Lecture 19 Slides
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OBESITY
DIABETES
and
METABOLISM
blood glucose:
held tightly at
~4 mM by hook
or crook
for
glucose
mg/dl =
18 x mM
fig 23-23
hormonal control
of blood glucose
Endocrine control: a hierarchy
fig 23-8
fig 23-4
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
Effect of insulin in type I…
LIVER
fasting
response
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
DIABETES MELLITUS
~ 230 million cases world wide
will double by 2030 (!)
strong genetic links
but
alarming incidence increase
indicates strong env. factors
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
New drugs for an old diseases: allosteric intervention
liver
specific
form
Joseph
Grippo
Grimsby et al. (2003) Science 301:370-3.
New drugs for an old diseases: allosteric intervention
Idea: Can a drug be developed that allosterically
activates liver-specific hexokinase (aka glucokinase)?
R0-28-1675: a synthetic glucokinase activator
Glucokinase activator works in vivo, orally
a poorly understood interplay between obesity and diabetes
diabetes
obesity
Prevalence of Obesity among
U.S. Adults, BRFSS, 1985
<10%
10-15%
>15%
Prevalence of Obesity among
U.S. Adults, BRFSS, 1998
<10%
10-15%
>15%
trends in obesity worldwide
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
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%.
ob/ob mice, and db/db mice: obesity genetics…
Leptin a signal from adipocytes that controls food
intake and energy metabolism
adipocyte
leptin
mediators
feeding
decrease
energy
consump.
increase
new
regulators
of appetite
peptides
from the
gut…
new regulators of appetite: peptides
PPY
appetite
ghrelin
appetite
can drugs be made to mimic
or alter these actions?
newer regulators of appetite: CB1 antagonists
newer regulators of appetite: CB1 antagonists
idea: endogenous cannabinoids control hunger
endogenous
cannabinoids
CB1
appetite
newer regulators of appetite: CB1 antagonists
idea: endogenous cannabinoids control hunger
endogenous
X
cannabinoids
CB1
CB1
blocker
appetite
newer regulators of appetite: CB1 antagonists
rimonabant (Acomplia®)
newer regulators of appetite: CB1 antagonists
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
changing lifestyle outpaces evolution..
changing lifestyle outpaces evolution..
by Eric Schlosser
The Obesity Scare?
“ but they never dreamt that
anyone would attempt to control
what we eat and drink.”
Richard Berman
corporate lawyer
food executive
lobbyist
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
The other poll of “medicine spectrum”
Premeds: SEE THIS!
Meat eaters: SEE THIS!
All others: SEE THIS!
We eat a CRAPLOAD of sugar…
If sugar is bad,
is it
FRUCTOSE or
AMOUNT…?
Watch “Sugar the Bitter Truth”
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?
Genetics and obesity: the Pima people
Genetics and obesity: the Pima people
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
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.
Organismal regulation of body fat
hunger/satiety
behavior
Serotonin
NPY
sensory
inputs
insulin
leptin
fat
cells
fat storage
adapted from Kahn, Nature Genetics (2000)
fat mobilization
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?
Two general types of diets
Fewer calories consumed
Different types of calories consumed
carbohydrates
protein
fat
Example: low carbohydrate diets
Atkins diet
“Zone” diet
South Beach
how do they work?
Is this something new?
Low carbohydrate diets
It’s all about calories…
mass
caloric
input
exercise
activity
What is the difference between exercise and activity?
calories
(per hour)
involved
in doing
stuff
Bicycling (10 mph)
Bowling
Ice Skating (leisurely)
Jumping Rope
Mountain Climbing
Playing Golf
Playing Pool (no beer!)
Racquetball
Running (7.5 mph)
Sitting
Sleeping
Standing
Swimming (recreational)
Walking On Level
Walking Up Stairs
420
270
300
750
600
270
120
540
750
100
80
140
600
360
1050
average adult intake ~ 2000/day
NEAT: Non-Exercise Activity Thermogenesis
The majority of our activity-caused calorie
use is not by exercise, but from NEAT
Playing Pool (no beer!)
Sitting
Standing
Walking On Level
vs.
Sleeping
120
100
140
360
80
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
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:
BMI obese:
23 +/- 2
33 +/- 2
“Interindividual variation in posture allocation: possible role
in human obesity” Levine et al., Science (2005) 307 530-1
NEAT: Non-Exercise Activity Thermogenesis
BMI 23
BMI 33
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
Role of NEAT in human obesity
A correlation: the chicken-egg problem...
LESS
NEAT
OBESITY
?
LESS
NEAT
?
OR
OBESITY
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 supervised weight loss over a period of 8 weeks.
The average wt. loss was 8 kg. Likewise,
we recruited 9 of the orginal lean volunteers and one additional volunteer to
undergo supervised overfeeding for a
period of 8 weeks. The average wt. gain
was 4 kg.”
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
Get UP!!!