Heritability of model-derived parameters of beta cell secretion during intravenous and oral glucose tolerance tests: a study of twins

Abstract

Aims/hypothesis: The genetic architecture of model-derived parameters of beta cell function has never been assessed. Therefore, we estimated heritability (h 2 ) for model-derived phenotypes of insulin secretion in twins. Methods: Thirty-three monozygotic (MZ) and 23 dizygotic (DZ) twin pairs from the Finnish Twin Cohort Study underwent an OGTT (plasma glucose/C-peptide at 0, 30, 60, 90 and 120 min). A subset of the twin pairs (21 MZ/20 DZ) also underwent an IVGTT (frequent sampling of plasma glucose/insulin from 0 to 60 min) followed by a 160-min euglycaemic-hyperinsulinaemic clamp (45 mU · min −1 ·m −2 ). Mathematical modelling was applied to the IVGTT and the OGTT to assess first-phase (readily releasable insulin [RRI]) and second-phase (sigma) secretion (IVGTT), and a global index of beta cell performance (OGTT beta index). Intraclass correlation coefficients and genetic and non-genetic components for trait variances were computed to assess the h 2 of model-derived parameters. Results: The intraclass correlation coefficients in MZ twins were 0.78 for RRI, 0.67 for sigma and 0.57 for OGTT beta index. In DZ twins the correlation coefficients were 0.23, 0.32 and 0.42, respectively. Using the most parsimonious model for each trait, the h 2 -the proportion of variance accounted for by genetic factors -was 76% (95% CI: 53-88%) for RRI, 28% (34-80%) for sigma and 53% (26-72%) for OGTT beta index. Conclusions/ interpretation: Our findings demonstrate that model-derived parameters of insulin secretion have a substantial genetic component and may be used in the search for genetic determinants of beta cell function in humans.

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

“…The heritability of first-and second-phase insulin secretion in response to glucose was 52% and 77% respectively. For the first phase our results fit neatly in the 35% to 76% range of heritability estimates previously reported using the IVGTT test [6,11,[15][16][17]. However, previous heritability estimates (28% and 58%) of second-phase insulin secretion in response to IVGTT were considerably lower [11,17] than those found in our hyperglycaemic clamp.…”

“…For the first phase our results fit neatly in the 35% to 76% range of heritability estimates previously reported using the IVGTT test [6,11,[15][16][17]. However, previous heritability estimates (28% and 58%) of second-phase insulin secretion in response to IVGTT were considerably lower [11,17] than those found in our hyperglycaemic clamp. This may reflect the greater precision inherent in the clamp method in comparison to the IVGTT, but may also be due to the different stimulation of the beta cell during the second phase of both tests (maintaining 10 mmol/l glucose vs decreasing glucose level).…”

“…In twin studies, the genetic contribution to beta cell function has been tested mostly by examining surrogate measurements of insulin secretion derived from fasting blood levels or in response to oral glucose. In five studies using IVGTT, heritability estimates of the acute insulin response to glucose ranged from 35% to 76% [6,11,[15][16][17]. The heritability of the second-phase insulin response to glucose in an IVGTT has been investigated in two of these studies only [11,17] and was estimated to be 28% and 58%.…”

Role of Reduced β-Cell Mass Versus Impaired β-Cell Function in the Pathogenesis of Type 2 Diabetes

“…Several lines of evidence, including twin studies (67), support the notion that the phenotype of β-cell functional mass is determined by genetic factors to quite a large extent. Over the last 6 years, genetic variability at >60 genetic loci has been firmly linked to type 2 diabetes risk (68).…”

Bivariate genetic modelling of the response to an oral glucose tolerance challenge: A gene × environment interaction approach

“…They have demonstrated significant heritable influence on glucose and insulin values, and on insulin resistance and beta cell function calculated from fasting levels or OGTT values [5][6][7][8][9][10][11][12][13][14][15], but there is no clear consensus on the degree to which genes explain the variance of fasting and 2 h glucose and insulin levels. Most studies have focused on the OGTT and have reported heritabilities of fasting and 2 h glucose and insulin ranging from 12% to 62% (see Electronic Supplementary Material [ESM] Table 1).…”