TCF7L2 And SLC30A8 Gene Polymorphisms Associated With Type 2 Diabetes

THE FIRST CHAPTER OF PARTⅠPANCREATICβ-CELL FUNCTION IN FIRST-DEGREE RELATIVES WITH A FAMILY HISTORY OF TYPE 2 DIABETESObjective To evaluate pancreaticβ-cell function in the first-degree relatives with different glucose tolerance of patients with type 2 diabetes (T2DM) in the Chinese population.Methods First-degree relatives of T2DM patients without a history of blood glucose abnormalities and their spouses, who did not have a family history of diabetes, underwent a 75-g oral glucose tolerance test (OGTT). Based upon the OGTT results, these two groups were further divided into three groups , including groups with normal glucose tolerance (NGT), impaired glucose regulation (IGR), and T2DM. Insulin resistance (IR) was evaluated using the homeostasis model assessment-IR (Homa-IR) and the insulin action index (IAI). Basal, first-phase, and post-glucose loadβ-cell function indices were measured by DI1 (Homa-β/Homa-IR), DI2 (△I30/△G30/oma-IR), and DI3 (MBCI×IAI).Results (1)Among the first-degree relatives and their spouses, the Homa-IR increased was highest in the T2DM group and lowest in the NGT group. However, the Homa-β, DI1, DI2, DI3, and IAI decreased progressively in these groups with statistical significance (P<0.01 or 0.05). (2)There were no differences in Homa-IR and IAI between the corresponding glucose tolerance subgroups of the first-degree relatives and their spouses.(3)DI1 and DI2 values of the NGT group of first-degree relatives (FNGT) were significantly lower than those of the spouse NGT (SNGT) group (3.98±0.43 vs 4.17±0.42 and 1.54±0.86 vs 1.67±0.84, P<0.05, respectively). DI1 and DI2 of the IGR group of first degree relatives (FIGR) were significantly lower than those of the spouse IGR (SIGR) group, and MBCI and DI3 values for the T2DM group of first-degree relatives (FT2DM) were significantly lower than those of the spouse T2DM (ST2DM) group.Conclusions Defects in pancreaticβ-cell function exist in the first-degree relatives, who have different glucose tolerance status, of T2DM patients. These defects are more profound when compared to their spouses in corresponding glucose tolerance subgroups.however ,there is no evident IR in the first-degree relatives with NGT. It suggests that the pancreaticβ-cell dysfunction which is related to genetic factor may be the predominant initiating factor in T2DM. THE SECOND CHAPTER OF PARTⅠDYSFUNCTION OF ISLETβ-CELL IN NEWLY DIAGNOSED DIABETIC PATIENTS IN TYPE 2 DIABETES FAMILIESObjective To investigate the dysfunction of isletβ-cell and insulin resistance in newly diagnosed type 2 diabetic patients with family history of type 2 diabetes and the role ofβ-cell function defect in worsening glucose tolerance.Methods 158 newly diagnosed type 2 diabetic patients in type 2 diabetes (T2DM) families , and their 62 spouses with normal glucose tolerance (NC group) who had no diabetes families underwent an oral glucose tolerance test (OGTT) and insulin release test. According to the level of fasting plama glucose , the subjects of T2DM were divided into 3 subgroups: DM1(FPG<6.1mmol/L),DM2(6.1≤FPG<7.8mmol/L)and DM3 group(FPG≥7.8mmol/L). Homeostasis model assessment of insulin resistance(Homa-IR) and insulin action index(IAI) were used to estimate insulin sensitivity. Three insulin release indices (Homa-β,△30/△G30: the ratio of incremental glucose and insulin 30min after glucose intake, and MBCI:modified beta-cell function index) and their correponding disposition indices (DI1= Homa-β/Homa-IR, DI2=△I30/△G 30/ Homa-IR, DI3=MBCI×IAI) were used to evaluate isletβ-cell function .Results (1) With increasing FPG , form DM1 through DM2 to DM3, the Homa-IR progressively increased,△I30/△G30, MBCI, DI1, DI2, DI3, and IAI progressively decreased(all P<0.01or 0.05) in newly diagnosed T2DM. Compared with the reduced insulin sensitivity, isletβ-cell function declined obviously.