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OBJECTIVE--To describe the association of BMI with mortality in patients diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS--Using records of 106,640 patients in Scotland, we investigated the association between [...]

OBJECTIVE--To assess associations of gestational diabetes, existing diabetes, and glycosuria with adiposity and cardiometabolic risk factors in offspring at adolescence. RESEARCH DESIGN AND METHODS--Multivariable regression analyses were conducted in a [...]

OBJECTIVE--People with type 1 diabetes have increased risk of hospital admission compared with those without diabetes. We hypothesized that [HbA.sub.1c] would be an important indicator of risk of hospital admission. RESEARCH DESIGN AND METHODS--The Scottish Care Information-Diabetes Collaboration, a dynamic national register of diagnosed cases of diabetes in Scotland, was linked to national data on admissions. We identified 24,750 people with type 1 diabetes during January 2005 to December 2007. We assessed the relationship between deciles of mean [HbA.sub.1c] and hospital admissions in people with type 1 diabetes adjusting for patient characteristics. RESULTS--There were 3,229 hospital admissions. Of the admissions, 8.1% of people had mean [HbA.sub.1c] CONCLUSIONS--People with type 1 diabetes with highest and lowest mean [HbA.sub.1c] values were associated with increased odds of admission. People with high [HbA.sub.1c] (> 10.8%/95 mmol/mol) were at particularly high risk. There is the need to develop effective interventions to reduce this risk., People with type 1 diabetes are at increased risk of hospital admission compared with the general population (1-3). A previous study in Tayside, Scotland found that 25% of people with [...]

OBJECTIVE--The study objective was to describe the effect of socioeconomic status (SES) on mortality among people with type 2 diabetes. RESEARCH DESIGN AND METHODS--We used a population-based national electronic diabetes [...]

OBJECTIVE--The goals of this study were to examine the influence of maternal type 1 diabetes during pregnancy on offspring adiposity and glucose tolerance at age 7 years and to assess [...]

OBJECTIVE--Alteration of placental structure may influence fetal overgrowth and complications of maternal diabetes. We examined the placenta in a cohort of offspring of mothers with type 1 diabetes (OT1DM) to assess structural changes and determine whether these were related to maternal A1C, fetal hematocrit, fetal hormonal, or metabolic axes. RESEARCH DESIGN AND METHODS--Placental samples were analyzed using stereological techniques to quantify volumes and surface areas of key placental components in 88 OT1DM and 39 control subjects, and results related to maternal A1C and umbilical cord analytes (insulin, leptin, adiponectin, IGF-I, hematocrit, lipids, C-reactive protein, and interleukin-6). RESULTS--Intervillous space volume was increased in OT1DM (OT1DM 250 ± 81 [cm.sup.3] vs. control 217 ± 65 [cm.sup.3]; P = 0.02) with anisomorphic growth of villi (P = 0.025). The placentas showed a trend to increased weight (OT1DM 690 ± 19 g; control 641 ± 22 g; P = 0.08), but villous, nonparenchymal, trophoblast, and capillary volumes did not differ. Villous surface area, capillary surface area, membrane thickness, and calculated morphometric diffusing capacity were also similar in type 1 diabetic and control subjects. A1C at 26-34 weeks associated with birth weight (r = 0.27, P = 0.03), placental weight (r = 0.41, P = 0.0009), and intervillons space volume (r = 0.38, P = 0.0024). In multivariate analysis of cord parameters in OT1DM, fetal IGF-I emerged as a significant correlate of most components (intervillous space, villous, trophoblast, and capillary volumes, all P < 0.01). By contrast, fetal insulin was only independently associated with capillary surface area (positive, [r.sup.2] = 6.7%; P = 0.02). CONCLUSIONS--There are minimal placental structural differences between OT1DM and control subjects. Fetal IGF-I but not fetal insulin emerges as a key correlate of placental substructural volumes, thereby facilitating feedback to the placenta regarding fetal metabolic demand., Maternal diabetes is associated with adverse consequences to mother and baby, with increased risks of perinatal morbidity and mortality, in particular in association with fetal macrosomia. The Pedersen hypothesis (1) [...]

