Abstract
BackgroundSingle nucleotide polymorphisms (SNPs) from GCK, GCKR, G6PC2 and MTNR1B were found to modulate the fasting glucose levels. The current study aimed to replicate this association in the Chinese population and further analyze their effects on biphasic insulin secretion.Methods/Principal FindingsSNPs from GCK, GCKR, G6PC2 and MTNR1B were genotyped in the Shanghai Chinese, including 3,410 type 2 diabetes patients and 3,412 controls. The controls were extensively phenotyped for the traits related to glucose metabolism and insulin secretion. We replicated the association between GCK rs1799884, G6PC2 rs16856187 and MTNR1B rs10830963 and fasting glucose in our samples (p = 0.0003∼2.0×10−8). GCK rs1799884 and G6PC2 rs16856187 showed association to HOMA-β, insulinogenic index and both first- and second-phases insulin secretion (p = 0.0030∼0.0396). MTNR1B rs10830963 was associated to HOMA-β, insulinogenic index and first-phase insulin secretion (p = 0.0102∼0.0426), but not second-phase insulin secretion (p = 0.9933). Combined effect analyses showed individuals carrying more risk allele for high fasting glucose tended to have a higher glucose levels at both fasting and 2 h during OGTTs (p = 1.7×10−13 and 0.0009, respectively), as well as lower HOMA-β, insulinogenic index and both first- and second-phases insulin secretion (p = 0.0321∼1.1×10−7).Conclusions/SignificanceWe showed that SNPs from GCK, G6PC2 and MTNR1B modulated the fasting glucose levels in the normoglycaemic population while SNPs from G6PC2 and GCKR was associated with type 2 diabetes. Moreover, we found GCK and G6PC2 genetic variants were associated to both first- and second-phases insulin secretion while MTNR1B genetic variant was associated with first-phase insulin secretion, but not second-phase insulin secretion.
Highlights
Fasting glucose plays a central role in the pathogenesis of diabetes and its complications [1,2]
Conclusions/Significance: We showed that SNPs from GCK, glucose-6-phosphatase catalytic subunit 2 (G6PC2) and melatonin receptor 1B (MTNR1B) modulated the fasting glucose levels in the normoglycaemic population while SNPs from G6PC2 and glucokinase regulatory protein (GCKR) was associated with type 2 diabetes
No interaction effect was detected between GCK, GCKR and G6PC2 SNPs
Summary
Fasting glucose plays a central role in the pathogenesis of diabetes and its complications [1,2]. These genes were identified originally from the European descent populations, replication studies in the Chinese populations confirmed some of their effects on the traits related to glucose metabolism. Two studies, focused on GCK and GCKR, were performed in other Chinese populations They found GCK rs1799884 was associated with high fasting glucose while GCKR rs780094 was associated with high triglyceride level and type 2 diabetes [9,10]. We identified the SNP rs16856187 was associated to the fasting glucose levels as well as type 2 diabetes risks in the Chinese [12]. These genes were linked to beta cell function in various populations mainly because of their association to HOMA-b. To investigate the effects of GCK, GCKR, G6PC2 and MTNR1B variants on biphasic insulin secretion, we tested the individual as well as combined effects of these variants on the traits related to glucose metabolism, especially multiple measurements on insulin secretion
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