Growth (Short Stature, Obesity) Diabetes Mellitus in Children

Growth (Short Stature, Obesity)Diabetes Mellitus in Children

Sioksoan Chan-Cua, MDAssociate Professor

Pediatric Endocrinologist

Learning Outcomes

Short stature• Identify causes of short stature• Acquire skill in history-taking, physical

examination in a child with short stature• Diagnose pathologic short stature• Propose diagnostic work-ups • Provide treatment plan

Growth - Height• Normal growth• Short stature

– Causes

• Diagnosis – history and physical examination– work-up– treatment / management plan

Growth Rate Through Adolescence

Girls (11 yr) 6 - 11 cm 2.5 - 4.5 inBoys (13 yr)  7 - 13 cm 3 - 5 in

Birth to 1 year:

18 - 25 cm (7 - 10 inches )

1 to 2 years:10 to 13 cm (4 to 5 inches)

2 years to pre-puberty :

5 to 6 cm (2 to 2.5 inches)

Puberty:

At birth, full-term baby’s Length: 50 cm (20 in )Weight: 3 kg (7 lb)

DEFINITIONS• SHORT STATURE

– Height < 3rd percentile for age

• GROWTH FAILURE– Growth rate < 5 cm/year

after age 2 years

Short Stature with Slow Growth Rate

Factors Affecting Growth

• Nutrition (malnutrition)• Diseases (chronic diseases)• Genes/ heredity• Hormones• Psychological factors

Genetic Control of Growth • Chromosomes

– Abnormalities – missing, or trisomy• Genes

– normal development & function of the pituitary – growth hormone / insulin-like growth factor axis

– Mutations of these genes • responsible for abnormal growth

– Growth hormone deficiency• GHD IA: AR, complete GH-1 gene deletion• GHD IB: AR, point mutation• GHD II: AD• GHD III: x-linked inheritance

Pituitary-specific transcription factors• Play a role in determination of pituitary cell lineages

Rpx (Hesx1) differentiation of pituitary (eg. SOD)

Ptx (Pitx/ P-OTX) Present in fetal and adult pituitaryPtx 2 is expressed in the somatotrophs (S), lactotrophs (L), thyrotrophs (T) & gonadotrophs

Lhx3 (LIM-3/ P-Lim) maintenance function

PROP – 1 required for S, L, T determination

Pit-1 (GHF-1, POU1F1)

development of S, L, Tcell-specific gene expression and regulation

Hormones Affecting Growth

1. Growth hormone (GH) 2. Thyroid hormone3. Glucocorticoids4. Sex hormones5. Insulin – important fetal growth factor

(infant of diabetic mother is macrosomic)

Hormonal Control of GrowthPituitary Gland and GH

GH is a protein with 191 amino acids and its secretion is pulsatile. GH may be influenced by ghrelin levels in the hypothalamic-pituitary portal circulation and the systemic circulation

Causes of Short Stature

Familial Short Stature

FAMILIAL SHORT STATURE

• Growth may be reduced between 6 & 18 months then growth becomes steady but below the 5th P

• No weight deficits for height and no bone age delay (BA = CA)

• TREATMENT: – None– Long term GH results in very modest height increase

Constitutional Growth Delay

CONSTITUTIONAL GROWTH DELAY

• A common cause of short stature & sexual infantilism in the adolescent

• Normal growth progression paralleling a lower percentile curve until catch up growth occurs

• Usually occurs in boys; occurs occasionally in girls • (+) family history

• TREATMENT: – Reassurance– Testosterone only if BA > 12 years for 4-6 months

CAUSES of SHORT STATUREPATHOLOGICAL • Disproportionate

– Bone development disorders (Skeletal dysplasia)

• Achondroplasia• Rickets• Other skeletal disorders

CAUSES of SHORT STATUREPATHOLOGICAL • Proportionate

– Chromosome defects– Endocrine disorders– Low birth weight short stature (IUGR)– Nutritional deficiency– Chronic systemic disease– Psychosocial deprivation

