Epicardial adipose tissue is a predictor of decreased kidney function and coronary artery calcification in youth- and early adult onset type 2 diabetes mellitus.

PURPOSE: To examine the association of epicardial and pericardial fat volume (EFV, PFV) with cardiovascular risk factors and kidney function in Native Americans of southwestern heritage with youth and early adult onset type 2 diabetes mellitus (T2DM) versus healthy controls. METHODS: Using computed tomography, we quantified EFV and PFV in 149 Native Americans (92 women, 57 men), 95 of which had T2DM (38 diagnosed prior to age 20 years). Duration of T2DM, mean carotid arterial mass (AM), coronary artery calcification (CAC), IL-6, and estimated glomerular filtration rate eGFRcr(CKD-EPI) were measured. RESULTS: EFV and PFV were associated with BMI (r = 0.37, p < 0.0001; r = 0.26, p = 0.001) and did not differ between onset age-groups and controls (p > 0.05). EFV was associated with AM only in controls (r = 0.51, p < 0.0001). After adjustment for BMI, T2DM duration, HbA1C, age, and sex, EFV was a predictor of CAC and IL-6 concentrations in early adult onset T2DM (ß = 0.05 ± 0.02 cm3, p = 0.03; ß = 0.05 ± 0.01 pg/ml/cm3, p = 0.002). EFV and PFV were independent predictors of reduced eGFRcr(CKD-EPI) in the youth onset T2DM group (ß = -0.3 ± 0.08 ml/min/cm3, p = 0.001; ß = -0.25 ± 0.05 ml/min/cm3, p < 0.0001). CONCLUSIONS: Epicardial fat volume may be a risk factor for heart disease in individuals with early adult onset T2DM and a predictor of decreased kidney function in individuals with youth onset T2DM.

Changes in glycemia, insulin and gut hormone responses to a slowly ingested solid low-carbohydrate mixed meal after laparoscopic gastric bypass or band surgery.

OBJECTIVE: To evaluate early changes in glycemia, insulin physiology and gut hormone responses to an easily tolerated and slowly ingested solid, low-carbohydrate mixed meal test (MMT) following laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB) surgery. SUBJECTS/METHODS: This was a prospective non-randomized study. Plasma glucose, insulin and c-peptide (to estimate hepatic insulin extraction; %HIE), incretins (GIP, aGLP-1) and pancreatic polypeptide (PP) responses to the MMT were measured at 4-8 weeks before and after surgery in obese, metabolically healthy patients (RYGB=10F or LAGB =7F/1M). Supplementary clamp data on basal endogenous glucose production (EGP) and peripheral insulin action (Rd=rate of glucose disposal) and metabolic clearance rates of insulin (MCR-INS) were available in five of the RYGB patients. Repeated measures were appropriately accounted for in the analyses. RESULTS: Following LAGB surgery, C-peptide and insulin MMT profiles (P=0.004 and P=0.0005, respectively) were lower with no change in %HIE (P=0.98). In contrast, in RYGB subjects, both fasting glucose and insulin (Δ=-0.66 mmol l-1, P⩽0.05 and Δ=-44.4 pmol l-1, P⩽0.05, respectively) decreased, and MMT glucose (P<0.0001) and insulin (P=0.001) but not c-peptide (P= 0.69) decreased. Estimated %HIE increased at fasting (Δ=8.4%, P⩽0.05) and during MMT (P=0.0005). Early (0-20 min) prandial glucose (0.27±0.26 versus 0.006±0.21 mmol l-1, P⩽0.05) and insulin (63(48, 66) versus 18(12, 24) pmol l-1, P⩽0.05) responses increased after RYGB. RYGB altered the trajectory of prandial aGLP-1 responses (treatment × trajectory P=0.02), and PP was lower (P<0.0001). Clamp data in a subset of RYGB patients showed early improvement in basal EGP (P=0.001), and MCR-INS (P=0.015). CONCLUSION: RYGB results in distinctly different changes in plasma glucose, insulin and gut hormone response patterns to a solid, slowly ingested low-carbohydrate MMT versus LAGB. Altered nutrient delivery, along with indirect evidence for changes in hepatic and peripheral insulin physiology, are consistent with the greater early improvement in glycemia observed after RYGB versus LAGB surgery.

Lower core body temperature and greater body fat are components of a human thrifty phenotype.

