Title: The Pyramid of Recent Trials
1LEPTIN acts in arcuate nucleus in
hypothalamus Via the JAK/STAT pathway Obese and
T2DM often insulin leptin resistance Not a good
treatment for weight loss Up regulated during
puberty
2resistin Elevated in insulin resistance and
t2DM Interferes with insulin receptor
signaling Receptor still unknown Too much-BAD
3Adiponectin Decreased in obesity, insulin
resistance and T2DM (NIDDM) Associated with
Cardiovascular health Acts on many tissues (liver
and muscle) Associated with Insulin
Sensitivity Various forms in circulation-monomer
to multimer G protein coupled, 2 receptors
4Links between obesity and T2DM Most T2DM are
obese Adipocytes make hormones that effect
overall body insulin sensitivity Weight loss can
reverse T2DM (early) One diabetes drug activates
an adipocyte transcription factor
5Excess Adipose Tissue ObesityPrinciples of
Energy Metabolism
6Body Energy Stores of Lean 70-kg Man
Liver triglyceride 450 kcal
Muscle triglyceride 3000 kcal
Liver glycogen 400 kcal
Muscle glycogen 2500 kcal
Adipose tissue triglyceride 120,000 kcal
7Obesity Is Caused by Long-Term Positive Energy
Balance
FatStores
8Components of Daily Energy Expenditure
Thermic effect of feeding
Energy expenditure of physical activity
Resting energy expenditure
8
17
8
32
75
60
Sedentary Person (1800 kcal/d)
Physically Active Person (2200 kcal/d)
Segal KR et al. Am J Clin Nutr. 198440995-1000.
9Components of Daily Energy Expenditure Energy
expended by physical activity depends on the
intensity and duration of activities and is the
most variable component of E expenditure. During
high-intensity aerobic exercise (vigorous running
or cycling), E consumed by working muscles can
increase more than 50-fold, causing a 15-fold
increase in total energy expenditure. Obese
individuals require the same amount of energy to
perform the same amount of work when body weight
is supported as do normal weight individuals. In
fact, obese persons expend more energy for the
same level of activity when the activity is
weight-bearing because of the increased work
involved in carrying more weight
10Relationship between Tissue Energy Expenditure
and Mass
80 60 40 20 0
Tissue energy expenditure Tissue weight
Weight ( Body Weight)
Energy Expenditure (REE)
Liver, Brain, Kidneys, Gut, Heart
SkeletalMuscle
AdiposeTissue,LeanPerson
AdiposeTissue,ObesePerson
REE Resting energy expenditure
11Relationship between Tissue Energy Expenditure
and Mass Different body tissues have markedly
different resting E requirements. Organs that
have large metabolic demands, such as the liver,
gut, brain, kidney, and heart, have the highest
energy requirements per gram of tissue. In a
lean adult, these organs account for
approximately 75 of resting E expenditure,
although they constitute only 10 of total body
weight. In contrast, resting skeletal muscle
consumes only 20 of resting metabolic rate,
although it represents approximately 40 of total
body weight. Adipose tissue consumes less than
5 of resting metabolic rate but usually accounts
for approximately 20 of body weight.
12Regulation of Food Intake
Brain
Central Signals
Stimulate
Inibit
NPY AGRP galanin
Orexin-A dynorphin
a-MSH CRH/UCN GLP-I
CART NE 5-HT
Peripheral signals
Peripheral organs
Glucose CCK, GLP-1,Apo-A-IVVagal
afferents Insulin GhrelinLeptinCortisol
Gastrointestinaltract
FoodIntake
Adiposetissue
Adrenal glands
13Lifetime Food Intake
Water 45,300 kg
Fat 2300 kg 21 kcal
Cholesterol 8000 kg 31 kcal
Protein 1900 kg 7 kcal
kcal in millions
14Cumulative Effect of Small Daily Imbalances in
Energy Intake on Body Fat Mass
1 million
Energyintake(kcal/y)
Energyexpenditure(kcal/y)
1 million
0 0.5 1 5
12 25 125
Excess intake ( total) Excess intake (kcal/d)
Rosenbaum M et al. N Engl J Med. 1997337396-408.
