Dr.Parisa Tajdini
Pediatric Endocrinologist
Assistant ProfessorType 1 Diabetes Mellitus (Immune Mediated)
Females and males are almost equally affected
Peaks of presentation occur in 2 age groups: at 5-7 yr of age and at the time of puberty.
The 1st peak may correspond to the time of increased exposure to infectious agents coincident with the beginning of school
The 2nd peak may correspond to the pubertal growth spurt induced by gonadal steroids and the increased pubertal growth hormone secretion .
GENETICS
•
Siblings 8% • Mother is affected 3-4% • Father is affected 5-6% • Monozygotic twins 30% to 65%, • Dizygotic twins 6–10%.• The parents of an affected child is estimated 3%.
Monogenic Type 1 Diabetes Mellitus
Single-gene defect• IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome Mutations of the FOXP3 and other genes function of regulatory T cells
diabetes (as early as 2 days of age) in approximately 80% of the children
• Wolfram syndrome (DIDMOD: diabetes insipidus, diabetes mellitus, optic atrophy, deafness)
autosomal recessive disease due predominantly to mutations in the WFS1 gene may be present in ~5% of patients with T1DM.
Genes
MHC on chromosome 6p21
The MHC is a large genomic region that contains a number of genes related to immune system function in humans. These genes are further divided into HLA classes I, II, III, and IV genes
• Class II genes are the ones most strongly associated with risk of T1DM,
• DQB1*0302 (high risk for diabetes)
• The DQB1*0201 allele (increased risk for diabetes) DQB1*0301 (protective against diabetes)
The presence of aspartate at this position 57 is usually, but not always, protective in white populations but not necessarily in other populations.
ENVIRONMENTAL FACTORS
Viral Infections
• Congenital Rubella Syndrome
The time lag between infection and development of diabetes may be as high as 20 yr.
No increase in risk of diabetes when rubella infection develops after birth or when live-virus
rubella immunization is used.
• Enteroviruses • Mumps Virus
Mumps alone is not a major causal factor in diabetes
The Hygiene Hypothesis: Possible Protective Role of Infections
Infectious agents may also play a protective role against diabetes.
Some call this theory the microbial deprivation hypothesis. The hygiene hypothesis states that lack of exposure to childhood infections may increase an individual’s chances of
developing autoimmune diseases, including T1DM.
Gastrointestinal Microbiome
Diet
• Early studies supported an association between early milk and/or gluten introduction and T1DM risk, but ????
• Some, but not all, studies have suggested that breastfeeding lowers the risk of T1DM .
• Omega-3 ، fatty acids, vitamin D, ascorbic acid, zinc, and vitamin E.( role in immune regulation),
Most observational studies have failed to find associations between vitamin D level or supplementation and T1DM risk
Psychologic Stress
PATHOGENESIS :
Autoimmunity against the host’s own β-cells
1. Presence of 2 or more islet autoantibodies with normoglycemia and presymptomatic; can last years to decades
2. β-cell autoimmunity with dysglycemia and presymptomatic
3. Onset of symptomatic disease; usually quite brief, weeks, rarely months 4. Transient remission, usually within weeks of onset, may last 6-12 mo
Autoimmunity
IAAs are usually the first to appear in young children Glutamic acid decarboxylase 65 kDa
Tyrosine phosphatase insulinoma–associated 2 and zinc transporter 8 antibodies.
The earliest antibodies are predominantly of the IgG1 subclass.
1 antibody will progress to diabetes 30% 2 antibodies 70%
Insulin performs a critical role in the storage and retrieval of cellular fuel. Insulin secretion in response to feeding
Thus, in normal metabolism, there are regular swings between the postprandial,
high-insulin anabolic state and the fasted, low-insulin catabolic state that affect liver, muscle, and adipose tissue
T1DM is a progressive low-insulin catabolic state in which feeding :
-) Insulinopenia, glucose utilization by muscle and fat decreases and postprandial hyperglycemia appears.
-) lower insulin levels, the liver produces excessive glucose via glycogenolysis and gluconeogenesis, and fasting hyperglycemia begins.
Osmotic diuresis (glycosuria) when the renal threshold is exceeded (180 mg/dL; 10
mmol/L).
The resulting loss of calories and electrolytes, as well as the worsening
The combination of insulin deficiency and elevated plasma counterregulatory
hormones is also responsible for accelerated lipolysis and impaired lipid synthesis, with resulting increased plasma concentrations of total lipids, cholesterol, triglycerides, and free fatty acids.
