Indices Of Insulin Action Research Articles

Sex- and trimester-specific impact of gestational co-exposure to organophosphate esters and phthalates on insulin action among preschoolers: Findings from the Ma'anshan birth cohort.

Prenatal exposure to organophosphate esters (OPEs) and phthalic acid esters (PAEs) is ubiquitous among pregnant individuals. However, research exploring the relationship between prenatal co-exposure to OPEs and PAEs and childhood insulin function remains limited. In this study, utilizing data from 2,246 maternal-fetal dyads in the Ma'anshan Birth Cohort, associations between co-exposure to OPEs and PAEs and insulin action were analyzed. Repeated measures of tris (2-chloroethyl) phosphate, six OPE metabolites, and seven PAE metabolites were collected from maternal urine. Homeostasis model assessment of insulin resistance (HOMA-IR) and the insulin action index (IAI) served as outcome measures. After adjusting for potential confounders, the effects of repeated exposure on insulin action were evaluated using generalized estimating equations, while mixture effects were assessed through BayesianKernel Machine Regression and Quantile-Based G-Computation. The average age of the children at the time of the study was 5.33years. Repeated measures analysis revealed that prenatal exposure to MEP was positively associated with increased HOMA-IR (β, 0.027; 95% CI: 0.002, 0.053), while IAI was inversely correlated with rising MEP levels (β, 0.025; 95% CI: -0.046, -0.004) and MEHHP exposure (β, -0.128; 95% CI: -0.218, -0.037). Mixed exposure modeling further indicated that co-exposure to OPEs and PAEs was positively linked to HOMA-IR (β, 0.058; 95% CI: 0.001, 0.114) and negatively correlated with IAI (β, -0.054; 95% CI: -0.097, -0.010), with stronger effects observed during the second trimester. Notably, the association was more pronounced in female children compared to males. This study provides the first epidemiological evidence highlighting the pregnancy- and sex-specific links between prenatal co-exposure to OPEs and PAEs and childhood insulin action.

Elevated heart rate and decreased muscle endothelial nitric oxide synthase in early development of insulin resistance.

Insulin resistance (IR) is a risk factor for the development of several major metabolic diseases. Muscle fiber composition is established early in life and is associated with insulin sensitivity. Hence, muscle fiber composition was used to identify early defects in the development of IR in healthy young individuals in the absence of clinical manifestations. Biopsies were obtained from the thigh muscle, followed by an intravenous glucose tolerance test. Indices of insulin action were calculated and cardiovascular measurements, analyses of blood and muscle were performed. Whole body insulin sensitivity (SIgalvin) was positively related to expression of type I muscle fibers (r = 0.49; P < 0.001) and negatively related to resting heart rate (HR, r = -0.39; P < 0.001), which was also negatively related to expression of type I muscle fibers (r = -0.41; P < 0.001). Muscle protein expression of endothelial nitric oxide synthase (eNOS), whose activation results in vasodilation, was measured in two subsets of subjects expressing a high percentage of type I fibers (59 ± 6%; HR = 57 ± 9 beats/min; SIgalvin = 1.8 ± 0.7 units) or low percentage of type I fibers (30 ± 6%; HR = 71 ± 11; SIgalvin = 0.8 ± 0.3 units; P < 0.001 for all variables vs. first group). eNOS expression was 1) higher in subjects with high type I expression; 2) almost twofold higher in pools of type I versus II fibers; 3) only detected in capillaries surrounding muscle fibers; and 4) linearly associated with SIgalvin. These data demonstrate that an altered function of the autonomic nervous system and a compromised capacity for vasodilation in the microvasculature occur early in the development of IR.NEW & NOTEWORTHY Insulin resistance (IR) is a risk factor for the development of several metabolic diseases. In healthy young individuals, an elevated heart rate (HR) correlates with low insulin sensitivity and high expression of type II skeletal muscle fibers, which express low levels of endothelial nitric oxide synthase (eNOS) and, hence, a limited capacity to induce vasodilation in response to insulin. Early targeting of the autonomic nervous system and microvasculature may attenuate development of diseases stemming from insulin resistance.

Impaired Diurnal Pattern of Meal Tolerance and Insulin Sensitivity in Type 2 Diabetes: Implications for Therapy.