15Consistent differences, even if very minor,
between E intake and E expenditure can lead to
large changes in body fat mass over time. In
the USA, most adults consume approximately
900,000 kcal per year. If energy balance were
positive by as little as 0.5 (12 kcal/d), 1
pound of fat would be gained in 1 year. Daily
ingestion of only 5 more calories than expended
could result in the accumulation of approximately
6 kg (13 lb) of adipose tissue in 1 year.
Ingestion of only 8 kcal/d more than expended
over 30 years could lead to an increase of 10 kg
in body weight, which is the average amount of
weight gained by American adults from 25 to 55
years of age 1. Rosenbaum M et al. Obesity. N
Engl J Med. 1997337396-408.
16The prevalence of obesity in adults in the USA
increases progressively from 20 to 50 years of
age, but begins to decline after 60 years of age.
The prevalence of obesity also varies by
ethnicity and gender. Obesity is particularly
common in many ethnic minority women (eg,
African-American, Mexican-American, Native
American, Pacific IslanderAmerican, Puerto
Rican, Cuban-American). In last decade,
incidence of Obesity had risen every year.
17- Although genetics is an important factor in the
pathogenesis of obesity, the recent increase in
obesity cannot be attributed to genetics alone
and must be a result of alterations in
environmental influences. - Obesity Epidemic- 50/50 ?????
- However, people with certain genetic backgrounds
are particularly predisposed to weight gain and
obesity-related diseases, especially when they
are exposed to a precipitating lifestyle.
18- A striking example of this is given by the Pima
Indians of Arizona. Lifestyle changes have
resulted in an epidemic of obesity/diabetes
within this population in the last 50 years 1. - Today, the Pimas of Arizona consume a high-fat
diet (50 of E as fat) provided by government
surplus commodities rather than their traditional
low-fat diet (15 of E as fat), and they are much
more sedentary than when they were farmers. -
19-
- In contrast, Pima Indians who live in the Sierra
Madre mountains of Northern Mexico, and
consequently who have been isolated from Western
influences, eat a traditional Pima diet and are
physically active as farmers and sawmill workers.
The Pimas of Mexico have a much lower incidence
of obesity and diabetes than their genetic
kindred in Arizona. - Pratley RE. Gene-environment interactions in the
pathogenesis of type 2 diabetes mellitus lessons
learned from the Pima Indians. Proc Nutr Soc.
199857175-181. - Ravussin E et al. Effects of a traditional
lifestyle on obesity in Pima Indians. Diabetes
Care 1994 171067-1074.
20Gene-Environment Interaction in the Pathogenesis
of Obesity
P lt0.0001
Pima Indians
Body Mass Index (kg/m2)
Maycoba, Mexico
Arizona
Ravussin E et al. Diabetes Care 1994171067-1074.
21 Environment, not genetics, resulted in epidemic
of obesity/diabetes within this population in the
last 50 years. Pima Indians an example
22Medical Complications of Obesity
23BMI-Associated Disease Risk
Classification BMI (kg/m2) Risk
Underweight lt18.5 Increased
Normal 18.5-24.9 Normal
Overweight 25.0-29.9 Increased
Obese I 30.0-34.9 High
II 35.0-39.9 Very High
III gt40 Extremely high
- Additional risks
- Large waist circumference (mengt40 in women gt35
in) - 5 kg or more weight gain since age 18-20 y
- Poor aerobic fitness
- Specific races and ethnic groups
Clinical Guidelines on the Identification,
Evaluation, and Treatment of Overweight and
Obesity in AdultsThe Evidence Report. Obes Res
19986(suppl 2).
24Body Mass Index Chart
Weight (lb)
25Relationship Between BMI and Percent Body Fat in
Men and Women (coorelate)
Women Men
Body Fat ()
0
10
30
40
60
20
50
Body Mass Index (kg/m2)
Adapted from Gallagher et al. Am J Clin Nutr
200072694.
