was significantly correlated with lower fasting glucose, HbA1c, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at baseline (P<0.05 for all). Significant interactions were observed between dietary protein intake and DNAm on changes in insulin (P-interaction=0.007) and HOMA-IR (P-interaction=0.009) at 6 months. In participants with the highest tertile of regional DNAm at TXNIP, average protein (15%) intake was associated with a greater reduction in insulin (β: −0.14; 95% CI: −0.24, −0.03; P=0.011) and HOMA-IR (β: −0.15; 95% CI: −0.26, −0.03; P=0.014) than high protein (25%) intake, whereas no significant associations were found in those with the lower tertiles (P>0.05). The interaction was attenuated to be non-significant at 2 years, presumably related to decreasing adherence to the diet intervention.Conclusions:Our data indicate that higher regional DNAm level at TXNIP was significantly associated with better fasting glucose, HbA1c, and HOMA-IR; and people with higher regional DNAm levels benefited more in insulin and HOMA-IR improvement by taking the average-protein weight-loss diet.

Abstract 10330: Intermittent Fasting Interacts with Red Cell Distribution Width to Differentially Improve Cardiometabolic Health

Introduction: Intermittent fasting reduces weight and cardiometabolic risk factors. In the WONDERFUL Trial (NCT02770313), intermittent fasting reduced homeostatic model assessment of insulin resistance (HOMA-IR) and the Metabolic Syndrome Score (MSS), with insulin having the largest decline. The red cell distribution width (RDW) measures the dispersion of red blood cell size, is strongly predictive of mortality and major adverse events, and may be a biomarker of general health. This post hoc study of subjects from the WONDERFUL Trial examined the interactive effect of intermittent fasting and baseline RDW on changes in insulin, glucose, HOMA-IR, and MSS. Methods: Subjects aged 21-70 years who had pre-diabetes, diabetes, or ≥1 other metabolic syndrome factor and modestly elevated LDL-C were enrolled if they were not taking anti-diabetic or statin medications and were free of chronic diseases (N=71; n=38 intermittent fasting, n=33 controls). Subjects were randomized to 24-hour water-only fasting (twice-weekly for 4 weeks followed by once-weekly for 22 weeks) or ad libitum eating (control) for 26 weeks. Results: Age averaged 49.1±11.1 years and 64.8% were female. Change scores stratified by RDW size distribution (RDW-SD) are shown in the Table. Results were similar when the RDW coefficient of variation (RDW-CV) was used. Intermittent fasting did not change RDW-SD (1.27±9.6 fL vs. control: -0.37±1.76 fL, p=0.34) or RDW-CV (-0.15%±0.55% vs. control: -0.11%±0.45%, p=0.76) over the 26-week trial. Conclusions: Compared to controls, intermittent fasting significantly decreased insulin more in subjects with higher baseline RDW than those with RDW ≤median. This differential effect may also apply to changes in HOMA-IR, glucose, and MSS. These findings should be validated and expanded in larger studies since RDW may identify people who would derive the most cardiometabolic benefit from engaging in intermittent fasting.

Abstract 10659: Blood DNA Methylation at TXNIP and Glycemic Changes in Response to Weight-Loss Diet Interventions: The POUNDS Lost Trial

