1. Insulin resistance in childhood
Dr Abdullah Al Fares Pediatric endocrinology Consultant Security Forces Hospital Riaydh.KSA

2. 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

3. INSULIN STRUCTURE
A Chain
B Chain

5. 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)
Chromosome 11

6. HOW INSULIN IS RELEASED?
Insulin secretion is continuous
BASAL INSULIN SECTRETION
Increases after carbohydrate consumption
BIPHASIC

7. 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

8. 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
Cell

9. 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

10. SU gastrin GIP ATP BETA CELL Fatty acids Amino acids Acetylcholine CCK
Secretin
GLUT 2
GLUT 2
Glycolysis SU K+ K+ K+
ATP K+ K+
BETA CELL
Ca++
Ca++
Ca++
Ca++
Ca++
Ca++
Ca++
Ca++

11. Chemical Hormonal Neural
FACTORS AFFECTING INSULIN SECRETION
Stimulatory agents or conditions
Hyperglycemia
Amino acids, Fatty acids
GIT hormones GIP-GLP1-Gastrin-Secretin, CCK
Acetylcholine
Sulfonylureas
Chemical
Hormonal
Neural
Inhibitory agents or conditions
Somatostatin
Norepinephrine
Epinephrine

12. 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

13. MECHANISM OF ACTION
Tyrosine
Kinase
Tyrosine
Kinase P 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.

14. P P ECF ICF IRS-1 Phospho Kinase Ins Ins G G G G MAP-K Grb2&SOS RAS
Tyrosine
Kinase
Tyrosine
Kinase
ICF P P
GLUT-4
MAP-K
IRS-1
Grb2&SOS
Phospho Kinase
RAS
RAF

15. HORMONE OF ABUNDANCE INSULIN ACTIONS Rapid Delayed Intermediate
Increased transport of Glucose, Amino Acids and K+ into insulin Sensitive Cells
Stimulation of Protein Synthesis
Activation of Glycolysis & Glycogen Synthesis
Inhibition of Gluconeogenesis
Increase in mRNAs for lipogenic and other enzymes
Skeletal Ms Cardiac Ms
Adipose Tissue
HORMONE OF ABUNDANCE

16. 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

18. Risk Factors

20. the most common cause of insulin resistance, is associated mainly with postreceptor abnormality but is also associated with a decreased number of insulin receptors.
OBESITY
Hi TG’s
Hi FFA’s
FFA*
TNF-alpha*
Leptin*
IL-6 (CRP)*
Tissue Factor*
PAI-1*
Angiotensinogen*
Intramuscular
Subcutaneous
Intrahepatic
Intra-
abdominal

21. Role of Free Fatty Acids in Hyperglycemia
Title
Subtitle
Role of Free Fatty Acids in Hyperglycemia
Adipose tissue insulin resistance
ADIPOSE TISSUE
MUSCLE
 Lipolysis
LIVER
Muscle
insulin
resistance
 FFA mobilization
Liver insulin
resistance
 FFA oxidation
 FFA oxidation
 Gluconeogenesis
 Glucose utilization
Hyperglycemia
Boden G. Proc Assoc Am Physicians. 1999;111:

22. Plasma Insulin (uU/ml)
INSULIN RELEASED IN DM 2
Loss of the first phase result in elevation of the postprandial glucose.
Delayed second phase- can result in post-meal hypoglycemia.
NORMAL
Plasma Insulin (uU/ml)
%%%%%%%%%%%%
TYPE 2 DM 5 10 15 20 25 30 35 40 45 50 55 60
Time (Minutes)

23. CLINICAL SPECTRUM

27. Possible mechanisms by which insulin resistance leads to the clinical manifestations of the ACANTHOSIS NIGRICANS AND polycystic ovary syndromE

28. PCOS – Insulin Resistance
IR and Obesity
Endocrine
Liver  SHBG
Ovary  Androgen
Adrenal Androgen
Metabolic
MS, DM
PCOS, Infertility, Irr. Menses, Hirsutism
CVD

29. Genetic causes of insulin resistance
The key feature of all insulin resistance syndromes are acanthosis nigricans, androgen excess and massively raised insulin concentrations in the absence of obesity
Leprechaunism
Rabson-Mendenhall syndrome
Lipoatropic diabetes
(Lorens syndrome)
Type A Ins resistance

30. 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 & GH- resistence
Recessive

31. Rabson-Mendenhall Congenital Extreme Growth retardation
Mental retardation
Abnormal dentition
Acanthosis Nigricans
Androgen Excess & Hypertrichosis
Gene involved Insulin receptor
Recessive

32. 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)

33. Type A Ins resistance Adolescence Ins-resistance in absence of obesity
Acanthosis Nigricans
Androgen Excess & Hypertrichosis
Gene involved Insulin receptor
Recessive

35. Metabolic Syndrome

36. 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.

37. 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

39. 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

40. Obesity IDF: WHO: ATP III:
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

42. 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)

43. Dyslipidemia IDF: WHO: ATP III:
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

44. Hypertension IDF: WHO: NCEP ATP III:
BP >130/85 or on Rx for previously Dxed hypertension
WHO:
BP >140/90
NCEP ATP III:
BP >130/80

45. 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

46. THERAPY

47. Multiple Risk Factor Management
Obesity
Glucose Intolerance
Insulin Resistance
Lipid Disorders
Hypertension
Goals: Minimize Risk of Type 2 Diabetes and Cardiovascular Disease

48. Lifestyle modification
Diet
Exercise
Prevention of type 2 diabetes
Oral hypoglycemic agents
Cardiovascular risk reduction
Prevention 

49. 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 min./day
10% reduction in body wt.

50. 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
Goals:
FBS - premeal <110,
postmeal <150.
HbA1c <7%

51. Proinflammatory state Lifestyle therapies; no specific interventions
Prothrombotic state Low dose aspirin for high risk
patients
Goals;low CRP
Proinflammatory state
Lifestyle therapies; no
specific interventions

52. 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

53. Lipid Control - How Important?
Multiple major studies show % 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)

54. Medications

55. 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

56. prevention