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ObjectiveWe evaluated the effect of optimizing metformin dosing on glycemia and body weight in type 2 diabetes.Research design and methodsThis was a prespecified analysis of 6,823 participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) taking metformin as the sole glucose-lowering drug who completed a 4- to 14-week (mean ± SD 7.9 ± 2.4) run-in in which metformin was adjusted to 2,000 mg/day or a maximally tolerated lower dose. Participants had type 2 diabetes for

Aim: Reduced renal insulin signalling is implicated in the pathogenesis of albuminuria. We sought to investigate whether insulin action and secretion, measured before diabetes onset, are associated with the development of albuminuria after diabetes onset. Materials and Methods: Baseline body composition, insulin sensitivity by hyperinsulinaemic‐euglycaemic clamp at submaximal and maximal insulin stimulation (240 and 2400 pmol/m2/min; M‐low and M‐high), and insulin secretion by intravenous glucose tolerance test [acute insulin response (AIR)] were measured in 170 Southwestern Indigenous American adults who subsequently developed diabetes. After diabetes onset and during the median follow‐up of 13.6 years, 81 participants (48%) developed albuminuria (urine albumin‐to‐creatinine ratio ≥30 mg/g). Separate associations of M‐low, M‐high and AIR (per 1‐SD change) with the risk of albuminuria were assessed by Cox regression models adjusted for age, sex and body fat (%). Results: Participants who developed albuminuria were of similar age (26.4 ± 5.4 vs. 27.5 ± 6.1 years), sex (46% vs. 48% male), body fat (36.4 ± 7.5 vs. 35.7 ± 7.9%) and AIR [2.3 ± 0.3 vs. 2.3 ± 0.3, pmol/L (log)] as those who did not develop albuminuria but had lower insulin sensitivity [M‐low: 0.33 ± 0.08 vs. 0.36 ± 0.12, p =.03; M‐high: 0.87 ± 0.11 vs. 0.91 ± 0.12, p =.02; mg/kg‐metabolic body size/min (log)]. In separate adjusted models, lower M‐low and M‐high were both associated with an increased risk for albuminuria [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.14, 2.00, p =.004; HR 1.31, 95% CI 1.06, 1.63, p =.01), whereas AIR was not (HR 1.15, 95% CI 0.87, 1.56, p =.3). Conclusions: Lower insulin sensitivity is associated with the development of albuminuria, suggesting a role for insulin signalling in the pathogenesis of proteinuria. [ABSTRACT FROM AUTHOR]

ContextPeripheral and central endocannabinoids and cognate acylethanolamides (AEs) may play important but distinct roles in regulating energy balance.ObjectiveWe hypothesized that in humans central/peripheral endocannabinoids are differently associated with adiposity and energy expenditure and differ by race.DesignWe examined associations of arachindonoylethanolamide, 2-arachidonoylglycerol, palmitoylethanolamide, and oleoylethanolamide (OEA) assayed in plasma and cerebrospinal fluid (CSF) with race, adiposity, and energy expenditure.Setting/participantsIn this monitored clinical inpatient study, CSF was obtained by lumbar puncture in 27 individuals (12 Caucasian, 11 American Indian, and four African-American). Twenty-four hour and sleep energy expenditure were measured by indirect calorimetry in a respiratory chamber.Main outcome measureSamples were analyzed from a previous study originally designed to test a blood-brain barrier leptin transport deficit in human obesity.ResultsCSF (but not peripheral) 2-arachidonoylglycerol was significantly increased in American Indians compared with Caucasians (18.48 ± 6.17 vs. 10.62 ± 4.58 pmol/ml, P < 0.01). In the whole group, peripheral AEs were positively but in CSF negatively associated with adiposity. However, in multivariate models adjusted for the other peripheral and CSF AEs, peripheral arachindonoylethanolamide was the only AE significantly associated with adiposity. Interestingly, CSF OEA concentrations were positively associated with adjusted 24 hour and sleep energy expenditure (r = 0.47, P < 0.05; r = 0.42, P < 0.05), but peripheral OEA was not.ConclusionsThese data indicate a central alteration of the endocannabinoid system in American Indians and furthermore show that AEs in both compartments play an important but distinct role in human energy balance regulation.