Introduction: Thioredoxin Interacting Protein ( TXNIP ) functions as a master regulator for glucose homeostasis. Hypomethylation at the 5'-cytosine-phosphate-guanine-3' (CpG) site cg19693031 of TXNIP has been consistently related to islet dysfunction, hyperglycemia, and type 2 diabetes. DNA methylation (DNAm) may reveal the missing mechanistic link between obesity and type 2 diabetes; however, little is known about whether the DNAm level at TXNIP in blood is associated with glycemic changes in response to weight-loss diet interventions. Hypothesis: We hypothesized that participants with varying DNAm level of TXNIP responded differentially to weight-loss diet interventions on glycemic changes. Method: We included 639 overweight and obese participants from Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial, who were randomly assigned to 1 of 4 weight-loss diets varying in macronutrient contents. Blood DNAm levels were profiled by a high-resolution methylC-capture sequencing at baseline. We defined regional methylation level of TXNIP as average methylation level over CpGs within 500 bp of cg19693031. Results: Higher regional methylation level at TXNIP was correlated with lower fasting glucose, HbA1c, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at baseline (p&lt;0.05 for all). Participants with distinct regional methylation level of TXNIP showed significantly different changes in fasting insulin (p-interaction=0.007) and HOMA-IR (p-interaction=0.009) in response to average- vs. high-protein diet intervention at 6 months, independent of weight loss. Among participants with an average-protein diet, higher regional methylation level at TXNIP was associated with a greater reduction of fasting insulin and HOMA-IR at 6 months, while an opposite association was found among those with a high-protein diet. Such difference was attenuated to be nonsignificant at 2 years. Conclusions: DNAm level at TXNIP in blood may modify the effects of diet interventions on changes in glycemic traits, independent of weight loss. Overweight and obese individuals with higher methylation level at TXNIP may benefit more in improving insulin and HOMA-IR by consuming an average-protein diet than a high-protein diet.

Change in Visceral Fat and Total Body Fat and the Effect on Cardiometabolic Risk Factors During Transgender Hormone Therapy.

IntroductionExcess visceral fat increases the risk of type 2 diabetes and cardiovascular disease and is influenced by sex hormones. Our aim was to investigate changes in visceral fat and the ratio of visceral fat to total body fat (VAT/TBF) and their associations with changes in lipids and insulin resistance after 1 year of hormone therapy in trans persons.MethodsIn 179 trans women and 162 trans men, changes in total body and visceral fat estimated with dual-energy X-ray absorptiometry before and after 1 year of hormone therapy were related to lipids and insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)] with linear regression analysis.ResultsIn trans women, total body fat increased by 4.0 kg (95% CI 3.4, 4.7), while the amount of visceral fat did not change (−2 grams; 95% CI −15, 11), albeit with a large range from −318 to 281, resulting in a decrease in the VAT/TBF ratio of 17% (95% CI 15, 19). In trans men, total body fat decreased with 2.8 kg (95% CI 2.2, 3.5), while the amount of visceral fat did not change (3 g; 95% CI −10, 16; range −372, 311), increasing the VAT/TBF ratio by 14% (95% CI 10, 17). In both groups, VAT/TBF was not associated with changes in blood lipids or HOMA-IR.ConclusionsHormone therapy in trans women and trans men resulted in changes in VAT/TBF, mainly due to changes in total body fat and were unrelated to changes in cardiometabolic risk factors, which suggests that any unfavorable cardiometabolic effects of hormone therapy are not mediated by changes in visceral fat or VAT/TBF.

Association between reproductive years and insulin resistance in middle-aged and older women: A 10-year prospective cohort study

ObjectivesWe hypothesized that reproductive years, a marker of total estrogen exposure, may play an important role in insulin resistance. Study designA total of 3327 middle-aged and older women (age range 40–69 years) from the Korean Genome and Epidemiology Study were included in this large prospective cohort study with a mean follow-up of 10.8 years. Main outcome measuresInsulin resistance and sensitivity were calculated using the homeostatic model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI). A linear mixed model for a repeated-measures covariance pattern with unstructured covariance within participants was used to assess longitudinal associations between baseline reproductive years and subsequent changes in HOMA-IR and QUICKI. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for new-onset insulin resistance according to quartiles of reproductive years. ResultsChanges in HOMA-IR were significantly greater in Q1 (fewest reproductive years) than in Q4 (most reproductive years) (beta[SE] = 0.038[0.016]; p-value = 0.022), while changes in QUICKI were significantly smaller in Q1 than in Q4 (beta[SE] = −0.001[0.000]; p-value = 0.048) after adjusting for possible confounders over time. Compared with Q1, HRs (95 % CIs) for the incidence of new-onset insulin resistance were 0.807 (0.654−0.994) for Q2, 0.793 (0.645−0.974) for Q3, and 0.770 (0.622−0.953) for Q4 after adjusting for possible confounders. ConclusionA short reproductive period is associated with elevated levels on the HOMA-IR and decreased levels on the QUICKI over time. The lowest quartile of reproductive years was significantly associated with a higher risk of new-onset insulin resistance.

