The Pyramid of Recent Trials

1
LEPTIN 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
2
resistin Elevated in insulin resistance and
t2DM Interferes with insulin receptor
signaling Receptor still unknown Too much-BAD
3
Adiponectin 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
4
Links 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
5
Excess Adipose Tissue ObesityPrinciples of
Energy Metabolism
6
Body 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
7
Obesity Is Caused by Long-Term Positive Energy
Balance
FatStores
8
Components 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.
9
Components 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
10
Relationship 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
11
Relationship 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.
12
Regulation 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
13
Lifetime Food Intake
Water 45,300 kg
Fat 2300 kg 21 kcal
Cholesterol 8000 kg 31 kcal
Protein 1900 kg 7 kcal
kcal in millions
14
Cumulative 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.
15
Consistent 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.
16
The 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.

20
Gene-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
22
Medical Complications of Obesity
23
BMI-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).
24
Body Mass Index Chart
Weight (lb)
25
Relationship 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.
26
Medical 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
27
Metabolic Syndrome

• Abdominal obesity
• Hyperinsulinemia
• High fasting plasma glucose
• Impaired glucose tolerance
• Hypertriglyceridemia
• Low HDL-cholesterol
• Hypertension

28
Evolution 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.
29
Characteristics 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.
30
Clinical 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.
31
Increasing Prevalence of Metabolic Syndrome with
Age
Men Women
Prevalence ()
Age
Ford E et al. JAMA. 2002287356-359.
32
It 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.
33
Prevalence 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.
34
Metabolic Syndrome Impact on Mortality
Without metabolic syndrome With metabolic syndrome


Mortality Rate ()
P lt 0.001.
Isomaa B et al. Diabetes Care. 200124683-689.
35
Metabolic Syndrome Impact on Cardiovascular
Health
Without metabolic syndrome With metabolic syndrome

Prevalence ()


P lt 0.001.
Isomaa B et al. Diabetes Care. 200124683-689.
36
Ectopic 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.
37
Ectopic Lipids or presence of fat in other
tissues in an important contributer to INSULIN
RESISTANCECan find ectopic fatin liver, muscle,
heart, and pancreas
38
Relationship 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.
39
Relationship 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.
40
Relationship 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.
41
Direct 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.
42
Increase 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.
43
Annual 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.
44
Basic Principles of Obesity Therapy
45
Obesity Therapy
Energy Intake
Energy Expenditure
Adipose tissue
46
Relationship 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.
47
Weight 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.
48
Prevention of Gallstone Formation by
Ursodeoxycholic Acid During Rapid Weight Loss
49
Short-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.
50
Long-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.
51
Obesity Treatment Pyramid
52
Obesity Treatment Guidelines
The Practical Guidecan be found at
NHLBI web sitewww.nhlbi.nih.gov NAASO web
sitewww.naaso.org
53
Guide 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
54
Medical 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
55
coronary 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.
56
Relationship 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.
57
Insulin 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.
58
Insulin Sensitivity Improves with EXERCISE even
in the absence of Weight Loss in obese Patients
with Type 2 Diabetes
59
Plasma 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.
60
Weight loss decreases systolic and diastolic
blood pressure.
61
Impact 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.
62
A bit more on the Metabolic Syndrome
63
Metabolic 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.
64
Treatment 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

65
Treatment 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

66
Summary 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