Insulin Resistance Syndrome

1
Insulin Resistance Syndrome

• Chou Chien-Wen MD.
• Endocrinology Metabolism Division
• Chi-Mei Medical Center
• 9 July 2004

2
ACE position statement

• Clinical manifestations include CVD,
  hypertension, PCOS, and nonalcoholic
  steatohepatitis NASH, and the list continues to
  expand.
• (AACE) championed the creation of the new ICD-9
  Code 277.7 for the Dysmetabolic Syndrome
• use the term Insulin Resistance Syndrome to
  describe the consequences of insulin resistance
  and compensatory hyperinsulinemia
• absence of a straightforward diagnostic test or
  definitive clinical trials, identification and
  treatment of a syndrome

3
Differentiation between the IRS and T2 diabetes
4
Disease-related consequences of IRS/compensatory
hyperinsulinemia
5
Identification of individuals at risk for IRS
6
Obesity and IRS

• Obesity is a physiological variable that
  decreases insulin-mediated glucose disposal
• BMI rather than abdominal circumference, be used
  to identify individuals at increased risk
• Abdominal circumference are neither routinely
  performed nor is its quantification as well
  standardized
• European Group for the Study of IR was not
  increased when abdominal circumference replaced
  BMI as the marker of obesity
• BMI and abdominal circumference were closely
  related r0.9 in 15,271 participants in NHANES
  III

7
Criteria for predicting IRS
8
(No Transcript)
9
Plasma insulin concentration and the IRS

• Plasma insulin concentrations are useful
  surrogate marker of IR
• Highly statistically significant correlations
  between measures of insulin-mediated glucose
  disposal and both fasting (r0.6) and
  post-glucose challenge (r0.8) plasma insulin
  concentrations
• Methods to quantify plasma insulin concentrations
  are not standardized
• Difficult to compare values measured in different
  clinical laboratories
• Has not been established that an increase in
  plasma insulin concentration, by itself, in the
  absence of any of changes listed in Table 3, can
  predict the development of CVD
• A research, not a clinical tool

10
Evaluation of the criteria (1)
11
Evaluation of the criteria (2)
12
Evaluation of the criteria (3)
13
The 1st World Congress on the Insulin Resistance
Syndrome

• was held in Los Angeles, 21-22 November 2003.

Diabetes care Volume 27(2)  February 2004 pp
602-609
14
IRS (1)

• included insulin resistance, hyperinsulinemia,
  dyslipidemia, hypertension, and increased risk of
  both diabetes and coronary heart disease.
• Other abnormalities associated with the IRS
  include glucose intolerance, small LDL particle
  size, postprandial accumulation of
  triglyceride-rich remnant lipoproteins,
  hypertriglyceridemia, and low HDL cholesterol.
• endothelial dysfunction increased circulating
  cell adhesion molecules, increased asymmetric
  dimethyl arginine (ADMA), an endogenous inhibitor
  of endothelial nitric oxide (NO) synthase (eNOS),
  decreased endothelium-dependent vasodilation
• increased plasminogen activator inhibitor-1,
  fibrinogen, and inflammatory markers, including
  C-reactive protein (CRP) and leukocyte count.

15
IRS (2)

• The IRS is associated with decreased renal urate
  clearance, increased sympathetic nervous system
  activity and renal Na retention, increased
  ovarian testosterone secretion, and
  sleep-disordered breathing
• Associated illnesses include cardiovascular
  disease (CVD), type 2 diabetes, hypertension, the
  polycystic ovarian syndrome, nonalcoholic fatty
  liver disease (NAFLD) , malignancies including
  breast cancer, and sleep apnea.

16
Factors that increase the likelihood of IRS

• include having CVD
• Hypertension
• polycystic ovarian syndrome
• acanthosis nigricans
• a family history of type 2 diabetes,
  hypertension, or CVD
• a history of gestational diabetes or glucose
  intolerance
• non-Caucasian ethnicity
• sedentary lifestyle
• obesity

17
Table of content

• Determinants of insulin sensitivity
• Mechanisms of insulin resistance
• Endothelial dysfunction and insulin resistance
• Nonalcoholic fatty liver disease
• Lifestyle approaches for the IRS
• Low-carbohydrate diet for atherogenic
  dyslipidemia
• Relationship between obesity and the IRS
• Adipocyte hormones and insulin action
• Inflammation and the IRS

