OBESITY DIABETES and METABOLISM

1. OBESITY DIABETES and METABOLISM

2. blood glucose: held tightly at ~4 mM by hook or crook for glucose mg/dl = 18 x mM fig 23-23

3. hormonal control of blood glucose

4. Endocrine control: a hierarchy fig 23-8

6. fig 23-4

8. DIABETES MELLITUS a state in which carbohydrate and lipid metabolism is improperly regulated by insulin TYPE I : patients are completely insulin dependent 5-10 % of cases

9. Effect of insulin in type I…

10. LIVER fasting response

11. DIABETES MELLITUS a state in which carbohydrate and lipid metabolism is improperly regulated by insulin TYPE I : patients are completely insulin dependent 5-10 % of cases TYPE II : defect in insulin action and secretion remaining cases frequently called NIDDM: non insulin-dep. diabetes mellitus

12. ~ 230 million cases world wide will double by 2030 (!) DIABETES MELLITUS strong genetic links but alarming incidence increase indicates strong env. factors

13. diabetes transgenic models: tissue specific receptor KO muscle no disease! liver overt diabetes adipose overt diabetes impared ins. secretion b-cells brain increased food intake obesity, systemic insulin resistance (?) fig 23-4

14. New drugs for an old diseases: allosteric intervention liver specific form Joseph Grippo Grimsby et al. (2003) Science 301:370-3.

15. New drugs for an old diseases: allosteric intervention Idea: Can a drug be developed that allosterically activates liver-specific hexokinase (aka glucokinase)?

16. R0-28-1675: a synthetic glucokinase activator

17. Glucokinase activator works in vivo, orally

18. diabetes obesity a poorly understood interplay between obesity and diabetes

19. <10% 10-15% Prevalence of Obesity among U.S. Adults, BRFSS, 1985 >15%

20. Prevalence of Obesity among U.S. Adults, BRFSS, 1998 >15% <10% 10-15%

21. trends in obesity worldwide

22. The BMI: body mass index A crude but easy-to-calculate indicator of body mass that is a useful indicator of obesity in populations BMI = body weight/height2 In kg/mt2 BMI calculator: http://www.cdc.gov/nccdphp/dnpa/bmi/calc-bmi.htm

24. Magnitude of Risk Women: RR is 18.1 for BMI ≥ 31 Men: RR is 50.7 for BMI ≥ 35 • WHO estimates BMI < 25 would prevent 64% of Type 2 DM in US men and 74% in US women. • Framingham study estimates BMI < 25 would reduce coronary heart disease by 25% and strokes and congestive heart failure by 35%.

25. ob/ob mice, and db/db mice: obesity genetics…

26. Leptin a signal from adipocytes that controls food intake and energy metabolism adipocyte leptin mediators energy consump. increase feeding decrease

27. new regulators of appetite peptides from the gut…

28. PPY appetite appetite ghrelin new regulators of appetite: peptides can drugs be made to mimic or alter these actions?

29. newer regulators of appetite: CB1 antagonists

30. endogenous cannabinoids CB1 appetite newer regulators of appetite: CB1 antagonists idea: endogenous cannabinoids control hunger

31. X CB1 blocker newer regulators of appetite: CB1 antagonists idea: endogenous cannabinoids control hunger endogenous cannabinoids CB1 appetite

32. newer regulators of appetite: CB1 antagonists rimonabant (Acomplia®)

33. newer regulators of appetite: CB1 antagonists

34. changing lifestyle outpaces evolution.. 50,000 years ago food scarce, famines common strong evolutionary bias towards storage of calories 100 years ago-present abundant, highly efficient production of food. Altered calorie availability based on fiscal imperatives

35. changing lifestyle outpaces evolution..

36. changing lifestyle outpaces evolution.. by Eric Schlosser

37. The Obesity Scare? Richard Berman corporate lawyer food executive lobbyist “ but they never dreamt that anyone would attempt to control what we eat and drink.”

38. One poll of the “medicine spectrum” “One of the myths of the modern world is that health is largely determined by individual choice.” — Barry R. Bloom (2000) Dean, Harvard School of Public Health

39. The other poll of “medicine spectrum” Premeds: SEE THIS! Meat eaters: SEE THIS! All others: SEE THIS!

40. We eat a CRAPLOAD of sugar…

41. If sugar is bad, is it FRUCTOSE or AMOUNT…? Watch “Sugar the Bitter Truth”

42. Genetics and obesity: the Pima people average adult onset diabetes in USA~ 6-8% Pima of S.W. USA (Pima people) ~ 50% 95% of Pima with NIDDM are obese What are the underlying causes of this difference?

43. Genetics and obesity: the Pima people

44. Genetics and obesity: the Pima people

45. Genetics and obesity: the Pima people The THRIFTY GENE model Poor name: almost certainly multiple genes Incredibly important resource What are the genes and environmental factors

46. Genetics and obesity: the Pima people It is believed that the obesity and diabetes observed in the Pima is due to a genetic propensity to respond poorly to the typical INDUSTRALIZED WESTERN diet.

47. Organismal regulation of body fat hunger/satiety behavior Serotonin NPY sensory inputs insulin leptin fat cells fat storage fat mobilization adapted from Kahn, Nature Genetics (2000)

48. How to lose weight CNS drugs alter satiety signals dietary changes exercise novel uncoupling strategies? consume fewer calories absorb fewer calories olestra, xenecal, surgery burn more calories

49. carbohydrates protein fat Two general types of diets Fewer calories consumed Different types of calories consumed

50. Example: low carbohydrate diets Atkins diet “Zone” diet South Beach how do they work? Is this something new?