To assess the diurnal patterns of postprandial glucose tolerance and insulin sensitivity, 19 subjects with type 2 diabetes (8 women; 60 ± 11 years; BMI 32 ± 5 kg/m2) and 19 anthropometrically matched subjects with no diabetes (ND; 11 women; 53 ± 12 years; BMI 29 ± 5 kg/m2) were studied during breakfast (B), lunch (L), and dinner (D) with identical mixed meals (75 g carbohydrates) on 3 consecutive days in a randomized Latin square design. Three stable isotopes of glucose were ustilized to estimate meal fluxes, and mathematical models were used in estimating indices of insulin action and β-cell function. Postmeal glucose excursions were higher at D versus B and at D versus L in type 2 diabetes (P < 0.05), while in ND they were higher at D versus B (P = 0.025) and at L versus B (P = 0.04). The insulin area under the curve was highest at B compared with L and D in type 2 diabetes, while no differences were observed in ND. Disposition index (DI) was higher at B than at L (P < 0.01) and at D (P < 0.001) in ND subjects, whereas DI was low with unchanging pattern across B-L-D in individuals with type 2 diabetes. Furthermore, between-meal differences in β-cell responsivity to glucose (F) and insulin sensitivity (SI) were concurrent with changes in the DI within groups. Fasting and postmeal glucose, insulin, and C-peptide concentrations, along with estimates of endogenous glucose production (EGP), Rd, SI, F, hepatic extraction of insulin, insulin secretion rate, extracted insulin, and DI, were altered in type 2 diabetes compared with ND (P < 0.011 for all). The data show a diurnal pattern of postprandial glucose tolerance in overweight otherwise glucose-tolerant ND individuals that differs from overweight individuals with type 2 diabetes. The results not only provide valuable insight into management strategies for better glycemic control in people with type 2 diabetes, but also improved understanding of daytime glucose metabolism in overweight individuals without impaired glucose tolerance or overt diabetes.

1181-P: Consumption of Naturally Enriched Complex Carbohydrate Meal Improves Insulin Sensitivity and Disposition Index in Type 2 Diabetes

The triple tracer method has enabled accurate and concurrent measurements of glucose turnover as well as indices of insulin action and beta cell function in people with diabetes. We have previously utilized the natural enrichment of 13C polysaccharide in commercially available grains, and compared indices obtained after a complex carbohydrate (CC) meal to those obtained after a simple carbohydrate (SC) mixed meal in healthy humans. We have now completed studies in 6 subjects with type 2 diabetes (4M, age 65±6 y; BMI 33±4 kg/m2; HbA1c 50±10 mM/mol) after ~75 gm of either sorghum (naturally enriched 13C) or glucose labeled with 13C mixed meals containing ~75 gm carbs and matched protein and fat in random order. Results in figure. Glucose, insulin and C-peptide concentrations achieved were significantly lower with CC meal as compared to SC meal (p Disclosure D. Romeres: None. A. Basu: None. Y. R. Yadav: None. C. Cobelli: None. C. Dalla man: Research Support; Self; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. R. Basu: None. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)

Improved postprandial glucose metabolism in type 2 diabetes by the dual glucagon-like peptide-1/glucagon receptor agonist SAR425899 in comparison with liraglutide.

AimTo gain further insights into the efficacy of SAR425899, a dual glucagon‐like peptide‐1/glucagon receptor agonist, by providing direct comparison with the glucagon‐like peptide‐1 receptor agonist, liraglutide, in terms of key outcomes of glucose metabolism.Research Design and MethodsSeventy overweight to obese subjects with type 2 diabetes (T2D) were randomized to receive once‐daily subcutaneous administrations of SAR425899 (0.12, 0.16 or 0.20 mg), liraglutide (1.80 mg) or placebo for 26 weeks. Mixed meal tolerance tests were conducted at baseline (BSL) and at the end of treatment (EOT). Metabolic indices of insulin action and secretion were assessed via Homeostasis Model Assessment (HOMA2) and oral minimal model (OMM) methods.ResultsFrom BSL to EOT (median [25th, 75th] percentile), HOMA2 quantified a significant improvement in basal insulin action in liraglutide (35% [21%, 74%]), while secretion enhanced both in SAR425899 (125% [63%, 228%]) and liraglutide (73% [43%, 147%]). OMM quantified, both in SAR425899 and liraglutide, a significant improvement in insulin sensitivity (203% [58%, 440%] and 36% [21%, 197%]), basal beta‐cell responsiveness (67% [34%, 112%] and 40% [16%, 59%]), and above‐basal beta‐cell responsiveness (139% [64%, 261%] and 69% [−15%, 120%]). A significant delay in glucose absorption was highlighted in SAR425899 (37% [52%,18%]).ConclusionsSAR425899 and liraglutide improved postprandial glucose control in overweight to obese subjects with T2D. A significantly higher enhancement in beta‐cell function was shown by SAR425899 than liraglutide.

Novel Indices of Glucose Homeostasis Derived from Principal Component Analysis: Application for Metabolic Assessment in Pregnancy.

