OBJECTIVETo examine the utility of commonly used insulin sensitivity indices in nondiabetic European Americans (EAs) and African Americans (AAs).RESEARCH DESIGN AND METHODSTwo-hundred forty nondiabetic participants were studied. Euglycemic-hyperinsulinemic clamp was the gold standard approach to assess glucose disposal rates (GDR) normalized by lean body mass. The homeostatic model assessment for insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) were calculated from fasting plasma glucose and insulin (FIL). Oral glucose tolerance test (OGTT) was performed to determine Matsuda index, the simple index assessing insulin sensitivity (SIisOGTT), Avignon index, and Stomvoll index. Relationships among these indices with GDR were analyzed by multiple regression.RESULTSGDR values were similar in EA and AA subgroups; even so, AA exhibited higher FIL and were insulin-resistant compared with EA, as assessed by HOMA-IR, QUICKI, Matsuda index, SIisOGTT, Avignon index, and Stumvoll index. In the overall study population, GDR was significantly correlated with all studied insulin sensitivity indices (/r/ = 0.381–0.513); however, these indices were not superior to FIL in predicting GDR. Race and gender affected the strength of this relationship. In AA males, FIL and HOMA-IR were not correlated with GDR. In contrast, Matsuda index and SIisOGTT were significantly correlated with GDR in AA males, and Matsuda index was superior to HOMA-IR and QUICKI in AAs overall.CONCLUSIONSInsulin sensitivity indices based on glucose and insulin levels should be used cautiously as measures of peripheral insulin sensitivity when comparing mixed gender and mixed race populations. Matsuda index and SIisOGTT are reliable in studies that include AA males.

Previous studies have used indirect measures of insulin sensitivity to link circulating amino acids with insulin resistance and identify potential biomarkers of diabetes risk. Using direct measures (i.e., hyperinsulinemic-euglycemic clamps), we examined the relationships between the metabolomic amino acid profile and insulin action (i.e., glucose disposal rate [GDR]). Relationships between GDR and serum amino acids were determined among insulin-sensitive, insulin-resistant, and type 2 diabetic (T2DM) individuals. In all subjects, glycine (Gly) had the strongest correlation with GDR (positive association), followed by leucine/isoleucine (Leu/Ile) (negative association). These relationships were dramatically influenced by BMI, the resting respiratory quotient (RQ), T2DM, and sex. Gly had a strong positive correlation with GDR regardless of BMI, RQ, or sex but became nonsignificant in T2DM. In contrast, Leu/Ile was negatively associated with GDR in nonobese and T2DM subjects. Increased resting fat metabolism (i.e., low RQ) and obesity were observed to independently promote and negate the association between Leu/Ile and insulin resistance, respectively. Additionally, the relationship between Leu/Ile and GDR was magnified in T2DM males. Future studies are needed to determine whether Gly has a mechanistic role in glucose homeostasis and whether dietary Gly enrichment may be an effective intervention in diseases characterized by insulin resistance.

Insulin resistance has been associated with the accumulation of fat within skeletal muscle fibers as intramyocellular lipid (IMCL). Here, we have examined in a cross-sectional study the interrelationships among IMCL, insulin sensitivity, and adiposity in European Americans (EAs) and African Americans (AAs). In 43 EA and 43 AA subjects, we measured soleus IMCL content with proton-magnetic resonance spectroscopy, insulin sensitivity with hyperinsulinemic–euglycemic clamp, and body composition with dual-energy X-ray absorptiometry. The AA and EA subgroups had similar IMCL content, insulin sensitivity, and percent fat, but only in EA was IMCL correlated with insulin sensitivity (r = −0.47, P < 0.01), BMI (r = 0.56, P < 0.01), percent fat (r = 0.35, P < 0.05), trunk fat (r = 0.47, P < 0.01), leg fat (r = 0.40, P < 0.05), and waist and hip circumferences (r = 0.54 and 0.55, respectively, P < 0.01). In a multiple regression model including IMCL, race, and a race by IMCL interaction, the interaction was found to be a significant predictor (t = 1.69, DF = 1, P = 0.0422). IMCL is related to insulin sensitivity and adiposity in EA but not in AA, suggesting that IMCL may not function as a pathophysiological factor in individuals of African descent. These results highlight ethnic differences in the determinants of insulin sensitivity and in the pathogenesis of the metabolic syndrome trait cluster.

Our data show for the first time that skeletal muscle protein-HNE adducts are related to the severity of insulin resistance in sedentary adults. These results suggest that muscle lipid peroxidation could be involved in the development of insulin resistance.

