Diabetes Mellitus

in
Children
By: Alebachew Demelash
9/29/2021 1
 Definition
▪ Common, chronic, metabolic syndrome characterized by:
▪ Hyperglycemia as a cardinal biochemical feature
▪ The major forms of diabetes are classified:
• Deficiency of insulin secretion due to pancreatic β-cell damage (T1DM)
• Insulin resistance at the level of skeletal muscle, liver, and adipose tissue, with various
degrees of β-cell impairment (T2DM)
▪ Individuals with T1DM confront serious lifestyle alterations:
• Absolute daily requirement for exogenous insulin
• The need to monitor their own glucose level
• The need to pay attention to dietary intake
9/29/2021 2
 Classification
▪ Major forms of diabetes include:
▪ T1DM:
• β-cell destruction
• Immune mediated & Idiopathic
• Usually leading to absolute insulin deficiency
▪ T2DM:
• Predominantly insulin resistance
• Dominant T2DM due to sulfonylurea receptor 1 mutation
• Relative insulin deficiency 9/29/2021 3
 Classification cont..
▪ Other specific types
• Genetic defects of β-cell function
• Genetic defects in insulin action
• Diseases of the exocrine pancreas
• Endocrinopathies
• Drug- or chemical-induced
• Infections
• Uncommon forms of immune-mediated diabetes
• Other genetic syndromes sometimes associated with diabetes
▪ Gestational DM
▪ Neonatal DM 9/29/2021 4
 Epidemiology
▪ Accounts for about 10% of all diabetes
▪ Affecting 15 million in the world and it accounts for most cases of DM in childhood
▪ Ethiopia???
▪ Modest female preponderance in some low-risk populations
▪ Peaks of presentation occur in 2 age groups:
• Age of 5-7 yr (time of increased exposure to infectious agents at beginning of school)
• Time of puberty (pubertal growth spurt induced by gonadal steroids and the increased pubertal
growth hormone secretion which antagonizes insulin)

9/29/2021 5
▪ Genetics Risk factors
▪ Environmental Factors
• Hygiene Hypothesis: Possible Protective Role of Infections
• T1DM is a disease of industrialized countries (lack of exposure to childhood infections may
increase an individual’s chances of developing autoimmune diseases, including T1DM)
• Virus-- infection of β cells by viruses resulting in lysis and release of self-antigens
• Congenital Rubella Syndrome-- Prenatal infection with rubella is associated with β-cell
autoimmunity in up to 70%, with development of T1DM in up to 40% of infected children
• Enteroviruses
• Mumps Virus
▪ Diet
• Early introduction of cow's milk
• Leads to early exposure to gluten (triggers inflammatory, immunological and autoimmune
reactions)
• Which in turn increases “leakiness” of the immature gut to protein antigens 9/29/2021 6
 Genetics
▪ T1DM familial clustering prevalence in siblings is 6% while the general
population prevalence in USA is only 0.4%
▪ The risk is 2% if mother has DM, but 7% when father has DM
▪ Monozygotic twins: Concordance rate ranges from 30-65%
▪ Dizygotic twins: concordance rate of 6-10%
▪ Genetic susceptibility for T1DM in parents of a child with DM is estimated 3%
▪ About 85% of newly diagnosed T1DM patients do not have a family member
with T1DM
• We cannot rely on family history for future development of T1DM
9/29/2021 7
 T1DM
▪ Formerly known as Insulin-dependent DM or juvenile diabetes
▪ Characterized by:
• Low or absent levels of endogenously produced insulin (autoimmune
destruction of pancreatic islet β-cells)
• Dependence on exogenous insulin
▪ Natural history includes 4 distinct stages:
A. Preclinical β-cell autoimmunity with progressive defect of insulin secretion
B. Onset of clinical diabetes
C. Honeymoon period
D. Established DM associated complications and decreased life expectancy
▪ Onset occurs predominantly at:
• Median age of 7-15 yr, but it may present at any age
▪ Both contribute to the pathogenesis:
• Genetic susceptibility
• Environmental factors 9/29/2021 8
 T1DM cont..
▪ Susceptibility to T1DM is genetically controlled by:
• Alleles of the major histocompatibility complex (MHC) class II genes expressing human
leukocyte antigens (HLAs)
▪ It is also associated with:
• Autoantibodies to islet cell cytoplasm (ICA)
• Insulin (IAA)
• Antibodies to glutamic acid decarboxylase (GADA or GAD65)
• ICA512 (IA2)
▪ T1DM is associated with other autoimmune diseases such as:
• Thyroiditis, celiac disease, multiple sclerosis, and Addison disease
▪ High intake of omega-3 polyunsaturated fatty acids and vitamin D in early childhood:
• Decreases the incidence of autoimmune T1DM in at risk children
9/29/2021 9
 Pathogenesis
▪ Genetically susceptible host develops autoimmunity against own β-cells
▪ This autoimmune process results in progressive destruction of β cells until:
• Critical mass of β cells is lost
• Insulin deficiency develops
▪ Insulin deficiency, in turn, leads to:
• Onset of clinical signs and symptoms of T1DM
▪ At the time of diagnosis:
• Some viable β cells are still present and
• Produce enough insulin to lead to honeymoon period
▪ Over time:
• Almost all β cells are destroyed and
• Patient becomes totally dependent on exogenous insulin for survival
• Some patients develop secondary complications of diabetes 9/29/2021 10
 Role of autoantibodies