The Relationship between Circulating Acetate and Human Insulin Resistance before and after Weight Loss in the DiOGenes Study.

Microbially-produced acetate has been reported to beneficially affect metabolic health through effects on satiety, energy expenditure, insulin sensitivity, and substrate utilization. Here, we investigate the association between sex-specific concentrations of acetate and insulin sensitivity/resistance indices (Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), circulating insulin and Matsuda Index) in the Diet, Obesity and Genes (DiOGenes) Dietary study at baseline and after a low-calorie diet (LCD, 800 kcal/d). In this analysis, 692 subjects (Body Mass Index >27 kg/m2) were included, who underwent an LCD for 8 weeks. Linear mixed models were performed, which were adjusted for mean acetate concentration, center (random factor), age, weight loss, and fat-free mass (FFM). At baseline, no associations between plasma acetate and insulin sensitivity/resistance indices were found. We found a slight positive association between changes in acetate and changes in HOMA-IR (stdβ 0.130, p = 0.033) in women, but not in men (stdβ −0.072, p = 0.310) independently of age, weight loss and FFM. We were not able to confirm previously reported associations between acetate and insulin sensitivity in this large European cohort. The mechanisms behind the sex-specific relationship between LCD-induced changes in acetate and insulin sensitivity require further study.

Association of a Workplace Sales Ban on Sugar-Sweetened Beverages With Employee Consumption of Sugar-Sweetened Beverages and Health

Reductions in sugar-sweetened beverage (SSB) intake can improve health, but are difficult for individuals to achieve on their own. To evaluate whether a workplace SSB sales ban was associated with SSB intake and cardiometabolic health among employees and whether a brief motivational intervention provides added benefits to the sales ban. This before-after study and additional randomized trial conducted from July 28, 2015, to October 16, 2016, at a Northern California university and hospital assessed SSB intake, anthropometrics, and cardiometabolic biomarkers among 214 full-time English-speaking employees who were frequent SSB consumers (≥360 mL [≥12 fl oz] per day) before and 10 months after implementation of an SSB sales ban in a large workplace, with half the employees randomized to receive a brief motivational intervention targeting SSB reduction. The employer stopped selling SSBs in all workplace venues, and half the sample was randomized to receive a brief motivational intervention and the other half was a control group that did not receive the intervention. This intervention was modeled on standard brief motivational interventions for alcohol used in the workplace that promote health knowledge and goal setting. Outcomes included changes in SSB intake, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and measures of abdominal adiposity. The primary associations tested were the correlation between changes in SSB intake and changes in HOMA-IR. Among the 214 study participants, 124 (57.9%) were women, with a mean (SD) age of 41.2 (11.0) years and a baseline mean (SD) body mass index of 29.4 (6.5). They reported a mean daily intake of 1050 mL (35 fl oz) of SSBs at baseline and 540 mL (18 fl oz) at follow-up-a 510-mL (17-fl oz) (48.6%) decrease (P < .001). Reductions in SSB intake correlated with improvements in HOMA-IR (r = 0.16; P = .03). Those not randomized to receive the brief intervention reduced their SSB intake by a mean (SD) of 246.0 (84.0) mL (8.2 [2.8] fl oz), while those also receiving the brief intervention reduced SSB intake by 762.0 (84.0) mL (25.4 [2.8] fl oz). From baseline to follow-up, there were significant reductions in mean (SE) waist circumference (2.1 [2.8] cm; P < .001). This study's findings suggest that the workplace sales ban was associated with a reduction in SSB intake and a significant reduction in waist circumference among employees within 10 months. The randomized clinical trial portion of this study found that targeting those at high risk with a brief motivational intervention led to additional improvements. Workplace sales bans may offer a promising new private-sector strategy for reducing the health harms of SSB intake. ClinicalTrials.gov identifier: NCT02585336.

