IGF-I gene promoter polymorphism is a predictor of survival after myocardial infarction in patients with type 2 diabetes.

OBJECTIVE: Previously we observed that non-carriers of the most common alleles of an IGF-I promoter polymorphism have low circulating IGF-I levels and an increased risk of developing myocardial infarction (MI), particularly in patients with type 2 diabetes. DESIGN: We investigated whether this IGF-I promoter polymorphism is associated with survival of type 2 diabetes in a Caucasian population aged 55 years and older. METHODS: The study was embedded in the Rotterdam Study, a prospective population-based cohort study. At baseline, 668 patients with type 2 diabetes were diagnosed, among which, 55 incident MI were ascertained during follow-up. For the present study, we used two genotype groups: non-variant carriers (homozygous for 192, 194, or 192/194 bp genotypes), and variant carriers. RESULTS: During a median follow-up of 8.8 years, 396 out of the 668 patients with type 2 diabetes (59.3%) died of various causes. The frequency of type 2 diabetes variant carrier and non-variant carriers was 28.7 and 71.3% respectively. The survival in patients with type 2 diabetes without an MI did not differ between the IGF-I genotype groups (hazard ratio (HR) = 0.8, 95% confidence interval (CI): 0.7-1.1, P = 0.1). In contrast, in those who developed an MI, variant carriers had a 2.4 times higher risk of mortality than non-variant carriers (95% CI: 1.2-4.8, P = 0.01). CONCLUSION: Our study suggests that genetically determined low IGF-I activity is an important determinant of survival in patients with type 2 diabetes who developed an MI. The IGF-I promoter polymorphism, therefore, may help to predict the future mortality risk in this group of patients.

An igf-I gene polymorphism modifies the risk of diabetic retinopathy.

The role of IGF-I in the pathogenesis of diabetic retinopathy is unclear. We studied, prospectively, the relationship between an IGF-I gene polymorphism, retinal vessel diameters, and incident diabetic retinopathy in subjects with impaired glucose tolerance (IGT) or type 2 diabetes. In all 5,505 participants of the population-based Rotterdam Study (775 with IGT, 394 with type 2 diabetes, and 4,336 control subjects), fundus color transparencies were taken at baseline (between 1990 and 1993) and at follow-up (from 1997 to 1999). The wild-type genotype (i.e., carriers of the 192- or 194-bp alleles) was present in 72.7% of the participants, while 27.3% were variant carriers. Variant carriers with IGT or type 2 diabetes appeared to have larger retinal arteriolar and venular diameters at baseline than individuals with the wild-type genotype, but these differences did not reach statistical significance. This trend was especially observed in subjects who developed retinopathy at follow-up. In variant carriers with IGT/diabetes, an increase (odds ratio 1.8 [95% CI 1.0-3.2]; P = 0.04) in the risk of retinopathy was observed compared with participants with the wild-type genotype. In conclusion, our findings suggest that this IGF-I gene polymorphism is associated with an increased risk of diabetic retinopathy.

An insulin-like growth factor-I promoter polymorphism is associated with increased mortality in subjects with myocardial infarction in an elderly Caucasian population.

We investigated whether an insulin-like growth factor I (IGF-I) promoter polymorphism is associated with excess mortality in elderly subjects with myocardial infarction (MI). This association was assessed in 7,983 subjects of the Rotterdam Study during 14 years of follow-up. Among 345 subjects who developed a MI, the risk of mortality was 1.49 times higher in the variant carriers of the IGF-I promoter polymorphism than in the nonvariant carriers (95% confidence interval 1.10 to 2.10, p = 0.02). The risk of death increased with the number of variant alleles. Our study suggests that genetically determined low IGF-I activity is an important determinant of mortality in subjects with MI.

Retinal vessel diameters and risk of impaired fasting glucose or diabetes: the Rotterdam study.