Context Surrogate indices of muscle and hepatic insulin sensitivity derived from an oral glucose tolerance test (OGTT) are frequently used in clinical studies. However, the predictive accuracy of these indices has not been validated. Design In this cross-sectional study, hyperinsulinemic-euglycemic glucose clamp with tritiated glucose infusion and a 75-g OGTT were performed in individuals (n = 659, aged 18 to 49 years, body mass index of 16 to 64 kg/m2) with varying degrees of glucose tolerance. A calibration model was used to assess the ability of OGTT-derived, tissue-specific surrogate indices [hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI)] to predict insulin sensitivity/resistance indices derived from the reference glucose clamp [Hepatic-IRbasal, a product of fasting plasma insulin and hepatic glucose production (HGP), Hepatic-IRclamp, reciprocal of the percent suppression of HGP during the insulin clamp corrected for plasma insulin concentration, and Muscle-ISclamp, a measure of peripheral glucose disposal]. Predictive accuracy was assessed by root mean squared error of prediction and leave-one-out, cross-validation-type square root of the mean squared error of prediction. Results HIRI and MISI were correlated with their respective clamp-derived indices. HIRI was negatively related to Muscle-ISclamp (r = –0.62, P < 0.0001) and MISI correlated with Hepatic-IR derived from the clamp (Hepatic-IRbasal: r = –0.48, P < 0.0001 and Hepatic-IRclamp: r = –0.41, P < 0.0001). However, the accuracy of HIRI and MISI to predict Hepatic-IR (basal or during clamp) was not significantly different. Likewise, the ability of HIRI and MISI to predict Muscle-ISclamp was also similar. Conclusion Our findings indicate that the surrogate indices derived from an OGTT are accurate in predicting insulin sensitivity but are not tissue specific. [ABSTRACT FROM AUTHOR]

Objective: To investigate the concurrent relationships between human plasma erythropoietin concentrations and energy expenditure (EE), body composition, plasma leptin concentrations, and associations with weight change.Methods: Plasma to measure erythropoietin and leptin; data for body composition; 24-h EE measured in a whole-room calorimeter; and 75 g oral glucose tolerance testing were available from 109 full-heritage Pima Indians (55% male) from a larger study designed to understand the causes of obesity. Seventy-nine subjects had data for weight at a later visit (mean follow-up = 4.3 ± 1.9 years) to calculate percent weight change per year.Results: Erythropoietin, adjusted for covariates, correlated with 24-h EE (r = 0.26, P = 0.007), sleeping EE (r = 0.29, P = 0.003), fat-free mass (r = 0.19, P = 0.05), and fat mass (r = 0.27, P = 0.005), but not insulin or glucose measures. The association of erythropoietin with 24-h EE was fully mediated by fat-free mass. Erythropoietin associated with leptin in women (ρ = 0.36, P = 0.01), but not in men (P = 0.9), independently from fat mass. The association of erythropoietin with percent weight change per year was in opposing directions (interaction: P = 0.002) in males (r = -0.35, P = 0.02) versus females (r = 0.37, P = 0.02).Conclusions: Non-hematopoietic endogenous erythropoietin action may be involved in body weight regulation in opposing directions in men and women, i.e., weight loss in men and weight gain in women. [ABSTRACT FROM AUTHOR]

New biomarkers for type 2 diabetes mellitus (T2DM) may aid diagnosis, drug development or clinical treatment. Evidence is increasing for the adaptive immune system’s role in T2DM and suggests the presence of unidentified autoantibodies. While high-density protein microarrays have emerged as a useful technology to identify possible novel autoantigens in autoimmune diseases, its application in T2DM has lagged. In Pima Indians, the HLA haplotype (HLA-DRB1*02) is protective against T2DM and, when studied when they have normal glucose tolerance, subjects with this HLA haplotype have higher insulin secretion compared to those without the protective haplotype. Possible autoantibody biomarkers were identified using microarrays containing 9480 proteins in plasma from Pima Indians with T2DM without the protective haplotype (n = 7) compared with those with normal glucose regulation (NGR) with the protective haplotype (n = 11). A subsequent validation phase involving 45 cases and 45 controls, matched by age, sex and specimen storage time, evaluated 77 proteins. Eleven autoantigens had higher antibody signals among T2DM subjects with the lower insulin-secretion HLA background compared with NGR subjects with the higher insulin-secretion HLA background (p<0.05, adjusted for multiple comparisons). PPARG2 and UBE2M had lowest p-values (adjusted p = 0.023) while PPARG2 and RGS17 had highest case-to-control antibody signal ratios (1.7). A multi-protein classifier involving the 11 autoantigens had sensitivity, specificity, and area under the receiver operating characteristics curve of 0.73, 0.80, and 0.83 (95% CI 0.74–0.91, p = 3.4x10-8), respectively. This study identified 11 novel autoantigens which were associated with T2DM and an HLA background associated with reduced insulin secretion. While further studies are needed to distinguish whether these antibodies are associated with insulin secretion via the HLA background, T2DM more broadly, or a combination of the two, this study may aid the search for autoantibody biomarkers by narrowing the list of protein targets. [ABSTRACT FROM AUTHOR]

