Renal gluconeogenesis in insulin resistance:A culprit for hyperglycemia in diabetes

Renal gluconeogenesis is one of the major pathways for endogenous glucose production.Impairment in this process may contribute to hyperglycemia in cases with insulin resistance and diabetes.We reviewed pertinent studies to elucidate the role of renal gluconeogenesis regulation in insulin resistance and diabetes.A consensus on the suppressive effect of insulin on kidney gluconeogenesis has started to build up.Insulin-resistant models exhibit reduced insulin receptor(IR)expression and/or post-receptor signaling in their kidney tissue.Reduced IR expression or post-receptor signaling can cause impairment in insulin’s action on kidneys,which may increase renal gluconeogenesis in the state of insulin resistance.It is now established that the kidney contributes up to 20%of all glucose production via gluconeogenesis in the post-absorptive phase.However,the rate of renal glucose release excessively increases in diabetes.The rise in renal glucose release in diabetes may contribute to fasting hyperglycemia and increased postprandial glucose levels.Enhanced glucose release by the kidneys and renal expression of the gluconeogenic-enzyme in diabetic rodents and humans further point towards the significance of renal gluconeogenesis.Overall,the available literature suggests that impairment in renal gluconeogenesis in an insulinresistant state may contribute to hyperglycemia in type 2 diabetes.

Role of small leucine zipper protein in hepatic gluconeogenesis and metabolic disorder

Hepatic gluconeogenesis is the central pathway for glucose generation in the body.The imbalance between glucose synthesis and uptake leads to metabolic diseases such as obesity,diabetes,and cardiovascular diseases.Small leucine zipper protein(sLZIP)is an isoform of LZIP and it mainly functions as a transcription factor.Although sLZIP is known to regulate the transcription of genes involved in various cellular processes,the role of sLZIP in hepatic glucose metabolism is not known.In this study,we investigated the regulatory role of sLZIP in hepatic gluconeogenesis and its involvement in metabolic disorder.We found that sLZIP expression was elevated during glucose starvation,leading to the promotion of phosphoenolpyruvate carboxylase and glucose-6-phosphatase expression in hepatocytes.However,sLZIP knockdown suppressed the expression of the gluconeogenic enzymes under low glucose conditions.sLZIP also enhanced glucose production in the human liver cells and mouse primary hepatic cells.Fasting-induced cyclic adenosine monophosphate impeded sLZIP degradation.Results of glucose and pyruvate tolerance tests showed that sLZIP transgenic mice exhibited abnormal blood glucose metabolism.These findings suggest that sLZIP is a novel regulator of gluconeogenic enzyme expression and plays a role in blood glucose homeostasis during starvation.