Objective: To investigate the effect of metformin (Met) on islet β-cell function in young rats with type 1 diabetes mellitus (T1DM) and its possible mechanisms of action. Methods: Healthy young rats were recruited in this study

12 in Control group

24 in induced type 1 diabetes model (T1DM model) group

and 24 in Met administration group (T1DM+Met group) after induction of T1DM. Glucose tolerance test

insulin tolerance test and high glucose clamp technique were used to detect islet function. The morphology of islet was observed by hematoxylin-eosin (HE) staining. Insulin and Ki67 immunofluorescence double staining method was used to determine the proliferation rate of β cells. Apoptosis of β cells was detected by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) assay. Western blot was used to detect the protein levels of pancreatic duodenal homeobox 1 (PDX-1)

B-cell lymphoma-2 (Bcl-2) and endoplasmic reticulum stress-related factors in pancreatic tissue. Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to detect mRNA levels of inflammation-related factors in pancreatic tissue. Results: Met could reduce the fasting blood glucose and insulin levels of T1DM young rats

and improve the abnormal glucose tolerance and insulin sensitivity. Met significantly increased the glucose infusion rate (GIR) value

the insulin secretion 1 min after intravenous glucose stimulation

and the maximum secretion capacity of islet β cells in the clamp steady state in the high glucose clamp experiment. Met restored the islet morphology to a certain extent

promoted β cells proliferation and inhibited their apoptosis by promoting the expression of PDX-1 and Bcl-2 protein levels. Met significantly down-regulated the expression of phosphorylated eukaryotic initiation factor 2 alpha (eIF2α)

eukaryotic initiation factor 4 (ATF4) and C/EBP-homologous protein (CHOP) (F=81.322

215.372

55.059

all P=0.000)

and also significantly down-regulated the mRNA levels of nuclear factor κappa-B (NF-κB)

interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) (F=570.275

369.184

474.006

all P=0.000). Conclusion: Met can improve the secretion function of islet β cells in type 1 diabetic rats by promoting differentiation

anti-apoptosis

relieving stress of endoplasmic reticulum stress and reducing inflammation

thereby promoting its proliferation and restoring islet morphology in young rats with T1DM.