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Growth (Short Stature, Obesity) Diabetes Mellitus in Children

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1 Growth (Short Stature, Obesity) Diabetes Mellitus in Children
Sioksoan Chan-Cua, MD Associate Professor Pediatric Endocrinologist

2 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

3 Growth - Height Normal growth Short stature Diagnosis
Causes Diagnosis history and physical examination work-up treatment / management plan

4 Growth Rate Through Adolescence
At birth, full-term baby’s Length: 50 cm (20 in ) Weight: 3 kg (7 lb) Birth to 1 year: cm ( 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) The growth rate (how fast the child is growing) is shown on the left side of the chart. The child's age in years is shown along the bottom. Pubertal growth spurt lasts about 2 years is accompanied by sexual development Normal growth stops when the growing ends of the bones fuse usually occurs between the ages of 13 and 15 for girls 14 and 17 for boys Puberty: Girls (11 yr) cm in Boys (13 yr)  cm in

5 Short Stature with Slow Growth Rate
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

6 Factors Affecting Growth
Nutrition (malnutrition) Diseases (chronic diseases) Genes/ heredity Hormones Psychological factors Optimal growth requires optimal health and nutrition. If a person is malnourished, has kidney problems, was born with a genetic disorder, or suffers from a number of other medical conditions, growth can be affected.

7 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

8 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 pituitary Ptx 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, T cell-specific gene expression and regulation Rpx (Hesx1): differentiation of pituitary (eg. SOD) Ptx (Pitx/ P-OTX): Pit 1 and Pit 2 Present in fetal and adult pituitary Ptx 2 is expressed in the somatotrophs, lactotrophs, thyrotrophs & gonadotrophs Lhx3 (LIM-3/ P-Lim) : maintenance function PROP – 1: required for S, L, T determination Pit-1 (GHF-1, POU1F1): dev’t of S, L, T cell-specific gene expression and regulation

9 Hormones Affecting Growth
Growth hormone (GH) Thyroid hormone Glucocorticoids Sex hormones Insulin – important fetal growth factor (infant of diabetic mother is macrosomic)

10 Hormonal Control of Growth Pituitary Gland and GH
When normal growth patterns change, it could be an indicator of an underlying endocrine disease. This hormone is a protein with 191 amino acids and its secretion is pulsatile, and may be influenced by ghrelin levels in the hypothalamic-pituitary portal circulation and the systemic circulation. 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

11 Causes of Short Stature

12 Familial Short Stature

13 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

14 Constitutional Growth Delay

15 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

16 CAUSES of SHORT STATURE
PATHOLOGICAL Disproportionate Bone development disorders (Skeletal dysplasia) Achondroplasia Rickets Other skeletal disorders

17 CAUSES of SHORT STATURE
PATHOLOGICAL Proportionate Chromosome defects Endocrine disorders Low birth weight short stature (IUGR) Nutritional deficiency Chronic systemic disease Psychosocial deprivation

18 Chromosomal Abnormality
Somatic Down syndrome Sex chromosome Turner syndrome Short stature (< 144cm) Gonadal dysgenesis Skeletal deformity Cubitus valgus Short metacarpals

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

20 Russell-Silver Syndrome
Intrauterine growth retardation Postnatal short stature Small triangular facies Limb asymmetry

21 Endocrine Causes of Short Stature
Hypopituitarism - GH deficiency (GHD) Hypothyroidism Hypercortisolism Hypogonadism

22 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

23 CHARACTERISTICS OF GHD
Diminished growth rate Delayed bone age GH (<10 μg/L) Growth response to treatment with hGH EARLY CLUES TO GH DEFICIENCY Hypoglycemia Micropenis Facial midline malformation Neonatal injury

24 Hypothyroidism Hypothyroidism → short stature Congenital Acquired

25 Congenital Hypothyroidism
History Autoimmune thyroid disease in the family Intake of anti-thyroid medication in the mother Familial congenital hypothyroidism Presence of congenital hypothyroidism associated with deafness and goiter Prolonged jaundice in the neonate Poor suck in the neonate Poor cry in the neonate Constipation in the neonate

26 Congenital Hypothyroidism
PE Hypothermia Mottled, dry, coarse skin Jaundice Large fontanelle Macroglossia Hoarse cry Distended abdomen Umbilical hernia Hypotonia  Goiter

27 Hypercortisolism – Cushing syndrome
Excessive cortisol Short and obese Causes: Endogenous: tumor Exogenous: prolonged steroid intake

28 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

29 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

30 Physical Examination Height Weight Arm span Upper & lower body segment
Dysmorphic features Associated anomalies

31 Work-ups X-ray for bone age Imaging – CT scan / MRI of sella
Blood tests: Blood chemistry Chromosomal analysis Hormonal stimulation tests Bone age delayed compared to chronological age in GHD and hypothyroidism

32 Blood Tests Blood tests Tests for GH Secretion GH Stimulation 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

33 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

34 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 To learn more about possible causes, the health care provier will ask questions such as the following: Family history How tall are the parents? grandparents? How tall are the siblings (brothers or sisters)? Are there other relatives that are less than average height? Have any family members been diagnosed with a disorder associated with short stature (see the causes section of this document)? At what age did the parents start puberty? Child's history Has the child begun to show signs of puberty? At what age did puberty signs begin? Has the child always been on the small side of the growth charts? Was the child growing normally and then the rate of growth began to slow? Other What other symptoms are also present?