BACKGROUND/OBJECTIVES: In small studies, a thrifty human phenotype, defined by a greater 24-hour energy expenditure (EE) decrease with fasting, is associated with less weight loss during caloric restriction. In rodents, models of diet-induced obesity often have a phenotype including a reduced EE and decreased core body temperature. We assessed whether a thrifty human phenotype associates with differences in core body temperature or body composition. SUBJECTS/METHODS: Data for this cross-sectional analysis were obtained from 77 individuals participating in one of two normal physiology studies while housed on our clinical research unit. Twenty-four-hour EE using a whole-room indirect calorimeter and 24-h core body temperature were measured during 24 h each of fasting and 200% overfeeding with a diet consisting of 50% carbohydrates, 20% protein and 30% fat. Body composition was measured by dual X-ray absorptiometry. To account for the effects of body size on EE, changes in EE were expressed as a percentage change from 24-hour EE (%EE) during energy balance. RESULTS: A greater %EE decrease with fasting correlated with a smaller %EE increase with overfeeding (r=0.27, P=0.02). The %EE decrease with fasting was associated with both fat mass and abdominal fat mass, even after accounting for covariates (ß=-0.16 (95% CI: -0.26, -0.06) %EE per kg fat mass, P=0.003; ß=-0.0004 (-0.0007, -0.00004) %EE kg(-1) abdominal fat mass, P=0.03). In men, a greater %EE decrease in response to fasting was associated with a lower 24- h core body temperature, even after adjusting for covariates (ß=1.43 (0.72, 2.15) %EE per 0.1 °C, P=0.0003). CONCLUSIONS: Thrifty individuals, as defined by a larger EE decrease with fasting, were more likely to have greater overall and abdominal adiposity as well as lower core body temperature consistent with a more efficient metabolism.

The impact of genetic variants on BMI increase during childhood versus adulthood.

BACKGROUND: Genetic variants that predispose individuals to obesity may have differing influences during childhood versus adulthood, and additive effects of such variants are likely to occur. Our ongoing studies to identify genetic determinants of obesity in American Indians have identified 67 single-nucleotide polymorphisms (SNPs) that reproducibly associate with maximum lifetime non-diabetic body mass index (BMI). This study aimed to identify when, during the lifetime, these variants have their greatest impact on BMI increase. SUBJECTS/METHODS: A total of 5906 Native Americans of predominantly Pima Indian heritage with repeated measures of BMI between the ages of 5 and 45 years were included in this study. The association between each SNP with the rates of BMI increase during childhood (5-19 years) and adulthood (20-45 years) were assessed separately. The significant SNPs were used to calculate a cumulative allelic risk score (ARS) for childhood and adulthood, respectively, to assess the additive effect of these variants within each period of life. RESULTS: The majority of these SNPs (36 of 67) were associated with rate of BMI increase during childhood (P-value range: 0.00004-0.05), whereas only nine SNPs were associated with rate of BMI change during adulthood (P-value range: 0.002-0.02). These 36 SNPs associated with childhood BMI gain likely had a cumulative effect as a higher childhood-ARS associated with rate of BMI change (ß=0.032 kg m(-2) per year per risk allele, 95% confidence interval: 0.027-0.036, P<0.0001), such that at age 19 years, individuals with the highest number of risk alleles had a BMI of 10.2 kg m(-2) greater than subjects with the lowest number of risk alleles. CONCLUSIONS: Overall, our data indicates that genetic polymorphisms associated with lifetime BMI may influence the rate of BMI increase during different periods in the life course. The majority of these polymorphisms have a larger impact on BMI during childhood, providing further evidence that prevention of obesity will need to begin early in life.

Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants.

BACKGROUND: In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. OBJECTIVE: The objective of this study is to compare BDNF concentrations of subjects with loss-of-function (LOF) and gain-of-function (GOF) MC4R variants with those of controls with common sequence MC4R. METHODS: Circulating BDNF was measured in two cohorts with known MC4R sequence: 148 subjects of Pima Indian heritage ((mean±s.d.): age, 15.7±6.5 years; body mass index z-scores (BMI-Z), 1.63±1.03) and 69 subjects of Hispanic heritage (10.8±3.6 years; BMI-Z, 1.57±1.07). MC4R variants were characterized in vitro by cell surface expression, receptor binding and cyclic AMP response after agonist administration. BDNF single-nucleotide polymorphisms (SNPs) rs12291186, rs6265 and rs7124442 were also genotyped. RESULTS: In the Pima cohort, no significant differences in serum BDNF was observed for 43 LOF subjects versus 65 LOF-matched controls (age, sex and BMI matched; P=0.29) or 20 GOF subjects versus 20 GOF-matched controls (P=0.40). Serum BDNF was significantly associated with genotype for BDNF rs12291186 (P=0.006) and rs6265 (P=0.009), but not rs7124442 (P=0.99); BDNF SNPs did not interact with MC4R status to predict serum BDNF. In the Hispanic cohort, plasma BDNF was not significantly different among 21 LOF subjects, 20 GOF subjects and 28 controls (P=0.79); plasma BDNF was not predicted by BDNF genotype or BDNF-x-MC4R genotype interaction. CONCLUSIONS: Circulating BDNF concentrations were not significantly associated with MC4R functional status, suggesting that peripheral BDNF does not directly reflect hypothalamic BDNF secretion and/or that MC4R signaling is not a significant regulator of the bulk of BDNF expression in humans.