PEPCK and Gluconeogenesis


Gluconeogenesis refers to a metabolic pathway that synthesizes a glucose molecule from non-carbohydrate precurser molecules and is the most intensely studied of PEPCK’s physiological roles.  Glucose is one of  the main energy sources in the human body, especially the brain which is unable to use fatty acids in the blood.  If blood glucose levels are above what is needed for cellular metabolism, the excess glucose can be stored by forming chains of glucose molecules called glycogen.   In times of reduced carbohydrate intake, glycogen stores are broken down as needed to supply glucose for metabolism.  However, in the human body glycogen stores are not very large, so during prolonged fasting or reduced carbohydrate intake the body needs to produce glucose to maintain normal blood glucose levels.   PEPCK is a rate-limiting step in gluconeogeneis, so activity of this enzyme determines the amount of glucose produced.  There are no cytoplasmic, or metabolic regulators of the enzymes activity, instead the cellular rate of PEPCK activity is determined by the total amount of PEPCK synthesized by a cell.  The control point is where the gene for PEPCK is transcribed from DNA to RNA, thus PEPCK is said to be transcriptionally regulated.  Read more about the molecular biology of PEPCK synthesis here.

The gluconeogenic pathway is intimately connected with the breakdown of glucose by glycolytic pathway.  Gluconeogenesis and glycolysis share many enzymes and metabolic intermediates, but gluconeogenesis is not simply the reversal of glycolysis.  The enzymes that are common for the two pathways catalyze reactions that are near thermodynamic equilibrium.  This means that the reaction can go forward (breaking down glucose in glycolysis) or backward (towards glucose synthesis in gluconeogenesis) depending on the relative concetrations of the product and reactant metabolites.  However, in some of the enzymatic reactions of glycolysis energy is released for other cellular functions.  These reactions do not easily go in the gluconeogensis direction,  So in order to produce a glucose molecule, an enymatic “bypass” reaction occur where energy is added.  The first of these bypass reactions in the conversion of oxaloacetate to phosphoenolpyruvate by PEPCK.  PEP is a higher energy molecule than OA, so PEPCK uses the energy from GTP to give PEP  a high energy phosphate bond. 

The primary gluconeogenic organ in the body is the liver.  However, even if hepatic gluconeogenesis is abolished, normal blood glucose levels can be maintained in rats.  Other gluconeogenic tissues are the kidney and small intestine.  The brain is interesting when it comes to actually prodcing glucose from precursor molecules.  Neurons express PEPCK in their synapses but are clearly not gluconeogenic.  They lack the enzymes pyruvate carboxylase and glucose-6-phosphatase and cannot produce glucose from precursor molecules.  However, about half of the volume of the brain is composed non-neuronal support cells called glial cells.  At least one type of glial cell, astrocytes do appear capable of gluconeogenesis.  Whether this happens in during normal functioning is unclear.

Separate contribution of diabetes, total fat mass, and fat topography to glucose production, gluconeogenesis, and glycogenolysis. Gastaldelli A, Miyazaki Y, Pettiti M, Buzzigoli E, Mahankali S, Ferrannini E, DeFronzo RA. J Clin Endocrinol Metab. 2004 Aug;89(8):3914-21. [PDF]

Obesity and type 2 diabetes impair insulin-induced suppression of glycogenolysis as well as gluconeogenesis. Basu R, Chandramouli V, Dicke B, Landau B, Rizza R. Diabetes. 2005 Jul;54(7):1942-8. [PDF]

Effects of free fatty acids on gluconeogenesis and autoregulation of glucose production in type 2 diabetes. Boden G, Chen X, Capulong E, Mozzoli M. Diabetes. 2001 Apr;50(4):810-6. [PDF]

The effect of rosiglitazone on the liver: decreased gluconeogenesis in patients with type 2 diabetes. Gastaldelli A, Miyazaki Y, Pettiti M, Santini E, Ciociaro D, Defronzo RA, Ferrannini E.  J Clin Endocrinol Metab. 2006 Mar;91(3):806-12.

Effect of physiological hyperinsulinemia on gluconeogenesis in nondiabetic subjects and in type 2 diabetic patients. Gastaldelli A, Toschi E, Pettiti M, Frascerra S, Quinones-Galvan A, Sironi AM, Natali A, Ferrannini E. Diabetes. 2001 Aug;50(8):1807-12. [PDF]
Copyright 2011 Steve Kriegler