Chromosomal Abnormality

• Somatic– Down syndrome

• Sex chromosome– Turner syndrome

• Short stature (< 144cm)• Gonadal dysgenesis

• Skeletal deformity– Cubitus valgus– Short metacarpals

Prader-Willi Syndrome• Obesity - hyperphagia • Moderate mental retardation • Short stature • Hypogonadism • Small hands and feet • Facies with narrow bifrontal diameter, almond

eyes, full cheeks

Russell-Silver Syndrome

• Intrauterine growth retardation• Postnatal short stature• Small triangular facies• Limb asymmetry

Endocrine Causes of Short Stature

• Hypopituitarism - GH deficiency (GHD)• Hypothyroidism• Hypercortisolism• Hypogonadism

PITUITARY DWARFISM

• PRIMARY PITUITARY DISEASE– Pituitary hormone deficiency– Intrasellar tumor– Other destructive processes (infection, trauma)

Short stature secondary to hypopituitarism is due to lack of stimulation of growth of long bone

CHARACTERISTICS OF GHD

1. Diminished growth rate2. Delayed bone age 3. GH (<10 μg/L) 4. Growth response to treatment with hGH

EARLY CLUES TO GH DEFICIENCY5. Hypoglycemia6. Micropenis7. Facial midline malformation8. Neonatal injury

Hypothyroidism• Hypothyroidism → short stature

– Congenital– Acquired

Congenital Hypothyroidism

History1. Autoimmune thyroid disease in the family2. Intake of anti-thyroid medication in the mother3. Familial congenital hypothyroidism4. Presence of congenital hypothyroidism

associated with deafness and goiter 5. Prolonged jaundice in the neonate6. Poor suck in the neonate7. Poor cry in the neonate8. Constipation in the neonate

Congenital Hypothyroidism

PE1. Hypothermia2. Mottled, dry, coarse skin3. Jaundice4. Large fontanelle5. Macroglossia6. Hoarse cry7. Distended abdomen8. Umbilical hernia9. Hypotonia10. Goiter

Hypercortisolism – Cushing syndrome

• Excessive cortisol

• Short and obese

• Causes:– Endogenous: tumor– Exogenous: prolonged

steroid intake

Abnormal levels of Sex Hormone

Hypogonadism- – both growth and sexual development may be retarded

Turner syndrome– insufficient amounts of the female sex hormone, estrogen– delays in growth and sexual development

• Precocious puberty– Early growth spurt and premature closure of epiphyses– Adult height: Short

HISTORY• Birth weight & birth length• Previous height and weight data (growth velocity)• Time of adolescent development• Dietary history• Past Illnesses• School performance

• Family patterns of growth– the heights of parents, grandparents, siblings, and other

close relatives– any history of early or late puberty (growth spurt and

sexual development) in family members

Physical Examination• Height• Weight

• Arm span• Upper & lower body segment

• Dysmorphic features• Associated anomalies

Work-ups• X-ray for bone age

• Imaging – CT scan / MRI of sella

• Blood tests:– Blood chemistry– Chromosomal analysis– Hormonal stimulation

testsBone age delayed compared to chronological agein GHD and hypothyroidism

Blood Tests• Blood tests

– BUN, Cr, Ca, P, alk phosphatase, SGPT– TSH, T4– Cortisol– insulin-like growth factor I (IGF-I)– Chromosomal analysis

• Tests for GH Secretion GH Stimulation tests– GH<10 μg/L

Treatment of Short Stature

• Depends on etiology– Hypothyroidism: levothyroxine – Growth hormone deficiency: GH– Cushing syndrome

• Tumor removal• Adjust dosage of steroid

– Turner syndrome/ Prader Willi syndrome: GH– Achondroplasia: limb lengthening

Indications of GH Use in Children

• Growth hormone deficiency• Turner syndrome• Small for gestational age (not catching up in

height)• Prader-Willi syndrome• Chronic renal insufficiency • Idiopathic short stature –