▪ Number of children antibody Vs risk of progression to DM:

• With 1 antibody=30%, With 2 antibodies=70%, With 3 antibodies=90%
▪ Children in whom IAAs appeared within the 1st 2 yr of life:
• Rapidly developed anti–islet cell antibodies and
• Progressed to DM more frequently than children in whom the 1st antibodies
appeared between ages 5-8 yr
Role of genetics
▪ Those with genetic susceptibility are:
• More likely to see progression of autoimmunity and
• Eventual development of diabetes
Role of environmental factors
▪ Incidence of T1DM in Finland is almost 4-fold higher than in Lithuania
• But the incidence of autoimmunity is similar in both countries
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 Influence of feeding Vs fasting
Site High plasma insulin (Postprandial) Low plasma insulin (Fasted)
Glucose Uptake Glucose Production
Glycogen Synthesis Glycogenolysis
1. Liver Absence Of Gluconeogenesis Gluconeogenesis
Lipogenesis Absence Of Lipogenesis
Absence Of Ketogenesis Ketogenesis
Glucose Uptake Absence Of Glucose Uptake
Glucose Oxidation Fatty Acid And Ketone Oxidation
2. Muscle
Glycogen Synthesis Glycogenolysis
Protein Synthesis Proteolysis And Amino Acid Release
Glucose Uptake Absence Of Glucose Uptake
3. Adipose
Lipid Synthesis Lipolysis And Fatty Acid Release
Tissue
Triglyceride Uptake Absence Of Triglyceride Uptake
9/29/2021 12
 Pathophysiology
▪ Insulin performs a critical role in the storage and retrieval of cellular fuel
▪ In normal metabolism, there are regular swings between:
• Postprandial (anabolic state)
• Fasted (catabolic state) that affect liver, muscle, and adipose tissue
▪ T1DM is a progressive low-insulin catabolic state in which:
• Feeding does not reverse, but rather exaggerates these catabolic processes
▪ With moderate insulinopenia:
• Glucose utilization by muscle and fat decreases
• Postprandial hyperglycemia appears
▪ At even lower insulin levels:
• Liver produces excessive glucose via glycogenolysis and gluconeogenesis
• Fasting hyperglycemia begins
▪ Hyperglycemia produces an osmotic diuresis (glycosuria) when:
• Renal threshold is exceeded (180 mg/dL; 10 mmol/L) 9/29/2021 13
 PP cont..
▪ Loss of calories and electrolytes, as well as the worsening dehydration:
• Produces a physiologic stress with hypersecretion of stress hormones (epinephrine, cortisol,
growth hormone, and glucagon)
▪ These hormones contribute to the metabolic decompensation by:
▪ Further impairing insulin secretion (epinephrine)
• Antagonizing its action (epinephrine, cortisol, growth hormone)
• Promoting glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis (glucagon, epinephrine,
growth hormone, and cortisol)
• Decreasing glucose utilization and glucose clearance (epinephrine, growth hormone, cortisol)
▪ The combination of insulin deficiency and elevated plasma values of the
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
9/29/2021 14
 PP cont..
▪ Insulin deficiency and glucagon excess shunts:
• Free fatty acids into ketone body formation
▪ Formation of ketone bodies (β-hydroxybutyrate & acetoacetate) exceeds:
• Peripheral utilization
• Renal excretion
▪ Accumulation of keto acids results in:
• Metabolic acidosis (DKA)
• Kussmaul respiration
▪ Acetone (nonenzymatic conversion of acetoacetate), is responsible for:
• Characteristic fruity odor of the breath
▪ Ketones are excreted in the urine in association with cations and thus further increase:
• losses of water
• Regenerating ability of electrolyte and bicarbonate
▪ Thus, dehydration, acidosis, hyperosmolality, and diminished cerebral O2 utilization
• Impaired consciousness--comatose 9/29/2021 15
 C/M
▪ In infants, most of the weight loss is acute water loss because:
• They will not have had prolonged urinary loss of calories from glycosuria
• Thus, there will be an increased incidence of DKA at diagnosis
▪ In adolescents, the course is usually more prolonged (over a few months), thus:
• Most of the weight loss represents fat loss from prolonged starvation
C/M includes:
• Poly signs (polyuria, polydipsia)
• Unexplained weight loss with glucosuria
• Hyperglycemia
• Ketonuria, glycosuria
• DKA and coma
9/29/2021 16
 Diagnosis

