Costus afer modulates the activities of glycolytic and gluconeogenic enzymes in streptozotocin induced diabetic rats

Background: Glycolytic enzymes (Hexokinase and α-glucosidase) and gluconeogenic enzymes (Glucose-6-phosphatase and fructose-1,6-disphosphatase) control carbohydrate metabolism and hence glucose hemostasis, an important approach for the control of diabetes. The present study was carried out to evaluate the effect of hydro-ethanolic leaf extract of Costus afer on these enzymes. Materials and methods: Streptozotocin-induced diabetic rats were administered hydro-ethanolic leaf extract of Costus afer (250, 500 and 1000 mg/kg body weight) orally for 8 weeks. Effect of the extract was monitored on the decrease in glycemia and the modulatory activities on glycolytic and gluconeogenic enzymes activities. The pancreas was also immunohistochemically examined for regeneration of the Islet cells. Results: Hydro-ethanolic extract significantly decreased the blood glucose concentration, serum glucose-6-phosphatase and fructose-1,6-disphosphatase activities which were associated with an increase in the activity of hexokinase in the liver and kidney. immunohistochemical examination of the pancreas, revealed the preservation and regeneration of the islet of the Langerhans cells. Conclusion: Thus, C. afer acts against hyperglycemia modulating the activities of glucose-6-phosphatase, fructose-1,6-bisphosphatase and hexokinase, and regeneration of β-cells.

Phosphoenolpyruvate carboxykinase in urine exosomes reflect impairment in renal gluconeogenesis in early insulin resistance and diabetes

Impaired insulin-induced suppression of renal gluconeogenesis could be a risk for hyperglycemia. Diabetes is associated with elevated renal gluconeogenesis; however, its regulation in early insulin resistance is unclear in humans. A noninvasive marker of renal gluconeogenesis would be helpful. Here, we show that human urine exosomes (uE) contain three gluconeogenic enzymes: phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-bisphosphatase, and glucose 6-phosphatase. Their protein levels were positively associated with whole body insulin sensitivity. PEPCK protein in uE exhibited a meal-induced suppression. However, subjects with lower insulin sensitivity had blunted meal-induced suppression. Also, uE from subjects with prediabetes and diabetic rats had higher PEPCK relative to nondiabetic controls. Moreover, uE-PEPCK was higher in drug-naïve subjects with diabetes relative to drug-treated subjects with diabetes. To determine whether increased renal gluconeogenesis is associated with hyperglycemia or PEPCK expression in uE, acidosis was induced in rats by 0.28 M NH4Cl with 0.5% sucrose in drinking water. Control rats were maintained on 0.5% sucrose. At the seventh day posttreatment, gluconeogenic enzyme activity in the kidneys, but not in the liver, was higher in acidotic rats. These rats had elevated PEPCK in their uE and a significant rise in blood glucose relative to controls. The induction of gluconeogenesis in human proximal tubule cells increased PEPCK expression in both human proximal tubules and human proximal tubule-secreted exosomes in the media. Overall, gluconeogenic enzymes are detectable in human uE. Elevated PEPCK and its blunted meal-induced suppression in human urine exosomes are associated with diabetes and early insulin resistance.

Dapagliflozin not only improves hepatic injury and pancreatic endoplasmic reticulum stress, but also induces hepatic gluconeogenic enzymes expression in obese rats

Background: With an increasing prevalence of obesity and metabolic syndrome, exploring the effects and delineating the mechanisms of possible therapeutic agents are of critical importance. We examined the effects of SGLT2 inhibitor-dapagliflozin on insulin resistance, hepatic gluconeogenesis, hepatic injury and pancreatic ER stress in high-fat diet-induced obese rats. Materials and methods: Male Wistar rats were fed with normal diet (ND) or high-fat diet for 16 weeks. Then high-fat rats were given vehicle (HF) or dapagliflozin (1 mg/kg/day; HFDapa) or metformin (30 mg/kg/day; HFMet) for another 4 weeks. Results: We found that dapagliflozin ameliorated high-fat diet-induced insulin resistance. The fasting plasma glucose level was comparable among groups, although dapagliflozin treatment led to substantial glycosuria. Hepatic gluconeogenic enzymes, PEPCK, G6Pase and FBPase, expression was not different in HF rats compared with ND rats. Meanwhile, dapagliflozin-treated group exhibited the elevation of these enzymes in parallel with the rise of transcription factor CREB, co-factor PGC1α and upstream regulator SIRT1. Hepatic oxidative stress, inflammation and NAFLD activity score as well as hepatic and pancreatic ER stress and apoptosis in obese rats were attenuated by dapagliflozin. Conclusion: We conclude that dapagliflozin improved obesity-related insulin resistance, hepatic and pancreatic injury independent of fasting plasma glucose level. Of note, dapagliflozin-induced glycosuria apparently triggered the up-regulation of hepatic gluconeogenic enzymes to prevent hypoglycemia.