– expected to grow shorter than • 5’3” for boys• 4’11” for girls

PHYSIOLOGIC EFFECTS OF GH

• Short-term administration of GH promotes– Lipolysis

• loss of visceral adipose tissue - the most dramatic metabolic effect of GH

– stimulates protein synthesis– increases lean body mass– stimulates bone turnover– causes insulin antagonism– alters total body water

Summary• Normal growth

–Growth velocity–Factors affecting growth

• Short stature– “normal” variants– Pathological short stature needs evaluation

• History, PE– Treatment depends on etiology

• GH therapy is approved in some conditions

Childhood Obesity

Sept,2, 2009

Learning Outcomes

Obesity• Identify causes of obesity• Acquire skill in history-taking, physical

examination in a child with obesity• Use growth charts and BMI charts• Propose diagnostic work-ups • Provide treatment plan

Childhood Obesity

1. Definition2. Epidemiology3. Physiology4. Causes5. Evaluation6. Treatment

Definition of Overweight and Obesity

BMI Category Former Terminology

Recommended Terminology

≥95th percentile Overweight or obesity

Obesity

85th - 94th P At risk of overweight

Overweight

5th to 84th P Healthy weight Healthy weight

< 5th percentile Underweight Underweight

Barlow SE and the Expert Committee. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: Summary report. Pediatrics. 2007;120;S164-S192.

OK135S057

Growth (Height and Weight ) Charts

Measurements of weight and height. Plot data on the growth charts.

CDC

Body Mass Index (BMI)

BMI = Weight (kg) Height (m2)

BMI charts – examples: CDC, WHO

OK135S060

In children, BMI is age and gender specific

http://www.cdc.gov/nchs/about/major/nhanes/growthcharts/charts.htm

BMI percentile can be used to identify childhood obesity

95th P

85th P

Obesity

Overweight

WHO BMI Cut-offs

• Overweight: > +1SD (= =BMI 25 kg/m2 at 19 years) • Obesity: > +2SD (= BMI 30 kg/m2 at 19 years) • Thinness: < -2SD• Severe thinness: < -3SD

Obesity

Overweight

Normal

Thinness

Severe Thinness

Epidemiology

Prevalence of overweight and obesity • Of the world’s children and

adolescents aged 5 -17 years, about 10% estimated to be overweight

among them, 1/4 obese (30-40 million) Report of the International Obesity Task Force to the WHO.Obesity Reviews, 2004

Globally, generally there is 2-3 x ↑Lancet 2002; 360:474

Epidemiology

In the Philippines, 7th National Nutrition Survey (FNRI):

Prevalence of overweight• 2.0% among 0-5 years-old children• 1.6% among 6-10 years-old children• 4.6% among 11-19 year-old adolescents

Prevalence of overweight and obesityAmong 2022 adolescents (10-19 years) in private and

public schools, Metro Manila (2007-2008)• 13% overweight (BMI 85-94th P)• 8% obesity (BMI ≥95th P)

0%

20%

40%

60%

80%

<5th 5th-84th 85-94th ≥95th Cua S. 2008

Study (S Cua, 2008):Adolescents (n=2022; age: 11-18 yr) from 6 high schools (3 private, 3 public)

The prevalence of overweight about 3-fold higher in the private school students The prevalence of obesity: 5-fold higher in the private school students

BMI distribution by school type

19.3%

71.9%

6.3%2.5%2.6%

66.2%

18.6%

12.5%

Underweight Healthy Overweight Obesity

Public school

Private school

Prevalence of overweight among students was higher in Private Schools in Metro Mla

• R. Florentino, et al, (2002) – 1208 male and female students, aged 8-10 yr

– the prevalence of overweight (BMI ≥ 95th P) among private school children was almost 4 x higher than those in public school

