Effects of Metformin Treatment on Liver Glucose Metabolism-Related Enzyme Levels in Streptozotocin-Induced Diabetic Rats

Background: Diabetes mellitus (DM) disrupts hepatic glucose handling and alters pathways involved in glycogen metabolism, glycolysis, the pentose phosphate pathway, and gluconeogenesis. This study examined hepatic glycogen content and glucose metabolism-related enzyme levels at defined stages of streptozotocin (STZ)-induced diabetes and evaluated the effect of metformin at week 8. Methods: Sixty-three adult male Wistar Albino rats were initially allocated to nine groups (n = 7/group): four time-matched control groups (C1–C4), four untreated diabetic groups (D1-D4), and one metformin-treated diabetic group (T). Diabetes was induced with a single intraperitoneal dose of STZ (35 mg/kg). D1/C1, D2/C2, D3/C3, and D4/C4 were evaluated at weeks 1, 3, 6, and 8, respectively; T received metformin (100 mg/kg/day) in drinking water and was evaluated at week 8. One animal each in D3, D4, and T died spontaneously before the scheduled endpoint, leaving 60 animals for final analyses. Hepatic glycogen and glucose metabolism-related enzyme levels were measured by rat-specific sandwich ELISA. Results: Time-matched comparisons showed significant diabetes-associated differences in hepatic glycogen and all measured enzyme levels at weeks 1, 3, 6, and 8. At week 8, metformin shifted glycogen, glycogen synthase (GS), glycogen phosphorylase (GP), lactate dehydrogenase (LDH), pyruvate kinase (PK), hexokinase (HK), glucose-6-phosphatase (G6Pase), glucose-6-phosphate dehydrogenase (G6PD), and fructose-1,6-bisphosphatase (FBP1) toward control values compared with untreated diabetic rats (Holm-adjusted p = 0.0035 for each comparison). However, T remained significantly different from C4 for every hepatic parameter, and final fasting blood glucose did not differ significantly between T and D4. Conclusions: STZ-induced diabetes was associated with marked alterations in hepatic glycogen and glucose metabolism-related enzyme levels. Metformin partially ameliorated these hepatic changes at week 8 despite persistent severe hyperglycemia, but it did not normalize the measured hepatic profile.