One-year treatment with gonadotropin-releasing hormone analogues does not affect body mass index, insulin sensitivity or lipid profile in girls with central precocious puberty.

Background Puberty is associated with a physiological decline in insulin sensitivity (IS). Overweight (OW) and obesity (OB) are common among girls with central precocious puberty (CPP). CPP is considered a risk factor for metabolic diseases. The aim of this study was to assess surrogate measures of IS, body mass index (BMI) and other metabolic parameters in CPP girls at diagnosis and during treatment with gonadotropin-releasing hormone analogues (GnRHa). Methods We present a prospective longitudinal study of CPP girls. The standard oral glucose tolerance test, homeostatic model assessment of insulin resistance (HOMA-IR), whole-body IS index (ISI) and fasting lipid profiles were evaluated at diagnosis, and at 6 and 12 months of treatment. Results Nineteen CPP girls were included; 17 were evaluable. At baseline, seven patients had normal weight (NW), five were OW and five were OB. During GnRHa treatment no significant changes were observed in BMI, HOMA-IR or ISI when considering the whole group. Whereas, when we analyzed patients according to BMI status, in NW patients, BMI increased significantly with no changes in HOMA-IR or ISI along treatment. In the OW/OB group, no significant differences were observed in BMI, HOMA-IR or ISI. Conclusions Girls with CPP showed a high frequency of OW/OB and a high prevalence of IR. GnRHa did not affect BMI, IS or the lipid profile when considering the whole cohort of patients. However, there was an increase in BMI in NW girls but not in OW/OB patients.

Anti-inflammatory effects of empagliflozin in patients with type 2 diabetes and insulin resistance

BackgroundInflammation might be a pathological mediator of cardiovascular events in patients with type 2 diabetes and high cardiovascular risk.MethodsWe investigated whether empagliflozin (EMPA) exerts anti-inflammatory effects that are reflected in decreased high-sensitivity C-reactive protein (hsCRP) values. Patients were allocated to receive a placebo (n = 51) or EMPA (n = 51) as an add-on treatment. Fasting blood samples were collected before and every 3 months after this intervention for 1 year.ResultsEmpagliflozin tended to elicit reductions in BMI, HbA1c, aspartate aminotransferase, alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase compared with the placebo, but the differences did not reach statistical significance. Levels of LDL-cholesterol, HDL-cholesterol, and triglycerides were unaltered, significantly increased, and decreased, respectively, by EMPA, but the differences were not statistically significant compared with the placebo. Empagliflozin for 12 months notably reduced the homeostatic model assessment of insulin resistance (HOMA-IR), remnant-like particle cholesterol (RLP-C), and hsCRP by 43%, 52% and 54%, respectively. The time courses of these reductions significantly differed from those of the placebo. Systolic and diastolic blood pressure were also significantly reduced by EMPA compared with the placebo. We applied multiple linear regression analysis to determine which factors were associated with changes in hsCRP induced by EMPA. The results revealed that alterations in hsCRP values (log [hsCRP at 12 months] minus log [hsCRP at month 0]) were significantly associated with changes in HOMA-IR, RLP-C, systolic blood pressure, HDL-C and ALT.ConclusionEmpagliflozin decreased hs-CRP and lowered levels of remnant related lipoproteins probably via ameliorating insulin resistance. The cardiovascular benefits conferred by EMPA might be driven at least partly by anti-inflammatory effects, and this mechanism might cooperate with other EMPA-induced changes including reduced blood pressure, to achieve the degree of cardioprotection revealed by the EMPA-REG OUTCOME trial.Trial registration UMIN Clinical Registry (UMIN000021552). Registered 21 March 2016, https://upload.umin.ac.jp/UMIN000021552

Metabolic Benefits of Prior Weight Loss with and without Exercise on Subsequent 6-Month Weight Regain.

