.

2. Outline
 Definition
 Review of Insulin Function
 Type 1 Diabetes Mellitus
 Type 2 Diabetes Mellitus
 Other Diabetes

3. Definition
 Disordered metabolism leading to hyperglycemia
secondary to insulin deficiency or decreased insulin
effectiveness
 Diagnostic criteria:
 Random Blood Sugar (RBS) ≥ 200 mg/dL with symptoms of
polyuria, polydypsia, polyphagia & weight loss
OR
 Fasting Blood Sugar (FBS) ≥ 126 mg/dL
OR
 2-hour Blood Sugar ≥ 200 during an oral glucose tolerance
test

5. Insulin Effect on Liver
 Increases glucose storage as glycogen & inhibits
glycogen breakdown
 Promotes triglyceride and very low density lipoprotein
synthesis
 Inhibits amino acids conversion to glucose
 Inhibits free fatty acid & amino acid conversion to
keto-acids

6. Insulin Effect on Muscle
 Increases protein synthesis
 Increase glycogen synthesis

7. Insulin Effect on Adipose Tissue
 Increased triglyceride storage

9. Epidemiology
 5-10% of all DM
 15 million people world wide are affected
 95% auto-immune, 5% idiopathic
 Most common form in children: median age 7-15 yrs
 Two peaks: 5-7 years and puberty
 50% of patients diagnosed after age 20 years

10. Pathogenesis
 Environmental triggers set off an autoimmune attack
against the beta cells of the pancreas in genetically pre-
disposed individuals
 T-cells directly attack beta cells
 Auto-anti-bodies to beta cell antigens
 Detectable months to years before diabetes onset
 Do not necessarily lead to disease; therefore, not useful for screening
 Main genetic risk factor is the major histocompatability
complex (MHC) on chromosome 6
 DR3-DQ2 & DR4-DQ8 alleles associated with increased risk

11. Pathogenesis
 Gradual and progressive
destruction of pancreatic
beta cells leading to
decreased insulin
secretion
 Clinical manifestations
occur when 80-90% of
beta cells have been
destroyed

12. Pathophysiology: Insulinopenia
leads to
 Hyperglycemia
 Osmotic diuresis (glucose >180mg/dL) → dehydration,
calorie & electrolyte wasting leading to polyuria,
polyphagia & polydipsia
 Decreased glucose use by body
 Mobilization of fat from adipose tissues and excess free
fatty acid production that are converted to ketone
bodies → ketonemia, ketonuria & metabolic acidosis
 Protein breakdown & impaired synthesis → muscle
wasting, retarded growth and weight loss

13. Pathophysiology: Physiologic stress
leads to
 Hyper-secretion of stress hormones which worsens
metabolic decompensation
 Impaired insulin secretion: epinephrine
 Antagonizes insulin: epinephrine, cortisol & growth
hormone
 Increased glycogenolysis, gluconeogenesis, lipolysis &
ketogenesis: cortisol, epinephrine, growth hormone &
glucagon
 Decreased glucose clearance and utilization:
epinephrine, cortisol & growth hormone

14. Pediatric Type 1 DM. Emedicine.com Accessed 2/23/2012

15. Phases of DM Type 1
 Initiation of auto-
immunity
 Pre-clinical auto-immunity
with progressive beta cell
loss
 Onset of clinical disease
 Transient Remission
(“Honeymoon Phase”)
 Established disease
 Development of
Complications

16. Clinical Manifestations
 Polyuria (secondary to
osmotic diuresis)
 Nocturia, bedwetting
 Polydipsia (in order to
maintain euvolemia)
 Polyphagia (to make up
for lost calories)
 Weight loss (secondary
to lost calories)
 Vaginitis (secondary to
glycosuria or candida)
 Fatigue & weakness (2/2
muscle wasting,
hypokalemia)
 Blurred vision (2/2
hyperosmolar effects on
vitreous humor & lens
 May present with
diabetic ketoacidosis
(DKA)
 Look for signs of other
autoimmune disease