1. Random/casual PG ≥200 mg/dL (11.1 mmol/L plus Symptoms of DM

(polyuria, polydipsia, and unexplained weight loss with glucosuria and ketonuria)
2. FPG (at least 8 hrs) ≥126 mg/dL (7.0 mmol/L)
3. OGTT (2 hrs PG during) ≥200 mg/dL
4. Hemoglobin A1C ≥6.5%

9/29/2021 17
 DKA
▪ End result of the metabolic abnormalities resulting from:
• Severe deficiency of insulin or insulin ineffectiveness
▪ Severe insulin ineffectiveness occurs during:
• Stress as counterregulatory hormones block insulin action
▪ DKA occurs in 20-40% of children with:
• New-onset DM and
• Children with known DM who omit insulin doses or who do not successfully manage an
intercurrent illness
▪ Classified as: mild, moderate, or severe
▪ There is:
• Large amount of ketonuria
• Increased ion gap
• Decreased serum bicarbonate and Ph
• Elevated effective serum osmolality
9/29/2021 18
 Classification of DKA
Features Normal Mild Moderate Severe
1. CO2 (mEq/L,
20-28 16-20 10-15 <10
venous)
1. pH (venous) 7.35-7.45 7.25-7.35 7.15-7.25 <7.15
Kussmaul Kussmaul or
Oriented, respirations; depressed
1. Clinical No change alert but oriented but respirations; sleepy
fatigued sleepy; to depressed
arousable sensorium to coma

9/29/2021 19
 DKA cont..

▪ Severe insulinopenia results in 3 general pathways:

1. Excessive production & reduced utilization of glucose raises serum glucose
▪ This produces osmotic diuresis, dehydration, & activation of renin–angiotensin–
aldosterone axis (accelerated potassium loss)
▪ If glucose elevation & dehydration are severe and persist for several hours, the risk of
cerebral edema increases
2. Increased catabolic processes---cellular losses of Na, K, and phosphate
3. Increased release of free fatty acids---hepatic ketoacid production
▪ When ketoacids accumulate, buffer systems are depleted and a metabolic acidosis ensues
9/29/2021 20
▪ Therapy must address both:
Treatment
• Insulinopenia and subsequent physiologic disruptions
▪ Reversal of DKA is associated with inherent risks that include:
• Hypoglycemia, hypokalemia, and cerebral edema
▪ Children with previously diagnosed diabetes who develop DKA are usually
transitioned to their previous insulin regimen
▪ Diabetes control involves many goals:
• Tight glucose control & avoiding hypoglycemia
• Eliminate polyuria and nocturia
• Prevent ketoacidosis
• Permit normal growth & development with minimal effect on lifestyle 9/29/2021 21
 Common types of insulin for children
Rapid acting: Short acting: Intermediate Basal-long Long acting:
acting: acting:

Aspart & Lispro Regular NPH Glargine Ultralente

type

9/29/2021 22
 Insulin therapy
Age (yr) Target Total daily Basal Bolus Insulin
glucose insulin insulin, %
(mg/dl) (u/kg/day) of total Units added Units
daily dose per added per
100mg/dl 15g at meal
above target

