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INSULIN RESISTANCE
IN CHILDHOOD
Dr Abdullah Al Fares
Pediatric endocrinology Consultant
Security Forces Hospital
Riaydh.KSA
PANCREAS
 Only 2% of the pancreas weight is beta cell.
 Those cell produce insulin in the rate of one
unit per each kilogram of body weight
INSULIN STRUCTURE
A Chain
B Chain
INSULIN
Insulin Degradation:
Chromosome 11
 2 main organs:
liver – 60%
kidney – 35-40%
 has a half-life of approximately 3-5 minutes once it is released
into the general circulation
 stimulated – glucose, amino acids, FFA, GIT hormones
 early phase (ready insulin)
 late phase (synthesis de novo)
HOW INSULIN IS RELEASED?
Insulin secretion is continuous
BASAL INSULIN SECTRETION
Increases after carbohydrate consumption
BIPHASIC
1) Food enters the system
and is digested in to simpler
units, [one being glucose]
2) Glucose enters the blood
stream
3) Insulin is produced by the
pancreas and is released
into the blood stream.
4) Insulin binds to the cell
allowing glucose to enter
1) Food enters the system
and is digested in to simpler
units, [one being glucose]
2) Glucose enters the blood
stream
3) Insulin is produced by the
pancreas and is released
into the blood stream.
4) Insulin binds to the cell
allowing glucose to enter
REGULATION OF INSULIN SECRETION
 Glucose rapidly increase the translation of the insulin mRNA and slowly
increases transcription of the insulin gene
 No insulin is produced when plasma glucose below 50 mg/dI
 Threshold of glucose-stimulated insulin secretion is 100 mg/dl.
 Half-maximal insulin response occurs at 150 mg/dl
 A maximum insulin response occurs at 300 mg/dl
 above 300 mg/dl platue
CCK
G
G
GLUT 2
Secretin
G
G
G
G
GLUT 2
Amino acids Acetylcholine
G
gastrin
Fatty acids
GIP
Glycolysis
SU
K+
K+
K+
K+
K+
ATP
BETA CELL
Ca++
Ca++
Ca++
Ca++
++
Ca++ Ca
Ca++
Ca++
FACTORS AFFECTING INSULIN SECRETION
Stimulatory agents or conditions
ChemicalHyperglycemia
Amino acids, Fatty acids
Hormonal
GIT hormones GIP-GLP1-Gastrin-Secretin, CCK
Acetylcholine
Neural
Sulfonylureas
Inhibitory agents or conditions
Somatostatin
Norepinephrine
Epinephrine
GLUCOSE TRANSPORTERS
Name
Tissue
Function
GLUT1 (erythrocyte)
wide distribution, esp.
brain, kidney, colon,
fetal tissues
Basal glucose
transport
GLUT2 (liver)
Liver, b-cells of
pancreas, small
intestine, kidney
Non-rate-limiting
glucose transport
GLUT3 (brain)
Wide distribution, esp.
neurons, placenta,
testis
Glucose transport in
neurons
GLUT4 (muscle)
Skeletal muscle,
cardiac muscle,
adipose tissue
Insulin-stimulated
glucose transport*
GLUT5 (small intestine) Small intestine, kidney,
skelatal muscle, brain,
adipose tissue
Fructose transport
Many individuals with insulin resistance are deficient in a glucose
transporter GLUT-4
MECHANISM OF ACTION
Tyrosine
Kinase
P
Tyrosine
Kinase
P
IRS-1
 Insulin binds to the α subunits of the insulin receptor, so
 increases glucose transport and causes autophosphorylation of the β subunit of the receptor, that
induces tyrosine kinase activity.
 Tyrosine phosphorylation, in turn, activates a cascade of intracellular signaling proteins that mediate the
effects of insulin on glucose, fat, and protein metabolism.
Ins
ECF
Ins
G
Tyrosine
Kinase
ICF
P
MAP-K
G
Tyrosine
Kinase
P
GLUT-4
IRS-1
Grb2&SOS
Phospho Kinase
RAS
RAF
G
G
G
G
INSULIN ACTIONS
Intermediate
Rapid
Increased transport of
Glucose, Amino Acids
and K+ into insulin
Sensitive Cells
Skeletal Ms Cardiac
Ms
Adipose Tissue
• Stimulation of Protein
Synthesis
• Activation of Glycolysis &
Glycogen Synthesis
• Inhibition of
Gluconeogenesis
Delayed
Increase in
mRNAs for
lipogenic and
other enzymes
HORMONE OF ABUNDANCE
INSULIN RESISTANCE
 Diminishe the ability of the cells to respond to the
action of insulin in transporting glucose from the
bloodstream into muscle and other tissues
Cells become less responsive to insulin  high
plasma insulin Compensatory hyperinsulinemia
causes down regulation of insulin receptor Defects
in insulin receptor  Reduction of glucose uptake/use
by cells  hyperglycemia
OBESITY
the most common cause of insulin resistance,
is associated mainly with postreceptor
abnormality but is also associated with a
decreased number of insulin receptors.
