Objective:

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The insulin resistance syndrome, pre diabetes
and obesity Shlomit Shalitin Institute for
Endocrinology and Diabetes, Schneider Childrens
Medical Center of Israel Petah Tiqva, and
Sackler Faculty of Medicine, Tel Aviv University,
Tel Aviv, Israel
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Prevalence of Childhood Obesity

• The prevalence of obesity in adolescence in the
  USA is 10-25
• Obesity prevalence in the USA among adolescents
  increased by 20 in the last decade

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Risks of Obesity

• Sudden death is more common in those who are
  naturally fat than in the lean Hipocrates
• BMIs in excess of 28 kg/m² are associated with a
  3- 4-fold increase in risk of hypertension,
  dyslipidemia, insulin resistance (IR) and type 2
  diabetes.

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Global Projections for the DiabetesEpidemic
2003-2025 (millions)
38.2 44.2 16
Europe
North America
Asia
25.0 39.7 59
81.8 156.1 91
Middle East
18.2 35.9 97
Africa
13.6 26.9 98
South Central America
10.4 19.7 88
Oceania
1.1 1.7 59
WORLD 2003 189 million 2025 324
million Increase 72
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• Type 2 diabetes mellitus in the young population
• The prevalence of type 2 diabetes in the young
• population is increasing throughout the world
• wherever childhood obesity is becoming more
• prevalent
• The risk of type 2 diabetes increases with the
• degree and duration of obesity and with a
• more central distribution of
• body fat.

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Genetics and Environment in obesity IR and type
2 diabetes
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Insulin resistance (IR)

• IR is defined as an impaired ability of plasma
  insulin at usual concentrations to adequately
  promote peripheral glucose disposal, suppress
  hepatic glucose, and inhibit VLDL output.
• IR can be inferred on clinical evidence and
  confirmed by insulin and glucose measurements
  made by fasting insulin/glucose screening, OGTT,
  and insulin/glucose clamp studies.

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The metabolic syndrome

• Diagnosis is made if 3 of the following
  criteria are met
• Obesity (BMI z score 2, adjusted for age
  gender).
• Hypertension (values gt95th percentile for age
  gender).
• Dyslipidemia (triglyceride gt95th percentile,
  HDL
• cholesterollt 5th percentile, adjusted for age
  gender).
• Insulin resistance, IGT or type 2 diabetes.
• Hepatic steatosis
• Hyperandrogenism /PCO
• Acanthosis nigricans, striae
• Pseudoacromegaly, low IGFBP-1
• Increased CRP, TNFa levels

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NEJM June 3 2004
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CLINICAL STUDY Type 2 diabetes and
impaired glucose tolerance in European children
and adolescents with obesity-a problem that is no
longer restricted to minority groups Wiegand S
et al, Paediatric Endocrinology, Charit?
Children's Hospital Humboldt University Berlin
Germany Eur J Endocrinol 2004
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Insulin resistance and impaired glucose
tolerance in obese children and adolescents
referred to a tertiary care center in Israel S
Shalitin, M Abrahami, P Lilos, M Phillip

• Aim To establish the prevalence of IR and IGT and
  their determinants in obese children and
  adolescents.
• Methods The group study included 234 patients
  (BMI 95th percentile for age sex) 22
  patients (BMI 85th-95th percentile for age
  sex) aged 5-22 ys who had been referred between
  1997-2003.
• Fasting blood samples were obtained for
  evaluation of glucose, insulin and lipid profile.
• Estimates of insulin resistance (HOMA-IR),
  insulin sensitivity (QUICKI, GF/IF) and ß- cell
  function (HOMAB) were derived from fasting
  measurements.
• An OGTT was performed in 192 patients to
  determine the presence of IGT.

