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Early puberty onset is associated with higher risk of diabetes, but most studies have not accounted for childhood factors that may confound the association. Using data from a study conducted in an Indigenous community in Arizona (1965–2007), we examined associations of timing and velocity of the adolescent growth spurt with type 2 diabetes, and whether these associations are mediated by childhood body mass index and insulinemia. Adolescent growth parameters were derived from the Preece-Baines growth model, a parametric growth curve fitted to longitudinal height data, for 861 participants with height measurements spanning the whole period of growth. In males, older age at take-off, age at peak velocity, and age at maturation were associated with decreased prevalence of diabetes (odds ratio (OR) = 0.43 per year, 95% confidence interval (CI): 0.27, 0.69; OR = 0.50, 95% CI: 0.35, 0.72; OR = 0.58, 95% CI: 0.41, 0.83, respectively), while higher velocity at take-off was associated with increased risk (OR = 3.47 per cm/year, 95% CI: 1.87, 6.42) adjusting for age, birth year, and maternal diabetes. Similar results were observed with incident diabetes. Our findings suggest that an early and accelerated adolescent growth spurt is a risk factor for diabetes, at least in males. These associations are only partially explained by measures of adiposity and insulinemia. [ABSTRACT FROM AUTHOR]

Context: Insulin secretion and sensitivity regulate glycemia, with inadequately compensated deficiencies leading to diabetes. Objective: We investigated effects of weight loss, an intensive lifestyle intervention (ILS), and metformin on the relationship between insulin secretion and sensitivity using repository data from 2931 participants in the Diabetes Prevention Program clinical trial in adults at high risk of developing type 2 diabetes. Methods: Insulin secretion and sensitivity were estimated from insulin and glucose concentrations in fasting and 30-minute postload serum samples at baseline and 1, 2, and 3 years after randomization, during the active intervention phase. The nonlinear relationship of secretion and sensitivity was evaluated by standardized major axis regression to account for variability in both variables. Insulin secretory demand and compensatory insulin secretion were characterized by distances along and away from the regression line, respectively. Results: ILS and metformin decreased secretory demand while increasing compensatory insulin secretion, with greater effects of ILS. Improvements were directly related to weight loss; decreased weight significantly reduced secretory demand (b=-0.144 SD; 95% CI (-0.162, -0.125)/5 kg loss) and increased compensatory insulin secretion (b=0.287 SD, 95% CI (0.261, 0.314)/5 kg loss). In time-dependent hazard models, increasing compensatory insulin secretion (hazard ratio [HR]=0.166 per baseline SD, 95% CI 0.133, 0.206) and weight loss (HR=0.710 per 5 kg loss, 95% CI 0.613, 0.819) predicted lower diabetes risk. Conclusion: Diabetes risk reduction was directly related to the amount of weight loss, an effect mediated by lowered insulin secretory demand (due to increased insulin sensitivity) coupled with improved compensatory insulin secretion. [ABSTRACT FROM AUTHOR]

Background: Obesity and energy expenditure (EE) are heritable and genetic variants influencing EE may contribute to the development of obesity. We sought to identify genetic variants that affect EE in American Indians, an ethnic group with high prevalence of obesity.Methods: Whole-exome sequencing was performed in 373 healthy Pima Indians informative for 24-hour EE during energy balance. Genetic association analyses of all high-quality exonic variants (≥5 carriers) was performed, and those predicted to be damaging were prioritized.Results: Rs752074397 introduces a premature stop codon (Cys264Ter) in DAO and demonstrated the strongest association for 24-hour EE, where the Ter allele associated with substantially lower 24-hour EE (mean lower by 268 kcal/d) and sleeping EE (by 135 kcal/d). The Ter allele has a frequency = 0.5% in Pima Indians, whereas is extremely rare in most other ethnic groups (frequency < 0.01%). In vitro functional analysis showed reduced protein levels for the truncated form of DAO consistent with increased protein degradation. DAO encodes D-amino acid oxidase, which is involved in dopamine synthesis which might explain its role in modulating EE.Conclusion: Our results indicate that a nonsense mutation in DAO may influence EE in American Indians. Identification of variants that influence energy metabolism may lead to new pathways to treat human obesity.Clinical Trial Registration Number: NCT00340132. [ABSTRACT FROM AUTHOR]

