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

Abstract

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 insulin-resistant state may contribute to hyperglycemia in type 2 diabetes.

Keywords: Diabetes; Gluconeogenic enzymes; Insulin; Insulin receptor signaling; Insulin-resistance; Renal gluconeogenesis.

Figure 1

Schematic overview of renal gluconeogenesis and glycolysis pathway and enzyme localization. The key enzymes of gluconeogenesis (1) pyruvate carboxylase; (2) phosphoenolpyruvate carboxykinase; (3) fructose-1,6-biphosphatase; and (4) glucose 6-phosphatase are predominantly localized in the renal cortical cells whereas, the glycolytic key enzymes (1) hexokinase; (2) phosphofructokinase; and (3) pyruvate kinase are found in the renal medulla.

Figure 2

Gluconeogenesis Pathway and cellular compartmentalization of the gluconeogenic enzymes. Pyruvate from lactate enters mitochondria by mitochondrial pyruvate transporter. Pyruvate provided by alanine transamination or lactate dehydrogenation is converted to oxaloacetate (OAA) by mitochondrial pyruvate carboxylase. OAA is either reduced to malate and exported out in the cytoplasm by malate ketoglutarate transporter or directly converted to phosphoenolpyruvate (PEP) by phosphoenolpyruvate carboxykinase (PCK) 2 (mitochondrial isoform) and exported out in the cytoplasm. In the cytoplasm, malate is first oxidized to OAA and then converted to PEP by PCK1 (cytoplasmic isoform). Fructose-1,6-bisphosphate (FBP) is then converted to fructose-6-phosphate by cytoplasmic FBP1. Glucose-6-phosphatase in the cytoplasm ultimately dephosphorylates glucose-6-phosphate to release glucose. G6Pase: Glucose-6-phosphatase; LDH: Lactate dehydrogenase; MPC: Mitochondrial pyruvate carrier; ALT: Alanine aminotransferase; FBP: Fructose-1,6-bisphosphate; OAA: Oxaloacetate; PCK: Phosphoenolpyruvate carboxykinase; PEP: Phosphoenolpyruvate; mMDH: Malate dehydrogenase; cAMP: Cyclic adenosine monophosphate.

Figure 3

siRNA mediated knockdown of insulin receptor in the human proximal tubule cells increased glucose production via gluconeogenesis stimulation.A: Western blot showing reduced insulin receptor insulin receptor (IR) expression in IR-siRNA treated human proximal tubule (hPT) cells relative to scrambled; B:cAMP/Dexa induced gluconeogenesis/glucose production in the hPT cell culture media; and C: Relative phosphoenolpyruvate carboxykinase mRNA transcript levels in scrambled and IR-siRNA treated hPT cells with or without insulin treatment. “Citation: Pandey G, Shankar K, Makhija E, Gaikwad A, Ecelbarger C, Mandhani A, Srivastava A, Tiwari S. Reduced Insulin Receptor Expression Enhances Proximal Tubule Gluconeogenesis. J Cell Biochem 2017; 118: 276-285 [PMID: 27322100 DOI: 10.1002/jcb.25632] Copyright © The Author(s) 2017. Published by John/Wiley & Sons, Inc[65]”

Figure 4

mRNA and protein levels of glucose-6-phosphatase, phosphoenolpyruvate carboxykinase, and fructose-1,6-bisphosphatase in diabetic rats and their non-diabetic controls. “Citation: Eid A, Bodin S, Ferrier B, Delage H, Boghossian M, Martin M, Baverel G, Conjard A. Intrinsic gluconeogenesis is enhanced in renal proximal tubules of Zucker diabetic fatty rats. J Am SocNephrol 2006; 17: 398-405 [PMID: 16396963 DOI: 10.1681/asn.2005070742] Copyright © The Author(s) 2006. Published by the American Society of Nephrology Inc[12]”