Aims This study is aimed at assessing the association of previously developed indices of glucose homeostasis derived from principal component analysis (PCA) with parameters of insulin action, secretion, and beta cell function during pregnancy. Methods In this prospective longitudinal study, an oral glucose tolerance test was performed in sixty-seven pregnant women at two prepartum (12+0 to 22+6 and 24+0 to 28+6) and one postpartum (2 to 11 months) visits. Three principal component scores (PCS) were calculated based on measurements of glucose, insulin, C-peptide, age, and BMI to assess their association with fasting and dynamic indices of insulin action, secretion, and β-cell function. Results PCS1 was positively associated with fasting and dynamic parameters of insulin sensitivity (Matsuda index: r = 0.93, p < 0.001), whereas a strong negative association was observed for early, late, and total insulin response. PCS2 was associated with higher mean glucose but negatively related to parameters of insulin secretion. PCS3 was significantly associated with fasting indices of insulin sensitivity. PCS1 to 3 assessed at early pregnancy were also associated with development of GDM, whereby random forest analysis revealed the highest variable importance for PCS1. PCS1 to 3 were significantly related to the oral disposition index explaining 49.0% of its variance. Conclusions PCS1 to 3 behaved similarly as compared to previous observations in nonpregnant women and were furthermore associated with the development of GDM. These findings support our hypothesis that PCS1 to 3 could be used as novel indices of glucose disposal during pregnancy.

Fibroblast growth factor-21 (FGF21) administration to early-lactating dairy cows. I. Effects on signaling and indices of insulin action

Modern dairy cows rely on hormonally driven mechanisms to coordinate the metabolic adaptations needed to meet the energy and nutrient deficits of early lactation. In the case of glucose, dairy cows cope with its scarcity during early lactation via reduced plasma concentrations of insulin and the insulin sensitizing hormone adiponectin and increased insulin resistance. Reduced insulin action promotes diversion of available glucose to the mammary gland but increases susceptibility to diseases if excessive. In earlier work, we reported that the insulin sensitizing hormone fibroblast growth factor-21 (FGF21) is increased in periparturient dairy cows and identified liver and adipose tissue as possible targets. These observations raised the possibility that FGF21 acts directly on these tissues to limit the insulin resistance of early lactation. To test this hypothesis, dairy cows were randomly assigned on d 12.6 ± 2.2 (± standard error) of lactation to receive either excipient (n = 6) or recombinant human FGF21 (n = 7), first as an FGF21 bolus of 3 mg/kg of body weight, followed 2 d later by a constant i.v. infusion of FGF21 at the rate of 6.3 mg/kg of metabolic body weight for 9 consecutive days. Biopsies of liver and adipose tissue were collected during the bolus phase of the experiment and used to analyze FGF21 signaling by Western blotting and expression of its receptor components by quantitative PCR. Bolus FGF21 administration caused a 4-fold increase in p44/42 MAPK (ERK1/2) activation in adipose tissue but had no effect on AKT and signal transducer and activator of transcription-3 (STAT3) signaling. The liver expressed negligible levels of the preferred FGF21 receptor FGFR1c and failed to mount any FGF21 signaling response. The FGF21 administered as a bolus had no effect on plasma glucose or insulin and did not stimulate an acute release of adiponectin from adipose tissue. Similarly, FGF21 infusion had no effect on plasma levels of glucose or insulin measured over the 9-d infusion or on glucose disposal during an i.v. glucose tolerance test performed on d 8 of infusion. Finally, the chronic FGF21 infusion had no effect on indices of adiponectin production, including plasma adiponectin and adipose tissue mRNA abundance of adiponectin and the endoplasmic reticulum chaperones ERO1A and DSBA-L involved in the assembly of adiponectin into multimeric complexes. These data show that human FGF21 does not act as an insulin sensitizer during the energy and glucose deficit of early lactation but do not rule out such a role in other physiological states.

A novel natural tracer method to measure complex carbohydrate metabolism

While the triple tracer isotope dilution method has enabled accurate estimation of carbohydrate turnover after a mixed meal, use of the simple carbohydrate glucose as the carbohydrate source limits its translational applicability to everyday meals that typically contain complex carbohydrates. Hence, utilizing the natural enrichment of [13C]polysaccharide in commercially available grains, we devised a novel tracer method to measure postprandial complex carbohydrate turnover and indices of insulin action and β-cell function and compared the parameters to those obtained after a simple carbohydrate containing mixed meal. We studied healthy volunteers after either rice (n = 8) or sorghum (n = 8) and glucose (n = 16) containing mixed meals and modified the triple tracer technique to calculate carbohydrate turnover. All meals were matched for calories and macronutrient composition. Rates of meal glucose appearance (2,658 ± 736 vs. 4,487 ± 909 μM·kg-1·2 h-1), endogenous glucose production (-835 ± 283 vs. -1,123 ± 323 μM·kg-1·2 h-1) and glucose disappearance (1,829 ± 807 vs. 3,606 ± 839 μM·kg-1·2 h-1) differed (P < 0.01) between complex and simple carbohydrate containing meals, respectively. Interestingly, there were significant increase in indices of insulin sensitivity (32.5 ± 3.5 vs. 25.6 ± 3.2 10-5 (dl·kg-1·min-2)/pM, P = 0.006) and β-cell responsivity (disposition index: 1,817 ± 234 vs. 1,236 ± 159 10-14 (dl·kg-1·min-2)/pM, P < 0.005) with complex than simple carbohydrate meals. We present a novel triple tracer approach to estimate postprandial turnover of complex carbohydrate containing mixed meals. We also report higher insulin sensitivity and β-cell responsivity with complex than with simple carbohydrates in mixed meals of identical calorie and macronutrient compositions in healthy adults.

