The Correlation Between Zinc-α2-Glycoprotein And Human With Different Glucose Tolerance

PART Ⅰ THE CORRELATION BETWEEN ZINC-a2-GLYCOPROTEIN AND HUMAN WITH INSULIN RESISTANCEObjective To investigate the relationship of circulating Zinc-a2-glycoproteins(ZAG) and adiponectin(ADI)with adiposity and insulin resistance in humans.Method A series of cross-sectional and interventional studies were conducted not only in normal glucose tolerance (NGT,n= 100),impaired glucose tolerance (IGT,n=85)newly diagnosed type 2 diabetes mellitus (nT2DM,n=100) and young women with PCOS and insulin resistance(n=15). Serum ZAG levels were determined with ELISA. The relationship between circulating ZAG and insulin resistance or metabolic parameters was also explored. ZAG mRNA and protein contents were measured by real-time quantitative PCR and western blot analyses.Results Circulating ZAG levels were lower in IGT and nT2DM subjects than in control subjects [(37.14±13.25)mg/L and (48.84±18.74) mg/L vs. (59.36±16.20) mg/L, P<0.05]. Circulating ZAG correlated positively with HDL-C and adiponectin (all P<0.01), and inversely with BMI, WHR, FAT%, DBP, TG, FBG, FIns, HbA1c, HOMA-IR (P<0.05 or P<0.01). On multivariate analysis, ZAG was independently associated with BMI, HOMA-IR, DBP and ADI (P<0.05 or P<0.01). Importantly, ZAG mRNA and protein were decreased in adipose tissue of T2DM patients. Moreover, circulating ZAG levels were lower in young women with PCOS than in healthy young women [(37.84±12.47) mg/L vs. (61.53±17.92)mg/L, P<0.01]. Finally, hyperglycemia or liraglutide administration elevated circulating ZAG levels, whereas insulin at an enough high level seems to act as a ZAG-suppressing hormone.Conclusion We conclude that serum ZAG correlated significantly with adiposity and insulin resistance. Moreover,circulating ZAG was regulated by glycemia, insulinemia or liraglutide.PART Ⅱ EFFICACY OF METFORMIN,DPP-IV INHIBITORS AND SGLT2 INHIBITORS ON NEWLY DIAGNOSED TYPE 2 DIABETES MELLITUS(nT2DM) AND INFLUENCE OF SREUM ZAG LEVELSObjective This 12-week trial assessed the efficacy and safety of initial combination therapy with metformin+sitagliptin vs. sitagliptin or dapagliflozin monotherapies in newly diagnosed type 2 diabetes mellitus. Meanwhile,to effect of dipeptidyl peptidase-Ⅳ (DPP-Ⅳ) inhibition with sitagliptin monotherapy on β-cell function in newly diagnosed type 2 diabetes mellitus. Secondly, to evaluate the effect of three therapeutic regiments on serum ZAG and adiponectin levels in T2DM subjects.Method 313 patients with newly diagnosed T2DM patients were randomly assigned to four groups, the treatment time of 12 weeks. Metformin combined with sitagliptin (metformin group:0.5g, po, bid; sitagliptin:100mg, po, qd, n=68), DPP-IV inhibitor group (sitagliptin: 100mg, po, qd, n=83), SGLT2 inhibitor group (dapagliflozin:10mg, po, qd,n=117), and placebo group(n=45). In addition,25 newly diagnosed T2DM patients were given DPP-IV inhibitors (sitagliptin:100mg, oral, once a day) treatment for 12 weeks.Oral 75g-glucose tolerance test and hyperinsulinemic euglycemie clamp to evaluate the effect of sitagliptin monotherapy on β-cell function in T2DM. Serum ZAG and ADI levels were determined with ELISA.Results At 12 weeks,metformin+sitagliptin demonstrated statistically significant decreases FPG,2hPBG, HbA1c% vs. sitagliptin and dapagliflozin monotherapies,(FPG:-2.06mmol/L vs.