Hyperproinsulinaemia in impaired glucose tolerance is associated with a delayed insulin response to glucose

Ruige, Johannes; Dekker, Joost; Nijpels, Giel; Popp-Snijders, C.; Stehouwer, Coen D.A.; Kostense, P.J.; Bouter, Lex M.; Heine, Robert J.

doi:10.1007/s001250051136

Cited by 24 publications

(32 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, results of clinical studies so far are mixed [22,23]. We measured proinsulin as an indicator of a defect in insulin secretion [24]. Although proinsulin levels were strongly associated with insulin levels and HOMAiR in our population, they were not different between carriers and non-carriers of the Arg-variant.…”

Section: Discussionmentioning

confidence: 63%

Metabolic risk markers in an overweight and normal weight population with oversampling of carriers of the IRS-1 972Arg-variant

et al. 2003

View full text Add to dashboard Cite

The relationship between the Gly972Arg polymorphism in the insulin receptor substrate-1 (IRS-1) gene and metabolic risk markers is not clear, possibly due to small sample sizes. Modification by body mass index (BMI) has also been suggested. Our aim was therefore to quantify the association of this 9 72Arg-variant with insulin, glucose and lipid levels in overweight and non-overweight subjects with oversampling of subjects with the 972Arg-\anaiA. We first genotyped 3684 subjects selected from a large population-based cohort (n ~ 23,000) according to BMI (26-40 or 18-24 kg/m 2 ). Next, we examined 600 of these subjects for fasting metabolic risk markers according to BMI-group and genotype. Subjects with the 972Arg-variant had significantly higher insulin concentrations (4.09 pmol/1 or 9.6%, P = 0.024) and lower triglyceride levels (0.13 mmol/1 or 11 %, P = 0.001) compared with non-carriers when adjusted for age, sex, waist-to-hip ratio, BMI, alcohol consumption, physical activity and cigarette smoking. These associations were more pronounced in the high BMI-group, although the interactions were not statistically significant Our large population-based sample shows that the IRS-1 Gly972Arg polymorphism relates to higher fasting insulin levels and lower triglyceride levels. The impact of this genotype and its modification by overweight may be smaller than suggested previously.

show abstract

Section: Discussionmentioning

confidence: 63%

Metabolic risk markers in an overweight and normal weight population with oversampling of carriers of the IRS-1 972Arg-variant

et al. 2003

View full text Add to dashboard Cite

show abstract

“…We have examined three cohorts with either NGT or IGT originating from three independent populations in the Netherlands and Germany. A limited part of our populations consisted of first-degree relatives of type 2 diabetic individuals and subjects with IGT (18,19). Both groups have an increased risk of developing type 2 diabetes (22).…”

Section: Discussionmentioning

confidence: 99%

“…Subjects with IGT (n ϭ 94) were all of Dutch origin (19). The IGT subjects (aged 57 Ϯ 7 years) were detected by population screening in the city of Hoorn.…”

mentioning

confidence: 99%

Genetic Factors and Insulin Secretion

et al. 2004

View full text Add to dashboard Cite

IGFs are important regulators of pancreatic ␤-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. IGFs are regulators of processes like growth and metabolism (1-3). IGF-I and IGF-II also contribute to pancreatic ␤-cell growth and development by regulating ␤-cell replication, renewal, and apoptosis (4,5). Deregulation of the balance between ␤-cell renewal and apoptosis due to alterations in IGF levels is potentially of great importance in the development of glucose intolerance. In addition, insulin-dependent glucose homeostasis may be affected by IGFs by sharing common steps in the signaling pathways of receptors for IGFs and insulin (6). Defects in the IGF/insulin-signaling pathways affect fetal growth and thus birth weight, which is a known risk factor for type 2 diabetes and other parts of the metabolic syndrome during life (7). Furthermore, it has been shown in animal models that ablation of the IGF-I receptor from pancreatic ␤-cells results in the absence of the first phase of glucose-stimulated insulin secretion and a strong reduction in second-phase insulin secretion (8,9). Together, these data make it plausible that defects at the level of IGF-I or IGF-II are associated with alterations in glucosestimulated insulin secretion resulting in glucose intolerance.Previously, it was shown that polymorphisms in the IGF-I and IGF-II genes are associated with features of the metabolic syndrome (10 -13). A (CA) n repeat in the promoter region of the IGF-I gene associates with type 2 diabetes, cardiovascular disease, and reduced birth weight (10,14). Gene variants in the IGF-II gene are found in association studies with BMI and IGF-II levels (11,12). However, conflicting results have been reported for both gene variants (15-17). Preliminary results, based on oral glucose tolerance test (OGTT) data, have suggested a ␤-cell defect in carriers of gene variants in both genes (13,14; N. Vaessen, personal communication).In this study, we analyzed glucose-stimulated insulin secretion in relation to the presence of the (CA) n repeat polymorphism in the IGF-I gene and the ApaI polymorphism in the IGF-II gene (10,13). As described previously,...

