1. Lecture 19 Slides rh

2. OBESITY
DIABETES
and
METABOLISM

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

4. hormonal control
of blood glucose

5. Endocrine control: a hierarchy
fig 23-8

7. fig 23-4

9. a state in which carbohydrate and lipid
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

10. Effect of insulin in type I…

11. LIVER
fasting
response

12. a state in which carbohydrate and lipid
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

13. ~ 230 million cases world wide
DIABETES MELLITUS
~ 230 million cases world wide
will double by 2030 (!)
strong genetic links
but
alarming incidence increase
indicates strong env. factors

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

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

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

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

18. Glucokinase activator works in vivo, orally

19. a poorly understood interplay between obesity and diabetes

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

21. Prevalence of Obesity among U.S. Adults, BRFSS, 1998
<10% %
>15%
Prevalence of Obesity among U.S. Adults, BRFSS, 1998 1

22. trends in obesity worldwide

23. A crude but easy-to-calculate indicator of body mass that is
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:

25. Magnitude of Risk Women: RR is 18.1 for BMI ≥ 31
• 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%.

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

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

28. new
regulators
of appetite
peptides
from the
gut…

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

30. newer regulators of appetite: CB1 antagonists

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

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

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

34. newer regulators of appetite: CB1 antagonists

35. 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

36. changing lifestyle outpaces evolution..

37. changing lifestyle outpaces evolution..
by Eric Schlosser

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

39. 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

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

41. We eat a CRAPLOAD of sugar…

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

43. 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?

44. Genetics and obesity: the Pima people

45. Genetics and obesity: the Pima people

46. 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

47. 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.

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

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

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

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

52. Low carbohydrate diets

53. The “It’s all about calories” model
mass
exercise
caloric
input
activity

54. What is the difference between exercise and activity?

55. average adult intake ~ 2000/day
calories
(per hour)
involved
in doing
stuff
Bicycling (10 mph) 420
Bowling 270
Ice Skating (leisurely) 300
Jumping Rope 750
Mountain Climbing 600
Playing Golf 270
Playing Pool (no beer!) 120
Racquetball 540
Running (7.5 mph) 750
Sitting
Sleeping 80
Standing 140
Swimming (recreational) 600
Walking On Level 360
Walking Up Stairs 1050
average adult intake ~ 2000/day

56. NEAT: Non-Exercise Activity Thermogenesis
The majority of our activity-caused calorie
use is not by exercise, but from NEAT
Playing Pool (no beer!) 120
Sitting 100
Standing 140
Walking On Level 360
vs.
Sleeping 80

57. 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

58. “To compare body posture and body motion in lean and obese people, we
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”
BMI lean: /- 2
BMI obese: /- 2
“Interindividual variation in posture allocation: possible role
in human obesity” Levine et al., Science (2005)

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

60. 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)

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

62. “To investigate whether there differences
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.”

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

64. Get UP!!!