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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
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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
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
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
~ 230 million cases world wide will double by 2030 (!) DIABETES MELLITUS 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 impared ins. secretion b-cells 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)?
diabetes obesity a poorly understood interplay between obesity and diabetes
<10% 10-15% Prevalence of Obesity among U.S. Adults, BRFSS, 1985 >15%
Prevalence of Obesity among U.S. Adults, BRFSS, 1998 >15% <10% 10-15%
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%.
Leptin a signal from adipocytes that controls food intake and energy metabolism adipocyte leptin mediators energy consump. increase feeding decrease
new regulators of appetite peptides from the gut…
PPY appetite appetite ghrelin new regulators of appetite: peptides can drugs be made to mimic or alter these actions?
endogenous cannabinoids CB1 appetite newer regulators of appetite: CB1 antagonists idea: endogenous cannabinoids control hunger
X CB1 blocker newer regulators of appetite: CB1 antagonists idea: endogenous cannabinoids control hunger endogenous cannabinoids CB1 appetite
newer regulators of appetite: CB1 antagonists rimonabant (Acomplia®)
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.. by Eric Schlosser
The Obesity Scare? Richard Berman corporate lawyer food executive lobbyist “ but they never dreamt that anyone would attempt to control what we eat and drink.”
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!
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 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 fat mobilization adapted from Kahn, Nature Genetics (2000)
How to lose weight CNS drugs alter satiety signals dietary changes exercise novel uncoupling strategies? consume fewer calories absorb fewer calories olestra, xenecal, surgery burn more calories
carbohydrates protein fat Two general types of diets Fewer calories consumed Different types of calories consumed
Example: low carbohydrate diets Atkins diet “Zone” diet South Beach how do they work? Is this something new?