Background. Inflammation linked to diabetic kidney disease (DKD) may affect white blood cell (WBC) counts and differentials. We examined the cross-sectional associations of total WBC count and WBC fractions with structural lesions of DKD in 108 Pima Indians with Type 2 diabetes who underwent research kidney biopsies. We also examined the longitudinal association of these WBC variables with renal function loss (RFL) in 941 Europeans with Type 2 diabetes from the SURDIAGENE study. Methods. Associations of WBC variables with morphometric parameters were assessed by linear regression. RFL was defined as ⩾40% loss of estimated glomerular filtration rate from baseline. Associations with RFL were evaluated by Cox regression. Hazard ratios (HRs) were reported per standard deviation increment of eachWBC variable. Results. After multivariable adjustment, lymphocyte (r =-0.20, P=0.043) and eosinophil (r=0.21, P=0.032) fractions in the Pima Indians correlated with glomerular basement membrane width. Eosinophil fraction also correlated with glomerular filtration surface density (r =-0.21, P=0.031). Lymphocyte fraction (r=0.25, P=0.013), neutrophil fraction (r =-0.23, P=0.021) and the neutrophil:lymphocyte ratio (r =-0.22, P=0.024) correlated with percentage of normally fenestrated endothelial cells. During median follow-up of 4.5 years, 321 SURDIAGENE participants developed RFL. Lower lymphocyte fraction [HR=0.67, 95% confidence interval (95% CI) 0.60-0.76] and higher neutrophil fraction (HR=1.35, 95% CI 1.20-1.52), total WBC count (HR=1.20, 95% CI 1.08-1.35) and neutrophil:lymphocyte ratio (HR=1.44, 95% CI 1.28-1.62) each predicted RFL in this cohort. Conclusions. WBC fractions associate with morphometric lesions of DKD and predict RFL in individuals with Type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background. Urinary monocyte chemoattractant protein-1 (MCP-1) and hepcidin are potential biomarkers of renal inflammation. We examined their association with development of diabetic nephropathy (DN) lesions in normotensive normoalbuminuric subjects with type 1 diabetes (T1D) from the Renin-Angiotensin System Study. Methods. Biomarker concentrations were measured in baseline urine samples from 224 subjects who underwent kidney biopsies at baseline and after 5 years. Fifty-eight urine samples below the limit of quantitation (LOQ, 28.8 pg/mL) of the MCP-1 assay were assigned concentrations of LOQ/v2 for analysis. Relationships between ln(MCP-1/Cr) or ln(hepcidin/ Cr) and morphometric variables were assessed by sex using multiple linear regression after adjustment for age, T1D duration, HbA1c, mean arterial pressure, albumin excretion rate (AER) and glomerular filtration rate (GFR). In models that examined changes in morphometric variables, the baseline morphometric value was also included. Results. Baseline mean age was 24.6 years, mean duration of T1D 11.2 years, median AER 6.4 µg/min and mean iohexol GFR 129 mL/min/1.73 m². No associations were found between hepcidin/Cr and morphometric variables. Higher MCP-1/Cr was associated with higher interstitial fractional volume at baseline and after 5 years in women (baseline partial r = 0.244, P = 0.024; 5-year partial r = 0.299, P = 0.005), but not in men (baseline partial r = -0.049, P = 0.678; 5-year partial r = 0.026, P = 0.830). MCP-1 was not associated with glomerular lesions in either sex. Conclusions. Elevated urinary MCP-1 concentration measured before clinical findings of DN in women with T1D was associated with changes in kidney interstitial volume, suggesting that inflammatory processes may be involved in the pathogenesis of early interstitial changes in DN. [ABSTRACT FROM AUTHOR]

