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METABOLIC
SYNDROME
DONALD FELIT TO, M.D.
DEFINITIONS
WHO Definition 1999
Diabetes or impaired fasting glycemia or IGT or insulin
resistance
Plus any two:
Obesity: BMI > 30, WTH ratio>0.9 male or >0.85 female.
Dyslipidemia: TG >or= 1.7mmol/liter or HDL cholesterol
<0.9 mmol/l male or <1.0mmol/l female.
Hypertension: BP > 140/90 mmHg
Microalbuminuria: albumin excretion >20mcg/min
European Group for the Study of
Insulin Resistance 1999
Insulin Resistance: hyperinsulinemia: top 25% of
the fasting insulin values from the non-diabetic
population.
Plus 2 or more of the following:
Central obesity: waist circumference > or = to 94
cm for male and 84 cm female
Dyslipidemia: TG > 2.0mmol/L or HDL
cholesterol > 1.0mmol/L
Hypertension: BP 140/90 and/or medication
Fasting plasma glucose > 6.1mmol/l
National Cholesterol Education Program’s
Adult Treatment Panel III (2001)
Three or more of the following:
Central Obesity: waist > 40 in. male and waist >
34 in. female.
TG > or = to 150
Low HDL cholesterol: < 40 male and less than 50
female.
Hypertension: BP > or = 135/85mm/Hg
Fasting plasma glucose > 110
American Association of Endocrinology Statement Insulin Resistance Syndrome
(2002)
Four Identifying Abnormalities:
High Triglycerides
Low HDL cholesterol
Hypertension
Elevated fasting or post load (75g)
glucose.
OBESITY is not a component of the definition.
Central Obesity
Blood Sugar >/= 100
Central obesity
BP > 140/90
BPS >/=130, BPD >/=
85
TG >150 or HDL. M
<35, F <39
Triglyceride >/= 150
Mcroalbuminuria
HDL <40M, <50F
Risk factor
Elevated fasting or
post load (75g)
glucose
Hypertension
Elevated
Triglycerides
Low HDL
(no mention of
obesity)
International Diabetes
Federation 2005
Impaired glucose
regulation (+2 other
risks,) IR, IGT, DM
Risk Factor (any 3 of
5 risk factors)
Am. Assoc. of Endo 2002
Risk Factor
ATP III 2001
WHO 1999
Comparison of Definitions
Risk Factor
Central Obesity (plus
>/= 2 factors)
BS>/=100 or DM
BPS>/=135, BPD
>/=85
TG > 150
HDL <40M, ,50F
Table 2: AHA/NHLBI criteria for
diagnosis of metabolic syndrome
Commonalities
A large waistline: Central Obesity/ Visceral Obesity
For women a waistline > 35” and for men >40”
Dyslipidemia: High Triglyceride and low HDL in the blood
Hypertension: 135/85 or 140/90
Some form of insulin resistance
Case Report
Mr. B. is a 63 year old man with a past medical history for
Hypertension, Dyslipidemia, Obesity and family history of
Type 2 Diabetes Mellitus was evaluated for weight loss.
The BMI was 36 kg/m2, BP was 144/84, fasting blood sugar
was 125, TC was 183, LDL cholesterol 112, TG 171, HDL
cholesterol 37.
The EKG showed old MI.
Prevalence of Metabolic Syndrome
USA Native Americans 45-49y/o: (58% women and
45% men)
USA Filipina-Americans: 50-69y/o (35%)
USA 30-79y/o: 25+% (>60y/o 40+%)
USA non-Hispanic white:30-79y/o (25%)
USA Mexican American 30-79y/o (30%)
Prevalence of Metabolic Syndrome
Weiss et al. (2004)
Severely obese children/adolescents, the
prevalence is 50%!
NHANES III 12-19y/o using ATPIII criteria for
metabolic syndrome – the prevalence is 4.2%.