2048-P: The Physiological Effects of VLCD in Overweight Nondiabetics

Background: Very Low-Calorie Diets (VLCD) are being increasingly used as a treatment for obesity and diabetes, yet concerns persist regarding reductions in muscle mass (as a crucial locomotory and insulin sensitive organ), while many physiological effects of VLCD are ill-defined. We thus explored the effects of VLCD on body composition, insulin sensitivity and vascular function in the overweight. Methods: Eight overweight men (47±7y; 103±14kg; BMI 32±4, mean±SD) were placed on a VLCD, of &amp;lt;800kcal/day for 6-weeks via meal replacements. Before/after VLCD, we conducted: OGTT, DXA to quantity fat and lean body mass, ultrasound (U.S.) to determine flow-mediated dilatation (FMD), and echocardiogram (ECHO) for left ventricular function (LVF). Insulin sensitivity was assessed via: i) HOMA-IR ii) area under the curve (AUC) for insulin and glucose iii) QUICKI iv) Matsuda Index. Results: VLCD reduced body weight (∆ -10.5±3 kg), fat mass (∆ -6.8±2 kg) and lean body mass (∆ -4.1±2 kg); all p&amp;lt;0.001. Significant improvements occurred in insulin sensitivity (HOMA-IR ∆ -0.6 ±0.6; AUC insulin ∆ -2147±2153 miliU/L*minute; QUICKI ∆ +0.05±0.03, and Matsuda Index ∆ 5.4±3.5); all P&amp;lt;0.05). No significant differences were observed in FMD (∆ 0.5±1.7%, P=0.5), LVF (∆ 1.4 ±6.9%, P=0.6), or AUC glucose (∆ -23.3±167.2 mmol/L*minute, P=0.7). No correlation was evident between degree of insulin sensitivity biomarkers and body weight or fat loss (e.g., Pearson -0.1&amp;lt;r&amp;lt;0.1, P&amp;gt;0.8). Conclusion: VLCD predictably induced marked weight loss and improved insulin sensitivity during just 6-weeks of VLCD, and this was associated with body fat loss and muscle wasting. Nonetheless, the poor correlation between total weight or body fat loss and improved indices of insulin action points to metabolic reprogramming of insulin sensitive tissues in response to energy restriction, rather than fat loss per se, in driving some of the health benefits of VLCD. Developing means to mitigate muscle atrophy with VLCD is crucial to maximizing therapeutic benefits, especially in aging. Disclosure M. Abdul Aziz: None. B.E. Phillips: None. I. Ramzan: None. J. Cegielski: None. K. Smith: None. I.R. Idris: None. P.J. Atherton: None. Funding Medical Research Council UK

Electrical pulse stimulation induces differential responses in insulin action in myotubes from severely obese individuals.

Exercise/exercise training can enhance insulin sensitivity through adaptations in skeletal muscle, the primary site of insulin-mediated glucose disposal; however, in humans the range of improvement can vary substantially. The purpose of this study was to determine if obesity influences the magnitude of the exercise response in relation to improving insulin sensitivity in human skeletal muscle. Electrical pulse stimulation (EPS; 24h) of primary human skeletal muscle myotubes improved insulin action in tissue from both lean and severely obese individuals, but responses to EPS were blunted with obesity. EPS improved insulin signal transduction in myotubes from lean but not severely obese subjects and increased AMP accumulation and AMPK Thr172 phosphorylation, but to a lesser degree in myotubes from the severely obese. These data reveal that myotubes of severely obese individuals enhance insulin action and stimulate exercise-responsive molecules with contraction, but in a manner and magnitude that differs from lean subjects. Exercise/muscle contraction can enhance whole-body insulin sensitivity; however, in humans the range of improvements can vary substantially. In order, to determine if obesity influences the magnitude of the exercise response, this study compared the effects of electrical pulse stimulation (EPS)-induced contractile activity upon primary myotubes derived from lean and severely obese (BMI≥ 40kg/m2 ) women. Prior to muscle contraction, insulin action was compromised in myotubes from the severely obese as was evident from reduced insulin-stimulated glycogen synthesis, glucose oxidation, glucose uptake, insulin signal transduction (IRS1, Akt, TBC1D4), and insulin-stimulated GLUT4 translocation. EPS (24h) increased AMP, IMP, AMPK Thr172 phosphorylation, PGC1α content, and insulin action in myotubes of both the lean and severely obese subjects. However, despite normalizing indices of insulin action to levels seen in the lean control (non-EPS) condition, responses to EPS were blunted with obesity. EPS improved insulin signal transduction in myotubes from lean but not severely obese subjects and EPS increased AMP accumulation and AMPK Thr172 phosphorylation, but to a lesser degree in myotubes from the severely obese. These data reveal that myotubes of severely obese individuals enhance insulin action and stimulate exercise-responsive molecules with contraction, but in a manner and magnitude that differs from lean subjects.

