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Basic Concepts in Metabolism and Regulation of Blood sugar levels

Basic Concepts in Metabolism and Regulation of Blood sugar levels. Dr.S.Chakravarty, MBBS,MD. The metabolic States. FASTING STATE OR POST ABSORPTIVE STATE :- 12 to 14 hrs after a meal 70- 110 mg/dl (5 to 7.2 mmol /L) POST PRANDIAL STATE :- AFTER A MEAL

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Basic Concepts in Metabolism and Regulation of Blood sugar levels

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  1. Basic Concepts in Metabolismand Regulation of Blood sugar levels Dr.S.Chakravarty, MBBS,MD

  2. The metabolic States • FASTING STATE OR POST ABSORPTIVE STATE :- 12 to 14 hrs after a meal • 70- 110 mg/dl (5 to 7.2 mmol/L) • POST PRANDIAL STATE :- AFTER A MEAL • generally upto 140mg/dl (<10mmol/L)due to prompt secretion of Insulin

  3. Two basal requirements during starvation 1.Glucose (must for some tissues like Brain and RBCs) 2. ATP

  4. PROXIMATE PRINCIPLES • CARBOHYDRATE • LIPIDS • PROTEINS

  5. Regulation of Blood Sugar Level Dr.S.Chakravarty M.D.

  6. Specific learning objectives • At the end of this lecture you should be able to describe • How blood sugar level is maintained during the absorptive and post absorptive states. • The secretion, functions and role of insulin in metabolism. • The role of hyperglycemic hormones like glucagon, epinephrine and cortisol in metabolism.

  7. BIOMEDICAL IMPORTANCE • BASAL REQUIREMENT FOR GLUCOSE :-There is always a basal requirement for Glucose, even when fat is supplying most of the caloric requirements. • GLUCOSE IS IMPORTANT FOR MAINTAINING THE INTERMEDIATES OF THE CITRIC ACID CYCLE EVEN WHEN FATTY ACIDS ARE THE MAIN SOURCE OF ENERGY. • OBLIGATORY REQUIREMENT FOR GLUCOSE :-There is an obligatory requirement of glucose for the brain and RBCs.(although the brain can utilize ketone bodies) • ONLY FUEL FOR SKELETAL MUSCLE IN ANAEROBIC CONDITIONS:- Glucose is the only fuel that will supply energy to skeletal muscle under anaerobic conditions. • PROFOUND CONSEQUENCES IN ACUTE GLUCOSE DEPLETION :-A sudden decrease in blood glucose will cause convulsions, as in insulin overdose. • However, lower concentrations can be tolerated if there has been progressive adaptation.

  8. The metabolic States • FASTING STATE OR POST ABSORPTIVE STATE :- 12 to 14 hrs after a meal • 70- 110 mg/dl (5 to 7.2 mmol/L) • POST PRANDIAL STATE :- AFTER A MEAL • generally upto 140mg/dl (<10mmol/L)due to prompt secretion of Insulin

  9. NORMAL RANGE

  10. Glucose uptake by cells:Major Glucose transporters (GLUT): • Km is inversely proportional to affinity:

  11. OVERVIEW OF BLOOD SUGAR REGULATION Plasma glucose 70-110mg/dl HYPERGLYCEMIC FACTORS Glycolysis Glycogen Synthesis Lipogenesis ______________ Hypoglycemic Hormone INSULIN HYPOGLYCEMIC FACTORS • Absorption from GI TRACT • Glycogenolysis • Gluconeogenesis _________________ Hyperglycemic hormones • Glucagon • Adrenalin • Corticosteroids • Growth Hormones USMLE CONCEPT !!

  12. Metabolic and Hormonal Mechanisms regulate the concentrations of Blood Glucose

  13. Blood Glucose is derived from the following :- • DIET • GLYCOGENOLYSIS • GLUCONEOGENESIS

  14. Diet • THE DIETARY CARBOHYDRATES that are actively digested contain glucose , galactose and fructose residues that are released in the intestine. • They are transported to the Liver via the portal vein . • Galactose and Fructose are converted to glucose in the Liver.

