1. OBESITY DIABETES and METABOLISM OBESITY DIABETES and METABOLISM

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

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. fasting response LIVER

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 (!) strong genetic links but alarming incidence increase indicates strong env. factors DIABETES MELLITUS

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

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. obesity diabetes a poorly understood interplay between obesity and diabetes

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

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

21. trends in obesity worldwide

22. The BMI: body mass index http://www.cdc.gov/nccdphp/dnpa/bmi/calc-bmi.htm A crude but easy-to-calculate indicator of body mass that is a useful indicator of obesity in populations BMI = body weight/height 2 In kg/mt 2 BMI calculator:

24. Women: RR is 18.1 for BMI ≥ 31Men: 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%. Magnitude of Risk

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

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

27. new regulators of appetite peptides from the gut…

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

29. newer regulators of appetite: CB1 antagonists

30. endogenous cannabinoids CB1 appetite idea: endogenous cannabinoids control hunger

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

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. by Eric Schlosser changing lifestyle outpaces evolution..

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

38. “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 One poll of the “medicine spectrum”

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

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

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

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

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

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

51. Low carbohydrate diets

52. It’s all about calories… mass caloric input activity exercise

53. It’s all about calories… mass caloric input activity exercise

54. It’s all about calories… mass activity exercise 1500 cal per day

55. It’s all about calories… mass activity exercise 1500 cal per day

56. What is the difference between exercise and activity?

57. Bicycling (10 mph) 420 Bowling270 Ice Skating (leisurely) 300 Jumping Rope750 Mountain Climbing600 Playing Golf270 Playing Pool (no beer!)120 Racquetball540 Running (7.5 mph)750 Sitting100 Sleeping80 Standing140 Swimming (recreational)600 Walking On Level360 Walking Up Stairs1050 calories (per hour) involved in doing stuff average adult intake ~ 2000/day

58. Playing Pool (no beer!)120 Sitting100 Standing140 Walking On Level360 vs. Sleeping80 NEAT: Non-Exercise Activity Thermogenesis The majority of our activity-caused calorie use is not by exercise, but from NEAT

59. NEAT: Non-Exercise Activity Thermogenesis NEAT varies substantially among individuals Question: Could natural variations in NEAT contribute to obesity in people? James A. Levine, M.D. Mayo Clinic, Rochester MN

60. NEAT: Non-Exercise Activity Thermogenesis “To compare body posture and body motion in lean and obese people, we recruited 20 healthy volunteers who were self-proclaimed “couch potatoes” “Interindividual variation in posture allocation: possible role in human obesity” Levine et al., Science (2005) 307 530-1 BMI lean: 23 +/- 2 BMI obese: 33 +/- 2

61. NEAT: Non-Exercise Activity Thermogenesis BMI 23 BMI 33

62. Role of NEAT in human obesity 25 milllion data points collected on BMI 23 and 33 groups to evaluate NEAT “Interindividual variation in posture allocation: possible role in human obesity” Levine et al., Science (2005) 307 530-1

63. A correlation: the chicken-egg problem... Role of NEAT in human obesity LESS NEAT OBESITY LESS NEAT OR ? ?

64. NEAT: Non-Exercise Activity Thermogenesis “To investigate whether there differences in posture allocation are a cause or a consequence of obesity, we asked 7 of the original volunteers to undergo super- vised weight loss over a period of 8 weeks. The average wt. loss was 8 kg. Likewise, we recruited 9 of the orginal lean volun- teers and one additional volunteer to undergo supervised overfeeding for a period of 8 weeks. The average wt. gain was 4 kg.”

65. When BMIs are switched and groups retested Role of NEAT in human obesity Obese group still has low NEAT after BMI drop Lean group still has higher NEAT after BMI increase

66. Get UP!!!