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Previously, we have shown that a mutation in the mitochondrial DNA--encoded tRN[A.sup.Leu(UUR)] gene is associated with type 2 diabetes. One of the consequences of this mutation is a reduced aminoacylation of tRN[A.sup.Leu(UUR)] In this study, we have examined whether variants in the leucyl tRNA synthetase gene (LARS2), involved in aminoacylation of tRN[A.sup.Leu(UUR)], associate with type 2 diabetes. Direct sequencing of LARS2 cDNA from 25 type 2 diabetic subjects revealed eight single nucleotide polymorphisms. Two of the variants were examined in 7,836 subjects from four independent populations in the Netherlands and Denmark. A -109 g/a variant was not associated with type 2 diabetes. Allele frequencies for the other variant, H324Q, were 3.5% in type 2 diabetic and 2.7% in control subjects, respectively. The common odds ratio across all four studies was 1.40 (95% CI 1.12-1.76), P = 0.004. There were no significant differences in clinical variables between carriers and noncarriers. In this study, we provide evidence that the LARS2 gene may represent a novel type 2 diabetes susceptibility gene. The mechanism by which the H324Q variant enhances type 2 diabetes risk needs to be further established. This is the first report of association between an aminoacyl tRNA synthetase gene and disease. Our results further highlight the important role of mitochondria in glucose homeostasis., Previously, we have shown that an A3243G mutation in the mitochondrial DNA-encoded tRN[A.sup.Leu(UUR)] gene is associated with maternally inherited diabetes and deafness (1,2). Carriers of the 3243 mutation have a [...]

Background: Gene-nutrient interactions affecting hepatic lipase (HL) activity may contribute to the interindividual variability of the cardiovascular disease risk associated with dietary fat intake. Objective: We determined the associations of dietary fat intake with postheparin HL activity and the possible modifying effect of the HL -480C [right arrow] T polymorphism on these associations. Design: Subjects were recruited from participants in the 2000-2001 follow-up examination of the Hoorn Study. HL activity was determined in postheparin plasma in a sample of 211 men and 218 women aged 60-87 y. Information about dietary intake of the participants was obtained with a validated food-frequency questionnaire. Linear regression was performed, adjusted for age. Results: Total dietary fat was positively associated with HL activity (standardized [beta]: 0.11; 95% CI: 0.02, 0.21), and this association was also seen for saturated fat (0.10; 0.01, 0.20) and monounsaturated fatty acid (0.10; 0.01, 0.19). We observed a significant interaction of the HL polymorphism with the relation between total fat intake and HL activity. The association of total fat with HL activity was stronger in subjects with CT (0.27; 0.11, 0.43) and TT (0.39; -0.22, 1.00) genotypes than in subjects with the CC genotype (0.06; -0.06, 0.18; P for interaction < 0.10). The interaction remained statistically significant in models that included age, sex, carbohydrate and protein intakes, and insulin or body mass index. Conclusions: Higher intakes of total and saturated fat were positively associated with higher HL activity. In addition, the observed association of total fat with HL activity was modified by the HL-480C [right arrow] T polymorphism, after adjustment for age, sex, carbohydrate and protein intakes, and insulin or body mass index. KEY WORDS Hepatic lipase, gene-nutrient interaction, fat intake

IGFs are important regulators of pancreatic β-cell development, growth, and maintenance. Mutations in the IGF genes have been found to be associated with type 2 diabetes, myocardial infarction, birth weight, and obesity. These associations could result from changes in insulin secretion. We have analyzed glucose-stimulated insulin secretion using hyperglycemic clamps in carriers of a CA repeat in the IGF-I promoter and an ApaI polymorphism in the IGF-II gene. Normal and impaired glucose-tolerant subjects (n = 237) were independently recruited from three different populations in the Netherlands and Germany to allow independent replication of associations. Both first- and second-phase insulin secretion were not significantly different between the various IGF-I or IGF-II genotypes. Remarkably, noncarriers of the IGF-I CA repeat allele had both a reduced insulin sensitivity index (ISI) and disposition index (DI), suggesting an altered balance between insulin secretion and insulin action. Other diabetes-related parameters were not significantly different for both the IGF-I and IGF-II gene variant. We conclude that gene variants in the IGF-I and IGF-II genes are not associated with detectable variations in glucose-stimulated insulin secretion in these three independent populations. Further studies are needed to examine the exact contributions of the IGF-I CA repeat alleles to variations in ISI and DI., IGFs are regulators of processes like growth and metabolism (1-3). IGF-I and IGF-II also contribute to pancreatic β-cell growth and development by regulating β-cell replication, renewal, and apoptosis (4,5). Deregulation [...]