Physiology• Control system of appetite and satiety

– Hypothalamus– Negative feedback loop

• Leptin• Glucose• Insulin• Neuropeptides (neuropeptide Y)• Corticotropin releasing hormone• Pro-opiomelanocortin (POMC)• Resistin (animal studies)• Ghrelin

PhysiologyObesity causes alterations in endocrine physiology. • ↓ serum GH and ↓ IGFBP-1• blunted prolactin response to TRH• ↓ SHBG

• ↑ GHBP• ↑ insulin level or insulin resistance • normal or ↑ IGF-1 and IGFBP-3• slightly ↑ T3• ↑ cortisol secretion rate but normal serum cortisol levels

and urinary free cortisol excretion • ↑ estrogen but ↓ testosterone in boys• ↑ both estrogen and androgen levels in girls

Causes Associated with ↑ growth velocity• Simple or exogenous obesity

– Etiology is multifactorial• Interaction of genetics and environment

Endocrine disruptors

– Energy imbalanceEnergy In - Energy Used = Energy Stored

For every 100 calories excess per day, one will put on 10 pounds per year

Causes

• Caloric intake has increased– Eating unsupervised, lack of family meals– Eating at multiple sites and frequent snacks – Eating out / take out food – Calorically dense food (fried food)– Big portion– Sugar-added beverages

Causes

• Physical activity has decreased– Schools with less physical education– After school programs– Safety concerns– Convenience activities– Increased sedentary activities: TV, computer,

video games

Causes

Associated with ↓ growth velocity• Endocrine causes of obesity

– Hypothyroidism– Glucocorticoid excess– GH deficiency– Brain tumors (craniopharyngioma)– Chromosomal defects

EvaluationHistory • Previous height and weight, including birth

weight and height• Height and weight of parents and siblings• History of diet and physical activity• Psychosocial history• Parental consanguinity• Symptoms of headache, polyuria, menstrual

irregularities in girls, hypotonia and feeding problem during infancy, neonatal hypoglycemia

Evaluation

Physical examination• Weight • Height• BMI• Waist circumference• Blood pressure

EvaluationPhysical examination• Dysmorphic features • Acanthosis nigricans• Striae• Plethora• Body hair (hirsutism)• External genitalia

Work-ups• FBS, insulin, HbA1c

• Lipid profiles (cholesterol, triglycerides, HDL, LDL)

• Liver function tests (SGPT or ALT, SGPT or AST)

• Sonography – Liver – fatty liver– Ovaries and uterus in girls – PCOS

Work-ups

• Hormonal assays when indicated– TSH, T4– LH, FSH– Others like testosterone, SHBG, cortisol

• Chromosomal analysis

• CT scan /MRI – Head – craniopharyngioma– Abdomen- adrenal tumor

Obesity-related complications

Tibia varaPsychosocial problems:

• Depression • Poor self esteem

DM and Dyslipidemia• Diabetes mellitus: FBS 126 mg/dl (7mM/L)• Impaired fasting glucose (IFG): >100

mg/dl (5.5 mM/L)

• Dyslipidemia:– Low HDL: Male: <40 mg/dl (1.03 mM/L)

Female: <50 mg/dl (1.29 mM/L)– High LDL: >110 mg/dl (>2.84 mM/L)– High triglycerides: >150 mg/dl (>1.69 mM/L)

IMPACT OF CHILDHOOD OBESITY IN ADULTHOOD

• Harvard Growth Study: – 2 x ↑ in mortality (all causes) in obese vs

nonobese adolescents as adults

– 2 x ↑ in CAD mortality

– ↑ risk of colon cancer in males

– ↑ risk of arthritis in females

CAD: Coronary artery disease

Summary of treatment proposals based on the consensus development conference (March 2004) [i]

Definitions Clinical overweight: BMI ≥85th P Clinical obesity: BMI >95th P on national charts Epidemiological or international studies: WHO / IOTF cutoffs

Preventive strategies

Action is required antenatally, in schools, community facilities, marketing, government and regulatory agencies. [i]

Screening Population screening is required to identify overweight children with BMI >85th P

[i] Speiser PW, Rudolf MCJ, Anhalt H, et al. CONSENSUS STATEMENT: Childhood Obesity. J Clin Endocrinol Metab, March 2005, 90(3):1871–1887.