Risk factors for developing
Metabolic Syndrome
Overweight
Obesity
Lack of physical activity (sedentary lifestyle)
Insulin resistance
Genetics
Older age
NHLBI 2007
Conditions that may play a
role
Fatty Liver (NASH)
Polycystic Ovarian Syndrome
Gallstones
Sleep Apnea
NHLBI 2007
The diagnosis of metabolic syndrome requires a tape measure or accurate eye; fasting lipogram
and plasma glucose measurements; and BP measurements.
Opie L H Circulation. 2007;115:e32-e35
Copyright © American Heart Association, Inc. All rights reserved.
Mechanisms
Abdominal adipose tissue is an endocrine organ which releases into circulation FFA,
Angiotensin II and adipokines.
Increased FFA in the blood inhibit uptake of glucose by muscle.
Excess FFA and AT II damage the pancreas. The pancreas makes extra insulin, it is an
insufficient to counter hyperglycemia
So, there is increased insulin levels and increased glucose. This is insulin resistance.
AT II increases BP through vasoconstriction.
Inflammatory cytokines are responsible IR and Hypertension
Hyperglycemia and increased circulating FFA contribute to increased manufacture of TG by
the liver. Circulating TG increase so that lipoproteins carry more TG and less HDL.
Circulation 2007;115:e32-e35
Mechanisms
Insulin resistance:
Increased postprandial insulin to maintain euglycemia.
Increased fasting insulin secretion to maintain euglycemia.
Eventually, hyperglycemia in many.
Hyperglycemia and increased FFA will increase insulin levels further.
Beta cell dysfunction, defective insulin secretion
Pathophysiology
AT II increases Blood Pressure
The adipose tissue liberates Tumor Necrosis Factor alpha and
interleukins that provoke an inflammatory reaction which promotes
insulin resistance and promotes and promotes hypertension.
Hyperglycemia and elevated levels of circulating FFA foster the
manufacture of triglycerides by the liver. Lipoproteins carry triglyceride
and TG level rises.
HDL molecules are small and they are easily secreted.
These physiologic reactions cause the high TG: HDL lipid abnormality.
Opie L H Circulation. 2007;115:e32-e35
Inflamation
Inflammation associated with Insulin resistance:
IL 6, TNF a, CRP, are increased.
IL 6 and other cytokines increase hepatic
glucose production, inc. hepatic production of VLDL
and increase insulin resistance in muscle tissue.
Cytokines plus FFA increase fibrinogen and
plasminogen activator inhibitor 1 (from the liver)
promote a prothrombotic state.
Adiponectin
Adiponectin:
Anti-inflammatory cytokine produced by adipose
tissue.
Enhances insulin sensitivity and inhibits
the inflammatory process.
Inhibits hepatic glucose production.
Enhances glucose transport to muscle.
It is reduced with insulin resistance.
Some associate low concentrations with progression
of subclinical CAD and MI.
The diagnosis of metabolic syndrome requires a tape measure or accurate eye; fasting lipogram
and plasma glucose measurements; and BP measurements.
Opie L H Circulation. 2007;115:e32-e35
Copyright © American Heart Association, Inc. All rights reserved.
Manifestations
Obesity and Physical Inactivity
Dyslipidemia
Insulin Resistance/IGT/Hyperinsulinemia (Na retention, SNS stimulation, HTN, increased
circulating FFA).
Prothrombotic state
Pro-inflammatory state
Hyperuricemia defects in insulin action on the renal tubular reabsorption of uric acid.
Asymmetric dimethylarginine (endothelial dysfunction)
Homocysteinemia
Microalbuminuria
Non-alcoholic fatty liver
OSA
? Leptin deficiency/dysfunction (TG accumulation and ?hyperinsulinism)
NHLBI 2007
Diagnosis of Metabolic
Syndrome
Large waistline
High TG and low HDL (3:1)
Blood Pressure >130/85
High FBS 100-125
About 85% of people with Type 2 Diabetes Mellitus
have Metabolic Syndrome
NHLBI 2007
Case Report
A 45 year old man with a PHx significant for MCD, Obesity,
Hyperlipidemia, HTN who despite counseling developed
Type 2 DM.
