Clinical Manifestations of Insulin Resistance

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• Clinical Manifestations of Insulin Resistance

Melissa Meredith, MD Associate Professor,
Department of Medicine University of Wisconsin
Medical School
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Insulin Resistance

• An impaired biological response to insulin
• Resistance to insulin-stimulated glucose uptake
• Increased lipolysis/FFAs
• An impairment of normal glucose uptake by muscle
  and/or restraint in glucose production in the
  liver
• Precedes type 2 diabetes in the majority of
  patients

McFarlane SI, et al. J Clin Endocrinol Metab.
200186(2)713-718. Reaven GM. Diabetes.
198837(12)1595-1607. Lebovitz H. Clin Chem.
199945(8 Pt2)1339-1345.
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The Metabolic Syndrome of Insulin Resistance
SystemicInflammation
ComplexDyslipidemia ? TG, sdLDL? HDL
EndothelialDysfunction
Insulin Resistance
DisorderedFibrinolysis
Atherosclerosis
Hypertension
DM2/IGT/IFG
VisceralObesity
Consensus Development Conference of the ADA.
Diabetes Care. 199821310-314. Adapted from
Pradhan et al. JAMA. 2001286327-334.
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Clinical Events Increase as a Function of
Insulin Resistance
30
CVA
25
T2DM
20
CHD
NumberofClinicalEvents
Cancer
15
HTN
10
5
0
4.4, 7.8
SSPG (mmol/L) Insulin Resistance
Steady-state plasma glucose (SSPG) an index
of insulin resistance. Adapted from Facchini FS,
et al. J Clin Endocrinol Metab.
200186(8)3574-3578.
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Metabolic Syndrome A Growing Concern

• Based on 2000 census and ATP III definition, 47
  million US residents have the metabolic syndrome
• Age-adjusted prevalence is 23.7
• Highest prevalence is among Mexican Americans
  (31.9)
• Age-adjusted prevalence is similar in men (24.0)
  and women (23.4) however,
• African American women have approximately
  a 57 higher prevalence than men
• Mexican American women have approximately a
  26 higher prevalence than men

Ford ES et al. JAMA. 2002287356-359.
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Prevalence Of The Metabolic Syndrome By ATP III
Criteria (NHANES III Population)

• Overall 22 for age 20 years and older

Age (y)
Adapted from Ford et al. JAMA. 2002287356-359.
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Insulin Resistance Inherited and Acquired
Influences
Acquired
Inherited

• Rare Mutations
• Insulin receptor
• Glucose transporter
• Signaling proteins
• Common Forms
• Largely unidentified

• Inactivity
• Over eating
• Aging
• Medications
• Obesity
• Elevated FFAs

INSULIN RESISTANCE
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The Bad News The Epidemic Of Obesity And
Diabetes Is Worsening In The USA

• CDC-BRFSS study of 184,450 people nationwide
• In 2000, the prevalence of obesity (BMI ?30
  kg/m2) was 19.8
• ? 61 since 1991
• Most adults are now overweight (BMI ?25 kg/m2)
  -56.4
• ? 25 since 1991
• No physical activity in 27
• no regular activity in additional 28
• Each ? 1 kg weight - ? 4.5-9 risk of diabetes

Mokdad et al. JAMA. 20012861195-1200.
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Visceral Fat DistributionNormal vs Type 2
Diabetes
Normal
Type 2 Diabetes
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Insulin Sensitivity and Central Adiposity
110
Variance in Si Accountedfor by Regional Fat
Mass Region R2 Value Central
abdomen 0.80 Trunk
0.60 All nonabdominal 0.44 Arms
0.30 Legs
0.10
100
High risk for type 2 Low risk for type 2
90
80
70
60
Insulin sensitivity (mmol/min/kg lean mass)
50
40