Insulin deficiency and glucagon excess shunts the free fatty acids into ketone
body formation; β-hydroxybutyrate and acetoacetate
Accumulation of these keto acids results in metabolic acidosis (
DKA)
compensatory rapid deep non-dyspneic breathing in an attempt to excrete excess CO2 (Kussmaul respiration).
Acetone or fruity odor of the breath.
Ketones are excreted in the urine .
With progressive dehydration, acidosis, hyperosmolality.
CLINICAL MANIFESTATIONS
The classic clinical manifestations of new onset diabetes in childre include polyuria, nocturia،
polydipsia, polyphagia, and weight loss.
Other common symptoms include fatigue, weakness, and a general feeling of malaise.
If the diagnosis is not recognized patients(20-40%) presenting with more advanced disease will
exhibit signs of DKA including:
Dehydration( The degree of dehydration may be clinically underestimated because intravascular volume is conserved at the expense of intracellular volume.)
Nausea, vomiting,
Ketoacids produce abdominal pain, nausea, and emesis
Kussmaul respirations (deep, heavy, non-labored rapid breathing), fruity breath odor (acetone)
Prolonged corrected Q-T interval
Falsely low HbA1c levels in:
hemolytic anemias pure red cell aplasia blood transfusions
anemias associated with hemorrhage cirrhosis
myelodysplasias
renal disease treated with erythropoietin
Stress-produced hyperglycemia
Transient hyperglycemia with glycosuria while under substantial physical
stress or illness
This usually resolves permanently during recovery from the stressors.
limited insulin reserve temporarily revealed by elevated counterregulatory
hormones.
Monitored for the development of symptoms of persistent hyperglycemia
and be tested with an HbA1c if such symptoms occur.
Formal testing in a child who remains clinically asymptomatic is not
TREATMENT
T1DM not progressed to ketoacidosis ،can be started on subcutaneous insulin therapy DKA
Biochemical abnormalities include:
• Elevations in blood and urine ketones • Increased anion gap
• Decreased serum bicarbonate (or total CO2) and pH • Elevated effective serum osmolality
• Hyponatremia (result of an osmotic dilution as water shifts into the extracellular fluid) • Potassium and phosphate depletion is common after prolonged polyuria but may
Hypernatremia (corrected Na >150 mEq/L) would also be classified as severe diabetic ketoacidosis. Severity of DKA: ISPAD
• Mild to moderate DKA pH ≥7.1 to <7.3 or serum bicarbonate ≥5-15 mmol/L
Hyperglycemia and Dehydration
NPO
2 IV Line
Monitor I/O, neurologic status.
CBC diff- BUN-Cr- BS- Cl- Na- K- ESR- CRP-Ca- P- HbA1C- ABG- U/A-U/C
Initial intravenous bolus of 10-20 mL/kg of glucose-free isotonic sodium salt solution such as Ringer lactate or 0.9% sodium chloride is given over 1 to 2 hr، may be repeated.
From 2nd hr fluid replacement then consists of 0.45% or 0.9% sodium chloride
with 40meq/L Kcl 15% (If there is no hyperkalemia( K>5.5 meq/L) in the Lab Test and ECG)
Insulin infusion at 0.05-0.1 unit/kg/h starting 1 hour after fluids
initiated.
50 unit insulin Reg + 500 cc N/S ، Discard the first 50 cc
If K <3 meq/L don’t start Insulin، first give IV 80 meq/L Kcl 15%
If Blood glucose ≤300 mg/dL or Blood glucose falls 90-100 mg /dL/h
Change to 0.45% or 0.9% saline; add glucose 5% to fluids to prevent hypoglycemia
If Blood glucose < 200 mg/dL add glucose 10 %.
If serum glucose levels fall below 100 mg/dL despite infusion of D10% containing IV fluids,
the IV insulin rate can then be decreased from 0.1 units/kg/hr.
No oral fluids until rehydration is well underway and significant electrolyte shifts are no
The sodium should increase by approximately 1.6 mmol/L for each 100
mg/dL decline in the glucose.
If the corrected Na value is greater than 150 mmol/L, severe hypernatremic
dehydration may be present and may require slower fluid replacement.
Declining sodium may indicate excessive free water accumulation and
Pancreatitis (usually mild) is occasionally seen with DKA, especially if
prolonged abdominal distress is present; serum amylase and lipase may be elevated. If the serum lipase is not elevated, the amylase is likely nonspecific or salivary in origin Serum creatinine adjusted for age may be falsely elevated owing to interference by
ketones in the autoanalyzer methodology.
