Insulin Insulin Resistance and Resistance and Metabolic Metabolic Syndrome Syndrome Thomas Repas D.O. Thomas Repas D.O. Diabetes, Endocrinology and Nutrition Center, Affinity Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin Medical Group, Neenah, Wisconsin Member, Inpatient Diabetes Management Committee, St. Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WI Elizabeth’s Hospital, Appleton, WI Member, Diabetes Advisory Group, Wisconsin Diabetes Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program Prevention and Control Program Website: www.endocrinology-online.com Website: www.endocrinology-online.com
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Insulin Resistance and Metabolic Syndrome Thomas Repas D.O. Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin Member,
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Insulin Resistance and Insulin Resistance and Metabolic SyndromeMetabolic Syndrome
Thomas Repas D.O.Thomas Repas D.O.Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, WisconsinDiabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin
Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WIMember, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WIMember, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program
Harris MI. In: Harris MI et al, eds. Diabetes in America. Bethesda, MD: USDHHS-NIH; 1995:DHHS Publication No. (NIH) 95-1468
Rubin RJ et al. J Clin Endocrinol Metab. 1994;78:809A
• Prevalence: 17 million Americans
– 1 in every 17 people (>90% type 2 diabetes)
– 1/3 undiagnosed
• Incidence: >1 million new cases diagnosed yearly
– >2000 cases diagnosed each day
Type 2 diabetes in children and adolescents
• Related to our society’s Obesity
Age
Growth of ethnic populations with high prevalence
Physical activity
Diabetes Mellitus in the US
Top Ten Causes of Death in U.S. 2000
1. Heart Disease
2. Cancer
3. Cerebrovascular Disease
4. COPD
5. Accidents
6. Diabetes
7. Pneumonia & Influenza
8. Alzheimer's Disease
9. Kidney Disease
10. Sepsis
No Data <4% 4%-6% 6%-8% 8%-10% >10%
Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 1990
Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and other obesity-related health risk factors, 2001. JAMA 2003 Jan 1;289(1).
Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 1991-92
Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and other obesity-related health risk factors, 2001. JAMA 2003 Jan 1;289(1).
Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 1993-94
Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and other obesity-related health risk factors, 2001. JAMA 2003 Jan 1;289(1).
Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 1995-96
Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and other obesity-related health risk factors, 2001. JAMA 2003 Jan 1;289(1).
Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 1995
Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and other obesity-related health risk factors, 2001. JAMA 2003 Jan 1;289(1).
Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 1997-98
Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and other obesity-related health risk factors, 2001. JAMA 2003 Jan 1;289(1).
Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 1999
Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and other obesity-related health risk factors, 2001. JAMA 2003 Jan 1;289(1).
Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 2000
Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and other obesity-related health risk factors, 2001. JAMA 2003 Jan 1;289(1).
No Data <4% 4%-6% 6%-8% 8%-10% >10%
Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 2001
Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and other obesity-related health risk factors, 2001. JAMA 2003 Jan 1;289(1).
Emerging Epidemic of Type 2 Diabetes in Children and Adolescents
• Type 2 diabetes is a growing epidemic in US children and adolescents, especially among minorities1,2
– African-American youth accounted for 70%–75% of type 2 diabetes in Ohio and Arkansas studies3,4
– 31% of Mexican-Americans <17 yr in California study had type 2 diabetes5
1Fagot-Campagna A et al. J Pediatr. 2000;136:6642Rosenbloom A et al. Diabetes Care. 1999;22:3453Pinhas-Hamiel O et al. J Pediatr. 1996;128:6084Pihoker C et al. Clin Pediatr. 1998;37:975Neufeld N et al. Diabetes Care. 1998;21:80
12.1
14.5
17.4
10
11
12
13
14
15
16
17
18
19
20
2002 2010 2020
Diabetes Care 26(3):917-932, 2003
Projections of US Population with Projections of US Population with Diagnosed Diabetes (millions)Diagnosed Diabetes (millions)
44% Increase by 202044% Increase by 2020
0
10
20
30
40
50
60
70
80
Esti
mate
d p
r evale
nce (
million
s)
Estimates of Diabetes Estimates of Diabetes Prevalence in World RegionsPrevalence in World Regions
2025202519951995 20002000
Africa Americas EasternMediterranean
Europe SoutheastAsia
WesternPacific
WHO Report 1997. World Health Organization. Geneva;1997.
Why is Type 2 Diabetes on the Why is Type 2 Diabetes on the rise?rise?
Link Between Obesity and Type 2 Diabetes:Link Between Obesity and Type 2 Diabetes:Nurses’ Health StudyNurses’ Health Study
Colditz GA, et al. Ann Intern Med. 1995;122:481-486.