Dpp4 Inhibitor Sitagliptin As A Potential Treatment Option In Metformin-Intolerant Obese Women With Polycystic Ovary Syndrome: A Pilot Randomized Study

Metformin has an established role in the management of polycystic ovary syndrome (PCOS). Some patients cannot tolerate it due to associated gastrointestinal adverse events. The present study evaluated the dipeptidyl peptidase 4 inhibitor sitagliptin as a potential treatment option in metformin-intolerant PCOS. We conducted a 12-week, prospective, randomized, open-label study with 30 obese metformin-intolerant women with PCOS (age 35.0 ± 7.2 years; body mass index, 36.9 ± 5.5 kg/m2). After metformin withdrawal, they were randomized to lifestyle intervention and sitagliptin 100 mg daily (SITA) or lifestyle intervention alone as controls (CON). All participants underwent anthropometric and endocrine measurements and oral glucose tolerance testing. Model-derived indexes of insulin resistance and beta-cell function were calculated. SITA improved beta-cell function as assessed by the homeostasis model assessment for beta-cell function index (HOMA-B) of 45.9 ± 35.8 ( P = .001), modified beta-cell function index (MBCI) of 7.9 ± 7 ( P = .002), and quantitative insulin-sensitivity check index (QUICKI) of -0.03 ± 0.03 ( P = .002). By contrast, beta-cell function decreased in CON. The between-group differences were significant for HOMA-B ( P = 0.001), MBCI ( P = .010), and QUICKI ( P = .025). The conversion rate to impaired glucose homeostasis was prevented in SITA: 3 of 15 subjects had impaired glucose tolerance (IGT) before and after the study. In CON, none had type 2 diabetes (T2D), and 4 had IGT at the beginning. After 12 weeks, IGT was observed in 2 and T2D in 3 subjects. SITA improved beta-cell function and prevented a conversion to IGT and T2D in metformin-intolerant obese PCOS patients. BMI = body mass index; DPP-4 = dipeptidyl peptidase-4; DXA = dual energy X-ray absorptiometry; GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1; HOMA-B = homeostasis model assessment for beta-cell function; HOMA-IR = homeostasis model assessment of insulin resistance; IAI = insulin action index; IGT = impaired glucose tolerance; IR = insulin resistance; MBCI = modified beta-cell function index; OGTT = oral glucose tolerance test; QUICKI = quantitative insulin sensitivity check index; PCOS = polycystic ovary syndrome; SHBG = sex hormone-binding globulin; T2D = type 2 diabetes.

Impaired Insulin Action Is Associated With Increased Glucagon Concentrations in Nondiabetic Humans.

Abnormal glucagon concentrations contribute to hyperglycemia, but the mechanisms of α-cell dysfunction in prediabetes are unclear. We sought to determine the relative contributions of insulin secretion and action to α-cell dysfunction in nondiabetic participants across the spectrum of glucose tolerance. This was a cross-sectional study. A subset of participants (n = 120) was studied in the presence and absence of free fatty acid (FFA) elevation, achieved by infusion of Intralipid (Baxter Healthcare, Deerfield, IL) plus heparin, to cause insulin resistance. An inpatient clinical research unit at an academic medical center. A total of 310 nondiabetic persons participated in this study. Participants underwent a seven-sample oral glucose tolerance test. Subsequently, 120 participants were studied on two occasions. On one day, infusion of Intralipid plus heparin raised FFA. On the other day, participants received glycerol as a control. We examined the relationship of glucagon concentration with indices of insulin action after adjusting for the effects of age, sex, and weight. Subsequently, we sought to determine whether an acute decrease in insulin action, produced by FFA elevation, altered glucagon concentrations in nondiabetic participants. Fasting glucagon concentrations correlated positively with fasting insulin and C-peptide concentrations and inversely with insulin action. Fasting glucagon was not associated with any index of β-cell function in response to an oral challenge. As expected, FFA elevation decreased insulin action and also raised glucagon concentrations. In nondiabetic participants, glucagon secretion was altered by changes in insulin action.