18
Determinants of insulin sensitivity (1)

• Reaven suggested that adiposity and physical
  fitness each account for 25 of the variability
  in insulin sensitivity
• with genetic factors, responsible for an
  additional 50 of this variation

19
Determinants of insulin sensitivity (2)

• Surrogate measures of insulin sensitivity (based
  on comparison with the SSPG) include fasting
  insulin or homeostasis model
• Glucose tolerance per se (IFG) has sensitivity
  0.10 and specificity 0.97, impaired glucose
  tolerance (IGT) 0.26 and 0.95, fasting insulin in
  the highest tertile 0.66 and 0.83, and insulin 2
  h after oral glucose 0.71 and 0.86, respectively
• Overweight is another strong predictor.
• Reaven suggested that triglyceride gt130 mg/dl,
  triglyceride-to-HDL ratio gt3, and insulin gt15
  µU/ml are considerably stronger markers of
  insulin resistance

20
Determinants of insulin sensitivity (3)

• In a group of 208 persons without diabetes who
  underwent SSPG measurement, measuring waist
  circumference with a tape measure held
  horizontally at the superior iliac crest while
  standing, the BMI and waist circumference showed
  identical correlation to SSPG with R 0.6 for
  both measures.
• Using a BMI cutoff of 25 kg/m2, 60 had insulin
  resistance, whereas with waist gt88 cm in women or
  102 cm in men, 68 had insulin resistance

21
Mechanisms of insulin resistance (1)

• Carbon NMR studies with a profound defect in
  muscle glycogen synthesis in persons with type 2
  diabetes
• Phosphorus NMR studies suggest transport defects
  at the level of hexokinase or GLUT4 to be primary
  
• offspring of persons with type 2 diabetes suggest
  this abnormality to precede the onset of the
  disease
• Further 13C NMR spectroscopy has suggested that
  the defect is at the level of GLUT4.
• The abnormality in GLUT4 is strongly predicted by
  the free fatty acid (FFA) level and, even more
  strongly, by intramyocellular triglyceride
  levels.

22
Mechanisms of insulin resistance (2)

• A potential mechanism by which fatty acid
  metabolites inhibit glucose transport activity
  appears to involve the insulin signaling cascade,
  with decreased phosphatidylinositol 3-kinase
  caused by activation of a serine kinase cascade
  via protein kinase C-theta decreasing the
  translocation of GLUT4 to the cell membrane.
• peroxisome proliferator-activated receptor
  gamma agonists act by increasing adipose tissue
  fat stores and preventing the increase in fatty
  acid metabolites in liver and muscle.

23
Endothelial dysfunction and insulin resistance

• Exercise increases eNOS, improving vasodilation,
  whereas obesity and insulin resistance are
  associated with deficiency of NO leading to
  endothelial dysfunction
• Insulin resistance is associated with elevations
  in circulating ADMA.
• ADMA acts as a competitive inhibitor of eNOS, and
  the enzyme dimethylarginine dimethylaminohydrolase
  (DDAH) increases ADMA metabolism, with insulin
  resistance decreasing DDAH levels and activity by
  increasing oxidative stress
• TZDs, metformin, ACEI, ARB, statins, and
  antioxidants all have been shown to decrease
  plasma ADMA levels, to improving vessel wall NO
  synthesis and decreasing superoxide anion levels.

24
Nonalcoholic fatty liver disease (1)

• NAFLD and nonalcoholic steatohepatitis (NASH),
  which he described as "the hepatic manifestation
  of the IRS"
• Approximately 40 of persons with NASH have
  diabetes, and an additional 20 have impaired
  glucose tolerance
• whereas 50 of persons with diabetes have NAFLD,
  of whom 20 have NASH, with perhaps 20 of these
  persons ultimately developing cirrhosis.

