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DIABETES MELLITUS

Dr. Justice Sylverken


OUTLINE
Incidence
Epidemiology
Aetiology
Pathogenesis & Pathophysiology
Clinical features Clinical features
Complications - Short term & long term
Diagnosis
Management
Initial and
long term
Recent advances
INCIDENCE
Increasing incidence
0.740/100,000 per yr. highest in Finland
More common in northern countries
(USA)
14.9 new cases/100,000 child population 14.9 new cases/100,000 child population
Preva1ence 1.9/1,000 school aged children
1 case /1,430 at 5yr
1 case /360 at 16 yr
WORLDWIDE PREVALENCE OF DIABETES
MELLITUS
AMOS, MCCARTY, AND ZIMMET. DIAB MED 1997;14:S1-S85.
EPIDEMIOLOGY
Girls = Boys affected
More common in Caucasians
African Americans - 1/3 ~ 2/3 of Caucasians
Mean age 7-15 (T1DM)
Age Peaks (T1DM) Age Peaks (T1DM)
5-7years
puberty
GLOBAL DIABETES PREVALENCE
BY AGE AND GENDER FOR 2000
WILD S ET AL. DIAB CARE 2004;27:1047-1053.
PATHOGENESIS OF DIABETES
MELLITUS
Type 1 Diabetes Mellitus
Pancreatic islet cell destruction by
autoimmune process
Beta cells which produce insulin
eventually destroyed eventually destroyed
Result is absolute lack of insulin
production
Type 2 Diabetes Mellitus
Relative lack of insulin production
Peripheral tissues resistant to effects
of circulating insulin
POSSIBLE ETIOLOGICAL DETERMINANTS AND
RISK FACTORS FOR TYPE 1 DIABETES MELLITUS
ZIMMET, ALBERTI, AND SHAW. NATURE 2001;414:782-787.
TYPES DM IN CHILDREN
Chronic Metabolic syn. -Hyperglycaemia
Type 1 DM (~ almost all are T1DM)
Absolute Insulin secretion deficiency
Pancreatic -cell damage Pancreatic -cell damage
Autoimmune mechanism
Type 2 DM (T2DM)
Insulin resistance at target organs level
Various degree of -cell impairment
TYPES DM IN CHILDREN CONT.
Other specific types (def. -cell function)
Chromosome 12, HNF-1 (MODY-3)
Chromosome 7, glucokinase (MODY-2)
Chromosome 20, HNF-4 (MODY-1) Chromosome 20, HNF-4 (MODY-1)
Neonatal Diabetes Mellitus
Transient-without recurrence (~1/3)
Transient-recurrence 7-20 yr later (~)
Permanent from onset (~)
AETIOLOGY
Genetic
30-50% concordance in identical twins (T1DM)
~ 100% concordance in identical twins (T2DM)
Increased risk if parent affected
HLA-DR3 &/or -DR4 ~7-10 fold increase risk HLA-DR3 &/or -DR4 ~7-10 fold increase risk
Environment
Viral infections
Dietary factors
Chemicals
PATHOGENESIS
Autoimmune injury
Genetic predisposition
Environmental factors
Autoimmune process Autoimmune process
against pancreatic islet (-cell destruction)
Sustained for prolonged periods
Destroyed 80-90% of pancreatic islet
Cytokine-mediated insulin secretion inhibition
Regeneration of new islets detected
INSULIN (POSTPRANDIAL STATE)
Glucose, Amino acid & Triglyceride uptake
Glycogen synthesis
Lipid synthesis
Protein synthesis Protein synthesis
Glucose oxidation
Absence of gluconeogenesis
Absence of ketogenesis
PROGRESSION TO TYPE 1 DM
Autoimmune destruction
Honeymoon
Diabetes threshold
Honeymoon
100% Islet loss
INSULIN DEFICIENCY (FASTED STATE)
Absence of glucose uptake
Absence of Triglyceride uptake
Gluconeogenesis
Glycogenolysis
Ketogenesis Ketogenesis
Fatty acid and ketone oxidation