Blood urea nitrogen may be elevated with prerenal azotemia and should be rechecked as the child is rehydrated.
Mildly elevated creatinine or blood urea nitrogen is not reason to withhold potassium therapy if good urinary output is present.
Bicarbonate therapy may increase the risk of hypokalemia and cerebral
edema so should be considered only in situations with severe acidosis (PH<6.9) unresponsive to standard DKA
If bicarbonate is considered necessary, cautiously give 1 to 2 mmol/kg over 60 minutes..
Persistent acidosis may indicate inadequate insulin or fluid therapy،
Urine ketones may be positive after ketoacidosis has resolved because the
nitroprusside reaction routinely used to measure urine ketones by dipstick measures only acetoacetate.
During DKA, most excess ketones are β-hydroxybutyrate, which increases the normal ratio to acetoacetate from 3 : 1 to as high as 8 : 1.
Cerebral Edema
Risk Factor: Abnormalities of sodium and potassium, and blood urea nitrogen Early bolus of Insulin
Younger age
New onset diabetes
Longer duration of symptoms
Greater hypocapnia at presentation after adjusting for degree of acidosis More severe acidosis at presentation
Bicarbonate treatment for correction of acidosis
Radiographic imaging is frequently unhelpful
closely monitoring and frequent neurologic checks for any signs of increasing
intracranial pressure, such as a change of consciousness, depressed respiration,
worsening headache, bradycardia, apnea, pupillary changes, papilledema, posturing, and seizures
RX:
Elevation of the head of the bed Reduction in IV fluid rate
Administration of mannitol (typically 0.5 to 1 g/kg IV over 10 to 15 minutes. The
effect of mannitol should be apparent after ~15 minutes, If necessary, the dose can be repeated after 30 minutes.
Hypertonic saline (3%), suggested dose 2.5 to 5 mL/kg over 10 to 15 minutes, may be
Transitioned to oral intake and subcutaneous insulin when DKA has resolved: o total CO2 > 15 mEq/L
o pH > 7.30
o sodium stable between 135 and 145 mEq/L o Anion gap closed
o no emesis
To prevent rebound hyperglycemia the first SC injection should be given 5 to 30 minutes (with rapid-acting insulin and Regular)
1 to 2 hours (with long-acting or NPH)
insulin (rapid-onset analogs ): Lispro, aspart(Novorapid), glulisine (Apidra)
Absorbed much quicker because they do not form hexamers (monomer).
Onset of action in as little as 10 min Better control of postmeal glucose
Reduces betweenmeal or nighttime hypoglycemia
Onset of action (h) 0.15-0.35 (5-10min) Peak of action (h) 1-3
Regular insulin
Regular insulin has a wide peak and a long tail for bolus insulin.
Prolonged peaks with excessive hypoglycemic effects between meals, and Increases the risk of nighttime hypoglyce mia
Neutral protamine Hagedorn (NPH)
Limitations as a basal insulin because it does not achieve a peakless . Hypoglycemic effect during the midrange of the duration.
When regular insulin is combined with NPH, the composite insulin profile poorly mimics normal endogenous insulin secretion
Long-acting analogs glargine(Lantus), detemir(Levemir), and degludec
Glargine forms a precipitate after subcutaneous injection, Onset of action (h) 2-4
Detemir to circulating albumin
Onset of action (h) 1-2 Peak of action (h) 4-7
Duration of action (h) 20-24 Degludec forms di-hexamers
Onset of action (h) 0.5-1.5
Combination of a rapid bolus (lispro, aspart, or glulisine) and basal insulin
(glargine ،detemir ، degludec) :
Basal-bolus regimens can be accomplished with multiple daily injections (MDIs)
Approximately 30% to 45% (sometimes ~50%) of total dose insulin should be basal insulin once or twice daily( younger children and obese adolescents will require twice daily) Some infants and toddlers may do well with a higher percentage of their daily insulin
The rest with adjusted doses for preprandial rapid-acting or regular insulin.
Rapid acting insulin immediately before eating Regular insulin 20 to 30 minutes before eating
The doses of short-acting insulin include 2 components:
carbohydrate ratio (typically expressed as 1 unit of insulin for a set
number of grams of carbohydrates) The 500 divided by the total daily.
Insulin sensitivity factor (ISF, also referred to as “correction factor,”
A 3-injection regimen
Combining NPH with a rapid analog bolus at breakfast Rapid-acting analog bolus at supper
2-injection regimen
Use of premixed insulin preparations that include both rapid- and intermediate-acting insulins (e.g., 70/30).