(2) In NC group, the level of FPG was mainly determined by Homa-IR.However, Homa-βwhich can explain the FPG change up to 90% in DM3 group was a more important contributor than Homa-IR for FPG in subgroups of newly diagnosed diabetes .Conclusion Both decreased insulin sensitivity and impairedβ-cell function are associated with increased glucose level in newly diagnosed diabetes.Furthermore ,β-cell function declines more obviously than insulin sensitivity.It indicates thatβ-cell function defect may be play more important role in the development and progression of type 2 diabetes. THE FIRST CHAPTER OF PARTⅡASSOCIATION OF POLYMORPHISMS IN TRANSCRIPTION FACTER 7-LIKE 2 (TCF7L2) GENE WITH TYPE 2 DIABETES IN CHINESE HAN POPULATIONObjective To study an association between TCF7L2 polymorphisms and T2DM in the Chinese Han Population,and to investigate the involvement of TCF7L2 in the etiology of type 2 diabetes (T2DM).Methods Two polymorphisms (rs7903146C/T and rs12255372G/T) of TCF7L2 gene were genotyped, in 449 patients with type 2 diabetes (T2DM group) and 303 Normal controls (NC group), using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Waist circumference,body mass index (BMI),plasma glucose, serum insulin and lipid profile, high-sensitivity C-reactive protein (hsCRP) and non-esterified fatty acid (NEFA) were measured. Homa-IR and Homa-βwere analyzed to estimate insulin resistance andβ-cell function.Results⑴In T2DM group,T allele frequency (χ2=14.33,P=1.2×10-3) and CT/TT genotypes frequencies (χ2=13.25,P=0.001) of rs7903146C/T was significantly higher than that in NC group. Logistic regression analysis showed the CT/TT genotypes might be a risk factor of type 2 diabetes with OR=2.25(95%CI=1.39-3.62 , P=0.001) and associated with the decrease of insulin secretion.⑵No significant association, for rs12255372G/T, was observed on its alleles and genotypes with T2DM.Conclusion These results indicate that TCF7L2 might be one of the candidates for conferring susceptibility to T2DM in the Chinese Han Population. THE SECOND CHAPTER OF PARTⅡASSOCIATION OF POLYMORPHISMS IN SLC30A8(SOLUTE CARRIER FAMILY30,MEMBER8) GENE WITH TYPE 2 DIABETES IN CHINESE HAN POPULATIONObjective An association between common variants of rs132666-34C/T in SLC30A8 (solute carrier family30, member8) gene and type 2 diabetes using the whole genome-wide association study has been reported in European and American Populations. To further investigate the involvement of SLC30A8 in the etiology of type 2 diabetes (T2DM), an association study between the six TagSNPS (rs11989843A/G,rs13270550C/T,rs7007057,rs10955804A/G,rs13266634C/T and rs3802177C/T)of SLC30A8 gene and T2DM was performed in the Chinese Han Population.Methods (1)The six TagSNPS of SLC30A8 gene were genotyped, in 454 patients with type 2 diabetes (T2DM group) and 311 normal controls (NC group), by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Waist circumference,body mass index (BMI) , plasma glucose, serum insulin and lipid profile, high-sensitivity C-reactive protein (hsCRP) and non-esterified fatty acid (NEFA) were measured. Homa-IR and Homa-βwere analyzed to estimate insulin resistance andβ-cell function.Results⑴In T2DM group,the frequencies of C allele (χ2=8.29,P=0.004) and CC genotype of rs13266634C/T were significantly higher than that in NC group (χ2=9.38,P=0.009). The C-allele of rs13266634C/T significantly increased T2DM risk with an allelic odd ratio (OR) of 1.36(OR=1.36,95%CI=1.11-1.67);Compared with non-carriers, heterozy- gous and homozygous carriers of C allele might be risk factors of type 2 diabetes with OR=1.55(95%CI=1.07-2.25,χ2=5.42,P=0.02)and 1.75(95%CI=1.17-2.61,χ2=7.38,P=0.006),respectively; The genotypes of CT and CC were associated with decreased insulin secretion but not increased insulin resistance. ( 2 ) No significant associations, for rs11989843A/G,rs13270550C/T,rs7007057A/G,rs10955804A/G,and rs3802177C/T were observed on its alleles and genotypes with T2DM.Conclusion These results indicated that SLC30A8 might be one of the candidates for conferring susceptibility to T2DM in the Chinese Han Population.