Proteolysis and amino acid release
Lipolysis and fatty acid release
STRESS HORMONES
Epinephrine, Cortisol, Glucagon & GH
Impair insulin secretion
Antagonizing insulin action
glucose utilization & clearance
Promote Promote
Gluconeogenesis
Glycogenolysis
Lipolysis
ketogenes
PATHOPHYSIOLOGY
Moderate insulinopenia
Glucose utilization by muscle & Fat tissue
Postprandial hyperglycaemia (IGT)
Severe insulinopenia
Gluconeogenesis & Glycogenolysis by liver Gluconeogenesis & Glycogenolysis by liver
Fasting hyperglycaemia (DM)
Hyperglycaemia osmotic diuresis loss of
calories, electrolyte + dehydration
physiologic stress stress hormones
CLINICAL FEATURES
Mean age 7-15yr with 2 peaks
Long prodromal phase
Early S/S
Late S/S (i.e. DKA) Late S/S (i.e. DKA)
+/- intercurrent illness or trauma
Infants; 50% present late, wt=water loss
Older Children 15% late, wt= fat loss
EARLY SYMPTOMS AND SIGNS
Polyuria / Nocturia
Polydypsia
Weight loss +/- subcutaneous fat
Polyphagia (compensatory)
Enuresis (secondary)
LATE SYMPTOMS AND SIGNS
DKA
Nausea, and Vomiting
Gastro-enteritis Vomiting but no diarrhea
Abdominal discomfort/pain
Dehydration But excessive urine output Dehydration But excessive urine output
Hypovolaemic shock
Hyperventilation due to acidosis
Respiratory distress But no lung findings
Drowsiness
Coma
DIAGNOSIS
DM
Symptomatic Child + RBS >11.1 mmol/L
Fasting Plasma Glucose 7.0 mmol/L
Glycosuria +/- Ketonuria
OGTT 2-hr plasma glucose 11.1mmol/L OGTT 2-hr plasma glucose 11.1mmol/L
IGT
Fasting plasma glucose 6.1-7.0 mmol/L
2-hr plasma glucose during the OGTT (rarely
needed) is 7.8 -11.1 mmol/L
DM COMPLICATIONS
Short term
Acute metabolic derangement
Hypoinsulinemic hyperglycaemic ketoacidosis
Long term (usually in adulthood)
Metabolic disturbances Metabolic disturbances
Affects small and large vessels
Arterial obstruction + extremities gangrene
Retinopathy -Nephropathy
Ischemic Heart Disease -Neuropathy
CASE PRESENTATION
PEU
10 yrs old boy presents with altered mental
status
2-week history of polyuria, weight loss
Complains of abdominal pain and weakness Complains of abdominal pain and weakness
o/e Lethargic with mild tachypnea.
Skin is pale, Cool to touch
Delayed Capillary time (CRT>3sec)
HR 150, RR 45, SBP 80/, SaO
2
100% (air)
What is your Differential Diagnosis?
INITIAL ASSESSMENT (1 OF 2)
PAT:
Abnormal APPEARANCE,
Normal WORK OF BREATHING,
Abnormal CIRCULATION TO SKIN Abnormal CIRCULATION TO SKIN
Vital signs:
HR 150, RR 45,
BP 80/palp,
O
2
sat 100% on room air
INITIAL ASSESSMENT (2 OF 2)
A: Good
B: Mild tachypnea with good air exchange,
no retractions no retractions
C: Skin pale and cool, skin turgor poor,
capillary refill time prolonged
D: Lethargic, arousable, cooperative
Bedside glucose check >28mmol/L
DETAILED PHYSICAL EXAM
Head: No evidence of trauma, eyes sunken, oral
mucosa dry, fruity breath odor
Neck: Supple
Lungs: Clear, mild tachypnea
Abdomen: Soft, mild, nonfocal tenderness, active Abdomen: Soft, mild, nonfocal tenderness, active
bowel sounds
Neuro: Lethargic, arousable, cooperative
Extremities: Cool to touch, delayed CRT
What is your general impression of this Child?
