Diabetes mellitus

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Diabetes mellitus in children BASIM
AL-ZOUBI
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• Types of DM in Children
• Type 1 DM
• Type 2 DM
• MODY Type
• Neonatal DM

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TYPE 1 DM
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• Maturity-onset diabetes in youth (MODY)
• autosomal dominant
• noninsulin-dependent diabetes
• onset in the second or third decade of life
• Neonatal DM
• Due to mutations in the genes encoding potassium
  channel of the beta-cell (KCNJ11, encoding the
  Kir6.2 subunit, and ABCC8, encoding the SUR1
  subunit) or a mutation in the insulin gene.
• In ABCC8 mutation treatment is possible with oral
  hypoglycemic agents that stimulate endogenous
  insulin secretion through binding to the
  sulfonylurea receptor (SUR1).

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Epidemiology The prevalence of diabetes among
school-aged children is about 2/1,000 in USA and
UK. The incidence is variable according to the
different countries and it varies from
0.6/100,000 in China to 42.9/100,000 in
Finland. There are small peaks in incidence at 4
to 6 years of age and a larger peak at 10 to 14
years of age.
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Pathogenesis Type 1 diabetes is caused by T
cellmediated autoimmune destruction of the beta
cells of the pancreas believed to be triggered by
an environmental factor in a genetically
susceptible individual and lead to absolute
insulin deficiency. The largest genetic
component of the risk of diabetes is the major
histocompatibility complex on chromosome 6,
including the DR3-DQ2 and DR4- DQ8 alleles that
increase risk and the DR2-DQ6 allele, which is
protective.
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Inheritance of HLA-DR3 or -DR4 antigens
increase the risk for the development of T1DM by
2- to 3-folds When both DR3 and DR4 are
inherited, the relative risk for the development
of diabetes is increased by 7- to 10-fold.
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However, only 10 to 20 of individuals who have
type 1 diabetes have a similar family history.
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Risk of developing type 1 diabetes for
individuals who have an affected relative For
siblings Overall 6 HLA identical 15 HLA
nonidentical 1 Offspring From father 6 From
mother 2 Both parents 30
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T1DM may be associated with other autoimmune
diseases such as thyroiditis, celiac disease,
multiple sclerosis, and Addison disease.
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• DM1 ANTIBODIES
• The islet cell antibodies (ICA)
• Insulin autoantibodies (IAA)
• Glutamic Acid Decarboxylase antibodies (GAD/GAD
  65)
• Transmembrane Tyrosine Phosphatase IA-2 or ICA512
  

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In the nonobese child, testing for autoimmunity
to ß cells is not necessary.
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Environmental risk Factors viral
infections Although the etiologic role of viral
infections in human T1DM is controversial,
coxsackie, cytomegalovirus, rubella, and mumps
can infect human ß cells. Seasons New cases
are seen more commonly in Autumn and
winter. Vit. D It has been found that Diabetes
risk may be increased by low vitmain D level in
young infants.
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Cow's milk Breastfeeding seems to provide
protection against the risk of developing type 1
diabetes. The reaction of an infant's immature
immune system to a protein found in cow's milk
infant formula called beta-lactoglobulin may
explain the suspected link between early
consumption of cow's milk and an increased risk
of developing type 1 diabetes later. Chemical
toxins Ingestion of the rodenticide vacor is
associated with the development of type 1
diabetes. Stress
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• Diagnosis
• symptoms of diabetes are
• polydipsia,
• polyuria,
• polyphagia, and weight loss.
• Bedwetting
• diabetic ketoacidosis (DKA) presention with
  nausea, vomiting, abdominal pain,
  dehydration, lethargy and coma .

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• Diagnostic criteria for DM
• Fasting plasma glucose at or above 126 mg/dL
  (7.0 mmol/L).
• Random plasma glucose at or more than 200 mg/dl
  associated with DM symptoms.
• 2-hour post challenge plasma glucose value at or
  above 200 mg/dL (11.1 mmol/L) on an oral glucose
  tolerance test.
• One third of new diabetes cases in children 10 to
  19 years of age were due to type 2 diabetes.

