Metabolic effects of Insulin and Glucagon Metabolism in the Well fed state

1. Integration of Metabolism • Metabolic effects of Insulin and Glucagon • Metabolism in the Well fed state • Metabolism in the Starvation and Diabetes Mellitus

2. Metabolic Map

3. Metabolism in the well-fed state. - After ingestion of meal  increase glucose, amino acids, fatty acids  increase insulin /glucagon ratio  this increase anabolic reactions (anabolic period)  increase synthesis of glycogen, TG, protein. During absorptive period all tissues use glucose as fuel. * Enzymatic changes in the fed state The flow of the intermediates through metabolic pathways is controlled by four mechanisms with different time scales. This allows the body to adapt to wide variety of physiologic situations. - In the well fed state, the regulatory mechanisms ensure that available nutrients are captured and stored as glycogen, TG and proteins.

4. Mechanisms for controlling the flow of intermediates through metabolic pathways: • A) Allosteric effectors. • - usually involve rate-determining reactions. • e.g : glycolysis is stimulated following a meal by an increase in fru 2,6-bisphosphate. Which is an allosteric activator of phosphofructokinase.- gluconeogenesis is inhibited by fruc-2,6 bisphosphate which is inhibitor for fruc-1,6 bisphosphatase. • B) Regulation of enzymes by covalent modification. • - many enzymes are regulated by covalent modification  by addition or removal of phosphate groups from specific serine, threonine or tyrosine residues. • In the fed state, most of enzymes regulated by covalent modification are in the dephosphorylated form (active form). Three exceptions that inactivated by their dephosphorylation. : • glycogen phosphorylase. • fructose bisphosphate phosphatase 2. • hormone-sensitive lipase of adipose tissue. • C) Induction and repression of enzyme synthesis. • - the increased (induction) or decreased (repression) of protein synthesis leads to changes of total population of active enzyme, not affecting the efficiency of existing enzyme molecules. • - enzyme subject to regulation of synthesis are that needed at stage of development or storage under selected physiologic conditions. • e.g : in fed state, elevated insulin levels result in increase in the synthesis of key enzymes involved in anabolic metabolism by affecting of gene expressions.

5. Regulation of enzymes by covalent modification

6. Liver: Nutrient distribution center - The liver can process and distribute nutrients because the portal vein passes to liver before going to the circulation. - So after a meal : the liver is bathed in blood containing the absorbed nutrients and elevated level of insulin secreted by pancreas. - During the absorptive period, the liver takes up CHO, lipids and most of amino acids. These nutrients are then metabolized, stored or directed to other tissues.

7. A- CHO metabolism • - liver normally glucose-producing rather than glucose utilizing tissue. • - In the well-fed state (after a meal) the liver becomes net consumer of glucose, that can take up 60% of glucose carried by portal circulation. • Hepatic metabolism of glucose is increased by the following mechanisms: • Increase phosphorylation of glucose: high level of intracellular glucose increase activity of Glucokinase (dominant in liver). Functions only at high glucose level (low affinity, high Km). • Increase glycogen synthesis: glucose 6-phosphate is converted to glycogen by activation of glycogen synthase and inactivation of glycogen phosphorylase. • Increase the activity of hexose monophosphate pathway (HMP): in the well-fed state  glu-6-p will enter HMP  increased NADPH which utilized in biosynthesis of fatty acids. • Increase glycolysis: glycolytic metabolism of glucose is increased during absorptive period. Glucose  acetyl-CoA is activated by insulin/glucagon. The acetyl-CoA is directly utilized as building block for fatty acids or enter TCA. • Decrease gluconeogenesis: decrease acetyl-CoA (utilized in fatty acid biosynthesis)  decrease activity of pyruvate carboxylase. • Also high insulin/glucagon level  inactivates enzymes in gluconeogenesis.