Abstract: The objective of the study was to evaluate the reproducibility and repeatability of the combined use of the hyperinsulinemic-euglycemic (H-E) clamp and tracer dilution techniques. Ten nondiabetic men underwent a low-dose (40 mU/[m2 min]) H-E clamp that was repeated within 3 to 4 days using porcine or human insulin in a double-blinded, randomized, crossover design. Coefficients of variation (CVs) for intraindividual differences and repeatability coefficient were calculated to evaluate reproducibility and repeatability. The Bland and Altman method was used to quantify repeatability. The CVs for intraindividual differences were 5.7% ± 3.5% for steady-state (SS) insulin; 6.7% ± 6.2% and 54.2 ± 38.3% for basal and SS endogenous glucose product (EGP), respectively; and 10.3% ± 8.5% for total insulin-stimulated glucose disposal (M) values. Basal EGP, SS EGP, and SS glucose and insulin concentrations were similar for the 2 clamps; but glucose infusion rate (P = .02) and M (borderline significant, P = .06) were higher in the first clamp than the second clamp. No significant correlations between mean of differences and average of basal and SS EGP, SS insulin concentration, and M between the 2 clamps were observed. We also found that the different values were less than the repeatability coefficients of these parameters and that the 95% limits of agreement and the interval of repeatability coefficient of these parameters were similar. There were no differences in metabolic responses between clamps when compared by the type of insulin (porcine vs human) infused. Our findings indicate that, although SS EGP has a high CV, the clamp, which measures insulin action (ie, SS insulin, M), and the tracer dilution technique for assessing basal EGP are repeatable and reproducible. Decreased glucose infusion rate and M over a short period in the second clamp may reflect an accumulative effect of continued physical inactivity. [Copyright &y& Elsevier]

Objective: In severely obese individuals and patients with diabetes, accumulation and activation of macrophages in adipose tissue has been implicated in the development of obesity-associated complications, including insulin resistance. We sought to determine whether in a healthy population, adiposity, sex, age, or insulin action is associated with adipose tissue macrophage content (ATMc) and/or markers of macrophage activation.Research Design and Methods: Subcutaneous ATMc from young adult Pima Indians with a wide range of adiposity (13-46% body fat, by whole-body dual-energy X-ray absorptiometry) and insulin action (glucose disposal rate 1.6-9 mg/kg estimated metabolic body size/min, by glucose clamp) were measured. We also measured expression in adipose tissue of factors implicated in macrophage recruitment and activation to determine any association with ATMc and insulin action.Results: ATMc, as assessed by immunohistochemistry (Mphi) and by macrophage-specific gene expression (CD68, CD11b, and CSF1R), were correlated with percent body fat, age, and female sex. Gene expression of CD68, CD11b, and CSF1R but not Mphi was correlated negatively with glucose disposal rate but not after adjustment for percent body fat, age, and sex. However, adipose tissue expression of plasminogen activator inhibitor type-1 (PAI-1) and CD11 antigen-like family member C (CD11c), markers produced by macrophages, were negatively correlated with adjusted glucose disposal rate (r = -0.28, P = 0.05 and r = -0.31, P = 0.03).Conclusions: ATMc is correlated with age and adiposity but not with insulin action independent of adiposity in healthy human subjects. However, PAI-1 and CD11c expression are independent predictors of insulin action, indicating a possible role for adipose tissue macrophage activation. [ABSTRACT FROM AUTHOR]

The article discusses a study which analyzed the association of peripheral and hepatic insulin action with abdominal and thigh adipose tissue in obese individuals. A total of 57 Pima Indians with normal glucose tolerance underwent magnetic resonance imaging and euglycemic-hyperinsulinemic clamp. The anthropometric and metabolic characteristics of the study population are outlined. Increased intraperitoneal and deep subcutaneous abdominal fat were shown to predict impaired peripheral and hepatic insulin action in obese Pima Indians.