BP controlled with ACEI.
Total cholesterol 303, TG 1498, Abnormal LFT’s, TC/HDL
cholesterol 9.2
A patient is found to have
Metabolic Syndrome; so what?
Metabolic Syndrome
Lifestyle
Metabolic
Syndrome
Obesity
High Sodium Intake
High Caloric Intake
Atherogenic diet
Hypertension
Hyperlipidemia
Insulin Resistance
Carbohydrate abuse
Sedentary living
plus
Predisposition
Tobacco
Abuse
Premature
Coronary
Heart Disease
•
•
•
•
Type 2
Diabetes
Mellitus
Neuropathy
Nephropathy
Retinopathy
Vasculopathy
Metabolic Syndrome is associated
with risk of cardiovascular disease
The risk of vascular complications (CHD, Type 2 Diabetes Mellitus and
Stroke) increase with the number of risk factors.
People with Metabolic Syndrome are twice as likely to develop CHD and
5 times as likely to develop Type 2 Diabetes Mellitus when compared to
patients who do not have Metabolic Syndrome.
Coagulopathy (propensity for blood clotting) and inflammation
(elevated C-Reactive Protein)
The risk must be added to finding of high LDL and smoking
NHLBI 2007
Risk of Metabolic Syndrome
Although the metabolic syndrome unequivocally
predisposes to type 2 diabetes mellitus,48,58–62
many investigators of cardiovascular diseases
consider this syndrome to be a multidimensional
risk factor for ASCVD.1,58 Several recent reports
show that the metabolic syndrome is associated
with greater risk for cardiovascular disease,63–73 but
once type 2 diabetes mellitus emerges,
cardiovascular risk increases even more.
Ann Intern Med. doi:10.7326/M14-1796
Metabolic Syndrome-Risk
Other metabolic risk factors likewise appear individually to be:
atherogenic diet
Hypertension
Elevated blood glucose
prothrombotic state
proinflammatory state.
Indeed, 3 of the metabolic risk factors—elevated apoB-containing
lipoproteins,1 low HDL-C levels,1 and hypertension91—are well
established, major risk factors. Each imparts increased risk even when
only marginally abnormal.
Ann Intern Med. doi:10.7326/M14-1796
THERAPY
Treatments
Healthy Lifestyle
Eating a healthy diet/losing weight
Increasing physical activity
Quitting the cigarette smoking habit
The Diabetes Prevention Program
A randomized clinical trial testing strategies to
prevent Type 2 Diabetes Mellitus.
High risk individuals with elevated fasting glucose
and impaired glucose tolerance.
3,234 participants 27 centers in the U.S.- 20% of
whom were over 65y/o.
Mean age 51y/o, BMI 34m/kg2.
Three interventions: intensive lifestyle intervention,
Metformin, Placebo.
Diabetes Prevention Program
Primary outcome was development of Type 2 DM
Secondary outcomes: CVD, changes in glycemia,
Beta cell function, insulin sensitivity, obesity, diet,
physical activity, health related QOL, occurrence of
adverse events.
Diabetes Prevention Program
Inclusion Criteria:
Age greater than or equal to 25y/o.
BMI >/= 24kg/m2.
IGT 2h plasma glucose 140-199
Elevated FPG (95-125mg/dl)
Diabetes Prevention Program
ILS reduced the incidence of Type 2 DM by 58%.
Metformin reduced the incidence of Type 2 DM by 31% over 2.8
years.
6.9 participants with IGT would need to be treated with ILS for 3
years to prevent one case of Type 2 DM.
For Metformin 14.3 participants for 3 yrs to prevent one case
Type 2 DM.
Cost analysis shows both therapies to be cost effective.