Hi TG’s
Hi FFA’s
Intramuscular
Subcutaneous
Intrahepatic
Intraabdominal
FFA*
TNF-alpha*
Leptin*
IL-6 (CRP)*
Tissue Factor*
PAI-1*
Angiotensinogen*
Role of Free Fatty Acids in Hyperglycemia
Adipose tissue
insulin
resistance
ADIPOSE TISSUE
MUSCLE
Muscle
insulin
resistance
 Lipolysis
LIVER
 FFA mobilization
Liver insulin
resistance
 FFA oxidation
 FFA oxidation
 Gluconeogenesis
 Glucose utilization
Hyperglycemia
Boden G. Proc Assoc Am Physicians. 1999;111:241-248.
NORMAL
• Loss of the first phase result in elevation
of the postprandial glucose.
• Delayed second phase- can result in postmeal hypoglycemia.
%%%%%%%%%%%%
Plasma Insulin (uU/ml)
INSULIN RELEASED IN DM 2
TYPE 2 DM
0
5
10
15
20
25 30 35 40
Time (Minutes)
45
50
55
60
CLINICAL SPECTRUM
POSSIBLE MECHANISMS BY WHICH INSULIN
RESISTANCE LEADS TO THE CLINICAL
MANIFESTATIONS OF THE ACANTHOSIS
NIGRICANS AND POLYCYSTIC OVARY
SYNDROME
PCOS – INSULIN RESISTANCE
IR and
Obesity
Endocrine
Liver 
SHBG
Ovary

Androgen
Metabolic
Adrenal
Androgen
PCOS, Infertility,
Irr.
Menses, Hirsutism
MS, DM
CVD
GENETIC CAUSES OF INSULIN
RESISTANCE
The key feature of all
insulin resistance
Rabson-Mendenhall syndrome
syndromes are
Lipoatropic diabetes
acanthosis nigricans,
(Lorens syndrome)
androgen excess and
massively raised insulin
Type A Ins resistance
concentrations in the
absence of obesity
Leprechaunism
LEPRECHAUNISM –DONAHUE SYNDROME
Congenital
Abnormal faces
Large genitalia
SGA and growth retardation
fasting hypoglycemia
Rarely survive infancy
Death within the first 1 to 2 years of life
Acanthosis Nigricans
Gene involved Insulin receptor & GHresistence
Recessive
RABSON-MENDENHALL
Congenital
Extreme Growth retardation
Mental retardation
Abnormal dentition
Acanthosis Nigricans
Androgen Excess & Hypertrichosis
Gene involved Insulin receptor
Recessive
LIPODYSTROPHY
LORENS SYNDROME
Congenital or Adolescence
Loss of subcutaneous fat – partial or total
Acanthosis Nigricans
Androgen Excess & Hypertrichosis
Insulin resistance,high TG,large fatty liver
Gene involved Total: Seipin & AGPAT2
(A.recessive) Partial :Lamin AC & PPARG
(dominant)
TYPE A INS RESISTANCE
Adolescence
Ins-resistance in absence of obesity
Acanthosis Nigricans
Androgen Excess & Hypertrichosis
Gene involved Insulin receptor
Recessive
Metabolic Syndrome
CHILDREN AND ADOLESCENTS
The International Diabetes Federation (IDF) definition of
metabolic syndrome in children 10 to 16 years old is
similar to that used by the IDF for adults
For children 16 years and older, the adult criteria can be
used
For children younger than 10 years of age, metabolic
syndrome cannot be diagnosed, but vigilance is
recommended if the waist circumference is ≥90
percentile.