• Adipocyte Products
• FFA
• TNF-?
• Leptin
• Resistin?
• Adiponectin

30
20
20
25
30
35
40
45
50
Central abdominal fat
Adapted from Carey DG et al. Diabetes.
199645633-638.
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Development of Insulin Resistance
Obesity
Resistin Adiponectin
Adipocytes
FFA Other Effectors
TNF-?
Postreceptor Signaling
Insulin Receptor Kinase
Insulin Resistance In Peripheral Tissues
Kahn. International Textbook of Diabetes
Mellitus, 2nd edition, 1997.
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Metabolic Syndrome (ICD-9 Code 277.7) NCEP ATP
III Criteria
Any 3 of 5

• Risk Factors Defining Level
• Abdominal obesity
• Men Waist 40 inches
• Women Waist 35 inches
• Triglycerides 150 mg/dL
• HDL cholesterol
• Men
• Women
• Blood pressure 130/85 mm Hg
• Fasting glucose 110 mg/dL (100 per ADA)

?130/?80 mm Hg per ADA guidelines.
NCEP ATP III. JAMA. 20012852486-2497. ADA.
Diabetes Care. 200225S33-S49.
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Approach to modifying insulin resistance

• Weight control
• Diet
• Exercise
• Body composition
• Medications
• Insulin sensitizers metformin,
  thiazolidinediones
• Weight loss medications

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Weight Loss Correlation of GlucoseDisposal With
Visceral Adipose Tissue
Lean control subjects Obese subjects before
weight loss Obese subjects after weight loss
Visceral adipose tissue (cm2)
Goodpaster BH et al. Diabetes. 199948839-847.
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Effects of Body Weight Changes on Cardiovascular
(CV) Risk
Analysis of 26-Year Framingham Study Data

• To minimize risk of cardiovascular disease, any
  weight gain of 5 to 10 lb should be reversed
• 20 weight loss in obese persons associated with
  ? 40 risk of CHD
• Optimal BMI to avoid cardiovascular risk 22.6
  kg/m2 for men and 21.1 kg/m2 for women

Kannel WB et al. Am J Clin Nutr.
199663(suppl)419S-422S.
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Risk Benefits of Modest Weight Loss (5)

• Example 220 11 loss
• Total cholesterol ? 16
• HDL cholesterol ?16
• SBP / DBP ?12 mmHg/9 mmHg
• Improved glycemic control
• Life expectancy ? 35!

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Insulin sensitizers

• Thiazolidinediones
• Troglitazone (now off the market)
• Rosiglitazone (Avandia)
• Pioglitazone (Actos)
• Biguanides
• Metformin

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Metformin Treatment Changes in Body Composition
Change from Decrease P baseline from
baseline value

• Weight (kg) 3.3 4 0.006
• Body mass index (kg/m2) 1.2 4 0.006
• Total body fat (L) 2.8 9 0.014
• Total subcutaneous fat (L) 2.1 7 0.025
• Abdominal subcutaneous fat (L) 1.2 11 0.013
• Visceral fat (L) 0.6 15 0.01
• Lean body mass 0 No change NS

Data are means. Duration of treatment 6 months.
Kurukulasuriya R et al. Diabetes. 199948A315
(Abstract 1399.5).
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Metabolic syndrome and glycemia

• Increased incidence of glucose intolerance and
  frank type 2 diabetes in people with the
  metabolic syndrome
• Prevalence of glucose intolerance is approx. 22
  in people age 45
• This stage of dysglycemia is also referred to a
  prediabetes