GENERAL IMPRESSION
General impression of this Child?
Shock (decompensated)
Severe dehydration and hypovolemic shock
(hypotension)
Suspected new onset diabetes and DKA
What are your initial management priorities?
MANAGEMENT PRIORITIES
Airway ~Position to maintain airway
Breathing (give Oxygen)
Circulation (Shock)
Place cardiorespiratory monitor Place cardiorespiratory monitor
IV access + blood sample for evaluation
IV fluid bolus (10-20ml/kg) N/S or RL
DIAGNOSTIC STUDIES
DKA defined as:
Hyperglycemia (glucose > 11.1mmol/L)
Acidosis (pH < 7.25 or bicarbonate <17)
Evidence of significant Ketosis
Blood: beta-hydroxybutyrate AND/OR Blood: beta-hydroxybutyrate AND/OR
Urine: acetoacetate
Electrolytes, BUN, Creatinine
B/F for MPs; FBC not very helpful !
Others e.g. ABG, Blood & Urine C/S
MISLEADING LABS
WBC COUNT
N = 247 DKA admissions over 6 years
Mean WBC = 17,519/mm
3
(+/- 9,582)
69% without infection 69% without infection
17.8% presumed viral infection
12.9% bacterial infection - more common in
children < 3 years of age
All need to be evaluated and re-evaluated if persistent acidosisis
Am J Emer Med 19: 270-3, 2001
Acidosis leads to flux of K
+
out of cells as H
+
enters cells to buffer
Dehydration and volume depletion
MISLEADING LABS
POTASSIUM
Dehydration and volume depletion
Aldosterone Na reabsorption and K
+
wasting
Serum K
+
usually normal or high, but total
body K
+
is low
BACKGROUND: DKA
DKA is the most important complication of type 1
diabetes mellitus.
Insulin concentrations are low.
Hyperglycemia with lipolysis, ketone bodies,
dehydration, acidosis
Causes of DKA in Diabetic children include
intercurrent illness (31%)
omission or incorrect insulin administn (69%).
CASE PROGRESSION
Glucose 34 mmol/L
Serum ketones: Positive
Na
+
130,
K 2.9,
Na 130,
K
+
2.9,
Cl
-
98,
Bicarbonate 10 mEq/L
Venous blood gas for pCO
2
28 mm Hg
BUN 25 mmol/L
Creatinine 0.7mg/dL
FURTHER MANAGEMENT DKA
Immediate life threatening issues
Failure to make the diagnosis
Hypovolemia /Cardiovascular collapse
Profound metabolic acidosis
Short term life threatening issues
Hypokalaemia / Hyperkalemia
Short term life threatening issues
Hypokalaemia / Hyperkalemia
Cerebral oedema
Hypoglycaemia
Aim to slowly
Correct dehydration
Bring down blood sugar
FLUID ADMINISTRATION IN DKA
Dehydration
Most DKA patients are 7-10% dehydrated.
Administer 10 -20 mL/kg NS or RL over 30 to
60 min, repeat to reverse shock. 60 min, repeat to reverse shock.
Other fluid deficits should be replaced gradually
over 36 to 48 hours.(1.5 X Maintenance fluid)
If no evidence of hypovolemia, be less
aggressive with fluid management.
INSULIN ADMINISTRATION IN DKA
Glucose is often lowered significantly with fluid
resuscitation.
Insulin at 0.05-0.1 U/kg/hr. IV/IVI/IM
Check bedside glucose hourly. Gradual decline
by 4mmol/L hrly is preferable. by 4mmol/L hrly is preferable.
Add glucose(5%) to IVF once glucose is 12-
14mmol/L to avoid hypoglycemia.
May Insulin when glucose < 10mmol/L
Change to SC insulin with oral feeds
METABOLIC ACIDOSIS
Due to lipolysis (ketoacids) and dehydration (lactic
acidosis)
Insulin and fluids are sufficient treatment. Insulin and fluids are sufficient treatment.