17. Laboratory Investigations
 Random blood sugar (≥
200 mg/dL)
OR
 Fasting blood sugar (≥ 126
mg/dL)
 Urinalysis
 Glycosuria
 Ketonuria
 Electrolytes
 Hyponatremia
 Hypokalemia
 Hypophosphatemia
 Venous blood gas
 Low pH
 Hemoglobin A1C
 Insulin, pro-insulin & C-
peptide levels
• Tissue transglutaminase
IgA and total IgA
• Antithyroid peroxidase
and antithyroglobulin
antibodies
 No testing for anti-beta
cells antibodies needed

18. Management Principles
 Goals:
 Insulin therapy for tight glycemic control; balanced with
hypoglycemia prevention
 Allow normal growth & development
 Surveillance & management of complications

19. Insulin Therapy
 Insulin Dosing
 Pre-pubertal: 0.7 U/kg/d
 Post-pubertal: 1-1.2 U/kg/d
 Must account for the “honeymoon period” which
reduces exogenous insulin need
 Usually give 60-70% of the full replacement dose
 Adjust insulin dose by frequent monitoring of sugars &
insulin requirement

20. Insulin Therapy
Types of Insulin
Type of
Insulin
Name Onset Peak Duration
Rapid
Acting
Lispro,
Glulisine &
Aspart
5- 10 mins 45-75 min 2-4 hrs
Short
Acting
Regular 30 mins 2-5 hrs 6-8 hrs
Intermediate
Acting
NPH &
Lente
1-3 hrs
2-4 hrs
6-9 hrs
6-12 hrs
12-14 hrs
18-26 hrs
Long
Acting
Glargine &
Detemer
1-2 hrs No peak
(theoretically)
12-24 hrs

21. Insulin Therapy, cont.
 Dosing Schedule
 2/3 in the morning
 1/3 in the evening
 Insulin Type
 1/3 regular insulin
 2/3 lente insulin
 Example: 9yF with new
onset T1DM, wt: 30kg
 Total Daily Dose of
Insulin: 0.7u/kg/day
 0.7u x 30kg = 21 units/day
 Dosing Schedule:
 2/3 in AM: 14units
 1/3 in PM: 7 units
 Insulin Type:
 AM: 5 units regular, 9 units
lente
 PM: 2 units regular, 5 units
lente

22. Dietary Management
 Nutritionally balanced diet with adequate
calories and nutrients for normal growth
 Diabetic diet should contain
 Carbohydrate ………..50%
 Fat ………………………..30%
 Protein …………………20 %
 Avoid readily absorbable refined carbohydrates

23. Exercise & Parental/Patient
Education
 To improve metabolic control
 To lower insulin requirement
Patient and parent education
 Diabetic diet
 Insulin injection, dose, storage and
complications of insulin and its treatment
 Home blood sugar monitoring
 Understanding symptoms and signs of
hyperglycemia and hypoglycemia

24. COMPLICATIONS

25. Acute
Complications
Hyperglycemia
Hypoglycemia
Diabetic Ketoacidosis

26. Hypoglycemia
 RBS <60
 Occurs secondary to management: DKA or normal
management
 Clinical manifestations: Dizziness, weakness,
sweatiness, tremor, palpitations, pallor, vomiting,
confusion, anxiety, seizure and coma
 Treatment: sweetened drink, glucose & glucagon

27. Diabetic Ketoacidosis
 Occurs in up to 20-40% of new-onset diabetics, poorly
managed patients and patients with inter-current illness
 Leading cause of morbidity and mortality in Type I-DM
 Presentation
 Nausea/emesis (2/2 ketone formation)
 Dehydration (Intracellular; 2/2 glucosuria)
 Lethargy which can progress to coma (2/2 DHN)
 Fruity odor of breath (2/2 acetoacetate conversion to acetone)
 Kussmaul respirations (deep, heavy, rapid breathing 2/2
acidosis)