  15. ROLE OF GLUCOKINASE • Glucokinase is important in regulating Blood Glucose after a meal.

  16. Difference between Glucokinase and Hexokinase USMLE CONCEPT !!

  17. Vmax 100 Hexokinase (Km= 0.05mol/L) Blood Glucose mmol/L Glucokinase (Km=10mmol/L) 50 0 5 10 15 20 25

  18. ROLE OF HORMONES HYPERGLYCEMIC HORMONES

  19. BASIC CONCEPT IN REGULATION • HYPERGLYCEMIC HORMONES (GLUCAGON , EPINEPHRINE etc) PHOSPHORYLATE KEY ENZYMES IN REGULATION Stimulates a protein kinase • INSULIN ALWAYS DEPHOSPHORYLATESi.e it stimulates a protein phosphatase USMLE concept !!

  20. Example :- Covalent modification of Pyruvate kinase : cAMP Glucagon (+) Inhibition of Glycolysis in liver and increase blood glucose Protein kinase A (+) PO4 ATP ADP Pyruvate Kinase Pyruvate Kinase Active Inactive (+) Protein phosphatase (+) USMLE concept !! Insulin

  21. Glucagon • Polypeptide with 29 amino acids • It is secreted by the alpha cells of the pancreas • Synthesized as a precursor –PROGLUCAGON • PLASMA t ½ is 5 mins • INACTIVATED IN LIVER • PHYSIOLOGICAL ACTIONS:- • Most POTENT HYPERGLYCEMIC hormone :- ANTI – INSULIN in nature • CAUSES GLYCOGENOLYSIS • Stimulates GLUCONEOGENSIS • CAUSES LIPOLYSIS

  22. MECHANISM OF ACTION • Liveris the primary target of glucagon action. • Glucagon Binds To Specific Receptors In Hepatic Cell Plasma Membrane , And This Activates AdenylylCyclaseThrough a G –Protein Linked Mechanism. • The c-AMP generated activates PHOSPHORYLASE and enhances rate of glycogen degradation while inhibiting glycogen synthase . • Glucagon has no effect on glycogenolysis in muscle. • It’s a potent lipolytic agent also. It increases adipose tissue c-AMP levels and this activates the hormone sensitive lipase which breaks down TAG to FA +Glycerol. • It also enhances gluconeogenesis • ( ACTIVATOR OF PEPCK AND FRUCTOSE 1,6 BPASE ).

  23. CLINICAL USE OF GLUCAGON • An injectable form of glucagon, manufactured by Eli Lilly and Company, is vital first aid in cases of severe hypoglycemia when the victim is unconscious or for other reasons cannot take glucose orally.

  24. Epinephrine • RELEASED FROM ADRENAL MEDULLA AS A RESULT OF STRESSFUL STIMULI ( fear , excitement, hemorrhage , hypoxia , hypoglycemia etc) • Promotes gycogenolysis in BOTH liver and muscle ( stimulates PHOSPHORYLASE )- MAIN IMMEDIATE ACTION • Increases gluconeogenesis • Enhances lipolysis • Glucocorticoids :- • They are secreted by adrenal cortex. • Increases Gluconeogenesismainly. • Increased protein catabolism  release of amino acids by the muscles  increased hepatic uptake of a.a . • Induces the enzymes PEPCK, fructose 1,6 Bisphosphatase , glucose 6-phosphatase and amino transferases.