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MANAEGEMENT OF TYPE 1 DM
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NUTRITION No special nutrition. No particular
food should be considered forbidden. It is
recommended that approximately 30-35 of dietary
energy intake should be derived from fat (mainly
mono- and polyunsaturated fats), 15 from protein
and 50-55 from carbohydrate. Approximately 70
of the carbohydrate content should be derived
from complex carbohydrates such as starch.
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The total daily caloric intake 20 at breakfast,
20 at lunch, and 30 at dinner, 10 for each of
the midmorning, midafternoon, and evening
snacks Intake of sucrose and highly refined
sugars should be limited. Alternative
sweeteners Use of a variety of sweeteners can be
used. Carbohydrate Counting Each carbohydrate
exchange unit is 15 g.
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• Meals and snacks should be taken at about the
  same time of the day every day.
• meal times and contents correlates with daily
  activities, e.g. taking physical exercise or
  sitting at a desk?
• Extra insulin when necessary, e.g. at parties,
  or when eating lots of sweet things.
• fresh fruit as a snack better than drinking
  fruit juice.
• A high fibre content in TH food.

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Glucose Monitoring Continuous Glucose Monitoring
System (CGMS) The interstitial glucose levels
lag 13 min behind the blood glucose values at any
given level. The CGMS values tend to have a
high correlation coefficient for blood glucose
values ranging between 40 and 400 mg/dL.
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Elevated fasting blood sugar at the morning may
be due Dawn Phenomenon Which due overnight
growth hormone secretion and increased insulin
clearance. Somogyi Phenomenon Which is due to
rebound from late night or early morning
hypoglycemia, thought to be due to an exaggerated
counter-regulatory response.
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• HbA1C
• Glucose is bound to haemoglobin in the red blood
  cells.
• The level of HbA1c depends on the blood glucose
  levels during the life span of the red blood
  cells.
• A red blood cell lives for about 120 days.
• HbA1c reflects the average blood glucose during
  the previous 2-3 months.

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Transplantation Transplantation of segment of
the pancreas is done usually in those patients
who need kidney transplantation at the same time
in which the immunosuppressive regimen is
indicated for the renal transplantation.
Transplantation of isolated islet cells have
been tried but only half of the cases remained
insulin free for 2 years. Stem cell
transplantation
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• Complications
• Acute Comlications
• DKA
• Hypoglycemia

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DKA DKA is the most common cause of death in
children who have type 1 diabetes and
isassociated with a significant risk of morbidity.
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Clinical manifestations of diabetic
ketoacidosis Dehydration Rapid, deep
(Kussmaul respiration) Nausea, vomiting, and
abdominal pain Progressive loss of
consciousness Fever only when infection is
present
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Definition of DKA Hyperglycemia (blood glucose
gt 11 mmol/L 200 mg/dL) Venous pH lt 7.3
or bicarbonate lt 15 mmol/L Ketonemia and
ketonuria
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Supportive measures Secure the airway Insert
peripheral intravenous catheter A cardiac
monitor should be used to assess T waves for
evidence of hyper- or hypokalemia Give oxygen
to patients with severe circulatory impairment or
shock.
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Monitoring Hourlyvital signs, neurological
evaluation, fluid input and output. Capillary
blood glucose should be measured hourly
Laboratory tests Na, K, glucose, blood urea
nitrogen and blood gases every 2 then 4 hours.
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Goals of therapy Correct dehydration Correct
acidosis and reverse ketosis Restore blood
glucose to near normal Avoid complications of
therapy Identify and treat any precipitating
event
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• Fluids and salt.
• In moderate DKA use 5-7 and in sever DKA use
  7-10 dehydration.
• If needed to restore peripheral circulation,
  give 0.9 saline 1020 mL/kg over 12 h, and
  repeat it, if necessary ( not more than 30
  ml/kg).
• Add calculated maintenance (for 24-48 hrs) and
  estimated deficit, subtract the amount already
  given as resuscitation fluid, and give the total
  volume over the next 24 - 48 hours. i.e.
• Subsequent fluid management should be with a
  solution with a tonicity equal to or greater than
  0.45 saline
• .

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• Insulin therapy
• Begin with 0.1 U/kg/h. insulin infusion. .
• The dose of insulin should usually remain at 0.1
  unit/kg/h at least until resolution of DKA (pH gt
  7.30, bicarbonate gt 15 mmol/L and/or closure of
  the anion gap).
• To prevent a rapid decrease in plasma glucose
  concentration and hypoglycemia, 5 glucose should
  be added to the 0.45 saline (5 glucose in 0.45
  saline ) when the plasma glucose falls to
  approximately 1417 mmol/L (250300 mg/dL.