The association between a smaller retinal arteriolar-to-venular ratio (AVR) and incident diabetes may be due to arteriolar narrowing, venular dilatation, or both. We investigated associations between baseline vessel diameters and incident impaired fasting glucose or diabetes in a population-based cohort (aged > or =55 years). Baseline retinal vessel diameters (1990-1993) were measured on digitized images of 2,309 subjects with a normal glucose tolerance test (postload glucose <7.8 mmol/l). At follow-up (1997-1999), impaired fasting glucose was defined as 6.1-7.0 mmol/l and diabetes as > or =7.0 mmol/l and/or antidiabetic medication use. Odds ratios (ORs) per SD increase in venular diameters were 1.13 (95% CI 1.00-1.29) for impaired fasting glucose and 1.09 (0.90-1.33) for diabetes. ORs per SD decrease in arteriolar diameters were 1.12 (0.98-1.27) and 1.08 (0.89-1.31) and per SD decrease in AVR were 1.29 (1.13-1.46) and 1.19 (0.98-1.45). After adjustment for cardiovascular risk factors, the associations were unaltered for venules and disappeared for arterioles. After stratification on age, associations between venular dilatation and impaired fasting glucose (1.23 [1.02-1.47]) or diabetes (1.18 [0.89-1.56]) were mainly present in participants aged <70 years. In conclusion, in our study, the risk of impaired fasting glucose and diabetes with AVR was explained by venular dilatation rather than arteriolar narrowing, warranting more focus on the causes of this dilatation.

Evidence that the mitochondrial leucyl tRNA synthetase (LARS2) gene represents a novel type 2 diabetes susceptibility gene.

Previously, we have shown that a mutation in the mitochondrial DNA-encoded tRNA(Leu(UUR)) gene is associated with type 2 diabetes. One of the consequences of this mutation is a reduced aminoacylation of tRNA(Leu(UUR)). In this study, we have examined whether variants in the leucyl tRNA synthetase gene (LARS2), involved in aminoacylation of tRNA(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.

Insulin-like growth factor-I gene polymorphism and risk of heart failure (the Rotterdam Study).

We studied 4,963 participants of the population-based Rotterdam Study and found that a genetically determined chronic exposure to low insulin-like growth factor-I (IGF-I) levels is associated with an increased risk for heart failure in elderly patients.

Genetic factors and insulin secretion: gene variants in the IGF genes.

IGFs are important regulators of pancreatic beta-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.

A polymorphism in the IGF-I gene influences the age-related decline in circulating total IGF-I levels.

OBJECTIVE: Recent studies have demonstrated an association between a 192 bp polymorphism of the IGF-I gene and total IGF-I serum levels, birth weight, body height and the risk of developing diabetes and cardiovascular diseases later on in life. This IGF-I gene polymorphism in the promoter region of the IGF-I gene may directly influence the expression of IGF-I. In the present study we evaluated the role of this polymorphism in the age-related decline in serum IGF-I levels. SUBJECTS AND METHODS: All subjects were participants of the Rotterdam Study, a population-based cohort study of diseases in the elderly. We studied a total group of 346 subjects, who comprised two subgroups: a randomly selected population-based sample of 196 subjects, and a group of 150 subjects selected on IGF-I genotype. In the total group of 346 individuals the relationship between this 192 bp polymorphism and the age-related decline in circulating total IGF-I levels was studied. RESULTS: Homozygous carriers of the 192 bp allele demonstrated significant decline in serum IGF-I with age (r=-0.29, P=0.002). This decline is similar to that seen in the general population. An age-related decline in serum total IGF-I was not observed in heterozygotes (r=-0.06, P=0.48) and non-carriers (r = -0.12, P=0.32). Interestingly, the relationship between age and serum IGF-binding protein-3 levels showed the same pattern. CONCLUSION: We observed only in homozygous carriers of the 192 bp alleles of the IGF-I gene an age-related decline in circulating total IGF-I levels, but not in heterozygotes and non-carriers of the 192 bp allele. We hypothesize that this IGF-I gene polymorphism directly or indirectly influences GH-mediated regulation of IGF-I secretion.