Suppression of lipid oxidation (Lox) by insulin is impaired in obesity and type 2 diabetes mellitus (T2DM). Here we tested whether high Lox represents a primary or acquired characteristic in the pathogenesis of T2DM. Hood-indirect calorimetry was performed under postabsorptive conditions and during a two-step hyperinsulinemic euglycemic clamp (insulin infusion rates in mU·m-2·min-1; 40 low and 400 high) in 465 Pima Indians: 317 with normal glucose tolerance (NGT), 117 with impaired glucose tolerance (IGT), and 31 with T2DM. The predictive effect of net lipid oxidation (Lox) on development of T2DM was assessed in 296 subjects (51 of whom developed T2DM), whereas the predictive effect of Lox on followup changes in insulin-mediated glucose disposal (M) and acute insulin response (AIR) was studied in 190 subjects with NGT at baseline. Cross-sectionally, after adjustment for age, sex, body fat (BF), and M low, Lox low was increased in T2DM compared with NGT and IGT subjects (P < 0.05). Prospectively, after adjustment for followup duration, age, sex, BF, M, and AIR, increased clamp Lox predicted T2DM [hazard rate ratios (95% CI): Lox low, 1.5 (1.1, 2.0), P < 0.01; Lox high, 1.3 (1.0, 1.8), P = 0.05]. High Lox low at baseline was also associated with subsequent worsening of M low (P = 0.04). These data indicate that the inability of insulin to suppress Lox may represent an early risk marker for insulin resistance and T2DM that is independent of adiposity, acute insulin secretion, and insulin action on glucose uptake. [ABSTRACT FROM AUTHOR]

The size of subcutaneous (SAT) and visceral adipose tissue (VAT) in the abdomen is negatively associated with insulin action. Deep portion of SAT (below subcutaneous fascia) and intraperitoneal portion of VAT (within abdominal cavity) are thought to be the principal determinants of this relationship, which according to some studies, is further modified by sex and obesity status. We studied obese Pima Indian men (n= 37) and women (n= 22) with normal glucose tolerance (mean age 27 [SD 8] years, BMI 36 [5] kg.m[sup -2]) who had measurements of body composition by DEXA, abdominal adipose tissue distribution by magnetic resonance imaging and insulin-mediated glucose disposal rate (M) by euglycemic-hyperinsulinemic clamp (insulin infusion rate 40 mU.m[sup -2]min[sup -1]). Women had more body fat (BF) and more superficial SAT compared to men (both P< 0.0001). After adjustment for age and BF, the differences in superficial SAT were no longer significant, while men had more total (P= 0.001) and deep SAT (P< 0.0001), and more total (P= 0.002) and intraperitoneal VAT (P= 0.003) compared to women. After adjustment for age and sex, M was related to SAT (r= -0.26, P= 0.05), deep SAT (r= -0.27, P=- 0.00), VAT (r= -0.36, P=0.006) and intraperitoneal VAT (r= -0.43, P= 0.0007). In sex specific analysis, deep SAT (r= -0.38, P= 0.02) and intraperitoneal VAT (r= -0.45, P= 0.006) were significant determinants of M in men but not in women (P= 0.7 and P= 0.1 respectively). Superficial SAT was the only significant determinant of M in women (-0.55, P= 0.01). The latter association was confirmed in the general linear regression analysis as significant gender-to-superficial SAT interaction (P= 0.000). Our results showed a sex-specific association between fat distribution in abdomen and insulin action in obese Pima Indians. This indicates that different mechanisms may underlie the association between abdominal obesity and insulin resistance in men and women. [ABSTRACT FROM AUTHOR]