To determine the 6-month follow-up effects after intentional 6-month weight loss alone (WL) and after weight loss with aerobic exercise (AEX + WL) on body composition, glucose metabolism, and cardiovascular disease risk factors in older postmenopausal women and to identify the mechanisms for weight regain. Women (n = 65, BMI > 25 kg/m2 ) underwent maximal oxygen consumption testing, dual-energy x-ray absorptiometry, computed tomography scans, and oral glucose tolerance tests before and after 6 months of AEX + WL or WL and at 12 months ad libitum follow-up. Insulin sensitivity (M) (hyperinsulinemic-euglycemic clamp) was measured at baseline and 6 months. Thirty WL and thirty-five AEX + WL women completed a follow-up at 12 months. Similar weight loss was observed (-8%) in both groups from 0 to 6 months. Total fat mass, fat-free mass, visceral fat area, subcutaneous abdominal and midthigh fat areas, fasting glucose, insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), insulin areas under the curve, and triglyceride levels decreased similarly after WL and AEX + WL and remained lower at 12 months than at baseline, despite weight regain at 12 months. Initial M was associated with weight regain (r = -0.40, P < 0.01). Weight regain was related to independent changes in leptin and HOMA-IR from 6 to 12 months in a multiple regression model (r = 0.77, P < 0.0001). Reductions in body fat and improvements in insulin sensitivity after AEX + WL and WL were maintained at 12 months despite modest weight regain. Baseline insulin resistance partially predicted the magnitude of weight regain in postmenopausal women.

Testosterone vs. aromatase inhibitor in older men with low testosterone: effects on cardiometabolic parameters.

Testosterone (T) replacement is being increasingly offered to older men with age-related decline in testosterone levels. The effects of long-term testosterone replacement and aromatase inhibition (AI) on glucose homeostasis and cardiometabolic markers were determine in older non-diabetic men with low testosterone levels. Men ≥65years, mean age 71±3years with serum total T<350ng/dL were randomized in a double-blind, placebo-controlled, parallel-group, proof-of-concept trial evaluating the effects of 5g transdermal testosterone gel (TT) (n=10), 1mg anastrozole (n=10) or placebo (n=9) daily for 12months. Homeostatic Model Assessment of insulin resistance (HOMAIR ) was the primary outcome. Secondary outcomes included OGIS in response to OGTT, fasting lipids, C-reactive protein (CRP), adipokines, and abdominal and mid-thigh fat by computed tomography. All outcomes were assessed at baseline and 12months. After 12months, absolute changes in HOMAIR in both treatment arms (TT group: -0.05±0.21); (AI group: 0.15±0.10) were similar to placebo (-0.11±0.26), as were CRP and fasting lipid levels. Adiponectin levels significantly decreased in the TT group (-1.8±0.9mg/L, p=0.02) and abdominal subcutaneous fat (-60.34±3.19cm2 , p=0.003) and leptin levels (-1.5±1.2ng/mL, p=0.04) were significantly lower with AI. Mid-thigh subcutaneousfat was reduced in both treatment arms (TT group: -4.88±1.24cm2 , p=0.008); (AI group: -6.05±0.87cm2 , p=0.0002). In summary, in this proof-of-concept trial, changes in HOMAIR AI were similar in all three groups while the effects of intervention on subcutaneous fat distribution and adipokines were variable. Larger efficacy and safety trials are needed before AI pharmacotherapy can be considered as a treatment option for low T levels in older men.

Changes in Insulin Resistance After Initiation of Raltegravir or Protease Inhibitors With Tenofovir-Emtricitabine: AIDS Clinical Trials Group A5260s.