  25. GROWTH HORMONE • GH secretion is stimulated by hypoglycemia. • It decreases glucose uptake by muscle cells. • It mobilizes FFA from adipose tissue which themselves inhibit glucose utilization.(decreases glycolysis ). • Chronic administration leads to diabetes. THYROID HORMONES :- • EXPERIMENTAL EVIDENCE THAT THYROIDECTOMY INHIBITS THE DEVELOPMENT OF DIABETES. • THYROTOXIC PATIENTS :- GLYCOGEN IS ABSENT IN LIVER. • FBS IS ELEVATED IN HYPERTHYROID PATIENTS AND DECREASED IN HYPOTHYROID PATIENTS. • HYPERTHYROID PATIENTS UTILIZE GLUCOSE AT AN INCREASED RATE AND HYPOTHYROID PATIENTS HAVE DECREASED ABILITY. • HYPOTHYROID PATIENTS ARE LESS SENSITIVE TO INSULIN THAN NORMAL OR HYPERTHYROID INDIVIDUALS.

  26. Structure of Insulin • Protein hormone with 2 polypeptide chains • A chain --> 21 a.a • B chain --> 30 a.a • Two chains are joined by interchain disulphide bonds, b/w A7 to B7 and A20 to B19. • Intrachain disulphide link in A chain b/w 6th and 11th A.A • SPECIES VARIATION  8,9,10 of A chain and C terminal of B chain

  27. A6 to A11 • 30th AMINO ACID • Thr (Human) • Ala (Bovine) • Ala (Pig) A7 to B7 A20 to B19 • 8th ,9th and 10th AMINO ACID • ALA –SER VAL (BOVINE) • THR-SER-ILE (HUMAN) • THR-SER-ILE (PIG)

  28. PRO INSULIN

  29. Insulin is a hexamer with 2 Zn ions and 1 Ca+2 ions

  30. BIOSYNTHESIS OF INSULIN • SYNTHESIZED AS A LARGER PRECURSOR POLYPEPTIDE CHAIN – > PRE-PRO-INSULIN WITH 109 AA PRO INSULIN ( 86 AA ) INSULIN(53 AA) INSULIN (51 AA) -23 AA IN E.R -C PEPTIDE (33 AA) BY PROHORMONE CONVERTASE 1 AND 2 (GOLGI APPARATUS ) -2 AA BY CARBOXYPEPTIDASE H

  31. FACTORS INCREASING INSULIN SECRETION • GLUCOSE • GI HORMONES :- Secretin, Pancreozymin , Gastrin • PROTEINS AND AA :- Leucine , Arginine • Parasympathetic and beta –adrenergic stimulation • Glucagon and growth hormone • INCRETIN HORMONES :- • GIP (Glucose dependent insulinotropic polypeptide ) • Glucagon like peptide 1 ( GLP-1 ,31 AA) • Drugs – Sulfonylureas(eg.Tolbutamide)

  32. ATP GATED K+ CHANNELS CLOSE AND MEMBRANE DEPOLARIZES GLU GLU Ca +2 GLU GLU Voltage gated calcium channel opens BETA CELL Glycolysis TCA ADENYLYL CYCLASE ATP cAMP INSULIN RELEASE

  33. FACTORS DECREASING INSULIN SECRETION • Epinephrine • Alpha adrenergic stimulation

  34. INSULIN DEGRADATION • Plasma t ½ of INSULIN is 5 mins • It is degraded by an insulin specific protease (INSULINASE) and a hepatic –glutathione –insulin –transhydrogenase. Normal Insulin level :- 2-25 µIU/ml ( 12-150 pmol/L) • Proinsulin contributes 5-10% of total insulin activity(1/3 biological activity as that of insulin) • In case of antibodies to insulin , measurement of C-peptide may be useful :- • t ½ 35 mins and Fasting range is: 0.78 - 1.89 ng/ml 0.26 - 0.62 nmol/L SI unit • Range one hour after a glucose load is: 5.00 -12.00 ng/ml” (During a glucose tolerance test)

  35. MECHANISM OF ACTION OF INSULIN • INSULIN RECEPTOR • Insulin acts by binding to a plasma membrane receptor on the target cells. • INSULIN RECEPTOR is a glycoprotein with 2 α and 2β subunits. • β- subunit has TYROSINE KINASE activity.