0
20
40
60
80
100
120
<22 22-22.9
23-23.8
24-24.9
25-26.9
27-28.9
29-30.9
31-32.9
33-34.9
>35
BMI (kg/m2)
Age
-Adj
uste
d Re
lativ
e Ri
sk
Obesity Trends* Among U.S. AdultsBRFSS, 1985
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1986
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1987
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1988
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1989
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1990
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1991
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1992
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1993
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1994
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1995
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1996
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1997
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1998
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1999
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 2000
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 2001
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
CV Risks of Type 2 DiabetesCV Risks of Type 2 Diabetes
40
15 13 1310
4 5
0
10
20
30
40
50
Perc
en
t of
death
s
Geiss LS, et al. In: Diabetes in America.
National Institutes of Health;1995.
Causes of Death in Causes of Death in People With DiabetesPeople With Diabetes
Isch
emic
hear
t di
seas
e
Oth
er h
eart
dise
ase
Dia
bete
s
Mal
igna
nt
neop
lasm
s
Cere
brov
ascu
lar
dise
ase
Pneu
mon
ia/
influe
nza
All ot
her
Hospitalization Costs for Chronic Hospitalization Costs for Chronic Complications of Diabetes in the USComplications of Diabetes in the US
American Diabetes Association. Economic Consequences of Diabetes Mellitusin the US in 1997. Alexandria, VA: American Diabetes Association, 1998:1-14.
Total costs 12 Total costs 12 billion US $billion US $
CVD accounts CVD accounts for 64% of for 64% of total coststotal costs
CVD Death Rates Are Higher CVD Death Rates Are Higher
in Patients With Diabetesin Patients With Diabetes
Seven-year incidence in a Finnish-based cohort.*P<.001Haffner SM, et al. N Engl J Med. 1998;339:229-234.
Type 2 Diabetes is a Cardiovascular Risk Type 2 Diabetes is a Cardiovascular Risk FactorFactor
Fat
al o
r N
onfa
tal M
I
0
10
20
30
40
50
Nondiabetic Subjects (n=1373)
Type 2 Diabetic Subjects (n=1059)
3.5%
20.2%18.8%*
45.0%*No Prior MI
Prior MI
Diabetes and prior myocardial infarction (MI) carry the same mortality risk
Matthaei, et al. Endocrine Reviews 21(6): 585-618.
New Definition of Impaired New Definition of Impaired Fasting GlucoseFasting Glucose
In 11/03, The Expert Committee on the In 11/03, The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Diagnosis and Classification of Diabetes Mellitus redefined IFG as being 100-125 mg/dlredefined IFG as being 100-125 mg/dl
It is estimated that this will increase the numbers It is estimated that this will increase the numbers of adults with “prediabetes” by approximately of adults with “prediabetes” by approximately 20%20%
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. . Diabetes Care VOLUME 26, NUMBER 11, 11/03.
Pathophysiology of Type 2 DiabetesPathophysiology of Type 2 Diabetes
Saltiel AR, Olefsky JM. Saltiel AR, Olefsky JM. DiabetesDiabetes. 1996;45:1661-1669.. 1996;45:1661-1669.
Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes
Risk of Macrovascular ComplicationsRisk of Macrovascular Complications
Insulin Insulin ResistanceResistance
IGTIGT
Insulin SecretionInsulin Secretion
Postprandial GlucosePostprandial Glucose
Risk of Microvascular ComplicationsRisk of Microvascular Complications
Fasting Blood GlucoseFasting Blood Glucose
Frank Frank DiabetesDiabetes
NGTNGT
Worsens with Time
Risk of Major CHD Event Associated with Insulin Risk of Major CHD Event Associated with Insulin Quintiles in Nondiabetic Subjects: Quintiles in Nondiabetic Subjects: Helsinki Helsinki
BP & HR• Increased LVH• Premature atherosclerosis• CVA
McFarlane SI, et al. Insulin Resistance and Cardiovascular Disease. McFarlane SI, et al. Insulin Resistance and Cardiovascular Disease. J Clin Endocrinol Metab. J Clin Endocrinol Metab. 2001; 86 (2) : 713-718. 2001; 86 (2) : 713-718.
The Metabolic SyndromeThe Metabolic Syndrome
Prothrombotic StateProthrombotic State HypertensionHypertension
DyslipidemiaDyslipidemia
Insulin ResistanceInsulin Resistance
EnvironmentEnvironmentGeneticsGenetics
Bogardus C, et al. Endocrinol Metab. 1985;11:E286-E291 Roberts K, et al. Nutr Rev. 2000 May;58(5):154-160.
Etiology of Metabolic SyndromeEtiology of Metabolic SyndromeEtiology of Metabolic SyndromeEtiology of Metabolic Syndrome
• The metabolic syndrome results from a complex The metabolic syndrome results from a complex interplay of two important factors:interplay of two important factors:
• The metabolic syndrome results from a complex The metabolic syndrome results from a complex interplay of two important factors:interplay of two important factors:
Kalff KG, et al. Aviat Space Environ Med. 1999 Dec;70(12):1223-1226.Hansen BC. Ann N Y Acad Sci. 1999 Nov 18;892:1-24.