[i] Davis MM, Gance-Cleveland B, Hassink S, Johnson R, Paradis G, Resnicow G. Recommendations for prevention of childhood obesity. Pediatrics. 2007;120(suppl 4):228–252

Summary of treatment proposals based on the consensus development conference (March 2004) [i]

Assessment Laboratory assessment of children >95th P:a) Thyroid and liver function tests, fasting

glucose, insulin and lipid profile.

b) Children at ↑ risk for the metabolic syndrome require periodic oral glucose tolerance tests from age 10.

c) Screening for other comorbidities: e.g., hypertension, sleep apnea, orthopedic problems, etc.

[i] Speiser PW, Rudolf MCJ, Anhalt H, et al. CONSENSUS STATEMENT: Childhood Obesity. J Clin Endocrinol Metab, March 2005, 90(3):1871–1887.

Summary of treatment proposals based on the consensus development conference (March 2004) [i]

Treatment Children with BMI ≥85th P should receive regular lifestyle counseling.Children with BMI >95th P require specialist pediatric care.

Service development

Children with comorbidity or severe obesity should receive their care in a multidisciplinary specialist service.

[i] Speiser PW, Rudolf MCJ, Anhalt H, et al. CONSENSUS STATEMENT: Childhood Obesity. J Clin Endocrinol Metab, March 2005, 90(3):1871–1887.

Recommendations for Weight Management

BMI >95th P BMI>95th P

Treatment

Weight Management• Diet• Physical Activity• Behavioral modification• Pharmacotherapy

• Multidisciplinary interventions

Treatment

• Treatment of obesity-related medical conditions– Hypertension– Dyslipidemia

• Treatment of specific disease– Adrenal tumor – excision– Craniopharyngioma – surgery/ radiotherapy

Childhood Obesity

1. Overweight / obesity2. Prevalence is rising3. Genetic and environmental factors4. Exogenous obesity and endocrine causes5. Obesity related conditions/ morbidities6. Treatment and prevention

Diabetes Mellitusin Children

Learning Outcomes

Diabetes mellitus• Identify types of DM• Recognize clinical presentation• Propose diagnostic work-ups • Provide treatment plan

Diabetes Mellitusin the Pediatric Population

• Diagnosis• Types and Pathophysiology• Clinical Presentation • Management

• Acute complication– DKA– Hypoglycemia

Diabetes Mellitus (DM)

A heterogeneous group of disorders– Insulin production and/or – insulin action

hyperglycemia

Diagnosis of DM

Diseases of abnormal carbohydrate metabolism

1. FPG 126 mg/dl (7.0 mmol/l)

2. RBS 200 mg/dl (11.1 mmol/l) & symptoms of DM

3. 2-h plasma glucose 200 mg/dl (11.1mmol/l) during an OGTT

Classification and Pathophysiology

TYPE PATHOPHYSIOLOGYInsulin secretion (IS) / Insulin resistance (IR)

Type 1 Autoimmune destruction of β cells

Type 2 ↑ IR and β cell insufficiency

Monogenic ↓ IS

Secondary(drugs/ dis)

Various: ↓ IS, ↑ IR

T1DMβ cell

specific autoimmunity

GenesVirusesToxins

Diet

Susceptibility

Autoantigen

DIABETES

Triggering factors

islet-cell (ICA)glutamic acid decarboxylase (anti-GAD)Insulin (IAA)tyrosine phosphatase IA-2

T1 DMLocal study (Metro Manila, 1998-1999)99 children (1-14 yr)