Background. Antiretroviral therapy (ART) can alter glucose metabolism, but little data exist on the association of raltegravir (RAL) with insulin resistance. Methods. A5260s was a substudy of A5257, a prospective open-label randomized trial in which human immunodeficiency virus (HIV)-infected treatment-naive participants were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or RAL over 96 weeks. Baseline and changes in insulin resistance as estimated by the homeostatic model assessment of insulin resistance (HOMA-IR) were assessed. Wilcoxon rank-sum tests were used to assess shifts in the distribution of fold increase from baseline between treatment arms, and Spearman correlation was used to assess associations between HOMA-IR and measures of inflammation and body composition. Results. Three hundred twenty-eight participants were randomized; 90% were male, baseline median age was 36, HIV ribonucleic acid copies were 4.55 log10 copies/mL, and CD4 cell count was 349/mm3. Overall, HOMA-IR increased significantly after 4 weeks (1.9-fold change; 95% confidence interval, 1.73-2.05) then plateaued over the remainder of the study. Changes in HOMA-IR were not different between the arms (P ≥ .23). Changes in HOMA-IR were associated with changes in body mass index at weeks 48 and 96 (r = 0.12-0.22; P ≤ .04). There was a trend with increases in HOMA-IR and increases in visceral abdominal fat at week 96 (r = 0.12; P = .06). At 48 and 96 weeks, HOMA-IR correlated with interleukin-6, high-sensitivity C-reactive protein, and soluble CD163 (r = 0.16-0.27; P ≤ .003). Conclusions. Insulin resistance increased rapidly and then plateaued in treatment-naive participants initiating ART with TDF/FTC, and no differences were found with RAL when compared with ATV/r or DRV/r.

Association between exercise-induced change in body composition and change in cardiometabolic risk factors in postmenopausal South Asian women.

The South Asian population suffers from a high prevalence of type 2 diabetes and cardiovascular disease (CVD). A unique obesity phenotype of elevated visceral adipose tissue (VAT) is associated with CVD risk among South Asians. Exercise-induced reduction in VAT and body fat is an effective mechanism to improve cardiometabolic risk factors but this has not been shown in South Asians. Whether exercise-induced changes in measurements such as waist circumference (WC) are independently related to changes in cardiometabolic risk factors in South Asians is unknown. Multi-slice computed tomography scanning was used to assess VAT, cardiometabolic risk factors through a fasting blood sample, and body fat using dual-energy X-ray absorptiometry. Forty- nine postmenopausal South Asian women who participated in two 12-week aerobic exercise programs were included. Bivariate correlations were used to assess associations between change in cardiometabolic risk factors and change in body composition. Regression analyses were conducted with change in glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) as dependent variables and change in body composition as independent variables of interest. There were significant associations between changes in fasting insulin, glucose, and HOMA-IR with change in VAT. The association between change in VAT and these cardiometabolic risk factors was independent of change in other body composition variables of interest. South Asian women should be encouraged to engage in aerobic activity to reduce their risk of type 2 diabetes and CVD, and physicians should be aware of improvements in glucose regulation with exercise training not observed through reductions in WC.

Changes in Alanine Aminotransferase/Aspartate Aminotransferase Ratio Are Associated with Changes in Insulin Resistance in Japanese Community-Dwelling Middle-Aged and Elderly Women

Liver marker {e.g., alanine aminotransferase (ALT) and aspartate aminotransferase (AST)} levels independently predict insulin resistance. The aim of the present study is to examine how changes in liver markers are associated with changes in insulin resistance after exercise in Japanese community-dwelling adults. The participants were 76 women aged 67 ± 6 years from a rural village. Nordic walk (NW) exercise of 120 min per week was performed for 12 weeks. Before and at the end of the 12-week intervention, various confounding factors and insulin resistance {e.g., Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)} were measured. The baseline, follow-up, and changes in ALT/AST ratio (β = 0.390, P β = 0.393, P β = 0.321, P = 0.004, respectively) were each significantly and independently associated with HOMA-IR. When the data were further stratified by baseline and change in ASL/AST ratio, changes in HOMA-IR decreased more significantly in participants with baseline ASL/AST ratio ≥ 0.762 and change in ALT/AST ratio of P = 0.002 and ASL/AST ratio ≥ 0.762, P = 0.047). This study is of interest because liver transaminase markers, which are inexpensive and routinely collected in clinical settings, may provide a simple and accurate enhancement to models currently used to identify subjects with changes in insulin resistance. These results suggest that a higher baseline and decreased change in ALT/AST ratio may be a predictor for decreased insulin resistance after a 12-week walking exercise in community-dwelling middle-aged and elderly women.