-1.08mmol/L vs. -1.22mmol/L, P<0.01; 2hPBG:-3.27mmol/L vs.-2.36mmol/L vs.-2.70mmol/L,P<0.01;HbAlc%:-0.87% vs.-0.36%vs.-0.53%).Proportion of patients achieving an HbAlc%<7% was 41.18% vs.8.43% vs. 17.95%.75g-oral glucose tolerance test shows the area under the curve of glucose(Gg-AUC) were significantly lower [(28.21±2.22) mmol/×min vs. (21.72±1.66) mmol/×min, P<0.01]. Insulin area under curve (INS-AUC) were significantly improved[(78.54±2.31) mU/L × min vs. (82.11±1.67)mU/L × min,P<0.01]. The first phase insulin secretion (Δ I30/Δ G30) were significantly improved[(4.62±2.53) vs. (13.12±6.81), P<0.01]. Hyperinsulinemic euglycemic clamp was show glucose metabolic clearance rate (M) was significantly increased [(5.02±1.70) mg/kg/min vs (6.19±1.63) mg/kg/min,P<0.01]. Insulin sensitive index (M/I) was significantly increased [(0.056±0.020) mg/kg/min × mU/L vs (0.062±0.017)mg/kg/min×mU/L,P<0.05]. Dapagliflozin showed the more weight reductions than metformin+sitagliptin and sitagliptin monotherapies (-2.1kg vs.-0.3kg vs.-0.7kg, P<0.05). At the same time, dapagliflozin can significant increase serum ZAG、ADI levels vs. metformin+sitagliptin and sitagliptin monotherapies [ZAG:(9.91 ±4.66) mg/Lvs. (8.18±7.29) mg/L vs. (5.93±4.60)mg/L, P<0.01; ADI:(4.65±2.18) μg/L vs.(2.48±1.38)μg/Lvs. (2.44±2.38)μg/L,P<0.01].Conclusion Metformin combination with sitagliptin as initial therapy could effectively control the blood glucose levels in Type 2 diabetes mellitus. Dapagliflozin has increasing urinary glucose excretion, decreasing plasma glucose levels and body weight. Dapagliflozin could increase the serum ZAG and ADI levels.PART ⅢASSOCIATION OF SERUM ZAG LEVELS WITH FAT MASSS PERCENTAGE IN NEWLY DIAGNOSED TYPE 2 DIABETES MELLITUSObjective To investigate the association of serum ZAG levels with fat mass percentage.Method A total of 438 newly diagnosed T2DM subjects from the first part and the second part. All the participants of physical examination, blood chemistry tests and serum ZAG was measured with the first, the second part. The data were analyzed using student-t test, ANOVA and logistic regression.Results 438 patients with T2DM(220 women and 218 men;age 53±8 years).A higher serum ZAG and ADI levels were shown in women as compared with those in men [ZAG:(36.25±10.58) mg/L vs. (33.91±12.13)mg/L, P<0.05; ADI:(32.40±9.37)μg/L vs. (24.49±9.78) μg/L,P<0.01]. Serum ZAG levels were decreased as FAT%, BMI, HbAlc, FINS, HOMA-IR by tertiled. Serum ZAG levels were increased as age, ADI, TG, FFA by tertiled. There was no significant difference in FPG, WHR, SBP, DBP, TC, HDL-C, LDL-C,2hINS and 2hPBG. Logistic regression analysis showed that serum ZAG levels were increased 11.1%(OR=1.111,95%CI:1.065-1.159, P<0.01) as age increased by increased one percent after all metabolic markers(such as gender、WHR、 SBP、DBP、lipid profile、HbAlc、FPG and HOMA-IR)were adjusted. The serum ZAG levels were decreased 25.5% and 8.9%(OR=0.740,95%CI: 0.671-0.817 vs. OR=0.908,95%CI:0.869-0.949, P<0.01) as BMI and fat mass percentage increased.Conclusion Serum ZAG levels in newly diagnosed type 2 diabetic patients were associated with age,BMI and fat mass percentage. Serum ZAG levels were increased as age increased and were decreased as BMI and fat mass percentage increased.