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Potassium replacement Start replacing potassium
after initial volume expansion (1-2 hours) and
concurrent with starting insulin therapy.
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Acidosis Alkali therapy may be given only to
patients with severe acidemia (arterial pH, 6.9),
and patients with life-threatening
hyperkalemia. Bicarbonate then may be given
cautiously at a dose of 12 mmol/kg over 60 min.
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Introduction of oral fluids and transition to SC
insulin injections Oral fluid should be given
only when there is substantial clinical
improvement.
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Treatment of cerebral edema Give mannitol
Reduce the rate of fluid administration by
one-third. Hypertonic saline (3), 510 mL/kg
over 30 min, may be an alternative to mannitol,
especially if there is no initial response to
mannitol. Elevate the head of the bed.
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LONG-TERM COMPLICATIONS RELATION TO GLYCEMIC
CONTROL. 1-microvascular complications,
specifically, retinopathy and nephropathy 2-
macrovascular complications, particularly
accelerated coronary artery disease,
cerebrovascular disease, and peripheral vascular
disease and 3- neuropathies, both peripheral
and autonomic, affecting a variety of organs and
systems . In addition, cataract may occur more
frequently.
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• Hypoglycemia
• Hypoglycemia, a blood glucose concentration less
  than 60 mg/dL (3.3 mmol/L.
• Symptoms of hypoglycemia include
• sweating, hunger, and palpitations, headache,
  dizziness, diplopia, and confusion. coma and
  seizures.
• Mild-to-moderate hypoglycemia is treated by
  ingesting 10 to 15 g of glucose
• Sever cases may need Glucagone injection or
  Dextrose 10 iv bolus.

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Insulin Therapy The initial total amount of
insulin varies from 0.5 to 2 U/kg per day.
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Glulisine
N Engl J Med 2005352174-83.
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• Rapid-acting insulin analogues
• insulin lispro approved in 1996
• insulin aspart approved June 7, 2000
• insulin glulisine approved in 2007
• Often referred to as bolus or prandial
  insulins.
• provide higher and more rapidly peaking insulin
  concentrations, which are required for peripheral
  glucose utilization following meals.

Clin Pharmacokinet 2008 47 (9) 595-610 Drugs
2008
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• Intermediate Insulins
• Isophane NPH insulins.
• Lente insulins
• Suitable for twice daily regimens and for prebed
  dosage in basal-bolus regimens.

Pediatric Diabetes 2007 8 (Suppl. 6) 4956
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• Premixed Insulins
• can reduce potential errors in drawing up
  insulin.
• Do not allow for much flexibility in adjusting
  for blood glucose levels or variability in food
  intake and activity, all of which
• are important factors in the management of T1DM
  in
• children.

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• Basal Insulin
• The new basal insulin analogues are
• Glargine approved April 20, 2000
• Detemir. Approved in 2005
• They show a more predictable insulin effect with
• less day-to-day variation compared with NPH
• insulin.
• Glargine is not approved in children younger than
  6 while Detemir is approved in children over 2
  years.

Pediatr Diabetes 2005 6 150154.
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The effect of glargine lasts for 20 to 24 h
while that for detemir is between 6 and 23 h
according to the dose given.
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Idealized insulin curves for prandial insulin
with a rapid-acting analogue (insulin aspart,
insulin lispro, or insulin glulisine) with basal
insulin given as insulin glargine or insulin
detemir
Chapter 20. The Management of Type 1 Diabetes
Irl B. Hirsch, M.D., and Jay S. Skyler, M.D.
Updated August 27, 2006
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• Basalbolus regimens
• Can be achieved by
• MDI
• INSULIN PUMP
• MDI
• by using a long-acting insulin analog as the
  basal insulin with rapid- or short-acting insulin
  for the meal (bolus) insulin.
• Other regimens for basal insulin include NPH
  accompanied by daytime boluses of rapid- or
  short-acting insulin.

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HONEYMOON Within 1 month of diagnosis, most
pediatric patients who have type 1 diabetes enter
a remission or honeymoon phase, although this
may not occur in very young children. Patients
require little exogenous insulin during this
phase, often less than 1/3 U/kg per day, but
they should not be weaned off insulin injections.
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Insulin Pumbs Several models of the latest
generation of insulin pumps incorporate
programming compatible with continuous glucose
monitoring technology, and they will eventually
have built-in algorithms to adjust the rate of
insulin delivery automatically, based on the
glucose value and the rate of change.
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