Weight Change-Adjusted Effects of Gastric Bypass Surgery on Glucose Metabolism: 2- and 10-Year Results From the Swedish Obese Subjects (SOS) Study.

It has been suggested that weight change-independent effects on fasting insulin and glucose levels are present after gastric bypass (GBP) but not after banding and vertical banded gastroplasty (VBG). We therefore evaluated weight change-adjusted effects of GBP, compared with restrictive surgical procedures, on long-term changes in fasting levels of glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) in the Swedish Obese Subjects (SOS) study. Participants who completed the 2-year (n = 1,762) and/or the 10-year (n = 1,216) follow-up were divided into three weight change classes (weight loss >30%, 20-30%, or ≤20%), and by surgical method (banding, VBG, or GBP). Glucose, insulin, and HOMA-IR changes were analyzed in relation to weight change over 2 and 10 years. Analyses were performed in the full cohort and also in subgroups based on baseline glucose status. Within weight change classes, reductions in glucose, insulin, and HOMA-IR were similar in the three surgery groups both at 2 and at 10 years. Reductions in glucose, insulin, and HOMA-IR increased with increasing weight loss, and changes were typically related to weight change within each surgery group. Moreover, the association between weight change and change in glucose, insulin, or HOMA-IR did not differ between the surgery groups at 2 and 10 years. When patients were subdivided also by baseline glucose status, similar relationships between weight changes and changes in glucose, insulin, and HOMA-IR were observed. Even though weight loss-independent effects are important for short-term diabetes remission, our results suggest that degree of weight loss is more important for long-term reductions in fasting insulin and glucose than choice of bariatric surgery procedure.

Insulin resistance may contribute to vascular dysfunction in patients with chronic obstructive pulmonary disease

Patients with chronic obstructive pulmonary disease (COPD) are at an increased cardiovascular risk; however, the underlying mechanisms for this relationship are ill defined. Altered glucose metabolism may increase cardiovascular risk via impaired endothelial function. We conducted a longitudinal pilot study to assess the interrelationship between systemic vascular function, glucose metabolism, and lung function in patients with COPD. Eighteen non-smoking patients with stable moderate-to-severe COPD [67 % male; median (first to third quartiles) Forced Expiratory Volume in 1 second (FEV1) % predicted: 38 % (28-55 %); body mass index: 26kg/m(2) (24-28kg/m(2))] free from cardiovascular risk factors were evaluated. Systemic vascular function was assessed by means of flow-mediated dilation technique of the brachial artery. Laboratory measurements included fasting blood glucose levels, circulating concentrations of insulin, C-reactive protein, and fibrinogen. Homeostatic model assessment of insulin resistance (HOMA-IR) was determined. Measurements were performed at baseline and were repeated after 12months. Flow-mediated dilation significantly decreased from 13.5 % (11-15 %) at baseline to 9.8 % (6-12 %; p = 0.002) at the follow-up visit, whereas both fasting blood glucose concentrations and HOMA-IR increased from 94mg/dl (86-103mg/dl) to 102mg/dl (94-111mg/dl; p = 0.027) and from 1.2 (0.8-2.1) to 1.7 (1.2-3.0; p = 0.023), respectively. There was a significant relationship between changes in endothelial function and changes in fasting serum glucose (r = - 0.483, p = 0.009), HOMA-IR (r = - 0.441, p = 0.019), and FEV1 (r = 0.336, p = 0.05). Altered glucose metabolism may be associated with progression of endothelial dysfunction in patients with COPD.