25
Nonalcoholic fatty liver disease (2)

• Pathologically, in fatty liver, replacement of
  the hepatocyte by small or large fat globules.
• Steatohepatitis includes evidence of cytologic
  ballooning and pericellular fibrosis.
• pathogenesis is that increased fatty acid
  delivery to the liver, in a setting of increased
  fatty acid oxidation causing oxidative injury and
  de novo triglyceride synthesis, causes the
  development of fatty liver, which is associated
  with mitochondrial paracrystalline inclusions
• both mitochondrial and peroxisomal fatty acid
  oxidation cause an increase in reactive oxygen
  species (ROS), one consequence of which is
  depletion of mitochondrial DNA

26
Lifestyle approaches for the IRS (1)

• body weight has increased 15 over the past
  century, with BMI gt25 and 30 kg/m2 in 46 and 14,
  respectively, of the population in 1980 and 65
  and 31 in 2000.
• One of the major approaches to management of the
  IRS is lifestyle change, with 7 weight loss and
  150 min/week exercise in the Diabetes Prevention
  Program reducing diabetes by 58.
• Realistic goals are a 5-10 weight loss

27
Lifestyle approaches for the IRS (2)

• Keeping a food diary, typical patients
  underreport calories by one-third and over-report
  exercise by one-half.
• structure eating and exercise patterns (for
  example, putting out exercise clothes before
  going to bed).
• small changes is the "100/100" plan eliminating
  100 cal by diet and increasing activity by 100
  cal, which should lead to a 20-lb annual weight
  loss.
• participate longer in treatment, and increase
  physical activity to at least 1 h/day are most
  likely to succeed.
• Strength training is as good as aerobic exercise
• Multiple short periods of exercise may be as good
  as one continuous bout of exercise

28
Lifestyle approaches for the IRS (3)

• Pharmacotherapy, very-low-calorie diet,
  residential diets, and "meal replacements" allow
  structured eating and are effective in producing
  sustained weight loss
• Sibutramine Trial on Obesity Reduction and
  Maintenance
• XENical in the prevention of Diabetes in Obese
  Subjects (XENDOS) study with orlistat, with
  4-year data showing new diabetes in persons with
  IGT decreased 37.
• BMI exceeds 40 kg/m2, bariatric surgery should be
  strongly considered.

29
Low-carbohydrate diet for atherogenic
dyslipidemia

• either weight loss or carbohydrate restriction
  can be effective in improving the atherogenic
  lipid phenotype

30
Relationship between obesity and the IRS (1)

• almost 5 of the population has BMI gt40 kg/m2.
• Insulin resistance is linearly associated with
  the BMI, although with wide scatter at any given
  level, so that 25-30 of the variance in insulin
  sensitivity is explained by BMI.
• In a study of 50 obese persons, 29 insulin
  resistant with mean SSPG 232 mg/dl and 21 insulin
  sensitive with mean SSPG 84 mg/dl, with similar
  age and BMI, the 2-h glucose was 144 vs. 112,
  triglyceride 199 vs. 125, and HDL 42 vs. 54
  mg/dl, with a triglyceride-to-HDL ratio 5.4 vs.
  2.5, suggesting that insulin resistance
  contributes to CVD risk independent of obesity.

31
Relationship between obesity and the IRS (2)

• Using the Stamford database of 500 persons whose
  SSPG had been measured, its correlation
  coefficients were 0.33 for fasting glucose, 0.56
  for insulin, 0.42 for triglyceride, and 0.41 for
  the triglyceride-to-HDL ratio.
• The best cut point for the triglyceride-to-HDL
  ratio was 3.0, with sensitivity 72 and
  specificity 63 for insulin resistance
• the optimal triglyceride cut point of 131 mg/dl
  showed similar sensitivity and specificity.
• The ATP III criteria had sensitivity 55 and
  specificity 85.

32
Adipocyte hormones and insulin action

• the role of adipocyte hormones in regulating
  insulin action, lipid metabolism, and energy
  homeostasis.
• Adipocytes produce many cytokines, including
  leptin, with effects on food intake
• leptin deficiency in humans in association with
  severe hyperphagia, suggesting lack of satiety
  response.
• Partial leptin deficiency is also associated with
  increased body fat
• insulin increases leptin production
• Adiponectin is produced by adipocytes, but levels
  are inversely proportional to total adipocyte
  mass and therefore are lower in obesity.