– 56 girls– 33 boys

• Prevalence: 2.8 cases /100,000

• Incidence: 0.55 – 0.60 cases /100,000

Japan: 2.4 / 100,000

Sy RA, Chan-Cua S, 1999

Age Distribution of Diabetic Children and Adolescents in PGH, 2010

0

2

4

6

8

10

12

14

<1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Age in year

Perc

ent

Male Female

• Pre-school age

• Pubertal age

9

8

7

6

51975 1980 1985 1990 1995

1

2

3

4

5

6

7

8

Year

Type

2 d

iabe

tes

inci

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00,0

00 p

er y

ear)

Obesity (%

)

Type 2 diabetes

Obesity

Pediatric T2DM and Obesity in Japan

Kitigawa T et al. Clin Pediatr (Phila) 1998; 37: 111-115

Bet

a-ce

ll fu

nctio

nInsulin resistance

Insulin resistance andbeta-cell functionNormal

glycaemia

AgePuberty

Glucoseintolerance

Type2 diabetes

T2DMCharacterized by • Insulin resistance• secretory defect

• Obesity (BMI >95thP for age & gender)

• Family hx: T2DM in a 1st or 2nd degree relative

• High-risk ethnic group (e.g., Aboriginal, African, Hispanic, South-Asian)

• A history of exposure to DM in utero

• Acanthosis nigricans (insulin resistance)

• Polycystic ovarian syndrome (PCOS)

T1 & T2 DM in children and adolescentsType 1 Type 2

Age of onset Throughout childhood Pubertal

Prominent race All (low in Asians) Asians

Onset Acute, severe Subtle to severe

Islet autoimmunity Present Unusual

Insulin secretion Very low Variable

Insulin sensitivity Normal Decreased

Ketosis, DKA at onset Common, up to 40% Uncommon

Obesity As in population >90%% of probands with affected 1o relatives

5-10% ~80%

Mode of inheritance Non-Mendelian, gen’ly sporadic

Non-Mendelian, strongly familial

Monogenic diabetes - MODY

• Autosomal dominant -(+) Family history

• Account for 1–5% of all cases of diabetes

Ledermann HM. Maturity-onset diabetes of the young (MODY) at least ten times more

common in Europe than previously assumed? Diabetologia 1995;38(12):1482.

• 6 causative gene mutations in insulin and glucose regulation and pancreatic beta cell function

Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of

maturity-onset diabetes of the young. N Engl J Med 2001;345(13):971-80

Maturity onset diabetes of the young (MODY)

Monogenic Diabetes - MODY

• MODY 1• MODY 2• MODY 3

• MODY 4• MODY 5• MODY 6

Genetic defects of β-cell functionGene mutated• Hepatocyte nuclear factor 4 α (HNF-4a)• Glucokinase (GCK) - mild• Hepatic nuclear factor 1 α (HNF-1α)

– early treatment with insulin• Insulin promoter factor-1 (IPF1)• Hepatic transcription factor 1 b (HNF-1b)• Neuro D1

Owen K, Hattersley AT. Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. Best Pract Res Clin Endocrinol Metab 2001;15(3):309-23

Confirmed diagnosis by genetic testing

Chromosome

20 712

13172

Monogenic Diabetes - MODYResembles T2DM• Relatively mild• May need no insulin • (-) antibodies

Different from T2DM• not obese• not insulin resistant

Monogenic diabetes - NDM

Transient • Half of NDM• No need of insulin after a few

weeks or months of age• 2 genes (chromosome 6q24)

HYMA1 and ZAC expressed only from paternal copy– A double dose of one or both

genes

Permanent – diverse etiology• Mutation of KCNJ11 gene

Encoding Kir6.2, a β-cell K channel crucial in regulation of insulin

– Response to sulfonylureas (glibenclamide/ glyburide)

• Mutations of EIF2AK3 gene

Neonatal Diabetes Mellitus (NDM): β-cell dysfunction

NDM - Wolcott-Rallison syndrome (WRS)

