Rh Lecture 19 Slides. OBESITY DIABETES and METABOLISM OBESITY DIABETES and METABOLISM.
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Transcript of Rh Lecture 19 Slides. OBESITY DIABETES and METABOLISM OBESITY DIABETES and METABOLISM.
rh
Lecture 19 Slides
OBESITYDIABETES
andMETABOLISM
blood glucose:held tightly at~4 mM by hookor crook
fig 23-23
forglucosemg/dl =18 x mM
hormonal controlof blood glucose
Endocrine control: a hierarchy
fig 23-8
fig 23-4
DIABETES MELLITUS
a state in which carbohydrate and lipidmetabolism is improperly regulated byinsulin
TYPE I : patients are completely insulin dependent
5-10 % of cases
Effect of insulin in type I…
fastingresponse
LIVER
DIABETES MELLITUS
a state in which carbohydrate and lipidmetabolism is improperly regulated byinsulin
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
~ 230 million cases world wide
will double by 2030 (!)
strong genetic links
but
alarming incidence increase indicates strong env. factors
DIABETES MELLITUS
diabetes transgenic models: tissue specific receptor KO
fig 23-4
muscle
liver
adipose
b-cells
brain
no disease!
overt diabetes
overt diabetes
impared ins. secretion
increased food intakeobesity, systemic insulinresistance (?)
New drugs for an old diseases: allosteric intervention
liver specific form
JosephGrippo
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
obesity
diabetes
a poorly understood interplay between obesity and diabetes
Prevalence of Obesity among
U.S. Adults, BRFSS, 1985
<10% 10-15% >15%
<10% 10-15% >15%
Prevalence of Obesity among
U.S. Adults, BRFSS, 1998
trends in obesity worldwide
The BMI: body mass index
http://www.cdc.gov/nccdphp/dnpa/bmi/calc-bmi.htm
A crude but easy-to-calculateindicator of body mass that is a useful indicator of obesity inpopulations
BMI = body weight/height2
In kg/mt2
BMI calculator:
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%.
Magnitude of Risk
ob/ob mice, and db/db mice: obesity genetics…
Leptin a signal from adipocytes that controls foodintake and energy metabolism
leptin
mediators
feedingdecrease
energyconsump.increase
adipocyte
newregulatorsof appetite
peptides from the gut…
new regulators of appetite: peptides
ghrelin appetite
PPY appetite
can drugs be made to mimic or alter these actions?
newer regulators of appetite: CB1 antagonists
newer regulators of appetite: CB1 antagonists
endogenouscannabinoids
CB1 appetite
idea: endogenous cannabinoids control hunger
newer regulators of appetite: CB1 antagonists
endogenouscannabinoids
CB1 appetite
CB1blocker
X
idea: endogenous cannabinoids control hunger
newer regulators of appetite: CB1 antagonists
rimonabant (Acomplia®)
newer regulators of appetite: CB1 antagonists
changing lifestyle outpaces evolution..
50,000 years agofood scarce, famines commonstrong evolutionary bias towardsstorage of calories
100 years ago-presentabundant, highly efficient productionof food. Altered calorie availability basedon fiscal imperatives
changing lifestyle outpaces evolution..
by Eric Schlosser
changing lifestyle outpaces evolution..
The Obesity Scare?
Richard Bermancorporate lawyerfood executivelobbyist
“ but they never dreamt thatanyone would attempt to controlwhat we eat and drink.”
“One of the myths of the modern world is that health is largely determined by individual choice.”
— Barry R. Bloom (2000)Dean, Harvard School ofPublic Health
One poll of the “medicine spectrum”
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 itFRUCTOSE orAMOUNT…?
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
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
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.
adapted from Kahn, Nature Genetics (2000)
sensory inputs
hunger/satiety behaviorSerotonin
NPY
fat storage fat mobilization
fatcells
insulinleptin
Organismal regulation of body fat
consume fewer calories
absorb fewer calories
burn more calories
CNS drugsalter satiety signalsdietary changes
exercisenovel uncoupling strategies?
olestra, xenecal, surgery
How to lose weight
Two general types of diets
Fewer calories consumed
Different types of calories consumed
carbohydratesprotein
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…
masscaloricinput
activity
exercise
What is the difference between exercise and activity?
Bicycling (10 mph) 420Bowling 270Ice Skating (leisurely) 300Jumping Rope 750Mountain Climbing 600Playing Golf 270Playing Pool (no beer!) 120Racquetball 540Running (7.5 mph) 750Sitting 100Sleeping 80Standing 140Swimming (recreational) 600Walking On Level 360Walking Up Stairs 1050
calories(per hour)involvedin doingstuff
average adult intake ~ 2000/day
Playing Pool (no beer!) 120Sitting 100Standing 140Walking On Level 360
vs.
Sleeping 80
NEAT: Non-Exercise Activity Thermogenesis
The majority of our activity-caused calorieuse is not by exercise, but from NEAT
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 bodymotion in lean and obese people, werecruited 20 healthy volunteers whowere 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 +/- 2BMI obese: 33 +/- 2
NEAT: Non-Exercise Activity Thermogenesis
BMI 23 BMI 33
Role of NEAT in human obesity
25 milllion data points collected on BMI 23 and33 groups to evaluate NEAT
“Interindividual variation in posture allocation: possible role in human obesity” Levine et al., Science (2005) 307 530-1
A correlation: the chicken-egg problem...
Role of NEAT in human obesity
LESSNEAT
OBESITY
OBESITYLESSNEAT
OR
?
?
NEAT: Non-Exercise Activity Thermogenesis
“To investigate whether there differencesin posture allocation are a cause or a consequence of obesity, we asked 7 ofthe 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 aperiod of 8 weeks. The average wt. gainwas 4 kg.”
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 higherNEAT after BMI increase
Get UP!!!