8. B- Fat metabolism 1) High fatty acid synthesis: liver is the primary tissue for the de-novo synthesis of fatty acids. In the well-fed state this pathway is activated. - Fatty acid synthesis is favored by availability of substrates (acetyl-CoA,NADPH derived from glucose metabolism). This activate acetyl-CoA carboxylase which mediates the rate limiting reaction. 2) Increasing of triglyceride synthesis: a) TG synthesis is favored because fatty acyl-CoA is available from: denovo synthesis from acetyl-CoA. b) Hydrolysis of TG component of chylomicron remnants removed from blood by hepatocytes. - Also glycerol 3-phosphate (backbone of TG) is provided from glycolytic metabolism of glucose. - TG synthesis in liver is excreted into blood in the form of VLDV to be utilized by extrahepatic tissue, mainly adipose tissue.

9. C- Amino acid metabolism 1) Increased amino acid degradation: in the absorptive period, more amino acid present in the liver than the liver can use in the synthesis of protein and other nitrogen-containing substances. So Amino acid can be released to be used in protein synthesis or catabolized by transamination and oxidative deamination to produce the carbon skeleton and urea. 2) Increase protein synthesis: the body can’t store protein, amino acid can be used in the synthesis of protein to replace other proteins.

10. Adipose tissue - In a 70 Kg man  18 Kg of fat - Nearly the entire volume of each adipocyte can be occupied by a droplet of triglycerol. A- CHO metabolism in fed state of adipocytes Increased glucose transport: glucose entrance to adipocytes is very sensitive to insulin, high insulin in the fed state (absorption state)  increase influx of glucose into adipocyte. Increase glycolysis: increase glycolysis  increase production of glycerol 3-phosphate for TG synthesis. Increased activity of the hexose monophosphate pathway (HMP): increase NADPH for denovo synthesis of fatty acid (not major)

11. B- Metabolism of Fat metabolism in the well-fed state • Increased synthesis of F.A:denovo synthesis of F.A from acetyl-CoA in adipocytes is very low.(not major pathway). • Increased TG synthesis:hydrolysis of TG of chylomicrons and VLDL provides adipose tissue with fatty acids after a lipid-rich meal. • In the well-fed state:insulin increase glucose uptake in adipocytes  glycerol 3-phosphate  TG stored in adipocytes. • Decreased TG degradation:increase insulin  increase dephosphorylation of hormone sensitive lipase  decrease TG degradation in adipocytes. F.A utilized by adipocytes Chylomicron VLDL Lipoprotein lipase

12. Metabolism at Skeletal muscle in the well-fed state - At rest muscle consumes 30% of the, O₂ and 90% in exercise. A- CHO metabolism in skeletal muscle (in the fed state) Increased glucose transport: after a CHO rich meal leads to increase insulin increase uptaking of glucose by skeletal muscle. Glucose  glucose 6-phosphate  energy. - In the case of low CHO (post absorptive state) keton bodies and fatty acids are the major fuels in resting muscle. -Increased glycogen synthesis: high level of insulin increase glycogen synthesis. B- Fat metabolism - Fatty acid released by chylomicrones and VLDL by lipoprotein lipase  utilized by muscle. - In well-fed state, fatty acids are secondary source of energy after CHO. C- Amino acid metabolism -Increased protein synthesis: excess amino acids will be utilized for synthesis of protein in skeletal muscle to replace the protein used in degradation or fuels. -Increased uptake of branched-chain amino acids: this amino acids used for protein synthesis and energy production.

13. Metabolism of Skeletal muscle in the well-fed state

14. Metabolism in Brain at the well-fed state - Brain contributes only 2% of adult weight, consumes 20% of energy in fast. - The brain uses energy at constant rate. Because it is vital, so priority of energy is for brain - Glucose is primary fuel  should pass BBB (Blood Brain Barrier). *Keton bodies only in starvation. A- CHO metabolism - In the well-fed state, brain uses glucose exclusiely as fuel. - Brain contain no glycogen so depend completely on blood glucose. B- Fat metabolism - The brain has no significant store of TG, and fatty acids don’t efficiently cross the BBB (Blood Brain Barrier).

15. The inter-tissue exchanges of the absorptive period

16. The End