33
Inflammation and the IRS (1)

• The initiating steps of atherosclerosis may
  involve inflammation due to lipoproteins,
  phospholipids, and other substances modified by
  oxidation or glycation, with subsequent
  expression by endothelial cells of
  chemoattractant molecules leading monocyte uptake
  into the arterial wall and activation into
  macrophages, which in turn produce
  proinflammatory molecules including TNF-alpha
  and interleukin (IL)-6.
• IL-6 acts as a messenger cytokine in the liver,
  leading to CRP and serum amyloid A production,
  further mediating atherosclerotic processes.
• CRP activates complement, stimulates cytokine
  secretion, increases endothelial cell adhesion
  molecule expression, decreases eNOS expression
  and bioactivity, increases plasminogen activator
  inhibitor-1 levels and activity, increases LDL
  uptake by macrophages, increases monocyte
  chemoattraction, increases expression of the
  angiotensin II type 1 receptor, and has many
  additional inflammatory effects.
• CRP is strongly associated with obesity

34
Inflammation and the IRS (2)

• levels should be measured twice, 2 weeks apart,
  to avoid effects of intercurrent illness,
  particularly if baseline levels exceed 10 mg/l.
• CRP elevation predicts future events in studies
  of both high- and low-risk populations
• Low-risk levels are lt1 mg/l, average-risk levels
  are 1-3 mg/l, and high-risk levels are gt3 mg/l
  and are associated with the doubling of CVD risk.
  
• CRP levels increase with age, are higher in
  women, and are associated with coronary disease
  and type 2 diabetes.
• Modifiable causes of CRP elevation include
  obesity, cigarette use, estrogen treatment, and
  chronic bronchial or periodontal inflammation.
• CRP decreases during treatment with statins,
  fibrates, antibiotics, metformin, and TZDs and
  with alcohol ingestion

35
Definitions of the Insulin Resistance Syndrome

• The Adult Treatment Panel III
• WHO Clinical Criteria
• AACE Clinical Criteria
• EGIR

Diabetes Care Volume 27(3) March 2004 pp 824-830
36
TABLE 1. ATP III Clinical Identification of the
Metabolic Syndrome
37
TABLE 2. WHO Clinical Criteria for Metabolic
Syndrome
38
Risk Factor Components
Cutpoints for Abnormality
TABLE 3. AACE Clinical Criteria for Diagnosis of
the Insulin Resistance Syndrome
39
Table of content

• IRS and CVD
• IRS and HT
• IRS and PCOSIRS in childhood
• IRS and malignancy

40
The Adult Treatment Panel III metabolic syndrome
(1)

• propose a new definition of the metabolic
  syndrome
• heightening awareness of the insulin resistance
  syndrome (IRS)
• not recommend routine measurement of insulin
  sensitivity or of inflammatory markers
• The 2-h glucose was not included
• Not calling the metabolic syndrome a CHD
  equivalent
• Accentuate the risk accompanying elevated LDL
  cholesterol
• Reverse its root causes of obesity and physical
  inactivity
• likely to be present in younger persons with CHD

41
The Adult Treatment Panel III metabolic syndrome
(2)

• metabolic syndrome is present in 10 of
  children.
• 52 of persons with but 23 of those without
  metabolic syndrome have increased carotid
  intima-media thickness (IMT)
• association of C-reactive protein with
  atherosclerotic risk
• Usefulness of measurement of ankle brachial
  systolic pressure ratio

42
The American Association of Clinical
Endocrinologists IRS (1)

• Differences from the ATP III included focus on
  the IRS rather than on CVD, a decision to
  specifically exclude persons with type 2
  diabetes, and recognition of the limitations of
  the fasting glucose and the usefulness of the 2-h
  postchallenge glucose in assessing insulin
  resistance.
• the IRS was felt to be a continuum of risk based
  on the number and severity of components.
• early recognition of the IRS
• Close follow-up

43
AACE IRS (2)

• Obesity, based on either BMI or waist
  circumference, was seen as a risk factor rather
  than a criterion for the syndrome
• Measures of obesity must be ethnically based, and
  one must recognize that in certain Asian
  populations, both BMI and waist circumference
  criteria must be reduced by 15-20.

