obesity diabetes and metabolism

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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 casesfrequently called NIDDM: non insulin-dep. diabetes mellitus

~ 230 million cases world widewill 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 interventionIdea: 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

fat

cells

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 retestedRole of NEAT in human obesity

Obese group still has low NEAT after BMI drop

Lean group still has higherNEAT after BMI increase

Get UP!!!