  36. I I Alpha subunit G G G G G G G Beta subunit GLUT-4 Cell membrane PHOSPHORYLATION OF TYROSINE RESIDUES GLUT-4 Insulin Response substrates

  37. Actions of Insulin on Carbohydrate metabolism

  38. EFFECT OF INSULIN ON LIPID AND PROTEIN METABOLISM

  39. METABOLIC EFFECTS OF INSULIN(summary) • 1)UPTAKE OF GLUCOSE BY TISSUES( GLUT 4) • 2)UTILIZATION OF GLUCOSE • STIMULATION OF GLYSOLYSIS • INHIBITION OF GLUCONEOGENSIS • INHIBITION OF GLYCOGENOLYSIS • 3)LIPOGENESIS • MORE Acetyl CoA from Glycolysis • INCREASED FA SYNTHESIS AND ESTERIFICATION AS TAG • PROVIDES NADHP FOR REDUCTIVE BIOSYNTHESIS • 4)ANTI –LIPOLYTIC EFFECT • INHIBITION OF LIPOLYSIS BY INHIBITION OF HSL • 5) ANTI KETOGENIC • DEPRESSES HMG CoA SYNTHASE • EFFECTIVE & COMPLETE UTILIZATION OF acetylCoA as OAA is abundant • 6)ANABOLISM • INCREASED PROTEIN SYNTHESIS, DECREASED BREAKDOWN • INCREASED CELL GROWTH AND REPLICATION

  40. INGESTED GLUCOSE Or CARBS ( 100 % ) GLYCOLYSIS ( ~ 50 %) CONVERTED TO FATS (30-40%) GLYCOGEN (10%) So , Obesity results even if you eat only excess CARBs and to reduce body weight both CARBS AND FATS MUST BE REDUCED(i.e TOTAL CALORIES SHOULD BE LESS)

  41. HYPOGLYCEMIA • CAUSES :- • 1. PHYSIOLOGICAL • DURING STARVATION • AFTER SEVERE EXERCISE • NEONATES ( esp .PREMATURE INFANTS AS THERE IS LESS ADIPOSE TISSUE + NON-FUNCTIONAL ENZYMES OF GLUCONEOGENESIS) • PREGNANCY (INCREASED DEMAND )

  42. 2.PATHOLOGICAL • 1. DUE TO EXCESS OF INSULIN • EXCESSIVE DOSAGE • NO FOOD INTAKE AFTER INSULIN ADMINISTRATION • TUMORS OF PANCREAS (insulinoma) • 2. ORAL HYPOGLYCEMIC DRUGS • 3.GLYCOGEN STORAGE DISORDERS • 4.IMPAIRMENT OF FATTY ACID OXIDATION • 5.HYPOACTIVITY OF THYROID, ADRENALS AND PITUITARY GLANDS

  43. Symptoms Symptoms you may have when your blood sugar gets too low include:- • Double vision or blurry vision • Fast or pounding heartbeat • Feeling cranky or acting aggressive • Feeling nervous • Headache • Hunger • Shaking or trembling • Sleeping trouble • Sweating • Tingling or numbness of the skin • Tiredness or weakness • Unclear thinking Sometimes your blood sugar may be too low, even if you do not have symptoms. If your blood sugar gets too low, you may:- • Faint • Have a seizure • Go into a coma

  44. MCQ 1 • Which of the following substances will BE elevated in a starving cell? • A. 5’AMP • B. c-AMP • C. ATP • D. GTP • E. glucose

  45. MCQ2 • Which of the following statements correctly describe human glucose metabolism? A. Liver is impermeable to glucose in the absence of insulin B. Pancreatic β-cells, liver and brain are freely permeable to glucose due to specific glucose transporters C. Liver glucokinasephosphorylates glucose at high rates under all conditions D. Extrahepatic tissues are permeable to glucose when glucagon is present E. Liver takes up glucose when serum glucose is normal but releases it when serum glucose is high

  46. Thank you

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