AIM:To establish a model of recurrent hypoglycemia(RH)in mice with type 1 diabetes mellitus(T1DM)and to investigate the expression and effects of glucagon-like peptide-1(GLP-1)in the intestines of the model mice.METHODS:The T1DM model was established by induction with streptozotocin.Starting from the 15th day of T1DM,the mice in RH group were injected intraperitoneally with short-acting insulin,experiencing 1 episode of hyperin-sulinemic hypoglycemia every 3 days over 5 episodes,to establish the RH model in T1DM mice.Body weight,blood glu-cose,and activity status of the mice were recorded.Enzyme-linked immunosorbent assay(ELISA)was used to measure plasma adrenaline,glucagon(GCG),GLP-1,and somatostatin(SST)levels after the fifth episode of hypoglycemia for 60 min.Immunofluorescence staining was utilized to detect the expression of intestinal GLP-1 and hormone secretions from pancreatic α and δ cells in each group.Western blot was employed to detect protein expressions of GLP-1,GLP-1 receptor(GLP-1R),and prohormone convertase 1/3(PC1/3)in the intestine.RESULTS:Blood glucose and body weight met the standards for T1DM mice.During the 5 episodes of hypoglycemia,blood glucose levels in the RH group dropped to(3.3±0.5)mmol/L for more than 60 min during each episode of hypoglycemia,along with levels of plasma adrenaline and gluca-gon and the behavioral changes of RH mice during hypoglycemia,which met the modeling criteria of RH and impaired hy-poglycemic counterregulation in diabetic mice.ELISA detection showed that the plasma adrenaline and GCG levels were lower in RH group than those in T1DM group(P<0.01),while the plasma active GLP-1 and SST levels in mice were sig-nificantly higher in RH group(P<0.01).Immunofluorescence analysis showed that intestinal GLP-1 expression and pan-creatic SST secretion increased in RH group(P<0.01),while GCG secretion decreased(P<0.01).Western blot analysis showed that the levels of intestinal active GLP-1 and GLP-1R in RH group were significantly higher than those in T1DM group(P<0.01).CONCLUSION:Recurrent hypoglycemia in T1DM mice leads to increased intestinal GLP-1 expres-sion and secretion,which is closely related to the formation or aggravation of impaired hypoglycemic counterregulation.

OBJECTIVE To systematically evaluate the regulatory effect of liraglutide on hypoglycemia in patients with type 1 diabetes mellitus （T1DM） and provide evidence for the prevention and control of hypoglycemia in the clinical treatment of T1DM. METHODS Electronic databases including The Cochrane Library， PubMed， Embase， Web of Science， China Biology Medicine Disc （CBM）， CNKI， Wanfang database， and VIP database were searched from the inception of the databases to June 30， 2023. The clinical randomized controlled trials （RCTs） of liraglutide on hypoglycemia in T1DM patients were screened according to inclusion and exclusion criteria. Data extraction， grouping， and subgroup meta-analysis were conducted for the included studies. RESULTS A total of 11 RCTs involving 1 685 patients were ultimately included. Meta-analysis results showed that treatment with 1.2 mg liraglutide could reduce the frequency of hypoglycemia in patients with T1DM [OR＝0.81， 95%CI （0.74， 0.88）， P＜0.01]， while treatment with 1.8 mg liraglutide could increase the frequency of hypoglycemia [OR＝1.33， 95%CI （1.23， 1.44）， P＜0.01]. The effect of liraglutide on hypoglycemia in patients with T1DM was not correlated with the duration of hypoglycemia [MD＝ －0.29， 95%CI （－1.21， 0.63）， P＝0.53]， and did not increase the incidence of severe hypoglycemia in these patients [OR＝0.87， 95%CI （0.57， 1.33）， P＝0.53]. Liraglutide could reduce the levels of glycated hemoglobin [MD＝－1.39， 95%CI （－2.65， －0.13）， P＝0.03]， weight [MD＝－4.28， 95%CI （－5.01， －3.55）， P＜0.01]， and body mass index [MD＝－1.20， 95%CI （－1.80， －0.60）， P＜0.01] in them. CONCLUSIONS Liraglutide has a bidirectional regulatory effect on hypoglycemia in patients with T1DM， which is correlated with the dose of liraglutide. An appropriate dose of liraglutide （1.2 mg） can inhibit hypoglycemia in these patients， while an increased dose of liraglutide （1.8 mg） can promote hypoglycemia in them.