Diabetes Care 9/03
Lifestyle changes
Losing weight
Reduce salt in the diet
DASH diet (Dietary Approaches to Stop
Hypertension)
Increase activity/Fitness
Therapy: Finnish Study
Study design:
Reduce fat intake
Reduce saturated fat
Increase Fiber
Increase exercise
Yield was a 60% reduction of Type II Diabetes.
Finnish Diabetes Prevention Study Group. Prevention of type-2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose
tolerance .Tuomilehto et al. N Engl J Med. 2001;344:1343–1350
Treatment of Metabolic Syndrome
Therapeutic Strategies:
1. Lifestyle changes, exercise, adherence to the Mediterranean diet, and
weight loss
less new diabetes
2. Metformin (less new diabetes, not as good as lifestyle changes)
3. Glitazones, for non-diabetics with high cardiovascular risk: reduce
fatty free acids, reduce insulin resistance, Increase HDL, must balance
these against possible weight gain and heart failure
4. Choice of antihypertensives: -blocker/diuretic much more likely to
cause metabolic syndrome than calcium channel blockers/angiotensinconverting enzyme inhibitors32
Opie L H Circulation. 2007;115:e32-e35
BEHAVIORAL COUNSELING TO PROMOTE A
HEALTHFUL DIET AND PHYSICAL ACTIVITY FOR
CARDIOVASCULAR DISEASE PREVENTION IN
ADULTS WITH CARDIOVASCULAR RISK
FACTORS CLINICAL SUMMARY OF U.S.
PREVENTIVE SERVICES TASK FORCE
RECOMMENDATION
Ann Intern Med. doi:10.7326/M14-1796
Importance of the
Recommendations
1. Obesity is associated with increased CVD
mortality
2. Adults who adhere to national guidelines for a
healthy diet and physical activity have a lower
cardiovascular morbidity and mortality than
those who do not
3. All persons, regardless of CVD risk status, can
accrue the health of improved nutrition, healthy
eating behaviors and increased physical activity.
AnnInternMed.doi:10.7326/M14-1796
Proof of Efficacy
The task force found adequate evidence that intensive
behavioral counseling interventions have moderate benefits
for CVD risk in overweight or obese adults who are at
increased risk for CVD, including:
 Decreases in blood pressure, lipid and fasting glucose
levels, and body mass index (BMI).
Increases in levels of physical activity.
The reduction in glucose levels was large enough to
decrease the incidence of a diabetes diagnosis.
Ann Intern Med. doi:10.7326/M14-1796
Case Report
A 45 year old man with a PHx significant for MCD, Obesity,
Hyperlipidemia, HTN who despite counseling developed
Type 2 DM.
BP controlled with ACEI.
Total cholesterol 303, TG 1498, Abnormal LFT’s, TC/HDL
cholesterol 9.2
Case Report: 57lb. Weight
Loss
Total Protein
1.6g/24h
Cholesterol
303mg/dl HDL 32.9
Tc/HDL 9.2
LDL CNC
TG 1498
320mg/24h
Cholesterol
191mg/dl
HDL 49mg/dl
Tc/HDL 3.89
LDL 95mg/dl
TG 236mg/dl
Treatments/Medications
If lifestyle changes are inadequate; medication may be
necessary:
Hypertension (Ace Inhibitors/Angiotensin Receptor
Blockers)
Dyslipidemia (Statins and fibrates)
High Blood Sugar (Metformin)
Excessive blood clotting (ASA may be indicated)
Ann Intern Med. doi:10.7326/M14-1796
Disease Burden
Cardiovascular disease is the leading cause
of death in the US
CVD risk factors are common in adults
Ann Intern Med. doi:10.7326/M14-1796
Disease Burden
The Center for Disease Control and Prevention estimates
that nearly half of all U.S. adults aged 20 years or older have
at least of the following CVD risk factors:
•Uncontrolled hypertension
•Elevated low density lipoprotein
•Current smoking
Nearly 70% of U.S. adults are either overweight or obese
Ann Intern Med. doi:10.7326/M14-1796
Low carbohydrate vs. Low fat diet
1.Foster GD, et al. A randomized trial of a low-carbohydrate diet for
obesity. New England Journal of Medicine, 2003.