26Medical Complications of Obesity
Idiopathic intracranial hypertension
Pulmonary disease abnormal function obstructive
sleep apnea hypoventilation syndrome
Stroke
Cataracts
Nonalcoholic fatty liver disease steatosis steatoh
epatitis cirrhosis
Coronary heart disease Diabetes
Dyslipidemia Hypertension
TYPE 2 diabetes
Severe pancreatitis
Gall bladder disease
Cancer breast, uterus, cervix colon, esophagus,
pancreas kidney, prostate
Gynecologic abnormalities abnormal
menses infertility polycystic ovarian syndrome
Osteoarthritis
Phlebitis venous stasis
Skin
Gout
27Metabolic Syndrome
- Abdominal obesity
- Hyperinsulinemia
- High fasting plasma glucose
- Impaired glucose tolerance
- Hypertriglyceridemia
- Low HDL-cholesterol
- Hypertension
28Evolution of Metabolic Syndrome
AKA Insulin Resistance Syndrome Syndrome X
Dysmetabolic Syndrome Multiple Metabolic Syndrome
1923 Kylin describes clustering of hypertension,
gout, and hyperglycemia
1988 Reaven describes Syndrome X
hypertension, hyperglycemia, glucose intolerance,
elevated triglycerides, and low HDL cholesterol
1998 World Health Organization defines
metabolic syndrome as clustering of
hypertension, low HDL, hypertriglyceridemia,
insulin resistance, glucose intolerance or type 2
diabetes, high waist-to-hip ratio, and
microalbuminuria
Isomaa B et al. Diabetes Care. 200124683-689.
29Characteristics of the Metabolic
SyndromeIncreases risk of DIABETES AND CVD
Abdominal obesity Glucose intolerance/ Insulin
resistance Hypertension Atherogenic
dyslipidemia Proinflammatory/ Prothrombotic state
Diabetes
CVD
National Cholesterol Educational Program (NCEP),
Adult Treatment Panel (ATP) III 2001.
30Clinical Identification of the Metabolic Syndrome
Diagnosis is established when gt3 of these risk
factors are present
Risk Factor Defining Level
Abdominal obesity
(Waist circumference)
Men gt102 cm (gt40 in)
Women gt88 cm (gt35 in)
TG gt150 mg/dL
HDL-C
Men lt40 mg/dL
Women lt50 mg/dL
Blood pressure gt130 / gt85 mm Hg
Fasting glucose gt110 (gt100) mg/dL
2003 New ADA IFG criteria (Diabetes Care)
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
31Increasing Prevalence of Metabolic Syndrome with
Age
Men Women
Prevalence ()
Age
Ford E et al. JAMA. 2002287356-359.
32It is usually said that the prevalence of the
metabolic syndrome in the United States is 23 or
24. However, this is not a useful statement
since the prevalence of the metabolic syndrome
markedly increases with age. The prevalence of
the metabolic syndrome is lt10 in individuals
aged 2029 years, 20 in individuals aged 4049
years, and 45 in individuals aged 6069 years.
Thus it might be more useful to suggest that the
estimated prevalence of the metabolic syndrome is
an individual's age minus 20.
33Prevalence of the Metabolic Syndrome Varies by
Sex and Race/Ethnicity (non institutionalized gt20
yrs of age)
36
28
26
25
23
21
20
Prevalence ()
16
Age
Ford E et al. JAMA. 2002287356-359.
34Metabolic Syndrome Impact on Mortality
Without metabolic syndrome With metabolic syndrome
Mortality Rate ()
P lt 0.001.
Isomaa B et al. Diabetes Care. 200124683-689.
35Metabolic Syndrome Impact on Cardiovascular
Health
Without metabolic syndrome With metabolic syndrome
Prevalence ()
P lt 0.001.
Isomaa B et al. Diabetes Care. 200124683-689.
36Ectopic Lipids and the Metabolic Syndrome
- Metabolic syndrome reflects failure of
intracellular lipohomeostasis, which prevents
lipotoxicity in organs of overnourished
individuals - Normal individuals lipohomeostasis (ie, lipid
overload confined to white adipocytes, designed
to store surplus calories) - Obese individuals adipocytes increase leptin
secretion in an attempt to enhance oxidation of
surplus lipid in nonadipocytes - Deficiency or nonresponsiveness to leptin
prevents these protective events and results in
ectopic accumulation of lipids - Pancreatic ?-cells and myocardiocytes are
cellular victims leading to type 2 diabetes
and lipotoxic cardiomyopathy
Unger RH. Endocrinology. 2003.