Randomized Controlled Trial of a MUFA or Fiber-Rich Diet on Hepatic Fat in Prediabetes.

Increased prevalence of type 2 diabetes mellitus and prediabetes worldwide is attributed in part to an unhealthy diet. To evaluate whether 12 weeks of high monounsaturated fatty acid (MUFA) or fiber-rich weight-maintenance diet lowers hepatic fat and improves glucose tolerance in people with prediabetes. Subjects underwent a [6, 6-2H2]-labeled 75-g oral glucose tolerance test to estimate hepatic insulin sensitivity and liver fat fraction (LFF) using magnetic resonance spectroscopy before and after intervention. Mayo Clinic Clinical Research Trials Unit. 43 subjects with prediabetes. Subjects were randomized into three isocaloric weight-maintaining diets containing MUFA (olive oil), extra fiber, and standard US food (control-habitual diet). LFF, glucose tolerance, and indices of insulin action and secretion. Body weight was maintained constant in all groups during the intervention. Glucose and hormonal concentrations were similar in all groups before, and unchanged after, 12 weeks of intervention. LFF was significantly lower after intervention in the MUFA group (P < 0.0003) but remained unchanged in the fiber (P = 0.25) and control groups (P = 0.45). After 12 weeks, LFF was significantly lower in the MUFA than in the control group (P = 0.01), but fiber and control groups did not differ (P = 0.41). Indices of insulin action and secretion were not significantly different between the MUFA and control groups after intervention (P ≥ 0.11), but within-group comparison showed higher hepatic (P = 0.01) and total insulin sensitivity (P < 0.04) with MUFA. Twelve weeks of a MUFA diet decreases hepatic fat and improves both hepatic and total insulin sensitivity.

Correlates of Medication Adherence in the TODAY Cohort of Youth With Type 2 Diabetes.

To identify factors that predict medication adherence and to examine relationships among adherence, glycemic control, and indices of insulin action in TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth). A total of 699 youth 10-17 years old with recent-onset type 2 diabetes and ≥80% adherence to metformin therapy for ≥8 weeks during a run-in period were randomized to receive one of three treatments. Participants took two study pills twice daily. Adherence was calculated by pill count from blister packs returned at visits. High adherence was defined as taking ≥80% of medication; low adherence was defined as taking <80% of medication. Depressive symptoms, insulin sensitivity (1/fasting insulin), insulinogenic index, and oral disposition index (oDI) were measured. Survival analysis examined the relationship between medication adherence and loss of glycemic control. Generalized linear mixed models analyzed trends in adherence over time. In this low socioeconomic cohort, high and low adherence did not differ by sex, age, family income, parental education, or treatment group. Adherence declined over time (72% high adherence at 2 months, 56% adherence at 48 months, P < 0.0001). A greater percentage of participants with low adherence had clinically significant depressive symptoms at baseline (18% vs. 12%, P = 0.0415). No adherence threshold predicted the loss of glycemic control. Longitudinally, participants with high adherence had significantly greater insulin sensitivity and oDI than those with low adherence. In the cohort, the presence of baseline clinically significant depressive symptoms was associated with subsequent lower adherence. Medication adherence was positively associated with insulin sensitivity and oDI, but, because of disease progression, adherence did not predict long-term treatment success.

One-hour plasma glucose as a predictor of the development of Type 2 diabetes in Japanese adults.

To test the hypothesis that 1-h plasma glucose in an oral glucose tolerance test is a better predictor of the development of diabetes than 2-h plasma glucose, independently of indices of insulin secretion or action in Japanese adults. A historical cohort study was conducted in 1445 Japanese workers who did not have diabetes. The association between 1-h plasma glucose and the development of Type 2 diabetes was analysed. Overall, 95 of the study participants developed Type 2 diabetes during a mean follow-up of 4.5 years. The area under the receiver-operating characteristic curve for 1-h plasma glucose for future diabetes [0.88 (95% CI 0.84-0.91)] was greater than that for 2-h plasma glucose [0.79 (95% CI 0.74-0.84)], and for insulinogenic [0.73 (95% CI 0.68-0.78)] and disposition indices [0.79 (95% CI 0.74-0.84); P < 0.05]. Compared with the first quartile, the hazard ratio for future diabetes in the fourth quartile of 1-h plasma glucose was 42.5 [95% CI 5.7-315.2 (P < 0.05)] and the hazard ratio in the fourth quartile of 2-h plasma glucose was 4.4 [95% CI 1.8-10.8 (P < 0.05)], after adjustments for covariates including fasting plasma glucose. The significance of the elevated hazard ratio in the fourth quartile of 1-h plasma glucose was maintained after adjustments for 2-h plasma glucose, insulinogenic index or disposition index, whereas the elevation of the hazard ratio in the fourth quartile of 2-h plasma glucose was diminished and was no longer significant after adjustments for 1-h plasma glucose. One-hour plasma glucose had a greater association with the future development of Type 2 diabetes than did 2-h plasma glucose, independently of oral glucose tolerance test-derived indices of insulin action in a Japanese population.