OBJECTIVE--Offspring of mothers with diabetes are at risk of obesity and glucose intolerance in later life. In adults, markers of subclinical inflammation (C-reactive protein [CRP] and interleukin [IL]-6) and endothelial [...]

OBJECTIVE--Offspring of mothers with type 1 diabetes (OT1DM) demonstrate increased fat deposition, hyperinsulinemia, and hyperleptinemia in utero. We examined the influence of maternal diabetes on cord lipids at birth and [...]

OBJECTIVE--In genetically diabetes-prone populations, maternal diabetes during pregnancy increases the risk of their children developing diabetes and obesity (the vicious cycle of type 2 diabetes). Fetal hyperinsulinemia at birth acts [...]

OBJECTIVE--By age 5 years, offspring of diabetic mothers (ODMs) are heavier and have altered glucose metabolism compared with offspring of mothers without diabetes (non-DMs). This study evaluates the growth pattern [...]

Adiponectin is an abundant adipose tissue-derived protein with important metabolic effects. Plasma adiponectin levels are decreased in obese individuals, and low adiponectin levels predict insulin resistance and type 2 diabetes. Two variants in the adiponectin gene ACDC have been previously associated with plasma adiponectin levels, obesity, insulin resistance, and type 2 diabetes. To determine the role of genetic variation in ACDC in susceptibility to obesity and type 2 diabetes in Pima Indians, we screened the promoter, exons, and exon-intron boundaries of the gene to identify allelic variants. We identified 17 informative polymorphisms that comprised four common (minor allele frequency > 15%) linkage disequilibrium clusters consisting of 1-4 variants each. We genotyped one representative polymorphism from each cluster in 1,338 individuals and assessed genotypic association with type 2 diabetes, BMI, serum lipid levels, serum adiponectin levels, and measures of insulin sensitivity and secretion. None of the ACDC variants were associated with type 2 diabetes, BMI, or measures of insulin sensitivity or secretion. One variant, single nucleotide polymorphism (SNP)-12823, was associated with serum adiponectin levels (P = 0.002), but this association explained only 2% of the variance of serum adiponectin levels. Our findings suggest that these common ACDC polymorphisms do not play a major role in susceptibility to obesity or type 2 diabetes in this population., Adiponectin is an adipose tissue--derived protein with important metabolic effects (1). Plasma adiponectin levels are decreased in individuals with obesity (2), insulin resistance (3), and type 2 diabetes (2), and [...]

OBJECTIVE--To compare risk of all-cause and cardiovascular disease (CVD) mortality in people with a lower-extremity amputation (LEA) attributable to diabetes and people without an LEA. RESEARCH DESIGN AND METHODS--The Strong [...]

Adiponectin is a circulating protein secreted by adipocytes and is thought to have insulin-sensitizing effects. We present genetic analysis of adiponectin levels in 517 Pima Indians without diabetes (from 162 families, 750 sib-pairs). Adiponectin concentrations were heritable, with 39% of the variance of age- and sex-adjusted adiponectin potentially accounted for by additive genetic influences in this population. In genome-wide linkage analyses, suggestive linkage (logarithm of odds [LOD] = 3.0) of adiponectin adjusted for age and sex was found on chromosome 9p at 18 cM. Linkage was also present after inclusion of adiponectin concentrations of siblings with type 2 diabetes not treated pharmacologically (total siblings 582, 182 families, 860 sib-pairs: LOD = 3.5). Tentative evidence of linkage was also found on chromosomes 2 (LOD = 1.7 at 89 cM), 3 (LOD = 1.9 at 124 cM), and 10 (LOD = 1.7 at 70 cM), offering some support to findings of a previous genome-wide scan of adiponectin. Our data suggest that quantitative trait loci on chromosomes 2, 3, 9, and 10 may influence circulating adiponectin concentrations in the Pima population. Diabetes 52:2419-2425, 2003, Adipose tissue expresses a variety secretory proteins of potential importance to metabolic and vascular disease. Recently, adiponectin, a 244-amino acid adipocyte-derived protein, was described (1), which, despite being solely derived [...]

OBJECTIVE--In adults, adiponectin is reduced in association with excess adiposity, type 2 diabetes, and hyperinsulinemia. We assessed whether adiponectin was 1) present in the fetal circulation, 2) altered in the [...]