OBJECTIVE--To assess the performance of the Cambridge Risk Score (CRS) to predict undiagnosed hyperglycemia in Caribbean and South Asian people living in the U.K. RESEARCH DESIGN AND METHODS--The CRS uses [...]

Background: The higher risk of type 2 diabetes in persons with a high waist-to-hip ratio (WHR) or waist-to-thigh ratio (WTR) has mostly been attributed to increased visceral fat accumulation. However, smaller hip or thigh circumference may also explain the predictive value of the WHR or WTR for type 2 diabetes. Objective: This study considered prospectively the association of hip and thigh circumferences, independent of waist circumference, with the incidence of type 2 diabetes. Design: The Hoorn Study is a population-based cohort study of diabetes. A total of 1357 men and women aged 50-75 y and non-diabetic at baseline participated in the 6-y follow-up examination. Glucose tolerance was assessed by use of a 75-g oral-glucose-tolerance test. Baseline anthropometric measurements included body mass index (BMI) and waist, hip, and thigh circumferences. Results: Logistic regression analyses showed that a 1-SD larger hip circumference gave an odds ratio (OR) for developing diabetes of 0.55 (95% CI: 0.36, 0.85) in men and 0.63 (0.42, 0.94) in women, after adjustment for age, BMI, and waist circumference. The adjusted ORs for a 1-SD larger thigh circumference were 0.79 (0.53, 1.19) in men and 0.64 (0.46, 0.93) in women. In contrast with hip and thigh circumferences, waist circumference was positively associated with the incidence of type 2 diabetes in these models (ORs ranging from 1.60 to 2.66). Conclusion: Large hip and thigh circumferences are associated with a lower risk of type 2 diabetes, independently of BMI, age, and waist circumference, whereas a larger waist circumference ix associated with a higher risk. Am J Clin Nutr 2003;77:1192-7. KEY WORDS Hip circumference, thigh circumference, waist-to-hip ratio, waist circumference, BMI, body composition, fat distribution, type 2 diabetes, insulin resistance, the Hoorn Study

An association between type 2 diabetes and genetic variation in the KIR6.2 gene has been reported in several populations. Based on in vitro studies with cell lines expressing the [Glu.sup.23]Lys (E23K) mutation, it was recently suggested that this mutation might result in altered insulin secretion. We have examined glucose-stimulated insulin secretion in relation to this KIR6.2 gene variant in two independent Dutch cohorts. Subjects with normal (n = 65) or impaired (n = 94) glucose tolerance underwent 3-h hyperglycemic clamps at 10 mmol/l glucose. We did not observe significant differences in first- or second-phase insulin secretion between carriers and noncarriers of the gene variant in either of the study populations (all P > 0.45). Furthermore, we found no evidence for a significant interaction with disease-associated gene variants in the sulfonylurea receptor (SUR1) gene. We conclude that the E23K mutation in the KIR6.2 gene is not associated with detectable alterations in glucose-stimulated insulin secretion in two independent populations from the Netherlands., The ATP-sensitive [K.sup.+] channel in the β-cell is an important regulator of insulin secretion. The channel is composed of two subunits in a heterooctomeric complex of four sulfonylurea receptor (SUR1) [...]

OBJECTIVE -- To study potential risk factors for retinopathy in diabetic and nondiabetic individuals. RESEARCH DESIGN AND METHODS -- The Room Study is a population-based study including 2,484 50- to [...]

Associations between type 2 diabetes (and/or parameters contributing to glucose homeostasis) and genetic variation in the genes encoding insulin receptor substrate (IRS)-1 and -2 have been reported in several populations. [...]