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Clinical characteristics of obese children and
adolescents
Total (n256) n () Girls )n147) n () Boys (n109) n () Characteristics
54 (21) 81 (31.6) 9 (3.5) 37 (25.2) 42 (28.6) 7 (4.8) 17 (15.6) 39 (35.8) 2 (1.8) Family history of type 2 diabetes or gestational diabetes (GDM) Diabetes in Parents Diabetes is 2nd degree relative (s) GDM
145 (56.6) 9 (62.6) 53 (48.6) Acanthosis nigricans
Obesity Complications
18 (7) 129 (50.3) 10 (3.9) 5 (1.9) 16 (6.3) 42 (32.8) 3 (1.2) 9 (6.1) 72 (49) 4 (2.7) 5 (3.4) 5 (3.4) 42 (32.8) 2 (1.4) 9 (8.3) 57 (52) 6 (5.5) 11 (10.1) 1 (0.9) Hypertension Dyslipidemia Fatty liver Pseudotumor cerebri Sleep apnea Hyperandrogenism/PCO Depression
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Clinical laboratory characteristics of obese
children and adolescents
Girls (n147) Mean SD Boys (n109) Mean SD Characteristics
13.8 3.7 13.0 3.3 Age (years)
32.7 7.0 32.2 5.5 BMI (kg/m²)
3.2 1.4 3.5 1.4 BMI SDS
176.8 36 169.7 30.5 Total cholesterol (mg/dL)
104 27.9 103.6 29.6 LDL- cholesterol (mg/dL)
45.4 11.1 42.7 9.3 HDL- cholesterol (mg/dL)
130.3 61 122.4 61 Triglycerides (mg/dL)
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Clinical laboratory characteristics of obese
children and adolescents (cont.)
Normal range Mean SD Girls (n147) Mean SD Boys (n109) Mean SD Characteristics
60-100 85.2 8.8 87.0 9.4 Glucose fasting (mg/dL)
lt20 21.0 16.0 21.3 20.8 Insulin fasting (µU/mL)
lt 140 116.8 27 109.1 24.3 Glucose 120' (on OGTT) (mg/dL)
134.4 96.6 89 74.7 Insulin 120' (on OGTT) (µU/mL)
lt5.8 5.5 0.3 5.5 0.4 HbA1C ()
lt2.0 4.5 4.4 4.8 5.3 HOMA-IR
gt0.339 0.319 0.029 0.322 0.033 QUICKI
5.9 4.8 6.8 4.8 GF/IF
378.2 317.3 330.2 281.5 HOMA- B
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Characteristics of obese children and adolescents
with normal or impaired glucose tolerance
p Value Impaired glucose tolerance (n26) Normal glucose tolerance (n165) Characteristics
NS 10 16 67 98 GenderBoysGirls
NS 14.0 2.8 13.65 3.47 Age (years)
NS 33.9 5.3 32.6 6.7 BMI
NS 3.48 1.27 3.28 1.46 BMI-SDS
lt0.05 89.2 10.6 85.9 6.5 Fasting glucose (mg/dL)
NS 23.2 16.2 19.4 15.0 Insulin fasting (µU/mL)
lt0.001 210.8 128.1 101.2 74.03 Insulin 120' (in OGTT) (µU/mL)
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Characteristics of obese children and adolescents
with normal or impaired glucose tolerance
p Value Impaired glucose tolerance (n26) Normal glucose tolerance (n165) Characteristics
NS 5.4 5.0 4.1 3.4 HOMA-IR
0.062 4.9 2.1 6.7 5.0 GF/IF
lt0.05 0.309 0.022 0.323 0.031 QUICKI
NS 333.5 174.7 332.9 300.4 HOMA- B
NS 181.9 29.6 172.3 34.1 Total Cholesterol (mg/dL)
NS 103.6 23.9 105.2 29.7 LDL- cholesterol (mg/dL)
NS 46.6 13.3 44.5 10.1 HDL- cholesterol (mg/dL)
0.002 156.9 68.9 117.4 53.1 Triglycerides (mg/dL)
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Results

• Insulin resistance was detected in 81.2 of the
  patients, IGT in 13.5, and silent diabetes in
  one adolescent girl.
• GF/IF QUICKI decreased significantly during
  puberty (plt0.005).
• Insulin resistance insulin sensitivity indexes
  were not associated with ethnicity, presence of
  acanthosis nigricans or type 2 diabetes in
  family.
• Only 2 patients with IGT also had impaired
  fasting glucose.

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Conclusions

• Insulin resistance is highly prevalent in obese
  children and adolescents.
• Neither fasting blood glucose or insulin levels
  nor HOMA-IR or HOMA-B are effective in the
  screening of IGT.
• As there are no predictive cut-point values of
  insulin resistance or insulin sensitivity indexes
  for IGT, an OGTT is required in all subjects at
  high risk.
• Improving insulin resistance may be crucial in
  the prevention of both type 2 diabetes and
  premature cardiovascular disease in this at-risk
  population.

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ADA recommendations for screening for type 2
diabetes in youth

• BMIgt 85th percentile for age and gender
• Any 2 or more of the following risk factors
• Family history of type 2 diabetes in first or
• second-degree relative
• Member of a high risk ethnicity
• Signs of insulin resistance acanthosis
• nigricans, hypertension, dyslipidemia, or
  PCOs.
• Screening should include a fasting plasma glucose
  (Begin testing at 10 years old or at onset of
  puberty).

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• As IR is the precursor of type 2 diabetes, and IR
  begins in childhood, then the earlier an
  intervention can be initiated in the natural
  history of the disease, the more effective it
  will be to prevent or delay progression to
  diabetes.
• Modest weight reductions of 5-10 significantly
  decrease the risk of complications of IR.

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Prevention and treatment

• Family based behavioral interventions for obese
  children have been associated with reductions in
  cholesterol, increases in HDL, and reductions in
  IR. Pasquali R, JCEM 1989.
• There are reports that with appropriate changes
  in lifestyle (diet physical activity) and
  weight reduction progression from IGT to diabetes
  can be delayed or prevented. Tuomilehro J et al.
  N Engl J Med, 2001.

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Prevention and treatment

• The STOP-NIDDM trial has shown that
  pharmacological
• intervention with Acarbose in adult patients with
  IGT
• can reduce the progression to type 2 diabetes by
  25.
• This trial also demonstrated that Acarbose
  increases
• the probability that IGT will revert to normal
  glucose
• tolerance over time.Chiasson-JL et al. Lancet,
  2002.

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Prevention and treatment
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• Thank you