Adipose tissue macrophage content increases with adiposity, and precedes obesity-induced hyperinsulinemia in animal models of insulin resistance. We investigated whether macrophage content in subcutaneous adipose tissue was associated with adiposity and insulin action in non-diabetic humans. We studied 65 Pima Indians (mean age 31 years [SD 8], BMI 34 [7] kg.m[sup -2], 24 women) who were enrolled in an ongoing study of risk factors for diabetes. For each subject measurements of body composition by DEXA, insulin action (M), as assessed by euglycemic-hyperinsulinemic clamp (insulin infusion rate 40 mU.m[sup -2].min[sup -1]), and aspiration biopsy of subcutaneous abdominal adipose tissue were obtained. Macrophage content was estimated by the number of CD68-expressing cells as determined by immunohistochemistry (CD68[sup +], in 45 subjects) and from the expression levels of macrophage markers (Cd68, Csf1r, Cd11b) determined by quantitative reverse transcriptase-polymerase chain reaction. The fraction of CD68[sup +] cells was associated with body fat (r= 0.33, P= 0.02) as was expression of macrophage markers (Cd68: r= 0.33, P= 0.007; Csf1r: r= 0.55, P< 0.0001; Cd11b: r=0.44, P= 0.0003) and these associations persisted after adjustment for age and sex (CD68[sup +]: P= 0.04; Cd68: P=0.05; Csf1r and Cd11b: P= 0.0008 both). M was. associated with body fat (r= -0.34, P= 0.006), expression of Csf1r (r= -0.33, P= 0.007) and Cd11b (r= -0.26, P=-0.04), and weakly with Cd68 expression (r= -0.24, P=0.06). M was not associated with the fraction of CD68[sup +] cells (r= -0.12, P= 0.4). The associations of M with Csf1r and Cd11b expression were not significant after adjustment for body fat (P= 0.2 and P= 0.5 respectively). Macrophage content in subcutaneous abdominal adipose tissue is associated with adiposity in Pima Indians. Our data indicate that increased macrophage content in subcutaneous adipose tissue does not provide a mechanistic link between increasing adiposity and worsening of insulin action. [ABSTRACT FROM AUTHOR]

Elevated body mass index and post-prandial state are associated with disadvantageous choices on the Iowa Gambling Task (IGT). Whether physiological factors including percent body fat, and peripheral glucose, insulin, and leptin concentrations, are associated with IGT performance is unknown. In196 healthy adults without diabetes, we measured body fat by DXA scan, glucose, insulin and leptin ( n = 138) concentrations during an oral glucose tolerance test and IGT performance after a standardized meal. Glucose was not associated with IGT performance. Disadvantageous IGT performance was associated with higher percent body fat ( r = − 0.16, p = 0.03), 30-min insulin concentrations (insulin 30 , r = − 0.27, p < 0.001), and 30-min leptin concentrations (leptin 30 , r = − 0.23, p = 0.008). Mediation analysis demonstrated that leptin 30 was almost completely responsible for the percent body fat effect on IGT performance. Even adjusted for age, sex, race, and education, insulin 30 ( b = − 46.5, p = 0.03) and leptin 30 ( b = − 50.9, p = 0.03) concentrations remained independently associated with IGT performance and interacted together such that higher leptin 30 blunted effects of higher insulin 30 ( b = 23.8, p = 0.048). These findings may indicate an internal metabolic signature of energy availability (higher body fat, insulin, and leptin levels) associated with disadvantageous IGT performance. [ABSTRACT FROM AUTHOR]

Abstract: Background: Type 2 diabetes is a risk factor for development of cognitive dysfunction. Impairments in glucose regulation have been associated with poorer performance on tests of executive function and information processing speed. Methods: We administered the Stroop Color Word Task, where higher interference scores are indicative of decreased selective attention, to 98 non-diabetic volunteers (64m; %fat=37±12; age=36±9yrs, race=41 NA/30 C/13 H/14 AA) on our inpatient unit. After 3d on a weight maintaining diet, % body fat was measured by DXA and a 75g oral glucose tolerance test (OGTT) was administered. Impaired glucose regulation (IGR) was defined as: fasting plasma glucose ≥100 and ≤125mg/dL and/or 2h plasma glucose between ≥140 and ≤199mg/dL (IGR; n=48; NGR; n=50). Total and incremental area under the curve (AUC) for insulin and glucose were calculated. Results: Stroop interference scores were not significantly associated with any measure of adiposity or insulin concentrations. Individuals with IGR had significantly higher interference scores than those with normal glucose regulation (NGR; p=0.003). Higher interference scores were significantly correlated with fasting plasma glucose concentrations (r=0.26, p=0.007) and total glucose AUC (r=0.30, p=0.02) and only trending so for iAUC and 2h plasma glucose (r=0.18, p=0.08; r=0.17, p=0.09 respectively). In separate multivariate linear models, fasting plasma glucose (p=0.002) and total glucose AUC (p=0.0005) remained significant predictors of Stroop interference scores, even after adjustment for age, sex, race, education and %fat. Conclusions: Individuals with IGR had decreased performance on a test of selective attention. Fasting plasma glucose was more strongly associated with lower performance scores than 2h plasma glucose. Our results indicate that even mild hyperglycemia in the non-diabetic range is associated with attentional processing difficulties in a sample of younger adults. Whether these impairments precede or are induced by impaired glucose regulation is not clear. [Copyright &y& Elsevier]