44
The IRS and CVD

• In 1,209 Finnish men aged 42-60 years, the
  10-year CVD risk was increased 2.1- and 2.5-fold
  with the ATP III and WHO IRS definitions,
  respectively
• In the Botnia study, there was a 1.8-fold
  increase in risk in persons satisfying the WHO
  IRS criteria
• Using the Hoorn Study data
• among men, high insulin predicted a 1.5-fold
  increase in CVD, increased waist circumference
  predicted a doubling, and hypertension predicted
  a two- to threefold increase in risk.
• Among women, high insulin and waist circumference
  predicted risk of nonfatal but not fatal CVD, and
  both low HDL and high triglyceride were
  significant factors predicting both total and
  fatal CVD.

45
The IRS and hypertension

• comparing persons with normal and increased blood
  pressure, with 50 of the hypertensive patients
  but 10 of those with normal blood pressure
  having evidence of hyperinsulinemia.
• Insulin does cause sodium retention

46
Association between the IRS and the PCOS (1)

• PCOS may be the most common endocrinopathy among
  young women and is a syndrome of chronic
  anovulation and hyperandrogenism that affects
  6-10 of women of childbearing age and accounts
  for 50-60 of female infertility due to
  anovulation.
• metformin monotherapy improved the ovulation rate
  3.9-fold over placebo and the combination of
  metformin and clomiphene improved both the
  ovulation and pregnancy rates 4.4-fold compared
  with clomiphene alone.
• PCOS is associated with a 30-50 rate of early
  pregnancy loss and that hyperinsulinemia is also
  a risk factor for miscarriage.

47
Association between the IRS and the PCOS (2)

• Women with PCOS have 30 and 10 prevalence of
  impaired glucose tolerance and diabetes,
  respectively
• Nurses' Health Study (NHS) of 101,073 women
  followed for 8 years, oligomenorrheic women had a
  twofold higher rate of conversion to type 2
  diabetes.
• Conversely, 25-28 of women with type 2 diabetes
  have evidence of PCOS, and 80 of women with type
  2 diabetes may have polycystic ovaries
• in the NHS, women with irregular menses had a
  doubled risk of fatal myocardial infarction

48
The IRS in childhood

• Type 2 diabetes is increasing in children
• Abnormal glucose tolerance is frequently seen
  among obese children, although it is noteworthy
  that fasting glucose is rarely abnormal
• significant correlation between parents and
  children in both weight and insulin sensitivity
• Using the ATP III criteria, the prevalence of
  metabolic syndrome was 2, 4, and 8 at ages 13,
  15, and 19, respectively.

49

• Figure 1. Effect of Insulin Resistance on the
  Prevalence of the Metabolic Syndrome in White
  Subjects (Panel A), Hispanic Subjects (Panel B),
  and Black Subjects (Panel C), According to the
  Degree of Obesity.

50

• Figure 2. C-Reactive Protein and Adiponectin
  Levels According to the Degree of Obesity and the
  Insulin-Resistance Category.

51
The IRS and malignancy

• link between insulin resistance,
  hyperinsulinemia, and cancer.
• association of breast cancer with
  hyperinsulinemia and diabetes.

52
Lifestyle and insulin resistance in cancer

• lifestyle factors, such as obesity, caloric
  intake, and physical activity, that may affect
  insulin resistance in cancer.
• Women's Health Initiative regarding the effects
  of energy intake and physical activity,
  suggesting that both physical activity and less
  food intake can reduce hyperinsulinemia.

53
Breast cancer

• a relationship between insulin resistance and
  breast cancer.
• Meta-analysis has shown a 1.56-fold increase in
  breast cancer associated with obesity
• Insulin resistance is also associated with worse
  breast cancer prognosis, with overweight women
  having a 1.8- to 1.9-fold increased rate of
  recurrence and a 1.4- to 1.6-fold increased
  mortality
• a study of 535 women with early-stage breast
  cancer, 15 of whom were obese, in which BMI was
  an important adverse prognostic factor for
  distant recurrence and death, with insulin levels
  also predictive of death and distant recurrence
  in both overweight and normal-weight women

54
Colorectal cancer

• an inverse association between physical activity
  and colon cancer, with a 30-50 risk reduction
  related to high activity.
• an association between BMI and colon cancer, with
  a 1.3- to 2-fold increased risk associated with
  BMI gt30 kg/m2
• type 2 diabetes is associated with a 1.5-fold
  increased risk of colon cancer.
• The risk of colon cancer is greatest in persons
  with type 2 diabetes at 11-15 years after
  diagnosis, suggesting a role of longstanding
  hyperinsulinemia