Objective To assess associations between nonalcoholic fatty liver disease (NAFLD) and measures of brain health in a population-based sample of adults. Methods Participants from the CARDIA study (Y25 exam; age 43–55 years) with concurrent CT quantification of liver fat, visceral adipose tissue (VAT) and brain magnetic resonance (MR) images were included (n=505). NAFLD was identified after exclusion of other causes of liver fat. Total tissue volume (TTV) and gray matter cerebral blood flow (GM-CBF) were estimated using 3T brain MR images. Results NAFLD prevalence was 18%. NAFLD was associated with lower TTV and GM-CBF after adjusting for intracranial volume, demographics, and health behaviors (p<0.04 for all). In models with additional adjustment for cardiovascular risk factors the association of NAFLD with GM-CBF remained significant (p=0.04), but was attenuated after adjustment for VAT (p=0.06), and eliminated with BMI (p=0.20). NAFLD was not associated with TTV after adjustment for cardiovascular risk factors (p=0.10), or additional adjustment for VAT (p=0.14) or BMI (p=0.05). Conclusions NAFLD is negatively associated with early brain health as assessed by MR measures of structure (TTV) and perfusion (GM-CBF). BMI and VAT attenuated this relationship providing insight into the potential metabolic role of liver fat in brain health and disease.

Aims/hypothesis The prospective association between cardiorespiratory fitness (CRF) measured in young adulthood and middle age on development of prediabetes, defined as impaired fasting glucose and/or impaired glucose tolerance, or diabetes by middle age remains unknown. We hypothesised that higher fitness levels would be associated with reduced risk for developing incident prediabetes/diabetes by middle age. Methods Participants were from the Coronary Artery Risk Development in Young Adults (CARDIA) study who were free from prediabetes/diabetes at baseline (year 0 [Y0]: 1985–1986). CRF was quantified by treadmill duration (converted to metabolic equivalents [METs]) at Y0, Y7 and Y20 and prediabetes/diabetes status was assessed at Y0, Y7, Y10, Y15, Y20 and Y25. We use an extended Cox model with CRF as the primary time-varying exposure. BMI was included as a time-varying covariate. The outcome was development of either prediabetes or diabetes after Y0. Model 1 included age, race, sex, field centre, CRF and BMI. Model 2 additionally included baseline (Y0) smoking, energy intake, alcohol intake, education, systolic BP, BP medication use and lipid profile. Results Higher fitness was associated with lower risk for developing incident prediabetes/diabetes (difference of 1 MET: HR 0.99898 [95% CI 0.99861, 0.99940], p < 0.01), which persisted (difference of 1 MET: HR 0.99872 [95% CI 0.99840, 0.99904], p < 0.01] when adjusting for covariates. Conclusions/interpretation Examining participants who had fitness measured from young adulthood to middle age, we found that fitness was associated with lower risk for developing prediabetes/diabetes, even when adjusting for BMI over this time period. These findings emphasise the importance of fitness in reducing the health burden of prediabetes and diabetes.

Study findings indicate that objectively assessed prepregnancy fitness, but not self-reported MVPA or television time, is associated with GDM. Clinicians should counsel women on the benefits of improving fitness in the preconception period, particularly among women at greater risk for GDM.

Sleep is a fundamental biological process, that when repeatedly disrupted, can result in severe health consequences. Recent studies suggest that both sleep fragmentation (SF) and dysbiosis of the gut microbiome can lead to metabolic disorders, though the underlying mechanisms are largely unclear. To better understand the consequences of SF, we investigated the effects of acute (6 days) and chronic (6 weeks) SF on rats by examining taxonomic profiles of microbiota in the distal ileum, cecum and proximal colon, as well as assessing structural and functional integrity of the gastrointestinal barrier. We further assayed the impact of SF on a host function by evaluating inflammation and immune response. Both acute and chronic SF induced microbial dysbiosis, more dramatically in the distal ileum (compared to other two regions studied), as noted by significant perturbations in alpha-and beta-diversity; though, specific microbial populations were significantly altered throughout each of the three regions. Furthermore, chronic SF resulted in increased crypt depth in the distal ileum and an increase in the number of villi lining both the cecum and proximal colon. Additional changes were noted with chronic SF, including: decreased microbial adhesion and penetration in the distal ileum and cecum, elevation in serum levels of the cytokine KC/GRO, and depressed levels of corticotropin. Importantly, our data show that perturbations to microbial ecology and intestinal morphology intensify in response to prolonged SF and these changes are habitat specific. Together, these results reveal consequences to gut microbiota homeostasis and host response following acute and chronic SF in rats.