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Glucose Tolerance Categories
FPG
2-Hour PG on OGTT
Diabetes Mellitus
Diabetes Mellitus
126 mg/dL
7.0 mmol/L
200 mg/dL
11.1
mmol/L
Impaired Fasting
Impaired Glucose
Glucose
Tolerance
100 mg/dL
5.5 mmol/L
140 mg/dL
7.8
mmol/L
Normal
Normal
Adapted from The Expert Committee on the
Diagnosis and Classification of Diabetes
Mellitus. Diabetes Care. 1997201183-1197.
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Distribution of Glycemic Abnormalities in US
Undiagnosed diabetes 6 million
Diagnosed type 1 diabetes 1.0 million
Additional 16 million with prediabetes
Diagnosed type 2 diabetes 12 million
CDC. Available at http//www.cdc.gov/diabetes/pub
s/estimates.htm ADA. Facts and Figures. Available
at www.diabetes.org/main/application/commercewf?
origin.jspeventlink(B1)
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Prevalence of Pre-diabetes
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Prevalence of pre-diabetes by age
NHANES III (1988-1994) data Diabetes Care
21(4)518-524, 1998
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IGT Progressively Increases Risk of CHD
Mortality Paris Prospective Study 10-Year
Follow-up
5
(135)
4
(158)
3
(690)
CHD mortality(Incidence rate/1,000)
2
(6,055)
1
0
GIGT
G200 mg/dL (Newly diagnosed diabetes)
Knowndiabetes
PEschwège E et al. Horm Metab Res.
198515(suppl)41-46.
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Progression to diabetes

• Pre-diabetes is the most predictive factor for
  those at risk of developing diabetes
• 20-34 risk with either IFG or IGT
• 38-65 risk with both IFG and IGT
• Age incidence of diabetes and IFG is 3.8 in
  people 20-39 years old, and increases to 15.4 in
  ages 40-59, and 33.6 with age60.
• BMI in the DPP, progression to diabetes was
  8.9 in subjects with BMI35

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Type 2 Diabetes in Children

• Becoming epidemic in areas with higher
  proportions of ethnic groups at risk1
• May be more likely than type 1 diabetes in
  children who develop diabetes2
• Comprised 2 to 4 of all childhood diabetesin
  1992 16 in 1994 ?45 in some areas in 19993
• Increased incidence probably due to increased
  obesity and decreased physical activity1

1. Rosenbloom AL et al. Diabetes Care.
1999223452. ADA. Diabetes Care. 2000233813.
Kaufman FR. J Pediatr Endocrinol Metab.
200215(suppl 2)737
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Reduction in Type 2 Diabetes With Lifestyle
Intervention vs Metformin

• 3234 participants - W 55, B 20, H 16, AI 5
• Age 50 BMI 34 Waist 105 cm
• FBG 106 HbA1c 5.9
• Placebo standard lifestyle advice vs.
• Metformin 850 mg bid lifestyle advice vs.
• Intensive lifestyle intervention
• low-calorie, low-fat diet (NCEP Step 1)
• wt loss goal 7 of base weight
• exercise 150 min per week
• Ref Diabetes Prevention Program Research Group
  (NEJM 2002)

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Changes in Body Weight (Panel A) and Leisure
Physical Activity (Panel B) and Adherence to
Medication Regimen (Panel C) According to Study
Group
N Engl J Med 346(6)396 2002
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Prevention of diabetes in Finland

• 522 overweight subjects (172 men and 350 women)
  with IGT
• Mean age 55 years, BMI 31
• Randomized to diet/exercise or control
• Diet was fat15 gm/1000 kcal
• Goals were at least 5 weight loss and moderate
  exercise of at least 30 min. per day

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Proportion of Subjects without Diabetes During
the Trial
58 reduction
N Engl J Med 344(18)1347 2001
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Lifestyle modification

• In Finnish study, only 43 reached weight goal
  and 36 reached the exercise goal
• In DPP, only 50 reached weight loss goal (ave.
  9 loss in 3 yrs) and 74 reached exercise goal
  (150 min/wk)
• Despite not attain study goals, incidence of
  diabetes was still significantly reduced

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Lifestyle recommendations

• Both studies also resulted in improvement in
  other risk factors such as blood pressure and
  lipids
• Lifestyle modification should be the cornerstone
  of treatment of the metabolic syndrome and
  pre-diabetes
• Goal for weight reduction is 5-10 of body weight
• Goal for physical activity is 30 min/day

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TRIPOD study

• 236 Hispanic women with previous history of GDM
  were randomized to placebo or troglitazone 400
  mg/day
• FPG done every 3 months, and OGTT yearly
• Median follow-up of 30 months