Study on clinical characteristics of metabolic-based obesity classification

Objective This study aimed to explore clinical characteristics of four types of obesity based on metabolic classification. Methods Forty-eight obese patients were divided according to their clinical characteristics into 4 groups including metabolic healthy obesity (MHO), hypometabolic obesity (LMO), hypermetabolic obesity (HMO), and metabolic obesity with inflammation (IMO). 20 normal weight individuals were also recruited as a control group. Body fat, body weight, visceral index, and basal metabolism were measured by Omron body fat meter. Fat content and its distribution were measured by dual energy X-ray absorptiometry. All participating patients underwent various tests for 75 g oral glucose tolerance, blood glucose, insulin, C peptide. Lipid profile, thyroid function and sex hormones levels, and inflammation factors were also measured. Results (1)Patients in MHO group had higher body fat content, but had no metabolic disorder and inflammation. Their hormones levels were normal. (2)Lower metabolic rate and lower hormones levels were found in the patients in LMO group with increasing visceral fat. Trunk/subcutaneous fat mass was significantly higher than that in MHO group(1.19±0.25 vs 0.97±0.32, P<0.05). There were abnormal lipid and glucose metabolism in LMO group. The insulin action index was significantly lower than that in MHO group(0.006 6±0.002 7 vs 0.012 1±0.009 5, P<0.05). The area under the curve of glucose concentration was significantly higher in LMO group than that in MHO group[(18.71±8.68 vs 12.70±4.63)mmol/L, P<0.05]. (3)Heart rate and blood pressure were higher in HMO group. The heart rate was significantly increased compared with that in MHO group [(90.50±8.24 vs 73.20±14.11) beat/min, P<0.05]. The waist circumference was significantly larger than that in MHO group [(111.88±10.54 vs 98.05±15.56)cm, P<0.05]. (4)In IMO group, insulin action index was significantly lower than MHO group (0.007 0±0.003 3 vs 0.012 1±0.009 5, P<0.05). The trunk fatmass and uric acid levels were significantly higher than MHO group [(17 236.38±4 610.60 vs 15 816.10±5 453.42)g and (468.28±121.32 vs 376.84±97.14) μmol/L, both P<0.05]. Patients in IMO group had acanthosis nigricans, but their glucose level was relatively normal. Conclusion The metabolic-based obese diagnosis is essential for understanding the obesity etiology and providing individualized treatment. (Chin J Endocrinol Metab, 2015, 31: 678-683) Key words: Obesity; Classification; Metabolism; Characteristics

Abstract T P114: Insulin Resistance in Skeletal Muscle of Chronic Stroke

Risk of glucose intolerance and diabetes increases in chronic stroke. The purpose of this study was to assess insulin sensitivity and glycogen synthase (GS), a known benchmark index of insulin action in skeletal muscle, and to compare the activity of this important regulatory enzyme between paretic (P) and non-paretic (NP) skeletal muscle in chronic stroke. We measured insulin sensitivity (M) and bilateral GS fractional activity (ratio of independent to total activity), in lyophilized microdissected muscle samples obtained after an overnight fast and 2 hrs into a 3-hr 80 mU . m -2. min -1 hyperinsulinemic-euglycemic clamp in 21 stroke survivors (n=15 men, n=6 women) (age: 59±2 yrs, BMI: 31±2 kg/m 2 , X±SEM). All had hemiparetic gait after ischemic stroke (&gt;6 months), low aerobic capacity (VO 2 peak, 19.7±1.3 ml/kg/min), and wide range of %body fat (11-48%). Leg lean mass was lower in P than NP (9.3±0.5 vs. 10.0±0.5 kg, P&lt;0.001). Subjects had either normal glucose tolerance (n=7), impaired glucose tolerance (n=7), or diabetes (n=7) and insulin resistance (M: 38.5±2.6 umol/kgFFM/min). Insulin robustly increased GS fractional activity (basal vs. insulin) in P (2.8±0.4 vs.7.5±0.8%, P&lt;0.00001) and NP (2.7±0.4 vs. 9.1±1.1%, P&lt;0.00001) muscle. The %change was greater in NP than P (213±32 vs. 296±36%, P=0.04). The effect of in vivo insulin to increase GS fractional activity was associated with M in P and NP muscle (r=0.59 and r=0.49, P&lt;0.05). In conclusion, muscle atrophy and a reduction in insulin action in paretic muscle likely contribute to whole body insulin resistance in chronic stroke.

Resistance training improves indices of muscle insulin sensitivity and β-cell function in overweight/obese, sedentary young men.

