No detectable effect of a type 2 diabetes-associated TCF7L2 genotype on the incretin effect

Abstract

The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes (T2D), possibly by modulation of incretin action. In this study, we evaluated the effect of the TCF7L2 rs7903146 T allele on the incretin effect and other glucometabolic parameters in normal glucose tolerant individuals (NGT) and participants with T2D. The rs7903146 variant was genotyped in cohorts of 61 NGT individuals (23 were heterozygous (CT) or homozygous (TT) T allele carriers) and 43 participants with T2D (20 with CT/TT). Participants were previously examined by an oral glucose tolerance test (OGTT) and a subsequent isoglycemic intravenous glucose infusion (IIGI). The incretin effect was assessed by quantification of the difference in integrated beta cell secretory responses during an OGTT and IIGI. Glucose and hormonal levels were measured during experimental days, and from these, indices of beta cell function and insulin sensitivity were calculated. No genotype-specific differences in the incretin effect were observed in the NGT group (P = 0.70) or the T2D group (P = 0.68). NGT T allele carriers displayed diminished glucose-dependent insulinotropic polypeptide response during OGTT (P = 0.01) while T allele carriers with T2D were characterized by lower C-peptide AUC after OGTT (P = 0.04) and elevated glucose AUC after OGTT (P = 0.04). In conclusion, our findings do not exclude that this specific TCF7L2 variant increases the risk of developing T2D via diminished incretin effect, but genotype-related defects were not detectable in these cohorts.

Association between Genotype and the Glycemic Response to an Oral Glucose Tolerance Test: A Systematic Review

“…A total of 49 eligible reports investigated the association between SNPs and the gAUC after an OGTT in 39 different cohorts, i.e., Quebec Family Study [ 12 , 13 , 14 , 15 , 16 , 17 ], Amish Family Diabetes Study [ 18 , 19 ], Ely Study [ 20 ], Tübingen Family Study (TÜF) [ 21 ], European Atherosclerosis Research Study (EARS II) [ 22 , 23 ], Sapphire Study [ 24 ], Metabolic Intervention Cohort Kiel (MICK) [ 25 , 26 ], European Network on Functional Genomics of Type 2 Diabetes (EUGENE2) [ 27 , 28 ], Metabolic Syndrome in Men (METSIM) [ 28 ], Metabolic Syndrome Berlin Potsdam Study (MESYBEPO) [ 29 ], Lifestyle Intervention in a General Population for Prevention of Ischaemic Heart Disease (Inter99) [ 30 , 31 ], Berlin Ernährung Geschwister Study (BErG-Study) [ 32 ], and further 27 cohorts without a specific study name [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ...…”

“…In most studies, a standardized OGTT with 75 g glucose was conducted. In one study, a glucose amount of either 50 or 75 g was used without any justification [ 42 ]. While in most of the reports, the duration of the OGTT lasted 120 min [ 20 , 21 , 22 , 23 , 24 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 36 , 37 , 38 , 39 , 41 , 43 , 44 , 45 , 47 , 48 , 50 , 52 , 53 , 54 , 56 , 57 , 58 , 59 , 60 ] or 180 min [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 35 , 40 , 42 , 49 , 51 , 55 ], in either two reports the OGTT was performed over 240 min [ 25 , 26 ] or 300 min [ 34 , 46 ].…”

“…In total, the association between SNPs and gAUC after an OGTT was assessed for 13 genes and 53 different SNPs. The most frequently examined genes included transcription factor 7 like 2 ( TCF7L2 ) with 15 eligible reports ( Table 1 ) [ 12 , 13 , 18 , 20 , 21 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 58 , 60 ], followed by peroxisome proliferator-activated receptor gamma ( PPARγ ) with ten reports ( Table 2 ) [ 14 , 15 , 22 , 24 , 25 , 37 , 38 , 39 , 40 , 59 ], and potassium inwardly rectifying channel subfamily J member 11 ( KCNJ11 ) with six reports ( Table 3 ) [ 12 , 13 , 33 , 34 , 35 , 36 ]. Furthermore, the following gene loci have been investigated in three to five reports: adiponectin ( ADIPOQ ) [ 16 , 24 , 26 ], CDK5 regulatory subunit-associated protein 1-like 1 ( CDKAL1 ) [ 12 , 13 , 21 , 28 ], cyclin-dependent kinase inhibitor-2A/B ( CDKN2A/2B ) [ 12 , 13 ,…”

“…An association between the TCF7L2 gene locus and gAUC after an OGTT was examined in 15 different cohorts ( Table 1 ) [ 12 , 13 , 18 , 20 , 21 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 58 , 60 ]. Most of the 17 SNPs within the TCF7L2 gene locus were investigated in one (13 SNPs) or two cohorts (2 SNPs), respectively.…”

Pharmacogenetics of new classes of antidiabetic drugs

“…It has been associated with proliferation and function of beta cells, insulin synthesis and secretion, and modulation of incretin action [67]. Interestingly, the rs7903146 T allele has been linked to impaired incretin-stimulated insulin secretion in some [68][69][70], but not all studies [71]. The impact of the rs7903146 C>T variant on the response to treatment with linagliptin was evaluated in 961 patients with T2D followed for two years [72].…”