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Cumulative incidence rates of type 2 diabetes in
women who returned for at least one follow-up
visit after randomization to placebo or
troglitazone. The rate in the troglitazone group
was significantly lower than the rate in the
placebo group (P0.009).
Diabetes 512798 2002
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TRIPOD results

• Overall 56 reduction in development of diabetes
• Protection from diabetes
• Was associated with a decrease in insulin
  resistance
• Persisted for 8 months after study medications
  was stopped
• Was associated with preservation of estimates of
  beta-cell function

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Lipid Abnormalities Associated With Insulin
Resistance

• Quantitative
• ? triglycerides
• ? HDL cholesterol
• ? LDL cholesterol
• Qualitative
• remnant-particle accumulation
• small, dense LDL
• cholesterol-enriched VLDL
• triglyceride-enriched HDL
• ? cholesterol-ester transfer protein (CETP)
  activity

American Diabetes Association. Diabetes Care.
200225(suppl 1)S74-S77. Syvänne and Taskinen.
Lancet. 1997350(suppl 1)20-23.
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Treatment Strategies for Diabetic Dyslipidemia

• Primary Strategy
• - Lower LDL cholesterol
• Secondary Strategy
• - Raise HDL cholesterol
• - Lower triglycerides
• Other Approaches
• - Non-HDL cholesterol
• - ApoB
• - Remnants

Adapted from American Diabetes Association.
Diabetes Care. 200023(suppl 1)S57-S60 Chait A,
Brunzell JD. Diabetes Mellitus. A Fundamental
and Clinical Text. Philadelphia Lippincott
Raven, 1996772-779 European Diabetes Policy
Group 1999. Diabet Med. 199916716-730.
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Blood Pressure and CVD Framingham Heart Study
MEN
WOMEN
No Glucose Intolerance Glucose Intolerance
No Glucose Intolerance Glucose Intolerance
174
119
113
Age-adjusted CV Event Rate/1,000
Age-adjusted CV Event Rate/1,000
90
77
74
59
56
50
48
38
36
31
23
24
15
105
135
165
195
105
135
165
195
Systolic BP (mmHg)
Systolic BP (mmHg)
Kannel WB et al. Am Heart J 19911211268-1273.
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Coronary Artery DiseaseBenefits of Risk Factor
Reduction

• Risk Factor Change Decrease in
• Heart Attack
• Cholesterol 10 decrease 30
• High blood pressure 6 point decrease 16
• (42 stroke)
• Cigarette smoking cessation 50
• Weight ideal body weight 35-55
• Exercise 3-4 x week 35-55

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Risk Factors for Insulin Resistanceand Diabetes
Mellitus

• Genetic/familial
• Overweight (BMI25 kg/m2)
• Ethnicity
• Age 45 years
• Previous IFG or IGT
• Hypertension (140/90)
• HDL 250 mg/dL
• History of gestational diabetes mellitus (GDM)
• Habitual physical inactivity
• Polycystic ovarian syndrome
• History of vascular disease

IFGimpaired fasting glucose. Diabetes Care.
200427(supp 1)S12.
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ADA Screening Recommendations

• Screen people ?45 yr old, particularly if BMI
  ?25 kg/m2
• Consider screening younger individuals if BMI ?25
  kg/m2 and if major risk factors present
• Screen those with normoglycemia, rescreen at 3-yr
  intervals

ADA. Diabetes Care. 200326(suppl 1)S21
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ADA Screening Recommendations

• Screening should be part of healthcare visit
• Screen with either FPG test or 2-hr OGTT (75-g
  glucose load) confirm positive test on another
  day
• If IFG or IGT, counsel re weight loss and
  increasing physical activity
• Monitor for development of diabetes every 12 yr
• Treat other CVD risk factors (eg, hypertension,
  dyslipidemia, tobacco use)

ADA. Diabetes Care. 200326(suppl 1)S33
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