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Objective The imbalance of glucagon secretion plays an important role in the development of diabetes. The newly discovered ACE2/Ang(1-7)/Mas pathway is an vital branch of the RAS system and has regulatory effects on islet function, but its effect on glucagon secretion is still unknown. The article aimed to investigate the effect and possible mechanisms of AVE0991, a Mas receptor agonist on glucagon secretion of diabetic db/db mice. Methods A tolal of 30 db/db mice were randomized to AVE group and model group (n=15), and their age-matched nondiabetic db/m mice were selected as the normal group (n=15). The mice in AVE group were treated with AVE0991 20mg/kg/d and those in model group were treated with placebo via gavage for 6 weeks. The metabolic indicators were measured every week. After 6 weeks of treatment, intraperitoneal glucose tolerance test (IPGTT) and islet perifusion were performed to evaluate glucagon release kinetics in vivo and vitro. Double-label immunofluoresence assay was adoppted to assess the content of α and β cells. Moreover, qRT-PCR and western blot were employed to detect the GCK expression in islets. Results The fasting blood sugar[(19.1±0.8)mmol/L] and glucose tolerance [(14.1±0.5) mU/L]of AVE group were significantly lower than those of the model group[(25.3±3.0)mmol/L,(17.3±1.8)mU/L](P＜0.05) and still higher than those of normal group[(6.3±0.5)mmol/L,(5.7±0.3)mU/L](P＜0.05). At the 30, 60, and 120 min after IPGTT, the blood glucose level and glucagon level in AVE group were lower than model group, but still higher than the normal group (P<0.05). During low glucose perfusion, the glucagon secretion level of the islets of normal group [(20.6±0.5 pmol/L)] was lower than that of model group [(29.1±0.7) pmol/L)] and AVE group [(27.6±0.8) Pmol/L], and the difference was statistically significant (P<0.05). During high glucose perfusion, there was a statistically significant difference in glucagon level between AVE group and model group at 30 and 60 min(P<0.05). Semi-quantitative analysis showed that the islet α-cell content of model group [(3.3±0.7) mg] was significantly higher than that of normal group [(1.2±0.3) mg] (P<0.05), and the β cell content [(2.4±0.6) mg] was significantly lower than that of normal group [(4.8±0.3) mg] (P<0.05); While compared with the model group, the islet α-cell content [(1.8±0.4) mg] decreased significantly (P<0.05) and the β-cell content [(4.2±0.5) mg] increased significantly in AVE group (P<0.05). The expression levels of GCK mRNA and protein in model group were lower than those in normal group (P<0.05). Conclusion Activation of Mas receptors can improve glucose metabolism by reducing the secretion of glucagon after glucose load in db/db diabetic mice. The mechanism may be related to the decrease of islet α cell content and the increase of islet GCK expression.
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[Summary] Drug naive, newly diagnosed type 2 diabetic subjects were randomized to Saxagliptin/Metformin / Rosiglitazone(Triple Therapy, n=23) or insulin 70 30 mix group(Intensive Insulin Therapy) (n=21) for 24 weeks. How did the 2 therapies influence fasting blood glucose, fasting insulin, C-peptide, and glucagon levels and the change of body weight were compared. This study was aimed to explore the comparative glycemic efficacy and impact on α/ β-cell function of two different antidiabetic therapies, triple combination therapy using saxagliptin/metformin/ rosiglitazone and intensive insulin therapy, for newly diagnosed type 2 diabetes mellitus. The results indicated that fasting blood glucose, HbA1C , insulin resistance index 2(HOMA 2-IR), glucagon and body mass index level were significantly decreased, and insulin secretion index 2 ( HOMA 2-% β) was increased significantly( P <0. 05) in triple therapy group, and the decreasing extent of HOMA 2-IR, glucagon, and body mass index were significantly greater than that in the intensive insulin group(P<0. 05). Triple therapy group has a stronger effect of reducing insulin resistance, as well as on inhibiting glucagon and promoting weight loss.
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Brief discussion on exchange roles of islet α-cell and β-cell in the pathogenesis of type 2 diabetes,and the possibility of HbA1C as a new marker for assessing both pancreatic islet α-cell and β-cell function,so as to provide a new perspective for clinical diagnosis and treatment of type 2 diabetes.
