Element 5; Lecture 5 Carbohydrate Metabolism Gluconeogenesis Ms. K. Rohini Lecturer - FoM

Learning Objectives Role of liver in glucose homeostasis Cori cycle Glucose – Alanine cycle Gluconeogenic pathway – synthesis of glucose from alanine, lactate and glycerol Regulation of gluconeogenesis. 03 Feb 2012Ms.Rohini FoM 2

3 Importance of Liver in Glucose Homeostasis The brain, skeletal muscle, kidney medulla, RBCs and testes prefer glucose as their primary energy source, but lack the enzyme machinery to synthesize it. Readily available glucose reserves in the body amount to only about 1 day’s supply. Hence, during fasting for more than one day or during intense exertion, there is a need for glucose to be synthesized by the process known as “gluconeogenesis”. The liver plays a predominant role in gluconeogenesis (about 90%). The kidney cortex contributes to a smaller extent (about 10%) but more during prolonged starvation.

Gluconeogenesis Synthesis of glucose from non carbohydrate sources: – Pyruvate and lactate – Glucogenic amino acids (Eg.Alanine) – Glycerol – All intermediates of TCA cycle – Propionyl CoA formed from odd chain fatty acids Site: Liver, lesser extent in renal cortex Partially mitochondrial and partially cytosolic

5 Glucose Homeostasis Gluconeogenesis is the synthesis of glucose from various sources including amino acids (except leucine and lysine). Lactate Pyruvate Amino Acids Oxaloacetate Triose phosphates Glucose Amino AcidsPropionate Glycerol Important for maintaining blood glucose levels. Oxidation of odd-chain fatty acids (even chain not glucogenic) Breakdown of triacylglycerols Two inter-tissue cycles important in gluconeogenesis - Cori Cycle and Glucose-Alanine Cycle. Intermediates of TCA Cycle

6 The Cori Cycle Glucose 2Pyruvate 2Lactate 2ATP 2Lactate 2Pyruvate Glucose 6ATP Muscle & RBC Blood Glycolysis Gluconeo- genesis The Cori cycle involves the utilization of lactate, produced by glycolysis in non- hepatic tissues, (such as muscle and erythrocytes) as a carbon source for hepatic gluconeogenesis. In this way the liver can convert the anaerobic byproduct of glycolysis, lactate, back into more glucose for re-use by non-hepatic tissues. LDH Liver

7 Glucose-alanine Cycle The glucose-alanine cycle is used primarily as a mechanism for skeletal muscle to eliminate nitrogen while replenishing its energy supply. Glucose oxidation produces pyruvate which can undergo transamination to alanine. This reaction is catalyzed by glutamate- pyruvate transaminase, GPT (also called alanine transaminase, ALT in Fig). Additionally, during periods of fasting, skeletal muscle protein is degraded for the energy value of the amino acid carbons and alanine is a major amino acid in protein. The alanine then enters the blood stream and is transported to the liver. Within the liver alanine is converted back to pyruvate which is then a source of carbon atoms for gluconeogenesis. The newly formed glucose can then enter the blood for delivery back to the muscle. The amino group transported from the muscle to the liver in the form of alanine is ultimately converted to urea in the urea cycle and excreted (see lecture on amino acid metabolism).

8 Glucose-Alanine Cycle (ALT) Glycolysis Gluconeo- genesis * NH 4 + from amino acids transferred to  -KGA to form glutamate in muscle by transmination reactions. * Glut-DH

Most of the reactions are the reverse of glycolysis Four reactions are irreversible and unique to gluconeogenesis Hence there are 4 key enzymes of gluconeogenesis – Pyruvate carboxylase – Phosphoenolpyruvate carboxy kinase – Fructose 1,6-bisphosphatase – Glucose 6-phosphatase Gluconeogenesis

Pyruvate Oxaloacetate CO 2 Pyruvate carboxylase ATP ADP biotin CO 2 Phosphoenol pyruvate carboxy kinase GTP GDP Phosphoenolpyruvate

reverse of glycolysis Fructose 1,6-bisphosphate Fructose 6-phosphate Pi H2OH2O Fructose 1,6 bisphosphatase

Fructose 6-phosphate reverse of glycolysis Glucose 6-phosphate GLUCOSE Pi H2OH2O Glucose 6 -phosphatase

Regulation of gluconeogenesis Reciprocal regulation 1.Pyruvate Carboxylase. 2.Citrate 3.ATP

Learning Outcomes Describe the gluconeogenic pathway from various sources including glycerol. Discuss the importance of the liver in gluconeogenesis. Describe the Cori Cycle and glucose-alanine cycle and their importance. 03 Feb 2012Ms.Rohini FoM 14