Prevalence of Metabolic Syndrome
– Approximately 20% to 30% of the middle-aged population in highly industrialized countries has the metabolic syndrome
– By the year 2010, the number of people with the metabolic syndrome in the US could rise to between 50 and 75 million
Risks of Metabolic SyndromeRisks of Metabolic Syndrome
19
40
34
51
0
10
20
30
40
50
60
No Metabolic Syndrome Metabolic Syndrome
Carotid Stenosis
Carotid Atherosclerosis
Five year Progression of Carotid Atherosclerosis and Coronary Heart DiseaseFive year Progression of Carotid Atherosclerosis and Coronary Heart Disease
3
8
0
1
2
3
4
5
6
7
8
9
No Metabolic Syndrome Metabolic Syndrome
No Metabolic Syndrome
Metabolic Syndrome
Bonora, et al. Diabetes Care, 26,4 4/03. 1251-
Bruneck StudyBruneck Study
Diagnosis of Metabolic SyndromeDiagnosis of Metabolic Syndrome
Diagnostic Criteria
Three expert groups have devised criteria for diagnosis of metabolic syndrome:
–WHO
–NCEP ATP III
–AACE
Alberti & Zimmet WHO 1998 Diabetic Medicine.
IGT/IFG or IGT/IFG or type 2 diabetestype 2 diabetes
Central ObesityCentral ObesityBMIBMI > 30 kg/m²> 30 kg/m²
MicroalbuminuriaMicroalbuminuriaUAE UAE 20 µg min 20 µg min
LevelLevel >40 in (m) >35 in (f)>40 in (m) >35 in (f) >150 mg/dl>150 mg/dl <40 (m) <50 (f)<40 (m) <50 (f) >130/85>130/85 >110>110
Dysmetabolic Syndrome = 3 out of 5Dysmetabolic Syndrome = 3 out of 5
ATP III, Nat. Chol. Ed. Program, NIH
Major criteria•Insulin resistance (denoted by hyperinsulinemia relative to glucose levels) Insulin resistance (denoted by hyperinsulinemia relative to glucose levels) or or •Acanthosis Nigricans Acanthosis Nigricans •Central Obesity (waist circumference > 102 cm for men and >88 cm for Central Obesity (waist circumference > 102 cm for men and >88 cm for women) women) •Dyslipidemia (HDL cholesterol <45 mg/dl for women, HDL cholesterol Dyslipidemia (HDL cholesterol <45 mg/dl for women, HDL cholesterol <35mg/dl for men, or triglycerides >150 mg/dl) <35mg/dl for men, or triglycerides >150 mg/dl) •Hypertension Hypertension •Impaired fasting glucose or Type 2 diabetes Impaired fasting glucose or Type 2 diabetes •HyperuricemiaHyperuricemia
The CDC does not require that a given number of components of Dysmetabolic Syndrome X be present when using ICD-9-CM diagnosis code 277.7. The code may be used if in the professional opinion of the physician Dysmetabolic Syndrome X is present
Please note the central obesity, hirsutism, acne, and acanthosis nigricans in this patient.Please note the central obesity, hirsutism, acne, and acanthosis nigricans in this patient.
Please note the central obesity, hirsutism, acne, and acanthosis nigricans in this patient.Please note the central obesity, hirsutism, acne, and acanthosis nigricans in this patient.
Close up of facial hirsutism in 17 year old female with PCOSClose up of facial hirsutism in 17 year old female with PCOSClose up of facial hirsutism in 17 year old female with PCOSClose up of facial hirsutism in 17 year old female with PCOS
Typical polycystic ovaries. Multiple small follicular Typical polycystic ovaries. Multiple small follicular cysts are apparent in the cut section. cysts are apparent in the cut section. Typical polycystic ovaries. Multiple small follicular Typical polycystic ovaries. Multiple small follicular cysts are apparent in the cut section. cysts are apparent in the cut section.
Pathophysiology of Insulin Resistance Pathophysiology of Insulin Resistance andand
Metabolic SyndromeMetabolic Syndrome
The Metabolic SyndromeThe Metabolic Syndrome
Prothrombotic StateProthrombotic State HypertensionHypertension
DyslipidemiaDyslipidemia
Insulin ResistanceInsulin Resistance
DyslipidemiaDyslipidemia
DyslipidemiaDyslipidemia
Diabetic DyslipidemiaDiabetic Dyslipidemia TriglyceridesTriglycerides HDLHDL Small, Dense LDLSmall, Dense LDL LDL-C may be “normal”LDL-C may be “normal”
Lipoprotein Classes and InflammationLipoprotein Classes and Inflammation
Doi H et al. Circulation 2000;102:670-676; Colome C et al. Atherosclerosis 2000;149:295-302; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.
HDLHDLLDLLDLChylomicrons,Chylomicrons,VLDL, and VLDL, and