• AR• Neonatal onset / < 6 months• Multiple epiphyseal dysplasia• Convulsions

• Retarded development• Short stature• Liver disease • Nephropathy

TD Manna. J Pediatr (Rio J). 2007;83(5 Suppl):S178-183Valerie Senee, et al.Diabetes 53:1876–1883, 2004

Mutations of EIF2AK3 gene – pancreatic eukaryotic initiation factor 2 kinase (2p12)

Genetic Defects/ SyndromesGenetic Syndromes• Down syndrome• Klinefelter syndrome• Turner syndrome• Prader-Willi syndrome• Wolfram syndrome

(DIDMOAD)– DI, DM, optic nerve

atrophy, sensorineural deafness

Genetic defects in insulin action

• Type A insulin resistance• Leprechaunism• Rabson-Mendenhall

syndrome• Lipoatrophic diabetes

Medication-induced DM• Glucocorticoids- severe hyperglycemia

requiring insulin therapy• Chemo-therapeutic agents (L-asparaginase)

and immunosuppressants (cyclosporine and tacrolimus) – direct pancreatic beta cell toxicity– interference with insulin secretion – induction of insulin resistance

• Atypical anti-psychotics and anti-seizure medications

Lindenmayer JP, Nathan AM, Smith RC. Hyperglycemia associated with the use of atypical antipsychotics. J Clin Psychiatry 2001;62 Suppl 23:30-8.

Endocrine Diosorders

• Acromegaly • Cushing's

syndrome • Glucagonoma • Pheochromocyto

ma

• ↓ glucose uptake/ ↑gluconeogenesis

• ↓ glucose uptake

• ↑ gluconeogenesis/ ↑ glycogenolysis

• ↓ glucose uptake/ ↑ glycogenolysis

Mostly ↑ counter-regulatory hormone effects

DM Children differ from adults

• Insulin sensitivity related to sexual maturity

• Physical growth

• Ability to provide self-care

• Neurologic vulnerability to hypoglycemia

Clinical Presentations of DM

• Non-emergency: 3 P’s– Polyuria, polydipsia, polyphagia– Recent onset of enuresis in a previously toilet-trained

child – Weight loss– Fungal infection – Oral / Vaginal candidiasis - in girls– Vomiting – Irritability and decreasing school performance– Recurrent skin infections

• Emergency: DKA

Diabetic Ketoacidosis (DKA)• ↓ ↓ ↓ insulin levels • ↑ keto acids

• Abdominal discomfort, nausea, and emesis• Dehydration • Weakness • Polyuria

• Kussmaul respirations (deep, heavy, rapid breathing), fruity breath odor (acetone)

• Diminished neurocognitive function• Coma

• About 20–40% of children with new-onset diabetes progress to DKA before diagnosis.

2006 American Diabetes Association. From Diabetes Care, Vol. 29, 2006; 1150–1159.

↓ insulin↑counter-regulatory hormones

Hyperglycemia

Absolute insulin deficiency

Stress, infection or insufficient insulin intake

↑ Lipolysis ↓Glucose utilization↑Proteolysis

↓Protein synthesis ↑Glycogenolysis

↑Gluconeogenesis

Acidosis

↑Ketogenesis

Monitoring

Nutrition Exercise Medication

Management of Diabetes Mellitus

Child & Family

Multidisciplinary team of specialists

Insulin Types and Action Profiles

Rapid- acting

Short-acting

Intermediate –acting (NPH)

Intermediate-acting (Lente)Long-actingPremixed (75/25)Premixed (70/30)Premixed (50/50)

Make a choice• Combination

Teach injection• How• Where

Dosage

0.5-1 U/ kg / day

Actions of Oral Hypoglycemic Agents Address Different Defects of Type 2 Diabetes

Oral sulfonylurea Increase insulin secretion

DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999; 131;281-303Felig P. Bergman M. The endocrine pancreas: diabetes mellitus. In: Felig P. Baxter JD, Frohman LA, eds.Endocrinology and Metabolism. New York NY: McGraw-Hill Inc: 1995:1107-1250.Saltiel AR: Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes. 1996;45:1661-1669.