OBJECTIVE -- To examine the association between adiponectin, a known predictor of diabetes in Pima Indians, and markers of inflammation and endothelial function in nondiabetic subjects and to assess whether [...]

OBJECTIVE -- To examine the risk of retinopathy and nephropathy in participants in whom type 2 diabetes was diagnosed in youth (before 20 years of age) compared with those in [...]

The insulin gene variable number tandem repeat (INS-VNTR) is proposed to exert pleiotropic genetic effects on birth weight and diabetes susceptibility. In our study, we examined the influence of a polymorphism in tight linkage disequilibrium with INS-VNTR (-23Hph1) on birth weight and type 2 diabetes in the Pima population. A parent-offspring 'trio' design was used to assess parent-of-origin effects and population stratification. The presence of the -23Hph1 T-allele was associated with lower birth weight (n = 192; -140 g per copy of the T-allele; P = 0.04), even after adjustment for effects of population stratification (P = 0.03). The effects of paternally transmitted T-alleles were greater than those of maternally transmitted alleles (paternally transmitted: -250 g, P = 0.05; maternally transmitted: -111 g, P = 0.43), but this difference was not statistically significant (P = 0.50). The -23Hph1 T-allele was associated with an increased prevalence of type 2 diabetes (P = 0.009), which family-based association analysis suggested was attributable to population structure (P = 0.04) without significant evidence of linkage disequilibrium between diabetes prevalence and genotype (P = 0.86). Thus allelic variation of the INS gene is associated with lower birth weight and increased prevalence of type 2 diabetes. Significant linkage disequilibrium was formal between -23Hph1 and birth weight but not type 2 diabetes, an observation that supports a potential functional role of INS polymorphisms in the regulation of birth weight., Low birth weight is associated with increased risk of type 2 diabetes (1). It has been suggested that this may be because of pleiotropic effects of one or more genes [...]

Low concentrations of plasma adiponectin, the most abundant adipose-specific protein, are observed in obese individuals and predict the development of type 2 diabetes. Administration of adiponectin to rodents prevented diet-induced weight gain, suggesting a potential etiologic role of hypoadiponectinemia in the development of obesity. Our aim was to prospectively examine whether low plasma adiponectin concentrations predict future weight gain in Pima Indians, explaining the predictive effect of adiponectin on the development of type 2 diabetes. We measured plasma adiponectin concentrations in 219 nondiabetic Pima Indians (112 M/107 F, age 31 ± 9 years, body weight 96 ± 20 kg [mean ± SD]) in whom body weight and height were measured and BMI calculated at baseline and follow-up. Cross-sectionally, plasma adiponectin concentrations were negatively associated with body weight (r = -0.28, P = 0.0001). Prospectively, plasma adiponectin concentrations at baseline were not associated with change in weight or BMI before or after adjustment for time of follow-up or after additional adjustment for age at follow-up and sex (all P > 0.3). Our data suggest that low plasma adiponectin concentrations do not play an etiologic role in development of obesity in Pima Indians. Therefore, the predictive effect of low plasma adiponectin concentrations on the development of type 2 diabetes seems to be mediated by factors other than increased adiposity., Adiponectin has been recently identified as an adipose-derived protein with important metabolic effects. It is exclusively expressed in adipose tissue and released into the circulation (1,2). Plasma adiponectin concentrations are [...]