Continue hrly insulin till acidosis is reversed
Bicarbonate treatment is not recommended and is
associated with cerebral edema.
ELECTROLYTE IMBALANCE
Factitious hyponatremia (hyperglycemia effect)
Corrected Na = measured Na + (1.6)(BGlu- 100)/100
Potassium level is falsely elevated.
Most patients have true potassium depletion.
Hypophosphatemia Hypophosphatemia
Once urine output is established, replace K, half
as KCl and half as Kphos (total 20-40 mEq/L may
give ~ 60-80mEq/L + ECG).
K
+
>5.5 give no potassium in IVF
K
+
4.5 5.5 give 20 mEq K
+
/L IVF
K
+
<4.5 give 40 mEq K
+
/L IVF
DKA CONTROVERSY
CEREBRAL EDEMA - TRUTHS ?
Idiogenic osmoles in
CNS accumulate fluid
Cerebral edema
present in 100% of
patients prior to
Acute
patients prior to
therapy
Rxment exacerbates
cerebral edema
Vigorous fluid & insulin
administration
Hypotonic fluids
Bicarbonate
Late
Sequelae
CEREBRAL EDEMA
Etiology is not known
Occurs exclusively in pediatric patients
Occurs in approximate 1% of DKA episodes
NEJM - Jan 2001
N = 6977 DKA patients;10 centers over 15 yrs N = 6977 DKA patients;10 centers over 15 yrs
61 developed cerebral edema (0.9%)
Major cause of mortality in childhood DKA
60 90% of all DKA-related death
20 - 25% with cerebral edema die
10 - 25% of survivors with significant morbidity
CEREBRAL EDEMA:
PHYSIOLOGICAL CONSIDERATION
Increased brain cell volume
Cell gain effective osmoles (Na
+
) and/or
effective osmolarity of plasma
(P
Effective osm
= 2P
Na
+ P
Glucose
) declines
Increased brain ECF volume
Undue rise in hydrostatic pressure
Large decline in colloid osmotic pressure
Pediatric Diabetes 2006: 7: 191-195
CEREBRAL EDEMA:
PROPOSED PATHOPHYSIOLOGY
Cytotoxic and Vasogenic edema
Dehydration and acidosis
Vasogenic due to increased BBB
permiability - hyperosmolality permiability - hyperosmolality
Cytotoxic due to idiogenic osmoles and
/or vasopressin dysregulation
Warning sign may be falling corrected
serum sodium
Glaser et al J Peds 2004;145:164-171
CEREBRAL EDEMA
At risk:
Initial pH < 7.1
Abnormal baseline mental status
Newly diagnosed, < 5 years old Newly diagnosed, < 5 years old
Rapid rehydration (> 50cc/ kg in first 4 hrs)
Hypernatremia/ persistent hyponatremia
Bicarbonate therapy
Bolus insulin therapy
CEREBRAL EDEMA
Know what to look for: do hourly neuro exam
Altered mental status/ seizures,
Headache, severe
Recurrence of vomiting
Inappropriate slowing of heart rate Inappropriate slowing of heart rate
(bradycardia)
Rising blood pressure
Decreased oxygen saturation
Clinical worsening despite improving lab
values
CEREBRAL EDEMA
Change in neurological status
Restlessness irritability;
increased drowsiness incontinence
Specific neurological signs, e.g., Specific neurological signs, e.g.,
cranial nerve palsies,
abnormal pupillary size &/or response,
posturing
CT/ MRI changes may not be seen in early
cerebral edema
CEREBRAL EDEMA BEDSIDE SCORE
Muir Diab Care 2004 27:1541-46
Note that patient needs to be significantly affected to meet diagnostic criteria
CEREBRAL EDEMA
CT or MRI if cerebral edema is suspected.
Treatment with
Hyperosmolar agents e.g. mannitol, (controversial)
Elevate the head of the bed
Decrease IVF rate and insulin infusion rate Decrease IVF rate and insulin infusion rate
Pediatric ICU management
Do not delay treatment until radiographic evidence
Glucocorticoid efficacy is unclear.