We examined the effects of RT on oral glucose tolerance test (OGTT)-derived indices of muscle insulin sensitivity, hepatic insulin resistance, β-cell function, and skeletal muscle proteins related to glucose transport in overweight/obese, sedentary young men. Twenty-eight participants [median body mass index (BMI) 30.9 kg/m(2); age 22 yr] completed 12 wk of RT (3 sessions/wk) and were assessed for changes in OGTT-derived indices, resting metabolic rate, body composition, serum adipokines, and skeletal muscle protein content [hexokinase 2 (HK2), glucose transporter type 4 (GLUT4), RAC-β serine/threonine-protein kinase (AKT2), glycogen synthase kinase 3β, and insulin receptor substrate 1]. Individualized responses to RT were also evaluated. RT significantly improved insulin and glucose area under the curve (both P < 0.03). With the use of OGTT indices of insulin action, we noted improved muscle insulin sensitivity index (mISI; P = 0.03) and oral disposition index (P = 0.03). BMI, lean body mass (LBM), and relative strength also increased (all P < 0.03), as did skeletal muscle protein content of HK2, GLUT4, and AKT2 (26-33%; all P < 0.02). Hepatic insulin resistance index, adiponectin, leptin, and total amylin did not change. Further analysis demonstrated the presence of highly individualized responsiveness to RT for glucose tolerance and other outcomes. RT improved oral indices of muscle insulin sensitivity and β-cell function but not hepatic insulin resistance in overweight/obese young men. In addition to the increase in LBM, the improvements in insulin action may be due, in part, to increases in key insulin signaling proteins.

Renal Sympathetic Denervation

See related article, pp 559–565 “Effects of renal sympathetic denervation on blood pressure, sleep apnea course and glycemic control in patients with resistant hypertension and sleep apnea” by Witkowski et al is an illuminating report.1 The authors confirm that renal denervation lowers blood pressure (BP) in patients with stage 2 (BP ≥160/≥100 mm Hg) treatment-resistant hypertension adherent to optimal doses of ≥3 antihypertensive medications, including a diuretic.2,3 Their report also endorses the work of Mahfoud et al4 documenting that renal denervation in humans improves indices of insulin action and glucose metabolism. It should be noted, however, that glycosylated hemoglobin levels declined significantly among patients in the current but not the previous report.1,4 The current publication extends previous work by documenting that the BP and metabolic benefits of renal denervation include patients with sleep apnea. However, this is not surprising, because most hypertensive patients with treatment-resistant hypertension have sleep apnea,1 and it is unlikely that renal denervation would have been effective in previous studies if benefits did not extend to patients with sleep apnea. The novel aspect of the current work is that renal sympathetic denervation improved sleep apnea in 7 of 8 patients with obstructive sleep apnea and 1 of 2 patients with both obstructive and central components. Although the mechanism(s) by which renal denervation may improve obstructive sleep apnea is unknown, the authors' hypothesis that changes in sodium-volume status are …

Association of APOE polymorphisms and insulin resistance with TCM syndromes in type 2 diabetes patients with macroangiopathy

To investigate the association between apolipo-proteinE (APOE) polymorphisms and insulin resistance and Traditional Chinese Medicine (TCM) syndromes in type 2 diabetes mellitus (T2DM) with macroangiopathy, 60 patients with T2DM macroangiopathy were enrolled and divided into three groups: dryness-heat due to deficiency of yin, Qi-Yin deficiency, and Yin-Yang deficiency, according to the TCM syndromes, with a control group of 20 healthy individuals. APOE genotype analysis was performed with polymerase chain reaction amplification and restriction fragment length polymorphism, and the results showed that the proportion of the ε4/4 and ε3/4 genotypes and frequencies of the ε4 and ε3 alleles were higher in the Qi-Yin deficiency group (P<0.05). Among the T2DM macroangiopathy patients, the E4 group had the largest number of cases, as well as a significantly longer disease course compared to the E2 group (P<0.05). The insulin resistance index (IRI), insulin action index and body mass index (BMI) of patients in the Yin-Yang deficiency group were significantly different from those of patients with dryness-heat due to deficiency of yin and Qi-Yin deficiency. Furthermore, correlation analysis of the BMI and IRI of patients in the Yin-Yang deficiency group revealed a correlation coefficient r=0.696 (P<0.01) and a typical correlation between them. In conclusion, the Qi-Yin deficiency in T2DM patients with macroangiopathy is associated with the APOE E4 and E3 genotypes. Thus, the APOE gene polymorphism can, to some degree, reflect the TCM syndrome types of T2DM patients with macroangiopathy. Insulin resistance plays an important role in the occurrence of T2DM macroangiopathy and is closely associated with the Yin-Yang deficiency according to the TCM differentiating types.