0-5 100-200 0.6-0.7 25-30 0.50 0.50

5-12 80-150 0.7-1.0 40-50 0.75 0.75

12-18 80-130 1.0-1.2 40-50 1.0-2.0[‡] 1.0-2.0
9/29/2021 23
 DKA treatment protocol
TIME THERAPY COMMENTS
1st hr ▪ 10-20 mL/kg IV bolus 0.9% NaCl or ▪ Quick volume expansion; may be repeated.
LR ▪ NPO.
▪ Insulin drip at 0.05 to 0.10 units/kg/hr ▪ Monitor I/O, neurologic status.
▪ Use flow sheet. Have mannitol at bedside; 1
g/kg IV push for cerebral edema
2nd hr until ▪ 0.45% NaCl: plus continue insulin drip ▪ IV rate=85ml/kg+maintainance-bolus/23 hrs
DKA resolution ▪ 20 mEq/L KPhos & 20 mEq/L KAc ▪ If K <3 mEq/L, give 0.5 to 1.0 mEq/kg as oral
▪ 5% glucose if blood sugar >250 K solution OR increase IV K to 80 mEq/L
mg/dL
Variable ▪ Oral intake with subcutaneous insulin ▪ No emesis; CO2 ≥16 mEq/L; normal
electrolytes
▪ Note that the initial IV bolus is considered part of the total fluid allowed in the 1st 24 hr and is subtracted before
calculating the IV rate
▪ Maintenance (24 hr) = 100 mL/kg (for the first 10 kg) + 50 mL/kg (for the second 10 kg) + 25 mL/kg (for all
remaining kg)
Sample calculation for a 30-kg child:
▪ 1st hr = 300 mL IV bolus 0.9% NaCl or LR
9/29/2021 24
▪ 2nd and subsequent hr=(85ml*30)+1750ml-300ml/23hr=175ml/hr
(0.45% NaCl with mEq L Kphos and mEq L KAc 20 / 20 / )
 Exercise in DM
▪ No form of exercise, including competitive sports:
• Should be forbidden to the diabetic child
▪ A major complication of exercise in diabetic patients is:
• Hypoglycemic reaction during or within hours after exercise
▪ The major contributing factor to hypoglycemia with exercise is:
• Increased rate of absorption of insulin from its injection site
▪ Higher insulin levels dampen hepatic glucose production so that:
• It is inadequate to meet the increased glucose utilization of exercising
muscle
▪ In patients with poor metabolic control:
• Vigorous exercise may precipitate DKA because of the exercise-induced
increase in the counter-regulatory hormones
9/29/2021 25
 T2DM
▪ Heterogeneous disorder, characterized by:
• Peripheral insulin resistance and
• Failure of the β-cell to keep up with increasing insulin demand
▪ Patients with T2DM:
• Have relative insulin deficiency
• Do not have autoimmune destruction of β-cells
• Are not ketosis prone but may develop in some circumstances
• Haven't any of the known causes of secondary diabetes
9/29/2021 26
 Natural history
▪ T2DM is considered a polygenic disease aggravated by:
• Environmental factors (low physical activity and excessive caloric intake)
• Central obesity (associated with the development of insulin resistance)
• Hepatic insulin resistance leads to excessive hepatic glucose
• Skeletal muscle insulin resistance leads to decreased glucose uptake in a major site of glucose
disposal
• Over time hyperglycemia worsens, the phenomenon attributed to:
o Glucotoxicity, Lipotoxicity, Increased triglyceride content, Decreased
insulin gene expression
▪ Prolonged hyperglycemia may be accompanied by the development of:
• Microvascular and macrovascular complications
▪ In time, β-cell function can decrease to the point of:
• Absolute insulin deficiency and dependent on exogenous insulin
▪ DKA is uncommon in patients with T2DM, but can occur usually:
• Associated with the stress of another illness such as severe infection 9/29/2021 27
 Genetics
▪ T2DM has a strong genetic component
▪ A study from Denmark showed that:
• Both monozygotic and dizygotic twins have a lifetime concordance of T2DM of around 70%
• Indicating that shared environmental factors may play a large role in development of T2DM
Epigenetics & Fetal programming
LBW & IUGR:
▪ LBW infants who gain weight more rapidly in the 1st few years of life:
• Are associated with increased T2DM risk
Thrifty phenotype hypothesis: postulates:
▪ Poor fetal nutrition somehow programs these children to:
• Maximize storage of nutrients
• Prone to future weight gain and development of diabetes
9/29/2021 28
 C/M
• Mild symptoms of polyuria and polydipsia
• Acanthosis nigricans (neck and in other flexural areas)
• Elevated HbA1c levels
• Elevated triglycerides and low-density lipoprotein cholesterol levels