Class Primary Site of Action Primary Mechanism of Action

Pancreas

LiverBiguanide

Thiazolidinedione

Alpha-glucosidaseinhibitor

Decrease gastrointestinalabsorption of glucose

Reduce basal hepatic glucose production

Enhance insulin-stimulatedGlucose uptake

Intestine

Muscle

Oral Hypoglycemic Agents

Principles of DM ManagementAims – • To attain good glycemic control• To ensure normal growth (height & weight)• To prevent acute complications• To prevent long-term vascular complications

Acute ComplicationsDKA

Diabetes Mellitusin the Pediatric Population

Islets of Langerhans

b-cell destruction Insulin Deficiency

Adipocytes

Muscle Liver

Decreased Glucose Utilization &Increased Production

Glucagon

IncreasedProtein Catabolism

IncreasedKetogenesisGluconeogenesis,Glycogenolysis

Increased Lipolysis

HyperglycemiaKetoacidosis

HyperTG

PolyuriaVolume Depletion

Ketonuria

StressEpi,Cortis

ol

GH

Threshold180 mg/dl

DKA

DKA

Hyperglycemia (BG >11 mmol/L = 200 mg/dL)

Venous pH <7.3

Bicarbonate <15 mmol/L

Ketonemia and ketonuria

HbA1c

CBC

DKAThe 3 useful signs for assessing dehydration in

young children and predicting acidosis are:• prolonged capillary refill time

(normal capillary refill is 1.5–2 s)• abnormal skin turgor (tenting or inelastic skin)• abnormal respiratory pattern (hyperpnea)

10% dehydration is suggested by the presence of • weak or impalpable peripheral pulses • hypotension• oliguria

Management of DKA• Provide fluid therapy to correct dehydration

• Correct electrolyte imbalance and acidosis

• Give insulin to restore blood glucose to near normal

• Monitor blood glucose

DKAShock

↓ consciousnessDehydration >5%,

acidotic, not in shockMild dehydration,

Tolerating oral fluid

total body deficit of K

DKA

Bicarbonate administration

• Generally, not needed• Patients with severe acidemia (pH < 6.9)

in whom – decreased cardiac contractility and peripheral

vasodilatation can further impair tissue perfusion

• patients with life-threatening hyperkalemia

There is no evidence that bicarbonate is either necessary or safe in DKA.

• Anion gap = Na - (Cl + HCO3)– normal is 12 ± 2 mmol/L

• In DKA the anion gap is typically 20–30 mmol/L;an anion gap >35 mmol/L suggests concomitant lactic

acidosis

• Na corrected = Na measured +2 x ([glucose - 5.6] / 5.6) mmol/L

• Effective osmolality = 2 x (Na + K) + glucose mOsm/kg

Warning signs and symptoms of cerebral edema

• Headache & slowing of heart rate• Change in neurological status (restlessness,

irritability, increased drowsiness, incontinence)• Specific neurological signs (e.g., cranial nerve

palsies)• Rising BP• Decreased O2 saturation

Admit to ICU

• Children with severe DKA – long duration of symptoms– compromised circulation– depressed level of consciousness– those who are at increased risk for cerebral

edema • 5 yr of age• severe acidosis• low PCO2, high BUN

Hypoglycemia• Sweating• Trembling• Dizziness• Mood changes• Hunger• Headache• Blurred vision• Extreme tiredness • Pallor

Management of complications: Hypoglycemia

• Immediate source of glucose – Juice– Milk

• Glucagon

• Dextrose infusion

Diabetes Mellitusin the Pediatric Population

SUMMARY• Diagnosis• Types and Pathophysiology• Clinical Presentation • Management

• Acute complication– DKA– Hypoglycemia