Details: 63 individuals were randomized to either a low-fat diet group,
or a low-carb diet group. The low-fat group was calorie restricted. This
study went on for 12 months.
Weight Loss: The low-carb group lost more weight, 7.3% of total body
weight, compared to the low-fat group, which lost 4.5%. The difference
was statistically significant at 3 and 6 months, but not 12 months.
Conclusion: There was more weight loss in the low-carb group,
significant at 3 and 6 months, but not 12. The low-carb group had
greater improvements in blood triglycerides and HDL, but other
biomarkers were similar between groups.
authoritynutrition.com
Low carbohydrate vs. Low fat diet
2. Samaha FF, et al. A low-carbohydrate as compared with a low-fat
diet in severe obesity. New England Journal of Medicine, 2003.
Details: 132 individuals with severe obesity (mean BMI of 43) were
randomized to either a low-fat or a low-carb diet. Many of the subjects
had metabolic syndrome or type II diabetes. The low-fat dieters were
calorie restricted. Study duration was 6 months.
Weight Loss: The low-carb group lost an average of 5.8 kg (12.8 lbs)
while the low-fat group lost only 1.9 kg (4.2 lbs). The difference was
statistically significant.
authoritynutrition.com
Low carbohydrate vs. Low carbohydrate diet
Conclusion: The low-carb group lost significantly more weight (about 3
times as much). There was also a statistically significant difference in
several biomarkers:
Triglycerides went down by 38 mg/dL in the LC group, compared to 7
mg/dL in the LF group.
Insulin sensitivity improved on LC, got slightly worse on LF.
Fasting blood glucose levels went down by 26 mg/dL in the LC group,
only 5 mg/dL in the LF group.
Insulin levels went down by 27% in the LC group, but increased slightly
in the LF group.
Overall, the low-carb diet had significantly more beneficial effects on
weight and key biomarkers in this group of severely obese individuals.
authoritynutrition.com
Low carbohydrate vs. Low fat diet
8. Meckling KA, et al. Comparison of a low-fat diet to a lowcarbohydrate diet on weight loss, body composition, and risk factors
for diabetes and cardiovascular disease in free-living, overweight men
and women. The Journal of Clinical Endocrinology & Metabolism,
2004.
Details: 40 overweight individuals were randomized to a low-carb and a
low-fat diet for 10 weeks. The calories were matched between groups.
Weight Loss: The low-carb group lost 7.0 kg (15.4 lbs) and the low-fat
group lost 6.8 kg (14.9 lbs). The difference was not statistically
significant.
authoritynutrition.com
Low carbohydrate vs. Low fat
diet
Conclusion: Both groups lost a similar amount of weight.
A few other notable differences in biomarkers:
Blood pressure decreased in both groups, both systolic and diastolic.
Total and LDL cholesterol decreased in the LF group only.
Triglycerides decreased in both groups.
HDL cholesterol went up in the LC group, but decreased in the LF group.
Blood sugar went down in both groups, but only the LC group had
decreases in insulin levels, indicating improved insulin sensitivity.
authoritynutrition.com
Low carbohydrate vs. Low Carbohydrate diet
19. Volek JS, et al. Carbohydrate restriction has a more favorable
impact on the metabolic syndrome than a low fat diet. Lipids, 2009.
Details: 40 subjects with elevated risk factors for cardiovascular disease
were randomized to a low-carb or a low-fat diet for 12 weeks. Both
groups were calorie restricted.
Weight Loss: The low-carb group lost 10.1 kg (22.3), while the low-fat
group lost 5.2 kg (11.5 lbs).
authoritynutrition.com
Low carbohydrate vs. Low fat diet
Conclusion: The low-carb group lost almost twice the amount of weight
as the low-fat group, despite eating the same amount of calories.
