Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and type 2 diabetes susceptibility.

AIMS: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic ß-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to type 2 diabetes in humans. METHODS: Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for type 2 diabetes susceptibility in up to 25 000 people (8148 with type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort. In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis. RESULTS: rs1800497 at the DRD2/ANKK1 locus was associated with a significantly increased risk for type 2 diabetes in women (odds ratio 1.14 (1.06-1.23); P = 4.1*104) but not in men (odds ratio 1.00 (95% CI 0.93-1.07); P = 0.92) or the combined group. Although rs1800497 was not associated with insulin secretion, we did find another single nucleotide polymorphism in this locus, rs6275, to be associated with increased first-phase glucose-stimulated insulin secretion in women (P = 5.5*104) but again not in men (P = 0.34). CONCLUSION: The present data identify DRD2/ANKK1 as a potential sex-specific type 2 diabetes susceptibility gene.

Effects of induced hyperinsulinaemia with and without hyperglycaemia on measures of cardiac vagal control.

AIMS/HYPOTHESIS: We examined the effects of serum insulin levels on vagal control over the heart and tested the hypothesis that higher fasting insulin levels are associated with lower vagal control. We also examined whether experimentally induced increases in insulin by beta cell secretagogues, including glucagon-like peptide-1 (GLP-1), will decrease vagal control. METHODS: Respiration and ECGs were recorded for 130 healthy participants undergoing clamps. Three variables of cardiac vagal effects (the root mean square of successive differences [rMSSD] in the interbeat interval of the heart rate [IBI], heart-rate variability [HRV] caused by peak-valley respiratory sinus arrhythmia [pvRSA], and high-frequency power [HF]) and heart rate (HR) were obtained at seven time points during the clamps, characterised by increasing levels of insulin (achieved by administering insulin plus glucose, glucose only, glucose and GLP-1, and glucose and GLP-1 combined with arginine). RESULTS: Serum insulin level was positively associated with HR at all time points during the clamps except the first-phase hyperglycaemic clamp. Insulin levels were negatively correlated with variables of vagal control, reaching significance for rMSSD and log10HF, but not for pvRSA, during the last four phases of the hyperglycaemic clamp (hyperglycaemic second phase, GLP-1 first and second phases, and arginine). These associations disappeared when adjusted for age, BMI and insulin sensitivity. Administration of the beta cell secretagogues GLP-1 and arginine led to a significant increase in HR, but this was not paired with a significant reduction in HRV measures. CONCLUSION/INTERPRETATION: Experimentally induced hyperinsulinaemia is not correlated with cardiac vagal control or HR when adjusting for age, BMI and insulin sensitivity index. Our findings suggest that exposure to a GLP-1 during hyperglycaemia leads to a small acute increase in HR but not to an acute decrease in cardiac vagal control.

Glucocorticoid receptor gene polymorphisms are associated with reduced first-phase glucose-stimulated insulin secretion and disposition index in women, but not in men.

AIM: Glucocorticoids are efficacious anti-inflammatory agents, but, in susceptible individuals, these drugs may induce glucose intolerance and diabetes by affecting ß-cell function and insulin sensitivity. We assessed whether polymorphisms in the glucocorticoid receptor gene NR3C1 associate with measures of ß-cell function and insulin sensitivity derived from hyperglycaemic clamps in subjects with normal or impaired glucose tolerance. METHODS: A cross-sectional cohort study was conducted in four academic medical centres in the Netherlands and Germany. Four hundred and forty-nine volunteers (188 men; 261 women) were recruited with normal glucose tolerance (n=261) and impaired glucose tolerance (n=188). From 2-h hyperglycaemic clamps, first- and second-phase glucose-stimulated insulin secretion, as well as insulin sensitivity index and disposition index, were calculated. All participants were genotyped for the functional NR3C1 polymorphisms N363S (rs6195), BclI (rs41423247), ER22/23EK (rs6189/6190), 9ß A/G (rs6198) and ThtIIII (rs10052957). Associations between these polymorphisms and ß-cell function parameters were assessed. RESULTS: In women, but not in men, the N363S polymorphism was associated with reduced disposition index (P=1.06 10(-4) ). Also only in women, the ER22/23EK polymorphism was associated with reduced first-phase glucose-stimulated insulin secretion (P=0.011) and disposition index (P=0.003). The other single-nucleotide polymorphisms were not associated with ß-cell function. Finally, none of the polymorphisms was related to insulin sensitivity. CONCLUSION: The N363S and ER22/23EK polymorphisms of the NR3C1 gene are negatively associated with parameters of ß-cell function in women, but not in men.

The heritability of beta cell function parameters in a mixed meal test design.

AIMS/HYPOTHESIS: We estimated the heritability of individual differences in beta cell function after a mixed meal test designed to assess a wide range of classical and model-derived beta cell function parameters. METHODS: A total of 183 healthy participants (77 men), recruited from the Netherlands Twin Register, took part in a 4 h protocol, which included a mixed meal test. Participants were Dutch twin pairs and their siblings, aged 20 to 49 years. All members within a family were of the same sex. Insulin sensitivity, insulinogenic index, insulin response and postprandial glycaemia were assessed, as well as model-derived parameters of beta cell function, in particular beta cell glucose sensitivity and insulin secretion rates. Genetic modelling provided the heritability of all traits. Multivariate genetic analyses were performed to test for overlap in the genetic factors influencing beta cell function, waist circumference and insulin sensitivity. RESULTS: Significant heritabilities were found for insulinogenic index (63%), beta cell glucose sensitivity (50%), insulin secretion during the first 2 h postprandial (42-47%) and postprandial glycaemia (43-52%). Genetic factors influencing beta cell glucose sensitivity and insulin secretion during the first 30 postprandial min showed only negligible overlap with the genetic factors that influence waist circumference and insulin sensitivity. CONCLUSIONS/INTERPRETATION: The highest heritability for postprandial beta cell function was found for the insulinogenic index, but the most specific indices of heritability of beta cell function appeared to be beta cell glucose sensitivity and the insulin secretion rate during the first 30 min after a mixed meal.

Genetic influences on the insulin response of the beta cell to different secretagogues.

AIMS/HYPOTHESIS: The aim of the present study was to estimate the heritability of the beta cell insulin response to glucose and to glucose combined with glucagon-like peptide-1 (GLP-1) or with GLP-1 plus arginine. METHODS: This was a twin-family study that included 54 families from the Netherlands Twin Register. The participants were healthy twin pairs and their siblings of the same sex, aged 20 to 50 years. Insulin response of the beta cell was assessed by a modified hyperglycaemic clamp with additional GLP-1 and arginine. Insulin sensitivity index (ISI) was assessed by the euglycaemic-hyperinsulinaemic clamp. Multivariate structural equation modelling was used to obtain heritabilities and the genetic factors underlying individual differences in BMI, ISI and secretory responses of the beta cell. RESULTS: The heritability of insulin levels in response to glucose was 52% and 77% for the first and second phase, respectively, 53% in response to glucose + GLP-1 and 80% in response to an additional arginine bolus. Insulin responses to the administration of glucose, glucose + GLP-1 and glucose + GLP-1 + arginine were highly correlated (0.62< r <0.79). Heritability of BMI and ISI was 74% and 60% respectively. The genetic factors that influenced BMI and ISI explained about half of the heritability of insulin levels in response to the three secretagogues. The other half was due to genetic factors specific to the beta cell. CONCLUSIONS/INTERPRETATION: In healthy adults, genetic factors explain most of the individual differences in the secretory capacity of the beta cell. These genetic influences are partly independent from the genes that influence BMI and ISI.