题名：High heritability and genetic correlation of intravenous glucose- and tolbutamide-induced insulin secretion among non-diabetic family members of type 2 diabetic patients.
作者：GJESING AP; HORNBAK M; ALLIN KH; EKSTROM CT; URHAMMER SA; EIBERG H; PEDERSEN O; HANSEN T;
来源：Diabetologia. 2014 Mar 7. [ IF= 6.49 ] ]
摘要：AIMS/HYPOTHESIS: The aim of this study was to estimate the heritability of
quantitative measures of glucose regulation obtained from a tolbutamide-modified
frequently sampled IVGTT (t-FSIGT) and to correlate the heritability of the
glucose-stimulated beta cell response to the tolbutamide-induced beta cell
response. In addition, single nucleotide polymorphisms (SNPs) having an exclusive
effect on either glucose- or tolbutamide-stimulated insulin release were
identified. METHODS: Two hundred and eighty-four non-diabetic family members of
patients with type 2 diabetes underwent a t-FSIGT with intravenous injection of
glucose at t = 0 min and tolbutamide at t = 20 min. Measurements of plasma
glucose, serum insulin and serum C-peptide were taken at 33 time points from
fasting to 180 min. Insulin secretion rate, acute insulin response (AIR),
disposition index (DI) after glucose and disposition index after tolbutamide
(DIT), insulin sensitivity (SI), glucose effectiveness (SG) and beta cell
responsiveness to glucose were calculated. A polygenic variance component model
was used to estimate heritability, genetic correlations and associations.
RESULTS: We found high heritabilities for acute insulin secretion subsequent to
glucose stimulation (AIRglucose h 2 +/- SE: 0.88 +/- 0.14), but these were
slightly lower after tolbutamide (AIRtolbutamide h 2 +/- SE: 0.69 +/- 0.14). We
also estimated the heritabilities for SI (h 2 +/- SE: 0.26 +/- 0.12), SG (h 2 +/-
SE: 0.47 +/- 0.13), DI (h 2 +/- SE: 0.56 +/- 0.14), DIT (h 2 +/- SE: 0.49 +/-
0.14) and beta cell responsiveness to glucose (h 2 +/- SE: 0.66 +/- 0.12).
Additionally, strong genetic correlations were found between measures of beta
cell response after glucose and tolbutamide stimulation, with correlation
coefficients ranging from 0.77 to 0.88. Furthermore, we identified five SNPs with
an exclusive effect on either glucose-stimulated (rs5215, rs1111875, rs11920090)
or tolbutamide-stimulated (rs10946398, rs864745) insulin secretion.
CONCLUSIONS/INTERPRETATION: Our data demonstrate that both glucose- and
tolbutamide-induced insulin secretions are highly heritable traits, which are
largely under the control of the same genes.