show abstract

“…Subjects with IGT were selected from a random sample of subjects 45±74 years of age taken from the population registry of the town of Hoorn in the Netherlands. Participants (n = 94) were included when they had a mean postload glucose concentration between 8.6 and 11.1 mmol/l after two oral glucose tolerance tests [8]. For both study groups written informed consent was given by the participants and the study protocol was approved by the local medical ethics committee.…”

Section: Methodsmentioning

confidence: 99%

“…Samples for the determination of insulin were taken at 2 or 2.5-min intervals during the first 10 minutes of the clamp; during the next 170 min, samples were taken at 10 to 20-min intervals. Methods for the calculation of beta-cell function and estimates of insulin sensitivity under stable constant hyperglycaemia are explained in detail elsewhere [7,8]. Subjects with a second-phase insulin secretion less than 25 pmol/l were excluded from calculations of the insulin sensitivity index (ISI) because these estimates might be unreliable as a result of a severely compromised beta-cell function (n = 3 for the NGT group and n = 12 for the IGT group, inclusion of these subjects in the analysis did not alter the results) [10,11].…”

Section: Methodsmentioning

confidence: 99%

Reduced second phase insulin secretion in carriers of a sulphonylurea receptor gene variant associating with Type II diabetes mellitus

et al. 2000

Self Cite

View full text Add to dashboard Cite

The sulphonylurea receptor (SUR) is a subunit of the ATP-sensitive potassium channel (K ATP channel) in the pancreatic beta cell [1,2]. The protein complex is involved in regulation of insulin secretion from the beta cell in response to glucose [1,2]. A mutation at nt ±3 of the splice acceptor site of exon 16 and a silent mutation in exon 18 in the gene coding for the sulphonylurea receptor (SUR1) associate specifically with Type II (non-insulin-dependent) diabetes mellitus [3±5]. We recently showed the association between the exon 16 ±3t allele and Type II diabetes mellitus in two cohorts from the Netherlands [6].The mechanism underlying the association observed between SUR1 gene variants and Type II diabetes is not known but could be related to changes in the process of glucose-induced insulin secretion or peripheral glucose disposal. We assessed if there was any association between the two SUR1 gene variants and beta-cell function and insulin sensitivity as mea- Diabetologia (2000) Abstract Aims/hypothesis. The sulphonylurea receptor is a subunit of the ATP-sensitive potassium channel in the pancreatic beta cell. Mutations at nt ±3 of the splice acceptor site of exon 16 and a silent mutation in exon 18 of the gene for the sulphonylurea receptor (SUR1) associate with Type II (non-insulin-dependent) diabetes mellitus in several independent populations. We investigated whether these gene variants associate with changes in the pattern of glucose-stimulated insulin secretion. Methods. Subjects who had normal glucose tolerance (n = 67) and subjects with an impaired glucose tolerance (n = 94), originating from two independent studies, were included in the study. Beta-cell function and insulin sensitivity were assessed by the hyperglycaemic clamp.Results. Frequencies of the exon 16 ±3t allele in the normal and impaired glucose tolerant groups were 46 % and 44 % respectively (p = NS). The more rare exon 18 T allele showed frequencies of 5 and 7 % respectively (p = NS). We observed an approximately 25 % reduced second-phase insulin secretion in carriers of the exon 16 ±3t allele in both groups (p < 0.05).Estimates of insulin sensitivity did not show differences between carriers and non-carriers. The variant in exon 18 and the combined presence of variants in exon 16 and exon 18 were not associated with differences in insulin secretion or insulin sensitivity in our study groups. Conclusion/interpretation. The diabetes associated exon 16 ±3t variant of the SUR1 gene associates with a functional change of the beta cell as reflected by reduced second-phase insulin secretion in response to a standardized hyperglycaemia in normal and impaired glucose tolerant subjects. [Diabetologia (2000)

show abstract

Hyperproinsulinaemia in impaired glucose tolerance is associated with a delayed insulin response to glucose

Cited by 24 publications

References 15 publications

Metabolic risk markers in an overweight and normal weight population with oversampling of carriers of the IRS-1 972Arg-variant

Metabolic risk markers in an overweight and normal weight population with oversampling of carriers of the IRS-1 972Arg-variant

Genetic Factors and Insulin Secretion

Reduced second phase insulin secretion in carriers of a sulphonylurea receptor gene variant associating with Type II diabetes mellitus

Contact Info

Product

Resources

About