The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

Abstract

Aims/hypothesis We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene. Methods We undertook genotyping of 81 healthy young Danish men for rs7903146 of TCF7L2 and carried out various beta cell tests including: 24 h glucose, insulin and glucagon profiles; OGTT; mixed meal test; IVGTT; hyperglycaemic clamp with co-infusion of glucagon-like peptide (GLP)-1 or glucose-dependent insulinotropic polypeptide (GIP); and a euglycaemic-hyperinsulinaemic clamp combined with glucose tracer infusion to study hepatic and peripheral insulin action. Results Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p<0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p<0.003), but not during an IVGTT. This was further supported by reduced late-phase insulinotropic action of GLP-1 (p=0.03) and GIP (p=0.07) during a 7 mmol/l hyperglycaemic clamp. Secretion of GLP-1 and GIP during the mixed meal test was normal. Despite elevated hepatic glucose production, carriers of the T allele Diabetologia (2009) 52:1298-1307 DOI 10.1007/s00125-009-1307-x Electronic supplementary

Translating TCF7L2: from gene to function

“…So rather than directly reducing incretin secretion, TCF7L2 must play a role in the pancreatic insulin secretory response to incretins. Pilgaard et al [9] add to the report by Schafer et al [11] that the insulin secretory response to GLP1, in this study at high physiological concentrations and at mild hyperglycaemia (7 mmol/l), is reduced in normoglycaemic carriers of the T allele at rs7903146. The marked effect of the TCF7L2 variant on the response to incretins contrasts with the minimal effect on the direct response to glucose and suggests a functional beta cell defect rather than, or in addition to, a loss of beta cell mass.…”

“…In contrast, Pilgaard et al report that 24 h glucagon concentration profiles are reduced in carriers of the diabetes rs7903146 risk allele [9]. They also report unpublished data for 580 individuals showing decreased plasma glucagon expression with other TCF7L2 SNPs, but not the established diabetes SNP rs7903146.…”

“…• Decreased beta cell mass Decreased beta cell proliferation following TCF7L2 knockdown [12] Decreased 'maximal' insulin secretion-response to arginine at 28 mmol/l glucose [10] • Impaired insulin processing or release Altered SLC30A8, Munc18-1 and Stx1A expression in mice with Tcf7l2 knockdown [13] Increased proinsulin:insulin ratio in rs7903146 T allele carriers [9,17] Decreased 'maximal' insulin secretion-response to arginine at 28 mmol/l glucose [10] • Impaired GLP1 signalling in beta cells [9,11] Response to GLP1 impaired to greater extent than that to i.v. glucose [10] • Decreased glucagon secretion reducing beta cell insulin secretion [9] Needs replicating…”

“…glucose [10] • Decreased glucagon secretion reducing beta cell insulin secretion [9] Needs replicating…”

“…In this issue of Diabetologia, Pilgaard et al [9] show that T allele carriers have impaired post-meal beta cell responsiveness, i.e. the amount of insulin secreted at a particular glucose concentration is reduced; this is a measure of the beta cell response not just to glucose but also to amino acids and incretins.…”