Aggressive hyperventilation is probably
detrimental.
CASE PROGRESSION/OUTCOME
His glucose levels and mental status improves.
His vomiting resolves.
His parents are taught to measure his blood
glucose and administer SC insulin.
Total daily dose 0.5-1.0U/kg Total daily dose 0.5-1.0U/kg
Before meals (~30min) 2X a day
Mixture of short and intermed./long acting
Many different regimes available*
TREATMENT OF TYPE 1 DM
Insulin therapy required for survival
May be used in combination with
certain oral agents if patient is obese
Diet Diet
Weight management
Exercise
SELECTION OF INSULIN REGIMEN
FOR TYPE 1 DIABETES MELLITUS
MOORADIAN AD ET AL. ANN INT MED. 2006;145:125-134.
Diabetic Ketoacidosis: Intravenous insulin
infusion with frequent monitoring and
titration of infusion insulin dose
Newly Diagnosed Type 1 DM: Combination
of basal insulin and pre-meal rapid-acting
insulin
of basal insulin and pre-meal rapid-acting
insulin
Long acting preferred over NPH for
basal insulin, and rapid-acting insulin,
preferred over regular for pre-meal
NPH twice daily with pre-meal rapid-
acting insulin
NPH twice daily, or at night with pre-
meal regular insulin
LONG TERM MANAGEMENT
Appr. Calories normal growth/development
Consistent timing & composition of feeds
Good diabetic control (near-normal)
< 5yrs 5.6 11.1 mmol/L < 5yrs 5.6 11.1 mmol/L
5-11yrs 4.5 10 mmol/L
12 -18yrs 4.5 8.4 mmol/L
Avoid hypoglycaemia
Prevent/delay acute & chro. Complications
Regular follow-up
STANDARD BLOOD GLUCOSE
MONITORS
INHALED INSULIN (EXUBERA)
INHALED INSULIN (EXUBERA)
INHALED INSULIN (EXUBERA)
Rapid-acting powdered insulin given via
inhalation for mealtime boluses
Approved for type 1 diabetes mellitus in
combination with longer-acting insulin
Contraindicated in smokers and those who Contraindicated in smokers and those who
quit smoking < 6 months ago
Contraindicated in patient with unstable
or poorly controlled lung disease because
of increased risk of hypo- and
hyperglycemia
INHALED INSULIN (EXUBERA)
Clinical trials showed small, non-progressive
declines in pulmonary function relative to
comparators, so pulmonary function studies
recommended at baseline, 6 months, and
yearly thereafter yearly thereafter
Clinical trial AEs included cough, dyspnea,
pharyngitis, increased phlegm, epistaxis,
hypoglycemia, chest pain, and dry mouth
Long-term safety in pediatric-age patients
not yet established
Insulin antibodies more frequent with inhaled
insulin that injected insulin, but no clinical
consequences to date
INHALED INSULIN (EXUBERA)
INDICATIONS FOR PANCREAS OR PANCREATIC
ISLET TRANSPLANTATION
RYAN EA ET AL. DIAB OBES METAB 2006;8:1-7.
Pancreas Transplantation
Type 1 DM with Chronic Kidney Disease
requiring renal transplantation
Pancreatic Islet Transplantation Pancreatic Islet Transplantation
Labile type 1 diabetes mellitus
Type 1 DM with severe recurrent
hypoglycemia
Type 1 DM with Chronic Kidney Disease
requiring renal transplantation
SUMMARY
AI Disease. Almost all T1DM
Results from autoimmune destruction of beta cells in
pancreatic islets Absolute /relative insulin deficiency
Multifactorial aetiology
Clinical features & Presentation Clinical features & Presentation
Hyperglycaemia Insulin therapy required with Edu.,
diet, exercise, and weight management as appropriate
DKA Fluid / Insulin / Potassium
Long term complications
Life Long Disease Pancreas or pancreatic islet
transplantation may be able to cure T1DM
QUESTIONS?