Effects Of Sitagliptin And Metformin On GLP-1and Glucagon Of Newly Diagnosed T2DM

Background and ObjectivesIn China, the morbidity of diabetes is high. The prevalence rate in adult is9.7%[1]. United Kingdom Prospective Diabetes Study(UKPDS) had proven that the pancreatic β cells function of diabetic patients has lost50%when first diagnosed, and the function will decrease with the extension of the course.In addition, compared with healthy people, the effect of T2DM patients intestinal incretin hormone reduces, and glucagon secretion increases[4]. Glucagon-like peptide-1(GLP-1), an incretin hormone produced in response to food intake, stimulates insulin secretion as well as insulin biosynthesis, and suppresses postprandial glucagon secretion. GLP-1also delays gastric emptying. Because its effects are glucose-dependent, it does not cause hypoglycemia. Glucagon, secreted by a cell, mainly increases gluconeogenesis and glycogenolysis through liver cells and fat cells. The abnormal responses to glucose and arginine also involve in the pathogenesis of diabetes. Unger et al considered that too much (Glucagon,GC) contributed to the hyperglycemia[7].Sitagliptin, a dipeptidyl peptidase-4(DPP-4) inhibitor, selectively inhibits DPP-4, the enzyme responsible for the degradation of GLP-1, thereby increasing endogenous GLP-1and leading to increased insulin secretion. As first-line drug for T2DM patients, it is well known that metformin can reduce hepatic glucose production and insulin resistance, improve lipid levels, lose weight and protect vascular endothelium. Lately studies have reported that metformin can inhibit the DPP-4activities, improve lipid toxicity. However there are seldom reports if metformin could increases GLP-1and reduces glucagon. Injection of insulin can accelerate the use of glucose, inhibit the production of glucose, promote the synthesis and storage of fat, suppress fat decomposition, promote protein synthesis, resulting in reduced blood glucose. However, in the case of stable blood sugar control, may metformin and insulin affect the GLP-1and glucagon? Compared with sitagliptin, is there anything different? So we cured the newly diagnosed T2DM patients by monotherapy with sitagliptin, metformin or insulin, compared the effects on blood glucose, GLP-1and glucagon of three medicines and explored the new hypoglycemic mechanism.Subjects and Methods1SubjectAccording to T2DM diagnosis standard formulated in1999by world health organization(WHO), we selected120T2DM patients(male78, female42, mean age51.87±10.45years, BMI25.93±3.67kg/m2), who were newly diagnosed and never treated with medicine.2GroupingSitagliptin group(SG):male26, female14, mean age52.34±9.12years old, BMI26.02±3.13kg/m2.Metformin group(MG):male27, female13, mean age51.56±9.68years old, BMI26.54±3.34kg/m2.Insulin group(IG):male24, female16, mean age50.03±9.76years old, BMI25.87±2.25kg/m2.Normal glucose tolerance group(NGTG):male13, female7, mean age51.90±7.23years old, BMI22.44±2.06kg/m2.3Observation itemWe developed diabetes education for patients, and signed the informed consent. We measured the BMI, blood pressure, lipid and HbA1c.We measured insulin at fasting,30minutes,60minutes,120minutes and180minutes, GLP-1and glucagon at fasting and120minutes in OGTT.4Drug dosage SG:Sitagliptin was administered orally as tablets at a dosage of100mg once daily.MG:Metformin was administered orally as tablets at a dosage of500mg twice daily firstly, then adjusted the dose according to the blood glucose, the maximum dose was1700mg daily.IG:Adjusted the insulin dosage according to the blood glucose.If the glucose of some subjects in sitagliptin and metformin-group did not meet the goal, we did not add another medicine, the goal was achieved by diet control and motortherapy.5Treatment time12weeks.6Follow-upRemeasured the observation item after12weeks.7StatisticsStatistic analyses were performed with the SPSS17.0. Measurement data were expressed by mean±sd(x±s); adopt pair T test within group, independent-sample T test among groups. Value were considered statistically significant at P<0.05.Results1the baseline comparisonCompared with the control group, SBP, DBP, blood sugar index, insulin level, GC level, HOMA-IR, TG, TC and LDL-C were higher significantly in T2DM group(all P＜0.05), HOMA-β and GLP-1level were lower in T2DM group(all P<0.05).The base lines among sitagliptin group, metformin group and insulin group had no difference. 