37Ectopic Lipids or presence of fat in other
tissues in an important contributer to INSULIN
RESISTANCECan find ectopic fatin liver, muscle,
heart, and pancreas
38Relationship Between BMI and Cardiovascular
Disease Mortality
Men Women
Relative Risk of Death
Lean
Overweight
Obese
lt18.5
18.520.4
20.521.9
22.0 23.4
23.5 24.9
25.0 26.4
26.527.9
28.0 29.9
30.0 31.9
32.034.9
35.0 39.9
gt40.0
Body Mass index
Calle et al. N Engl J Med 19993411097.
39Relationship Between BMI and Risk of Type 2
Diabetes
93.2
Men Women
54.0
Age-Adjusted Relative Risk
42.1
40.3
27.6
21.3
15.8
8.1
5.0
11.6
4.3
2.9
2.2
6.7
4.4
1.5
1.0
1.0
1.0
Body Mass index (kg/m2)
Chan J et al. Diabetes Care 199417961. Colditz
G et al. Ann Intern Med 1995122481.
40Relationship Between Weight Gain in Adulthood and
Risk of Type 2 Diabetes Mellitus
Men Women
Relative Risk
Weight Change (kg)
Willett et al. N Engl J Med 1999341427.
41Direct Cost of Chronic Diseases in the United
States
53.2
51.6
38.7
Direct Cost ( Billions)
18.4
18.1
Type 2Diabetes
Obesity
CoronaryHeart Disease
Hyper-tension
Stroke
Adjusted to 1995 dollars.
Wolf AM, Colditz GA. Obes Res. 1998697-106. Hodg
son TA, Cohen AJ. Med Care. 199937994-1012.
42Increase in Healthcare Costs Among Obese Compared
with Lean (BMI lt25 kg/m2) Patients
Increase in Cost Compared with Lean Subjects ()
BMI 30-34 kg/m2
BMI gt35 kg/m2
HMO Setting Northern California Kaiser
Permanente.
Quesenberry CP Jr et al. Arch Intern Med.
1998158466-472.
43Annual Medical Expenditures Attributable to
Obesity in US
- Obesity prevalence for US estimated at 20 of
total adult population - Prevalence varies considerably by state
- Overall range 15 (CO) 25 (WV)
Finkelstein, et al Obes Res. 2004 1218-24.
44Basic Principles of Obesity Therapy
45Obesity Therapy
Energy Intake
Energy Expenditure
Adipose tissue
46Relationship Between Rate of Weight Loss and
Gallstone Formation
8
9
Incidence of Gallstone Formation ( subjects/wk)
7
5
3
4
6
2
1
0
0.5
1
1.5
2
2.5
Rate of Weight Loss (kg/wk)
Weinsier et al. Am J Med 199598115. Reprinted
with permission from Excerpta Medica.
47Weight loss is associated with an increased risk
of gallstones because weight loss increases bile
cholesterol supersaturation, enhances cholesterol
crystal nucleation, and decreases gallbladder
contractility. The incidence of new gallstones
is approximately 2535 in obese patients who
experience rapid weight loss after treatment with
a very-low-calorie, low-fat diet (lt600 kcal/d
13 g fat/d) or gastric surgery. The risk of
gallstone formation increased markedly when the
rate of weight loss exceeded 1.5 kg (1.5 of
body weight) per week 5.
48Prevention of Gallstone Formation by
Ursodeoxycholic Acid During Rapid Weight Loss
49Short-term Obesity Therapy Does Not Result in
Long-term Weight Loss
Diet alone Behavior therapy Combined therapy
Change in Weight (kg)
5-yearFollow-up
1-yearFollow-up
End ofTreatment
Baseline
Wadden et al. Int J Obes 198913 (Suppl 2)39.
50Long-term Weight Loss is Improved with Long-term
Maintenance Therapy
No maintenance tx Maintenance tx
Weight Loss ()
Diet andbehaviormodificationtherapy
P lt0.05
Perri et al. J Consult Clin Psychol 198856529.