This study is particularly interesting because it matched calories
between groups and measured so-called “advanced” lipid markers.
Several things are worth noting:
Triglycerides went down by 107 mg/dL on LC, but 36 mg/dL on the LF
diet.
HDL cholesterol increased by 4 mg/dL on LC, but went down by 1 mg/dL
on LF.
Apolipoprotein B went down by 11 points on LC, but only 2 points on LF.
LDL size increased on LC, but stayed the same on LF.
On the LC diet, the LDL particles partly shifted from small to large
(good), while they partly shifted from large to small on LF (bad).
authoritynutrition.com
Case Report
Mrs. D. is a 46 year old woman with a PMH significant for Type 2
Diabetes Mellitus, Hypertension, Dyslipidemia, microalbuminuria, and
morbid obesity who was seen in the clinic for weight loss management.
BP was 126/80, BMI 54.3kg/m2,
2-14-14: HbA1C 7.6
5-25-14: TC 163, LDL 89, HDL 56, TG 90
6-14-14: weight 356 lbs
After weight loss of 60lbs, 70/30 insulin requirement has dropped.
From 70/30 110 units bid to 30 units bid
7-29-14: HbA1C has likewise dropped to 6.4
Physical Activity
Figure 1. A, Joint associations of waist circumference and physical activity with CHD, the Nurses’
Health Study 1986 to 2000. *Adjusted for age (<50, 50 to 54, 55 to 59, 60 to 64, ≥65), parental history
of CHD, postmenopausal status and hormone use (never-use, past, current), physical activity (5
categories), aspirin use (<1, 1 to 2, 3 to 6, 7 to 14, 15+/wk), BMI (<25, 25 to 29.9, ≥30 kg/m2), and
alcohol consumption (0, 0.1 to 4.9, 5 to 14.9, ≥15 g/d).
Li T Y et al. Circulation. 2006;113:499-506
Copyright © American Heart Association, Inc. All rights reserved.
Figure 2. Joint associations of WHR and BMI and CHD, the Nurses’ Health Study 1986 to 2000.
*Adjusted for age (<50, 50 to 54, 55 to 59, 60 to 64, ≥65), parental history of CHD, postmenopausal
status and hormone use (never-use, past, current), physical activity (5 categories), aspirin use (<1, 1
to 2, 3 to 6, 7 to 14, 15+/wk), and alcohol consumption (0, 0.1 to 4.9, 5 to 14.9, ≥15 g/d).
Li T Y et al. Circulation. 2006;113:499-506
Copyright © American Heart Association, Inc. All rights reserved.
Goals of Therapy
Prevent risk of heart disease
Prevent Type 2 Diabetes Mellitus
Manage risk factors that can be controlled
(weight and sedentary lifestyle) and smoking
Ann Intern Med. doi:10.7326/M14-1796
Prevention and Delay of
Metabolic Syndrome
Regular follow up with the primary care physician
A lifelong commitment to a healthy lifestyle (eating
habits and exercise)
Long-term effort
Because of the rise in the prevalence of obesity,
Metabolic Syndrome may overtake smoking as the
leading cause of Coronary Heart Disease.
Ann Intern Med. doi:10.7326/M14-1796
Summary
Onset of Type 2 DM can be delayed.
The results have been replicated in Finland and
China.
Assess CVD risks in each patient
Managing each cardiac risk factor with ILS
interventions and the appropriate medications can
reduce CVD morbidity and mortality.
Thank you…….
Pathophysiology
Adipose tissue is an endocrine organ. It liberates excess FFA,
AT II and adipokines
The rise of FFA in the blood inhibit uptake of glucose by
muscle.
Excess FFA + AT II damage the pancreas (Lipotoxicity)
Pancreas increases insulin but not enough to counter the
rise of blood sugar, therefore; both insulin and blood sugar
rise.
Opie L H Circulation. 2007;115:e32-e35