2Blood sugar indexAfter treatment, the FPG,2hPG and HbAlc all reduced in three groups (P<0.05). SG:FPG reduced by an average of1.25±1.40mmol/1,2hPG decreased3.12±1.95mmol/1, HbA1cdecresaed0.94±0.71%, the control rate of HbA1c was63%. MG:FPG reduced by an average of1.87±0.66mmol/1,2hPG decreased3.43±1.92mmol/1, HbA1c decreased0.98±0.47%, the control rate of HbA1c was67%. IG:FPG reduced by an average of2.22±1.00mmol/1,2hPG decreased4.04±1.65mmol/1, HbA1c decreased1.49±0.29%, the control rate of HbA1c was84%.3GLP-1and GCAfter treatment, the FGLP-1and2hGLP-1increased in sitagliptin group, metformin group and insulin group(P<0.05). The FGLP-1of sitagliptin group increased by an average of7.74±4.23pmol/1(37.6%), the2hGLP-1increased by an average of9.17±5.43pmol/1(45.4%). The FGLP-1of metformin group increased by an average of3.00±3.38pmol/1(14.4%), the2hGLP-1increased by an average of3.09±2.57pmol/1(14.5%). The FGLP-1of insulin group increased by an average of1.77±3.48pmol/1(8.6%), the2hGLP-1increased by an average of1.67±3.25pmol/1(8.1%). Comparison among groups, sitagliptin group increased the most significant, metformin group second(P<0.05). After the treatment, the FGLP-1and2hGLP-1in sitagliptin group had no difference compared with the NGTG. But the same targets in metformin group and insulin group were lower than the NGTG (P<0.05).After treatment, the FGC and2hGC reduced in sitagliptin group, metformin group and insulin group(P<0.05). The FGC of sitagliptin group decreased by an average of5.85±2.17pmol/1(12.4%), the2hGC decreased by an average of5.48±3.65pmol/1(11.8%); The FGC of metformin group decreased by an average of2.06±4.13pmol/1(4.4%), the2hGC decreased by an average of2.68±3.68pmol/1(5.8%). The FGC of insulin group decreased by an average of3.41±2.41pmol/1(7.1%), the2hGC decreased by an average of3.40±5.84pmol/1(7.2%). Comparison among groups, sitagliptin group decreased the most significant(P<0.05). Compared with the NGTG, the FGC and2hGC of the three groups were higher after the treatment(P<0.05). 4Islet cell function and related indicatorsAfter the treatment, HOMA-IR of sitagliptin group and metformin group reduced(P<0.05). HOMA-β of three groups increased (P＜0.05); comparison between groups, insulin group increased the most significant, metformin group second (P＜0.05). The FIns and2hIns of three groups increased(P<0.05); compared between groups, insulin group increased the most significant, sitagliptin group second (P＜0.05).5BMI, blood pressure, blood fatAfter treatment the BMI of metformin group decreased(P＜0.05); there was no siginificant difference in sitagliptin group and insulin group(P>0.05).After treatment, the SBP of three groups decreased, the DBP of metformin group and insulin group decreased(P＜0.05). Comparison between groups, the SBP and DBP of metformin group decreased more (P＜0.05).After treatment, the TG, TC and LDL-C of sitagliptin group and metformin group decreased (P＜0.05), the TC and LDL-C of insulin group decreased (P＜0.05). Comparison between groups, the TC and LDL-C of metformin group decreased more significant(P＜0.05).Conclusions1. Monotherapy of sitagliptin, metformin or insulin could effectively control the blood sugar and improve β cell function of newly diagnosed T2DM. The effect of insulin was better than sitagliptin and metformin;2. Metformin could increase GLP-1,reduce GC sightly. This might be one of mechanism of metformin reducing blood sugar;3. Sitagliptin and metformin could improve lipid metabolism disorder.