Protein
High-protein intakes may contribute to diabetic nephropathy. Therefore, 12–20% of energy is recommended
Snacks
Snacks vary according to individual needs
3 snacks per day for children
Self-monitoring of blood glucose blood glucose at least 4 times daily:
before breakfast, lunch, and supper, and at bedtime.
When insulin therapy is initiated ،at 12 midnight and 3 AM to detect nocturnal
hypoglycemia
Blood glucose targets are 90-130 mg/dL before meals and 90-150 mg/dL before bedtime
Glycosylated Hemoglobin (HbA1c)
3-4 times/yr to obtain a profile of long-term glycemic control.
The lower the HbA1c level, the more likely it is that microvascular
complications such as retinopathy and nephropathy will be less severe, delayed in appearance.
HbA1c values may be spuriously elevated in thalassemia (or other conditions with
elevated hemoglobin F)
HbA1c values may be Spuriously lower in sickle cell disease (or other conditions with
high red blood cell turnover)
Fructosamine can be used instead of HbA1c in these patients.
The HbA1c target for all children with diabetes is <7.5%;
Exercise
A major complication of exercise: hypoglycemic reaction
during
or
within
hours after exercise.
One contributing factor to
hypoglycemia with exercise
is an
increased
rate
of absorption of insulin from its injection site .
Regular exercise
also
improves glucoregulation
by increasing insulin receptor
number.
Poor metabolic control
,
vigorous exercise
may
precipitate ketoacidosis
because of
Hypoglycemic Reactions
The very young have an increased risk of permanently reduced cognitive
function as a long-term sequela of severe hypoglycemia
.
pallor, sweating, apprehension or fussiness, hunger, tremor, and tachycardia,
all as a result of the surge in catecholamines as the body attempts to counter the excessive insulin effect.
As glucose levels decline further, cerebral glucopenia occurs with drowsiness,
Behavioral changes such as tearfulness, irritability, and aggression are more
prevalent in children
.
Prolonged severe hypoglycemia can result in a depressed sensorium or
strokelike focal motor deficits that persist after the hypoglycemia has resolved.
Because the early warning signals of a declining glucose level are as a result of
catecholamine release. Recurrent hypoglycemic episodes associated with tight
15 g should be given as juice or a sugar-containing beverage or candy and
blood glucose checked 15-20 min later.
Administration of glucagon when the child cannot take glucose orally and not response
to eat carbohydrate twice.
Dose of glucagon is 0.5 mg if the child weighs less than 20 kg
1 mg if more than 20 kg.
Intramuscular
Dawn Phenomenon and Somogyi Phenomenon
Increase blood glucose in the early morning Dawn phenomenon:
Overnight growth hormone secretion and increased insulin clearance. Modestly elevates most morning glucose levels.
Somogyi phenomenon:
Management During Infections( sick day guidelines )
Infections are no more common in diabetic children than in nondiabetic ones. They can often disrupt glucose control and may precipitate DKA
children younger than 3 yr of age tend to become hypoglycemic
Older children tend toward hyperglycemia
Frequent blood glucose monitoring Monitoring of urine and/or blood ketones
Adjustment of insulin doses
Basal insulin:
Glargine or detemir basal insulin should be given at the usual dose and time.
NPH and Lente should be reduced by half if blood glucose <150 mg/dL and the oral intake is limited
Give usual dose for carbohydrate intake if glucose >150 mg/dL
. ketones <1.5 mmol/L
Oral fluids: sugar-free if blood glucose >250 mg/dL (14 mmol/L)
sugar-containing if blood glucose <250 mg/dL.
Call physician or nurse if:
Blood glucose remains elevated after 3 extra doses
Management During Surgery
For the majority of elective and other smaller surgical procedures: Patients can simply be continued on their typical home basal regimens
(Injection of the usual dose of long-acting insulin at the usual time for patients on shots. )
Glucose should be monitored hourly during the procedure and perioperatively Hyperglycemia can be corrected using the standard home ISF
For major procedures، trauma or situations where a prolonged period of
decreased oral intake is expected postoperatively:
IV insulin drip at the time of surgery and Serum glucose levels should be
In patients who are found to be hyperglycemic preoperatively (serum glucose
> 250 mg/dL), it is advisable to check for ketones prior to starting surgery. If significant ketosis is identified, surgery should be delayed (if possible) until the ketosis can be treated and resolved.
Postoperatively, the patient should not be discharged until blood glucose levels are
