Effects of GCK, GCKR, G6PC2 and MTNR1B variants on glucose metabolism and insulin secretion.
BACKGROUND
Single 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.


RESULTS
SNPs 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 = 0.0003-2.0x10(-8)). GCK rs1799884 and G6PC2 rs16856187 showed association to HOMA-beta, insulinogenic index and both first- and second-phases insulin secretion (p = 0.0030-0.0396). MTNR1B rs10830963 was associated to HOMA-beta, 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 = 1.7x10(-13) and 0.0009, respectively), as well as lower HOMA-beta, insulinogenic index and both first- and second-phases insulin secretion (p = 0.0321-1.1x10(-7)).


CONCLUSIONS
We 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.
Hu
Cheng
C
Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Zhang
Rong
R
Wang
Congrong
C
Yu
Weihui
W
Lu
Jingyi
J
Ma
Xiaojing
X
Wang
Jie
J
Jiang
Feng
F
Tang
Shanshan
S
Bao
Yuqian
Y
Xiang
Kunsan
K
Jia
Weiping
W
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000483:Alleles; D044466:Asian People / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics; D005260:Female; D005838:Genotype; D000081410:Germinal Center Kinases; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D044094:Receptors, Melatonin / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; C485100:GCKR protein, human; D000081410:Germinal Center Kinases; D007328:Insulin; D044094:Receptors, Melatonin; D017346:Protein Serine-Threonine Kinases; D005952:Glucose-6-Phosphatase; C492194:G6PC2 protein, human; D005947:Glucose