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Objective To evaluate the functions of pancreatic islet α-cells and β-cells in different disease courses of type 2 diabetes mellitus.Methods Two hundred and eighty three patients with type 2 diabetes mellitus were divided into 4 groups according to their disease courses:group A (course of disease ≤1 years),group B (1 years ＜ course ≤ 5 years),group C (5 years ＜ course ≤ 10 years) and group D (course ＞ 10 years).Oral glucose tolerance test (OGTT),insulin releasing test and glucagon releasing test were performed to observe the differences of glucagon,glucagon/insulin,ratio of insulin increment/glucose increment 30 min after glucose-load (△I30/△G30),area under curve (AUC) of insulin in receiver operational characteristic (ROC) curve of insulin (AUCI) and glucagon among 4 groups and the correlation analysis was performed between glucagon and other indicators.Results (1) Glucagon,glucagon/insulin and AUC of glucagon increased significantly with the prolonged course of disease (P ＜0.05),0、30、60、120、180 min of group A were (71 ± 20)、(106 ± 36)、(143 ± 54)、(133 ± 68) 和 (87 ± 55) ng/L respectively,glucagon increased significantly with the prolonged course of disease,0、30、60、120、180 min of group D (80 ±19)、(125 ± 36)、(167 ± 47)、(178 ± 64)、(129 ± 65) ng/L respectively.(2) There were no significant differences in homeostasis nodel assessment for insulin resistance index (HOMA-IR) and insulin sensitive index (ISI) among 4 groups (P ＞0.05); compared to group A,HOMA of β-cell function (HOMA-β),△I30/△G30,AUCI in groups B,C and D were significantly lower (F =3.75,3.77 and 3.07 respectively,all P ＜ 0.05).(3) Multiple stepwise regression analysis showed that glucagon was positively correlated with FPG and AUC of glucose (AUCG) (t =6.23 and 3.41,all P ＜ 0.05),and negatively correlated with AUCI/AUCG (t =-2.13,P ＜ 0.05).Conclusions In order to reach the blood glucose control target,in the early stage of diabetes attentions should be given to regulation of glucagon while protect the β-cell function.
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Based on the result of oral 75 g glucose tolerance test (OGTT),55 pregnant women during the second trimester (gestational age 24-28 weeks) were selected and divided into gestational diabetes mellitus (GDM)group (n =25) and normal glucose tolerance (NGT) group (n =30).Women with GDM were older than those in NGT group.Blood glucose and insulin levels during the OGTT,incremental area under the glucose curve (AUCGLU) and insulin curve (AUCINs) during the OGTT,and basic insulin secretion index (HOMA-β) in the GDM group were higher compared with those in NGT group (P＜0.05).However,in GDM group,insulin sensitivity index (ISI-Matsuda),dynamic insulin secretion index(Stumvoll 1-and 2-phase insulin secretion indices),and insulin secretion-sensitivity index (ISSI)were lowered (all P＜ 0.05),so was AUCINS/AUCGLU (P ＜ 0.01),as compared with those in NGT group.Blood glucagon levels during OGTF and incremental area under the glucagon curve (AUCGL) showed no significant differences between 2 groups (P ＞ 0.05).Multiple linear regression analysis showed that ISI-Matsuda,ISSI,HOMA-β,Stumvoll 1-and 2-phase insulin secretion indices accounted partially for the change of plasma glucose and ISI-Matsuda was the most important one among them.The function of islet α-cell seems to be normal while the function of β-cell is impaired in the patients with GDM,and failure of insulin secretion to overcome insulin resistance is the main reason for GDM.
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To compare the early-phase secretion between islet α cells and β cells in subjects with normal glucose tolerance and to explore the influencing genetic factors on the function of islet cells.40 subjects with normal glucose tolerance and family history of diabetes ( FH+ ) and 55 healthy volunteers without family diabetes history ( FH ) were collected.Fasting and L-arginine stimulating insulin,glucagon,and tasting free fatty acid,as well as other indicators were determined in all subjects.Insulin resistance was evaluated by homeostasis model assessment for insulin resistance.After adjnsting for sex,age,and body mass index,the insulin secretion peak of the two groups reached both at two min,and began to decline at four min,the peak multiple of FH+group was significantly less than that of FH-group (7.29 vs 8.88,P＜0.05) ; glucagon secretion peak of both groups reached at two min and began to decline by four min.Fasting glucagon and peak multiple were not significantly different (P＞0.05) ; The ratio of fasting insulin to fasting glucagon of the two groups was without significantly difference ( P＞0.05 ).Under diabetes genetic background,the function of β cells decreases even in subjects with normal glucose tolerance.