2. Regulation of Blood Sugar Level at the Whole Animal Owen M c Guinness January 11, 2010 Course: MPB 333 Contact info: Phone: 343-4473 Office: 831C Light Hall e-mail:Owen.mcguinness@vanderbilt.edu

3. Regulation of Glucose Homeostasis: the Metabolic Challenge of Insulin Resistance

4. What is a normal fasting Glucose concentration? n Normal fasting level=<110 mg/dl n Impaired glucose intolerance=110- 125 mg/dl n Diabetes mellitus>125mg/dl

5. Where is glucose?

6. ISFCellCapillary Diffusion Glucose =100 mg/dl Glucose =? mg/dl Glucose diffuses down a concentration gradient

7. If the arterial glucose=100 mg/dl and insulin is at a basal concentration, what is the glucose concentration in a muscle cell? 1. 100 mg/dl 2. Slightly less than 100 mg/dl (~98 mg/dl) 3. Very low ~2 mg/dl 4. Greater than 100 mg/dl

8. Blood flow Cell Glu-6P Glu A V GLU= 100 mg/dlGLU= 98 mg/dl 3.Very low ~2 mg/dl

9. Glucose Glucose-6 P Glycogen Pyruvate Lactate CO 2 + H 2 O GLUT HK II Multiple Metabolic Fates of Glucose GS PFK PDH

10. If arterial glucose=100 mg/dl,what is the interstitial glucose concentration outside a muscle cell? 1. 100 mg/dl 2. Slightly less than 98 mg/dl 3. Very low ~2 mg/dl 4. Greater than 100 mg/dl

11. A V Blood flow Cell GLU= 100 mg/dlGLU= 98 mg/dl Glu-6P Glu #2.Slightly less than 98 mg/dl

12. Steady State In=Out Out=Clearance x Concentration Plasma Glucose

13. Relationship between Mass and Concentration

14. Glucose mass (70 kg individual) n Total body water (TBW)=60% Body Weight n 42 L TBW (=0.60 *70 kg) n Extracellular fluid volume (ECF)=1/3 TBW n 14 L ECF {~volume of distribution of glucose} n Glucose 100 mg/dl=1 mg/ml=1 g/L n 14 grams glucose in ECF n 9 g/hr flux rate= rate of liver glucose production

15. Glucose Ingestion (75 g) In=Out=9 g/h Out=Clearance x Concentration Plasma Glucose (14 g)

16. Ingest 75 grams glucose n 75 grams in 300 ml water (~2 cokes) n Assuming it takes about 20 min to absorb the glucose (225 g/h) n By 180 minutes the glucose concentration returns to normal n Removed 5.3 times the mass of glucose in the body in 180 min

17. 75 grams

18. 75 g glucose load n If you did nothing n glucose level exceed 500 mg/dl

19. Liver 9 g/hr Glucose=90 mg/dl CNS Brain 6 g/hr Muscle Fat 3 g/hr Insulin + + Glucagon Insulin Overnight fasted state ? ?

20. Liver 12 g/hr  Glucose=~130 mg/dl CNS Brain 6 g/hr Muscle Fat 32 g/hr  Insulin + +  or  Glucagon  Insulin Fed state Intestine 50 g/hr  Cholinergic

21. Liver 7 g/hr  Glucose=~70 mg/dl CNS Brain ~5 g/hr Muscle Fat 2 g/hr  Insulin + +  Glucagon  Insulin Prolonged fasted state Ketones

22. Liver 46 g/hr Glucose=~90 mg/dl CNS Brain 6 g/hr Muscle Fat 40 g/hr  Insulin + +  Glucagon  Insulin “Fight or Flight” state Adrenergic Increased Muscle Energy Demand

23. Liver 26 g/hr  Glucose>~300 mg/dl CNS Brain 6 g/hr Muscle Fat <1 g/hr +  Glucagon Type I Diabetic state ( loss of insulin secretion) Kidney ~19 g/hrKetones

24. Net Organ Uptake (A-V) * flow = uptake

25. Hepatic vein

26. Net Splanchnic uptake (Artery-HepaticVein) * flow = uptake Splanchnic bed: liver Intestine Spleen pancreas

27. Splanchnic Bed Producer and/or glucose consumer Liver Intestine

28. Splanchnic metabolism during hyperglycemia n Persistent glucose production in diabetic (i.e. negative balance) n Failure to take up glucose with additional insulin n The failure to activate uptake and suppress production both contribute DiabeticNon-Diabetic Low insulinHigh insulin

29. Individuals with type II diabetes The liver produces glucose despite high glucose levels

30. n Tissue glucose uptake increases in proportion to the available glucose n Insulin facilitates this process in tissues that respond to insulin –  transport –  phosphorylation –↑Glycogen synthesis –↑Glucose oxidation n Insulin resistance impairs this process Insulin Resistant Normal

31. Steady State In=Out Out=Clearance x Concentration Plasma Glucose

32. Source: www.cdc.gov. Diabetes Trends* Among Adults in the U.S., (Includes Gestational Diabetes)BRFSS, 1990,1995 and 2001 19901995 2001 No Data 10%

33. Liver 9 g/hr Glucose=120 mg/dl CNS Brain 6 g/hr Muscle Fat 3 g/hr  Insulin + + Glucagon  Insulin Overnight Fasted Insulin Resistant state

34. Compensation for insulin resistance n Increase insulin secretion n Mild to severe hyperglycemia (Diabetes Type II; NIDDM) because of inadequate pancreas compensation n Glucose production by liver and uptake by peripheral tissues can be normal or increased

35. Tools used in vivo to assess glucose homeostasis and insulin action

37. MEASUREMENT OF GLUCOSE PRODUCTION IN VIVO Tracer Method ( dilution principle) 3- 3 H Glucose infusion Data analysis with two compartment model A-V Difference Method Blood glucose difference across organ Blood flow across organ

38. x

43. Sampling site: Portal Vein and Artery n If you infuse a substance into the portal vein, the concentration of the substance in the portal vein will be greater than in any other vessel

45. Impact of insulin on tissues n Enhance muscle glucose uptake n Decrease liver glucose production n Decrease arterial glucose level n Inhibit lipolysis n To prevent hypoglycemia exogenous glucose is given

46. The “gold standard” for quantifying insulin sensitivity in vivo Primed-constant Insulin Infusion Variable Glucose Infusion Insulin Glucose Radioactive Glucose Tracers Endogenous Glucose Production (basal and clamp) Glucose Disappearance (Rd) Exogenous Glucose Infusion rate (GIR)

47. Defronzo RA et al AJP E214,1979

48. Peripheral insulin sensitivity

50. Hepatic Insulin Sensitivity Basal Insulin

51. Peripheral vein

52. Diabetes and insulin resistance n Insulin resistance –Normal or elevated insulin levels –Inappropriately increased lipolysis –Insulin ineffective and in many cases pancreatic defects limit adaptation –Underlying inflammation can aggravate defects

53. The End