Association Study Of GLP-1 And Its Receptor Gene Polymorphism And Bone Metabolism Parameters

Part I Effect of oral and intravenous glucose tolerance test on bone turnover markers in adults with normal glucose toleranceObjective: Our aim was to compare the influence of oral and intravenous glucose on bone turnover markers(BTMs) in adults with normal glucose tolerance(NGT).Methods: 75 g oral glucose tolerance test(OGTT) and intravenous glucose tolerance test(IVGTT, 0.3g/Kg) were conducted in 24 subjects with NGT. Blood samples were collected at different time points, then serum levels of bone formation marker procollagen type I N-terminal propeptide(P1NP) and resorption marker C-terminal cross-linking telopeptides of collagen type I(β-CTX) were measured.Results: During OGTT and IVGTT(0-60min), serum P1 NP levels did not change significantly compared with baseline levels,while serum β-CTX levels fell gradually and reached 66.0% and 80.4% of basal value respectively at 60 min. The β-CTX suppression ratios at 15 min, 30 min, 60 min during OGTT were significantly higher than those of IVGTT(13.1% vs. 8.2%,21.8% vs. 14.6%,34.0% vs. 19.6%, respectively, all P<0.05).Conclusion: Our study indicates that OGTT results in greater bone resorption suppression compared with IVGTT, which may be associated with incretin.Part II Postprandial response of bone turnover markers in newly diagnosed type 2 diabetic patientsObjective: To investigate the postprandial response of bone turnover markers in newly diagnosed type 2 diabetic patients.Methods: Forty six male patients with newly diagnosed type 2 diabetes(T2DM) and forty healthy male individuals matched for age were included in the study. All participants underwent an 100 g standardized steamed bread meal test after an overnight fast and serum levels of glucagon-like peptide 1(GLP-1), bone formation marker procollagen type I N-terminal propeptide(P1NP) and resorption marker C-terminal telopeptide of type I collagen(β-CTX) were measured.Results: Fasting serum P1 NP and β-CTX were significantly lower in T2 DM group compared to control group, while serum GLP-1 was similar in two groups. After meal, area under curve(AUC) of GLP-1 in T2 DM group was significantly lower than that of control group. During meal test, serum P1 NP level did not change significantly in both T2 DM and control groups. However, serum β-CTX level in two groups fell gradually and reached a nadir at 120 minutes. At 120 minutes after meal, T2 DM group had a less suppression of β-CTX compared to control group(34.6% vs. 45.2%, P<0.05), and β-CTX suppression ratio was positively correlated with AUC of GLP-1.Conclusions: Postprandial suppression of bone resorption is impaired in newly diagnosed type 2 diabetic patients, which may be associated with impaired secretion of GLP-1.Part III Effect of GLP-1 receptor agonist on bone turnover markers and bone mineral density in obese patients with newly diagnosed type 2 diabetesObjective: To explore the effect of GLP-1 receptor agonist on bone turnover markers(BTMs) and bone mineral density(BMD) in obese patients with newly diagnosed type 2 diabetes(T2DM).Methods: 28 newly diagnosed obese T2 DM patients were enrolled in this study. All patients were treated with exenatide for 24 weeks. Glycosylated hemoglobin A1c(Hb A1c),body weight, BMD, fasting serum concentration of BTMs including procollagen type I N-terminal propeptide(P1NP) and C-terminal cross-linking telopeptides of collagen type I(β-CTX) were assessed at baseline and week 24.Results: At week 24, Hb A1 c improved(- 1.9 ± 0.2 %) and body weight decreased remarkably(- 4.7 ± 0.8 Kg) in all patients. Serum P1 NP and β-CTX increased by 11.0% and 6.9% respectively, but not statistically significant; However, β-CTX/P1 NP ratio decreased significantly by 5.6%. BMD was similar after 24-week therapy.Conclusion: 24-week treatment with exenatide improved glucose control and reduced weight in obese patients with newly diagnosed T2 DM, but had no impact on BTMs or BMD.Part IV Association between GLP-1R gene polymorphism with p BMD and body compostion in Chinese male nuclear familiesObjective: To investigate the relationship between glucagon-like peptide 1 receptor(GLP-1R) gene polymorphism and peak bone mineral density(p BMD), lean mass(LM) and fat mass(FM) in young Chinese men.Methods: 427 male nuclear families were recruited in this study. Six tag SNPs of GLP-1R gene were selected and genotyped. Bone mineral density(BMD) in lumbar spine 1-4, left proximal femur and total hip, fat mass(FM) and lean mass(LM) were measured using dual energy X-ray absorptiometry. The relationship between polymorphism of GLP-1R gene and peak BMD, FM and LM were performed using the quantitative transmission disequilibrium test(QTDT) program and ANCOVA.Results: In the within-family association, QTDT results showed that rs1042044 in GLP-1R gene was associated with LM in young men, while the SNP rs3765467 was associated with FM(P<0.05). All tag SNPs in this gene were not associated with p BMD in young men(P>0.05). The FM and LM were positively correlated with bone mineral density in all sites. The multiple regression analysis showed that LM has a greater effect than FM on BMD, they explained 13.5%~17.3% and 4.8~5.8% of the BMD variance in young men, respectively.Conclusion: Our findings showed that GLP-1R gene polymorphisms were associated with FM and LM in young men, but we failed to find a significant association between GLP-1R genotypes and peak BMD.