The metabolic characteristics of type 2 diabetes, insulin resistance, and diminished insulin secretion are costly to measure directly. To evaluate the utility of several simple indices derived from insulin and glucose measurements, the indices were examined from 1982 to 1997 with respect to correlation with more sophisticated measures of insulin sensitivity and secretion in Pima Indians in the Gila River Indian Community of Arizona. Ability to predict the incidence of diabetes in 1, 731 persons was also examined. Indices were calculated from fasting and 2-hour glucose (G0, G120) and insulin (I0, I120) concentrations obtained during an oral glucose tolerance test. Fasting serum insulin concentration and the insulin sensitivity index (104/(I0 × G0)) each showed a moderate correlation with the estimate of insulin sensitivity derived from the hyperinsulinemiceuglycemic clamp (|r| ≈ 0.60). They also strongly predicted the incidence of diabetes (incidence rate ratio comparing the most and least insulin-resistant tertile groups ≈ 3.0). Corrected insulin response (I120/(G120 × (G120 − 70))) was modestly correlated with insulin secretion as measured by an intravenous glucose tolerance test (r = 0.35). Impaired insulin secretion assessed by this index predicted incidence of diabetes, particularly after control for insulin sensitivity index (incidence rate ratio = 1.6). Thus, simple indices of insulin sensitivity and secretion may be responsible surrogates for more sophisticated measures in epidemiologic studies. Am J Epidemiol 2000; 151:190-8. [ABSTRACT FROM PUBLISHER]

The metabolic characteristics of type 2 diabetes, insulin resistance, and diminished insulin secretion are costly to measure directly. To evaluate the utility of several simple indices derived from insulin and glucose measurements, the indices were examined from 1982 to 1997 with respect to correlation with more sophisticated measures of insulin sensitivity and secretion in Pima Indians in the Gila River Indian Community of Arizona. Ability to predict the incidence of diabetes in 1,731 persons was also examined. Indices were calculated from fasting and 2-hour glucose (G0, G120) and insulin (I0, I120) concentrations obtained during an oral glucose tolerance test. Fasting serum insulin concentration and the insulin sensitivity index (104/(I0 x G0)) each showed a moderate correlation with the estimate of insulin sensitivity derived from the hyperinsulinemic-euglycemic clamp (absolute value r approximately 0.60). They also strongly predicted the incidence of diabetes (incidence rate ratio comparing the most and least insulin-resistant tertile groups approximately 3.0). Corrected insulin response (I120/(G120 x (G120 - 70))) was modestly correlated with insulin secretion as measured by an intravenous glucose tolerance test (r = 0.35). Impaired insulin secretion assessed by this index predicted incidence of diabetes, particularly after control for insulin sensitivity index (incidence rate ratio = 1.6). Thus, simple indices of insulin sensitivity and secretion may be reasonable surrogates for more sophisticated measures in epidemiologic studies. [ABSTRACT FROM AUTHOR]

The relationship between oestrogen replacement therapy and breast cancer risk was examined based on data obtained from a population-based case-control study of breast cancer on Long Island, New York, USA. Cases were defined as female residents of two Long Island counties, aged 20–79, who were diagnosed with breast cancer between 1 January 1984 and 31 December 1986. Age- and county-matched controls were selected from driver's licence files. Among all postmenopausal women, there was no significant association between ever-use of hormones to treat menopausal symptoms and breast cancer risk. There was also no significant positive association in any subgroup defined by type of menopause (natural, hysterectomy with at least one ovary intact, bilateral oophorectomy) or age at menopause. Additionally, there was no increasing trend in risk with duration of use either overall or in any subgroup, nor was there an effect at any interval since last use. A significant elevation in risk was observed in women with 10–19 years since first exposure, which was concentrated in women with a natural menopause or hysterectomy with at least one ovary remaining, and women aged >45 at menopause. Results of logistic regression analysis revealed no important confounding by any of several established breast cancer risk factors. However, a significant interaction was observed between body mass index (BMI) and oestrogen use, with an effect of oestrogen use being seen only in the thinnest tercile. Although biologically plausible explanations for this finding exist, the effect of chance cannot be ruled out. [ABSTRACT FROM PUBLISHER]

Determines whether genetic variations at uncoupling proteins (UCP) 2 and 3 contribute to variation in energy metabolism and obesity in Pima Indians, a population prone to obesity and diabetes. Three polymorphisms revealed by the DNA sequencing of UCP2 and 3; Analysis of UCP2 gene expression.