51Obesity Treatment Pyramid
52Obesity Treatment Guidelines
The Practical Guidecan be found at
NHLBI web sitewww.nhlbi.nih.gov NAASO web
sitewww.naaso.org
53Guide for Selecting Obesity Treatment
BMI Category (kg/m2)
Treatment 25-26.9 27-29.9 30-34.9 35-39.9 gt40
Diet, Exercise, Behavior Tx
Pharmaco-therapy With co-morbidities
Surgery With co-morbidities
The Practical Guide Identification, Evaluation,
and Treatment of Overweight and Obesity in
Adults. October 2000, NIH Pub. No.00-4084
54Medical Benefits of Modest Weight Loss Modest
weight loss, of as little as 5 of initial body
weight, can improve many of the concurrent
medical complications associated with obesity and
prevent the development of new obesity-related
illnesses
55coronary heart disease (CHD) in men and women,
who were followed for 16 years, was directly
related to the number of coronary heart disease
risk factors (high cholesterol, low
HDL-cholesterol, high body mass index, high
systolic blood pressure, high triglyceride
levels, and high blood glucose). Each of these
risk factors also is associated with obesity.
56Relationship Between Weight Change and CHD Risk
Factor Sum Framingham Offspring Study
Weight Change During 16-y Follow-up
Loss gt2.25 kg
Gain gt2.25 kg
37
20
Change in Risk Factor Sum ()
-40
-48
Men
Women
Plt0.002 vs baseline.
Wilson et al. Arch Intern Med 19991591104.
57Insulin Sensitivity Improves with Weight Loss in
obese Patients with Type 2 Diabetes
Insulin (pmol/L)
Before
0-2.4
2.5-6.9
7.0-14.0
gt15
Weight Loss at 1 Year ()
Plt0.01 vs before.
Wing et al. Arch Intern Med 19871471749.
58Insulin Sensitivity Improves with EXERCISE even
in the absence of Weight Loss in obese Patients
with Type 2 Diabetes
59Plasma Lipids Improve with Weight Loss
Meta-analysis of 70 Clinical Trials
TG
HDL-C(weightstable)
HDL-C(activelylosing)
TotalCholesterol
LDL-C
? mmol/L kg of Weight Loss
? mg/dL per kg of Weight Loss
Plt0.05.
LDL-Clow density lipoprotein cholesterol
HDL-Chigh-density lipoprotein cholesterol
TGtriglycerides
Dattilo et al. Am J Clin Nutr 199256320.
60Weight loss decreases systolic and diastolic
blood pressure.
61Impact of Weight Loss on Risk Factors
5Weight Loss 5-10Weight Loss
HbA1c
Blood Pressure
Total Cholesterol
HDL Cholesterol
Triglycerides
1
1
2
2
3
3
3
3
4
1. Wing RR et al. Arch Intern Med.
19871471749-1753. 2. Mertens IL, Van Gaal LF.
Obes Res. 20008270-278. 3. Blackburn G. Obes
Res. 19953 (Suppl 2)211S-216S. 4. Ditschunheit
HH et al. Eur J Clin Nutr. 200256264-270.
62A bit more on the Metabolic Syndrome
63Metabolic Syndrome Increases Risk for CHD and
Type 2 Diabetes
HighLDL
MetabolicSyndrome
Type 2Diabetes
Coronary Heart Disease
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA 20012852486-2497.
64Treatment of the Metabolic Syndrome in Overweight
or Obese Patients
- Weight loss induced by diet and increased
physical activity is the cornerstone of therapy - Weight loss induced by drug therapy can also
improve specific features of the metabolic
syndrome - Bariatric surgery is the most effective weight
loss therapy for extremely obese subjects and
improves all features of the metabolic syndrome
65Treatment of Metabolic Syndrome in Patients with
Diabetes
- 80-85 of diabetic subjects in North America and
Europe have the metabolic syndrome - However, most subjects with the metabolic
syndrome do not have diabetes - Statin therapy is effective in diabetic subjects
- Blood pressure therapy is effective in diabetic
subjects
66Summary Metabolic Syndrome
- The metabolic syndrome predicts the development
of both diabetes and CHD - Insulin resistance and obesity characterize most
individuals with the metabolic syndrome, although
insulin resistance and obesity are not required
features of the metabolic syndrome - Initial therapy for the metabolic syndrome should
consist of caloric restriction and increased
physical activity - Conventional cardiovascular risk factors such as
lipids and blood pressure should be treated in
individuals with the metabolic syndrome, although
no national recommendations have so far suggested
intensification of risk factor management - No consensus exists on whether insulin
sensitizers should be used in nondiabetic
individuals with the metabolic syndrome