It has been proposed that liver dysfunction may contribute to the development of type 2 diabetes. The aim of the present study was to examine whether elevated hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], or γ-glutamyltranspeptidase [GGT]) are associated with prospective changes in liver or whole-body insulin sensitivity and/or insulin secretion and whether these elevated enzymes predict the development of type 2 diabetes in Pima Indians. We measured ALT, AST, and GGT in 451 nondiabetic (75-g oral glucose tolerance test) Pima Indians (aged 30 ± 6 years, body fat 33 ± 8%, ALT 45 ± 29 units/l, AST 34 ± 18 units/l, and GGT 56 ± 40 units/l [mean ± SD]) who were characterized for body composition (hydrodensitometry or dual-energy X-ray absorptiometry), whole-body insulin sensitivity (M), and hepatic insulin sensitivity (hepatic glucose output [HGO] during the low-dose insulin infusion of a hyperinsulinemic clamp) and acute insulin response (AIR) (25-g intravenous glucose challenge). Sixty-three subjects developed diabetes over an average follow-up of 6.9 ± 4.9 years. In 224 subjects, who remained nondiabetic, follow-up measurements of M and AIR were available. At baseline, ALT, AST, and GGT were related to percent body fat (r = 0.16, 0.17, and 0.11, respectively), M (r = -0.32, -0.28, and -0.24), and HGO (r = 0.27, 0.12, and 0.14; all P < 0.01). In a proportional hazard analysis with adjustment for age, sex, body fat, M, and AIR, higher ALT [relative hazard 90th vs. 10th centiles (95% CI): 1.9 (1.1-3.3), P = 0.02], but not AST or GGT, predicted diabetes. Elevated ALT at baseline was associated prospectively with an increase in HGO (r = 0.21, P = 0.001) but not with changes in M or AIR (both P = 0.1). Higher ALT concentrations were cross-sectionally associated with obesity and whole-body and hepatic insulin resistance and prospectively associated with a decline in hepatic insulin sensitivity and the development of type 2 diabetes. Our findings indicate that high ALT is a marker of risk for type 2 diabetes and suggest a potential role of the liver in the pathogenesis of type 2 diabetes. Diabetes 51:1889-1895, 2002, Aminotransferases are considered indicators of hepatocellular health, whereas γ-glutamyltranspeptidase (GGT) also reflects biliary tract function. Alanine aminotransferase (ALT) is found primarily in the liver. Aspartate aminotransferase (AST) and GGT are [...]

Adiponectin, the most abundant adipose-specific protein, has been found to be negatively associated with degree of adiposity and positively associated with insulin sensitivity in Pima Indians and other populations. Moreover, adiponectin administration to rodents has been shown to increase insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and also increase whole-body insulin sensitivity. To further characterize the relationship between plasma adiponectin concentration and insulin sensitivity in humans, we examined 1) the cross-sectional association between plasma adiponectin concentration and skeletal muscle IR tyrosine phosphorylation and 2) the prospective effect of plasma adiponectin concentration at baseline on change in insulin sensitivity. Fasting plasma adiponectin concentration, body composition (hydrodensitometry or dual energy X-ray absorptiometry), insulin sensitivity (insulin-stimulated glucose disposal, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) were measured in 55 Pima Indians (47 men and 8 women, aged 31 ± 8 years, body fat 29 ± 8% [mean ± SD]; 50 with normal glucose tolerance, 3 with impaired glucose tolerance, and 2 with diabetes). Group 1 (19 subjects) underwent skeletal muscle biopsies for the measurement of basal and insulin-stimulated tyrosine phosphorylation of the IR (stimulated by 100 nmol/l insulin). The fold increase after insulin stimulation was calculated as the ratio between maximal and basal phosphorylation. Group 2 (38 subjects) had follow-up measurements of insulin-stimulated glucose disposal. Cross-sectionally, plasma adiponectin concentration was positively associated with insulin-stimulated glucose disposal (r = 0.58, P < 0.0001) and negatively associated with percent body fat (r = -0.62, P < 0.0001) in the whole group. In group 1 plasma adiponectin was negatively associated with the basal (r = -0.65, P = 0.003) and positively associated with the fold increase in IR tyrosine phosphorylation (r = 0.69, P = 0.001) before and after the adjustment for percent body fat (r = -0.58, P = 0.01 and r = 0.54, P = 0.02, respectively). Longitudinally, after adjustment for age, sex, and percent body fat, low plasma adiponectin concentration at baseline was associated with a decrease in insulin sensitivity (P = 0.04). In conclusion, our cross-sectional data suggest a role of physiological concentration of fasting plasma adiponectin in the regulation of skeletal muscle IR tyrosine phosphorylation. Prospectively, low plasma adiponectin concentration at baseline precedes a decrease in insulin sensitivity. Our data indicate that adiponectin plays an important role in regulation of insulin sensitivity in humans. Diabetes 50:1884-1888, 2002, Adipose serves not only as an energy tissue storage organ, but also secretes hormones and metabolites that are thought to regulate insulin sensitivity and energy metabolism (1,2). Adiponectin, the most [...]

