ABSTRACT
Aim To investigate the regulatory effect of glucagon on gluconeogenesis in liver, kidney and intes¬tine during different fasting periods and the underlying mechanism. Methods The 8-week-old male C57BIV 6J mice were randomly divided into six groups ( n = 6) :control group, control + glucagon group, fasting 18 h group, fasting 18 h + glucagon group, fasting 36 h group, and fasting 36 h + glucagon group. Glucose, triglyceride ( TG) and free fatty acids ( FFAs ) kits were used to detect their serum contents in mouse in-traperitoneal injection of glucagon at different fasting time points. Besides, liver/muscle glycogen assay kit and PAS staining were used to detect the glycogen con¬tents in liver tissue. RT-PCR method was used to observe the effects of glucagon on the gene expressions of peroxisome proliferators-activated receptor y coactivator la (PGC-1α), glucose-6-phosphatase (G6Pase) and phosphoenol pyruvate carboxykinase 1 (PEPCK) in liver, kidney and intestine of mice at different fasting time. Western blot was employed to detect the protein expressions of PGC-1α, G6Pase, PEPCK, phosphoryl-ase protein kinase A ( p-PKA) , protlein kinase A (PKA) , phosphorylase cAMp-response element binding protein (p-CREB) and cAMp-response element binding protein (CREB) in liver, kidney and intestine of mice were. Results (1) Glucagon increased the serum glucose level, reduced serum TG and FFAs levels, and reduced the hepatic glycogen content. (2) Glucagon promoted gluconeogenesis via upregulation of PGC-1α. On the stimulation of glucagon, PGC-1α gene and protein expressions in liver were significantly raised by glucagon when the mice were fasted 18 h and 36 h, while the gene and protein expressions of PGC-1α in kidney were obviously up-regulated by glucagon after fasting 18 h. However, PGC-1α gene and protein expressions in intestine were significantly elevated by glucagon at 36 h after fasting. (3 ) Glucagon induced gene and protein expressions of gluconeogenesis-related enzymes G6Pase and PEPCK in liver, kidney and intestine after fasting. (4 ) Glucagon upregulated p-PKA/PKA and p-CREB/CREB in liver. Conclusions Glucagon shows temporal difference in the gluconeo-genic response of liver, kidney and intestine in mice. Glucagon promotes the gene and protein expressions of key gluconeogenic enzymes G6Pase and PEPCK by increasing PGC-1α gene and protein expression, and thus increasing fasting blood glucose. Besides, glucagon promotes hepatic gluconeogenesis via PKA/CREB signaling pathway.
ABSTRACT
In recent years, type 2 diabetes mellitus (T2DM) has an increasing incidence worldwide along with the improvement of people' s living standards, and emerged as a serious threat to human health. T2DM is a progressive metabolic disease characterized by hyperglycemia, and its routine therapies include diet control, the use of oral hypoglycemic drugs or subcutaneous injection with insulin. At present, in addition to chemical drugs, such as metformin and thiazolidinediones, researchers have also found that natural medicines and traditional Chinese medicine compounds have mild hypoglycemic and insulin sensitizing effects. Besides, these drugs also have effects in alleviating diabetes complications and maintaining glucose homeostasis. Berberine is an isoquinoline alkaloid mainly isolated from Coptis chinensis with multiple pharmacological activities. Currently, berberine is considered to be one of the most promising natural hypoglycemic agents for the treatment of type 2 diabetes mellitus. However, mechanisms of the hypoglycemic effect of berberine were complex. In this review, we summarized the pharmacological mechanisms of hypoglycemic effect of berberine, including improving insulin resistance, promoting insulin and glucagon-like peptide-1 (GLP-1) secretion, inhibiting hepatic gluconeogenesis, reducing glucose absorption in intestinal cells, suppressing oxidative stress and inflammation and modulating gut microbiota, clarified the mechanisms of hypoglycemic effect of berberine could help to understand the pharmacology of berberine in the treatment of diabetes mellitus and provided evidence for rational application of berberine in the treatment of type 2 diabetes.