CRITERIA FOR DIAGNOSIS
World Health Organization (WHO)
International Diabetes Federation (IDF) - European
Association for the Study of Diabetes (EASD)
National Cholesterol Education Project, Adult
Treatment Panel (NCEP-ATP III)
Others
NECESSARY CRITERIA TO MAKE DIAGNOSIS
 IDF:
Require central obesity plus two of the other
abnormalities
 WHO:
Also requires microalbuminuria - Albumen/
creatinine ratio >30 mg/gm creatinine
 ATP III:
Require three or more of the five criteria
OBESITY
 IDF:
Central obesity - waist circumference >94 cm for
men, >80 cm women with ethnicity
specific values for other groups
 WHO:
Waist-hip ratio >0.9 - men or >0.85 – women
 ATP III:
Waist circumference >101.6 cm in men and 88.9
cm in women
GLUCOSE ABNORMALITIES
IDF:
FPG >100 mg/dL (5.6 mmol.L) or previously
diagnosed type 2 diabetes
WHO:
Presence of diabetes, IGT, IFG, insulin resistance
ATP III:
FBS >110 mg%, <126 mg (ADA: FBS >100)
DYSLIPIDEMIA
IDF:
Triglycerides - >150mg/dL (1.7 mmol/L)
HDL - <40 mg/dL (men), <50 mg/dL (women)
WHO:
Triglycerides - >150 mg/dL (1.7 mmol/L)
HDL - <35 mg/dL (men),- <39 mg/dL) women
ATP III:
Same as IDF
HYPERTENSION
IDF:
BP >130/85 or on Rx for previously Dxed
hypertension
WHO:
BP >140/90
NCEP ATP III:
BP >130/80
BIOCHEMICAL MARKERS
In nondiabetic, normotensive overweight individuals :
 serum triglyceride concentration,
 the ratio of triglyceride to high density lipoprotein (HDL)
 cholesterol concentrations
 fasting insulin concentration
 CRP ,TSH ,LFT ,Fasting glucose,GTT,HBA1C, and uric acid.
 Reduced serum levels of adiponectin (a hormone made by fat
tissue) and elevated leptin concentration are also features of
conditions associated with the metabolic syndrome or
cardiovascular disease.
 are useful markers for identifying those who may be insulin
resistant
THERAPY
MULTIPLE RISK FACTOR MANAGEMENT
Obesity
Glucose Intolerance
Insulin Resistance
Lipid Disorders
Hypertension
Goals: Minimize Risk of Type 2 Diabetes
and Cardiovascular Disease
Lifestyle modification
Diet
Exercise
Prevention of type 2 diabetes
Oral hypoglycemic agents
Cardiovascular risk reduction
Prevention
LIFE-STYLE MODIFICATION: IS IT IMPORTANT?
 Abdominal obesity
Year 1: reduce body weight 7 to 10 percent
Continue weight loss thereafter with ultimate goal BMI <25 kg/m2
 Exercise
Improves CV fitness, weight control, sensitivity to insulin, reduces
incidence of diabetes
 Atherogenic diet
Reduced intake saturate fat, trans fat, cholesterol
 Weight loss
Improves lipids, insulin sensitivity, BP levels, reduces incidence of diabetes
 Goals:
Brisk walking - 30 min./day
10% reduction in body wt.
DIABETES CONTROL - HOW IMPORTANT?
For every 1% rise in Hb A1c there is an 18% rise in risk of
cardiovascular events & a 28% increase in peripheral
arterial disease
Evidence is accumulating to show that tight blood sugar
control in both Type 1 and Type 2 diabetes reduces risk of
CVD

Prothrombotic state
Low dose aspirin for high risk
patients
 Goals;low CRP
Proinflammatory state
Lifestyle therapies; no
specific interventions
BP CONTROL - HOW IMPORTANT?
MRFIT and Framingham Heart Studies:
- Conclusively proved the increased risk of
CVD with long-term sustained hypertension
- Demonstrated a 10 year risk of
cardiovascular disease in treated patients vs
non-treated patients to be 40%
- 40% reduction in stroke with control of HTN
• Goal: BP <130/80
LIPID CONTROL - HOW IMPORTANT?
Multiple major studies show 24 - 37% reductions in
cardiovascular disease risk with use of statins and
fibrates in the control of hyperlipidemia
Goals: LDL <100 mg/dL (<3.0 mmol /l)
(high risk <70 mg/dL- <2.6 mmol/L)
TG <150 mg% (<1.7 mmol /l)
HDL >40 mg% (>1.1 mmol /l)
Medications
 Hypertension:
ACE inhibitors, ARBs
Others - thiazides, calcium channel blockers, beta
blockers, alpha blockers
 Hyperlipidemia:
Statins, Fibrates, Niacin
 Platelet inhibitors:
ASA
 Insulin Resistance/Diabetes
Insulin Sensitizers:
- Biguanides - metformin
- PPAR α, γ & δ agonists - Glitazones, Glitazars
Can be used in combination
Insulin Secretagogues:
- Sulfonylureas - glipizide, glyburide, glimeparide,
glibenclamide
- Meglitinides - repaglanide, netiglamide
prevention