9/29/2021 29
 Diagnosis
▪ Overweight (BMI >85th percentile for age and sex, WFH>85th percentile, or weight
>120% of ideal for height)
Plus
Any 2 of the following risk factors:
▪ Family history of T2DM in 1st- or 2nd-degree relative
▪ Race/ethnicity (Native American, African-American, Hispanic, Asian/Pacific Islander)
▪ Signs of insulin resistance or conditions associated with insulin resistance
(acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome)
▪ Age of initiation: age 10 yr or at onset of puberty if puberty occurs at a younger age
▪ Frequency: every 2 yr
▪ Test: fasting plasma glucose preferred
9/29/2021 30
 Treatment
▪ Treatment should be done based on the natural course of the disease:
• Oral hypoglycemic agents (metformin) be introduced at the time of
diagnosis
• The usual starting dose is 500 mg once daily
• This may be increased to a maximum dose of 2,000 mg/day
▪ Adding insulin when hypoglycemic oral agent failure occurs
▪ Patients who present with DKA or with markedly elevated HbA1c (>9.0%)
• Require treatment with insulin using protocols similar to those used for
treating T1DM
▪ Lifestyle modification (diet and exercise) 9/29/2021 31
 Complications
▪ Hypertension
▪ Hypertriglyceridemia
▪ Decreased high-density lipoprotein
▪ Increased waist circumference
▪ Microalbuminuria
▪ Diabetic retinopathy
▪ Sleep apnea
▪ Fatty liver disease
▪ Nephropathy
▪ Neuropathy
▪ Macrovascular disease
▪ Thyroid disease
▪ Celiac disease
9/29/2021 32
 Features associated with T1DM VS T2DM
Features T1DM T2DM
Typical age of diagnosis 10-30 >25
(yr)
Diabetic ketoacidosis Common Rare
Insulin dependent Yes No
Parental history of <15% >50% in young onset
diabetes
Presence of β-cell P >90% Negative
antibodies
C-peptide concentrations Undetectable/low Normal/high
Optimal first-line Insulin Metformin
treatment 9/29/2021 33
 DM of the newborn
Transient neonatal DM
▪ Prevalence is approximately 50% of cases
▪ 50-60% of these patients develop permanent diabetes at an average age of
14 yr
▪ Its onset is in the 1st wk of life & persists several weeks to months
before spontaneous resolution (median duration is 12 wk)
▪ It occurs most often in infants who are small for gestational age
▪ Characterized by:
• Hyperglycemia and pronounced glycosuria
• Severe dehydration and, metabolic acidosis
• Minimal or no ketonemia or ketonuria
▪ There may also be findings such as umbilical hernia or large tongue
9/29/2021 34
 Treatment
▪ Administration of insulin is mandatory during the active phase of DM in the
newborn
▪ 1-2 units/kg/24 hr of an intermediate-acting insulin in 2 divided doses
usually results in dramatic improvement and accelerated growth and gain in
weight
▪ Attempts at gradually reducing the dose of insulin may be made as soon as
recurrent hypoglycemia becomes manifested or after 2month of age

9/29/2021 35
 Permanent neonatal DM
▪ Caused in approximately 50% of the cases by genes mutations of:
▪ KCNJ11 (potassium inwardly-rectifying channel J, member 11) and
▪ ABCC8 (adenosine triphosphate–binding cassette, subfamily C, member 8)
▪ These genes code for the Kir6.2 and SUR1 subunits of ATP–sensitive potassium channel, which is
involved in an essential step in insulin secretion by the β cell.
▪ Some cases are caused by pancreatic agenesis of:
▪ Homozygous mutations in the IPF-1 gene
▪ Mutations in the insulin gene
▪ Almost all these infants are small at birth because of the role of insulin as an
intrauterine growth factor.
9/29/2021 36
 Treatment
▪ Several protocols for switching the patient from insulin to glibenclamide are available
and patients are usually stabilized on doses ranging from 0.4-1 mg/kg/day
▪ Approximately 50% of neonatal diabetics have K-channel mutations:
• That can be switched to sulfonylurea therapy
• Have dramatic improvement in glycemic control and quality of
life
▪ All patients with DM diagnosed before 6 mo of age (and perhaps even those
diagnosed before 12 mo of age):
• Should now be screened for these mutations by genetic testing
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