28. Diabetic Ketoacidosis, cont.
Parameter Normal Mild Moderate Severe
Bicarbonate
(mEq/L)
20-28 16-20 10-15 <10
pH 7.35-7.45 7.25-7.35 7.15-7.25 <7.15
Clinical
Manifestations
No Change •Oriented
•Alert
•Fatigued
•Kussmaul
breathing
•Lethargic
•Kussmaul
breathing
•Depressed
Sensorium to
coma

29. DKA Management Principles
 Insulin Replacement Therapy
 Fluid Replacement
 Electrolyte Correction

30. Intermittent Insulin therapy
Regular insulin dose ; initial 0.5 U/kg ½ im ½ iv and
then, sc , 0.5 U/kg s.c every 6 hrs

31. DKA, Insulin Replacement, cont.
 Transition to subcutaneous insulin & oral intake
 Consider with laboratory & clinical improvement:
 Bicarb >15 mEq/L, pH >7.30, Na normal, RBS 250- 300mg/dl,
LOW URINE KETONES
 No emesis, able to tolerate PO, improved mental status
 Monitoring
 RBS every 6 hours
 Urinalysis for ketones & glucose
 Then transition to combined regular & lente insulin

32. DKA Treatment Protocol
TIME THERAPY COMMENTS
1st hour 10–20 mL/kg IV bolus 0.9%
NaCl or LR
Quick volume expansion;may
be repeated. NPO. Monitor
I/O, neurologic status. Use
flow sheet. Have mannitol at
bedside;1 g/kg IV push for
cerebral edema
Insulin drip at 0.05 to 0.10 μ
/kg/hr
Iv rate= 85ml/kg+maint.-bolus
48 hrs
2nd hour until DKA resolution 0.45% NaCl:plus continue
insulin drip
20 mEq/L KPhos and 20
mEq/L KAc
5% glucose if blood sugar
<250 mg/dL (14 mmol/L)
If K < 3 mEq/L, give 0.5 to 1.0
mEq/kg as oral K solution OR
increase IV K to 80 mEq/L

33. DKA, Electrolyte Replacement
 No need to treat hyponatremia
 sodium is reduced by 1.6 mEq/L for each 100 mg/dL rise
in blood glucose
 Potassium chloride replacement
 Potassium phosphate replacement

34. DKA, Complications
 Cerebral edema
 Secondary to rapid changes in osmolarity (rehydrating
too fast)
 Clinical Manifestations: headache, sudden decline in
mental status and hypertension
 Monitor patients for Cushing’s triad: hypertension,
bradycardia & abnormal respirations
 Treatment: raise head of bed, hyperventilation,
mannitol

35. Complications, cont.
 Infections
 At higher risk 2/2 blood stasis & metabolic
derangements
 Most common:
 Skin: staphylococcal folliculitis, cellulitis, superinfected
fungal infection
 Urinary Tract: genital candidal infections, urinary tract
infections & acute pyelonephritis
 Injection Site Hypertrophy

36. Complications, cont.
 Somogyi response:
 Hypoglycemia induced morning hyperglycemia
 Due to larger doses of evening insulin and an exaggerated counter-
regulatory response
 Dawn Phenomenon:
 Morning hyperglycemia with out preceding hypoglycemia
 Due to overnight growth hormone secretion and
increased insulin clearance
 Brittle Diabetes:
 Marked fluctuation of blood glucose often with recurrent DKA
despite frequent insulin dose adjustment