Chronic low-grade inflammation may be involved in the pathogenesis of insulin resistance and type 2 diabetes. We examined whether a high white blood cell count (WBC), a marker of inflammation, [...]

We examined the hypothesis that imprinted genes may affect the propensity to type 2 diabetes and obesity in Pima Indians. Multipoint variance component methods were used to assess linkage of BMI (kg/[m.sup.2]) and age-adjusted diabetes to loci derived from either father ([LOD.sub.FA]) or mother ([LOD.sub.MO]) in a genome-wide scan. Tentative evidence of loci where imprinted genes might be acting was found for diabetes with maternally derived alleles on chromosomes 5 ([LOD.sub.MO] = 1.5) and 14 ([LOD.sub.MO] = 1.6). Evidence of linkage of BMI to maternally derived alleles was found on chromosome 5 ([LOD.sub.MO] = 1.7) and to paternally derived alleles on chromosome 10p ([LOD.sub.FA] = 1.7). Additional analyses of sibling pairs who were affected by diabetes and younger than 25 years of age showed an increase of sharing of maternally derived alleles on chromosome 6 ([LOD.sub.MO] = 3.0). We also examined sites of a priori interest where action of imprinted genes has been proposed in diabetes or obesity. We found no evidence of parent-specific linkage (of either diabetes or BMI) on chromosome 11p, a region that contains several imprinted genes, but observed weak evidence of linkage of diabetes to paternally derived alleles ([LOD.sub.FA] = 0.9) in the region of chromosome 6q, believed to contain an exclusively paternally expressed gene or genes that cause transient neonatal diabetes mellitus. In conclusion, we determined regions of interest on chromosomes 5, 6, and 10 where imprinted genes might be affecting the risk of type 2 diabetes or obesity in Pima Indians., The causes of type 2 diabetes and obesity are unknown in the majority of cases but are believed to reflect a mixture of genetic and environmental factors. Several pieces of [...]

It has been proposed that inflammation or infection may contribute to the development of type 2 diabetes. We examined whether serum gamma globulin, a nonspecific measure of the humoral immune [...]

OBJECTIVE--To establish the incidence of nontraumatic lower-extremity amputation (LEA) in people with diabetes in Scotland. RESEARCH DESIGN AND METHODS--This cohort study linked national morbidity records and diabetes datasets to establish [...]

OBJECTIVE--To assess the association of fetal hormones with placental growth and fetal weight-to-placental weight ratio index (FPI) in pregnancies complicated by maternal diabetes. RESEARCH DESIGN AND METHODS--We conducted a prospective [...]

Intrauterine exposure to diabetes is associated with an excess of diabetes and obesity in the offspring, but the effects of intrauterine exposure are confounded by genetic factors. To determine the [...]

OBJECTIVE -- The offspring of mothers who had diabetes during pregnancy experience increased risk later of diabetes and obesity later. We hypothesized that, in light of the historical improvements in [...]

Vagally-mediated hyperinsulinemia is a common abnormality in various rodent models of genetic and hypothalamic obesity and diabetes. We hypothesized that Pima Indians, a population with a high prevalence of hyperinsulinemia, [...]

We have examined the hypothesis that imprinted genes may affect the propensity to type 2 diabetes. Multipoint linkage to age and sex adjusted diabetes score was carried out on 1,111 [...]

Children of mothers who had diabetes during pregnancy experience increased risk of diabetes and obesity in later life. We hypothesized that, in the light of improvements in the management of [...]

The Role of Paternal Inheritance in the Association of Low Birth Weight and Diabetes Lower birth weight is associated with an increased occurrence of type 2 diabetes in later life. [...]

Medical and social factors, including patient choice, influence the chosen method of renal replacement therapy (RRT) in patients with diabetes and may affect survival. Our aim was to determine whether [...]

Intrauterine exposure to diabetes is associated with an excess of diabetes and obesity in the offspring, but the effects of intrauterine exposure per se are confounded by genetic factors. To [...]