37. Long-Term Complications
 Secondary to glycosylation of tissue proteins
 Microvascular:
 Eye: Retinopathy (up to 80%)→ Blindness; Cataracts
 Kidney: Nephropathy (20-30%)→ End Stage Renal Disease
 Nervous System: Neuropathy (50%; sensory peripheral &
autonomic)
 may also have cranial nerve & painful motor nerve involvement;
gastroparesis
 Increases risk for atherosclerotic disease
 Macrovascular:
 Heart: Coronary artery disease → Myocardial Infarction
 Brain: Cerebral vascular disease → Stroke
 Peripheral Vascular Disease

38. Outpatient Follow-Up
 Signs and symptoms of
hypo- or hyperglycemia
 Growth assessment
 Injection site assessment
 Blood pressure
 Signs of auto-immune
disease
 After age 11:
opthalmologic exam and
urine for
microalbuminuria

40. Epidemiology
 Incidence has increased more than 10-fold secondary
to obesity epidemic
 Prevalent in U.S. minority communities
 Represents 8-45% of all new cases of DM
 Mean age of onset 12-16 years

41. Pathogenesis
 Peripheral insulin resistance
 Beta cells unable to meet increasing insulin demand
 Relative insulin deficiency
 Disease worsened by high caloric intake, low physical
activity & obesity (central)

42. Pathophysiology
 Decreased glucose induced insulin secretion
 Hyperglycemia secondary to decreased glucose uptake
by liver & muscle
 Glucotoxicity results in decreased insulin gene
expression
 Hyperglycemia is moderate therefore patients may not
present for months to years

43. Risk Factors
 Strong genetic component
 Low birth weight & IUGR –
“Thrifty Phenotype
Hypothesis”
 Obesity
 Intake of high-calorie
foods
 Decreased physical activity
 Increased “screen time”
 Low socioeconomic status
(in developed countries)

44. Clinical Features
 Family history of T2DM
 Usually obese
 Mild poly symptoms
 DKA is rare presentation (10%)
 Signs of insulin resistance: dyslipidemia, hypertension,
polycystic ovarian syndrome, acanthosis nigricans

45. Laboratory Investigations
 Random blood sugar (≥ 200 mg/dL)
OR
 Fasting blood sugar (≥ 126 mg/dL)
 Urinalysis: microalbuminuria
 Hemoglobin A1C
 Lipid profile
 Insulin & C-peptide
 Autoimmune markers usually negative

46. Treatment
 Lifestyle Management
 Low-calorie, low-fat diet
 30-60 minutes of exercise 5x/week
 1-2 hrs of screen time/day
 Oral hypoglycemics
 Metformin is most commonly used; reduces hepatic glucose
production and increases peripheral insulin sensitivity
 Insulin
 If lifestyle management & oral hypoglycemics fails to decrease
glucose levels or patient presents with DKA
 Regimen similar to T1DM

47. Complications
 Long-term complications are the same as T1DM
 92% of T2DM have 2 or more elements of metabolic
syndrome – hypertension, hypertriglyceridemia,
increased weight circumference, decreased HDL.

49.  Genetic defects of insulin action: Maturity Onset
Diabetes of Youth (MODY)
 Genetic defects of insulin receptor: Leprechaunism
 Disease of exocrine pancreas: cystic fibrosis,
pancreatitis, pancreatic trauma or resection
 Drug-induced: thyroid hormone, steroids, beta
agonists, dilantin, thiazide diuretics

50.  Infections: rubella, CMV
 Endocrinopathies: Acromegaly, Cushing’s,
Hyperthyroidism, Pheochromocytoma
 Genetic syndromes associated with DM: Klinefelter’s,
Friedrich’s ataxia, Turner’s, Prader-Willi, Down’s
syndrome

51. Congenital Rubella
 70% develop beta cell autoimmunity
 40% develop Type I DM
 More likely to develop in those who are genetically
susceptible
 No increased risk if infection develops after birth

52. References
 Nelson’s Textbook of Pediatric Medicine, 1th Edition
 Basic & Clinical Endocrinology, 7th Edition
 Gondar DKA Protocol
 DM in Children Powerpoint from GUH files

53. Thanks!!!