35 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

36 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

37 Childhood Obesity Sept,2, 2009

38 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

39 Childhood Obesity Definition Epidemiology Physiology Causes Evaluation
Treatment

40 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 < 5th percentile Underweight a Expert committee recommendations, (*** New recommendations 2007, published in Pediatrics.1) b CDC recommendations, 2002. c International Obesity Task Force, 2000. d Institute of Medicine, 2005. 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.

41 Growth (Height and Weight ) Charts
CDC Measurements of weight and height. Plot data on the growth charts. OK135S057

42 Body Mass Index (BMI) BMI charts – examples: CDC, WHO
BMI = Weight (kg) Height (m2) BMI charts – examples: CDC, WHO

43 In children, BMI is age and gender specific
BMI percentile can be used to identify childhood obesity Obesity 95th P 85th P Overweight BMI is widely used to define overweight and obesity, because it correlates well with more accurate measures of body fatness and is derived from commonly available data—weight and height. Clinical judgment must be used in applying these criteria to a patient, because obesity refers to excess adiposity rather than excess weight, and BMI is a surrogate for adiposity. It has also been correlated with obesity-related comorbid conditions in adults and children. Pediatricians should 'calculate and plot BMI once a year in all children and adolescents' and then use a 'change in BMI to identify rate of excessive weight gain relative to linear growth BMI between 85th and 95th percentile for age and sex is considered at risk of overweight, and BMI at or above the 95th percentile is considered overweight or obese. If a child's BMI reaches the thP, it is time to start intervening aggressively. OK135S060

44 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

45 Obesity Overweight Normal Thinness Severe Thinness

46 Epidemiology Prevalence of overweight and obesity
Of the world’s children and adolescents aged 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 National Center for Health Statistics (NCHS): approximately 1 in 5 children in the United States is overweight Troiano RP, et al. Overweight prevalence and trends for children and adolescents. The National Health and Nutrition Examination Surveys, 1963 to 1991. Arch Pediatr Adolesc Med. 1995;149:1085–1091 Troiano RP, Flegal KM, Kuczmarski RJ, Campbell SM, Johnson CL. Overweight prevalence and trends for children and adolescents. The National Health and Nutrition Examination Surveys, 1963 to 1991. To develop guidance for physicians, nurse practitioners, dietitians/ nutritionists, and others who care for overweighta children, the Maternal and Child Health Bureau, Health Resources and Services Administration, the Department of Health and Human Services convened a conference in Washington, DC, on March 18–19, 1997. Globally, generally there is 2-3 x ↑ Lancet 2002; 360:474

47 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 year-old adolescents

48 Prevalence of overweight and obesity
Among 2022 adolescents (10-19 years) in private and public schools, Metro Manila ( ) 13% overweight (BMI 85-94th P) 8% obesity (BMI ≥95th P) 0% 20% 40% 60% 80% <5th 5th-84th 85-94th ≥95th Fig. Prevalence by BMI 1186 males, 836 females Cua S. 2008

49 Study (S Cua, 2008): Adolescents (n=2022; age: 11-18 yr) from 6 high schools (3 private, 3 public)
The prevalence of overweight in the private school students was 18.6% (205/1101), about 3-fold higher than that of the public school students, 6.3% (58/921). The prevalence of obesity in the private school students was 12.5% (138/1101), which was 5-fold higher than that of public school students, 2.5% (23/921). 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

50 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 [iv] Florentino, RF, Villavieja GM, Lana RD. Regional study of nutritional status of urban primary schoolchildren. 1. Manila, Philippines. Food Nutr Bull 2002; 23(1):

51 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

52 Physiology Obesity 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

53 Causes Associated with ↑ growth velocity Simple or exogenous obesity
Etiology is multifactorial Interaction of genetics and environment Endocrine disruptors Energy imbalance Energy In - Energy Used = Energy Stored For every 100 calories excess per day, one will put on 10 pounds per year

54 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

55 Causes Physical activity has decreased
Schools with less physical education After school programs Safety concerns Convenience activities Increased sedentary activities: TV, computer, video games

56 Causes Associated with ↓ growth velocity Endocrine causes of obesity
Hypothyroidism Glucocorticoid excess GH deficiency Brain tumors (craniopharyngioma) Chromosomal defects

57 Evaluation History 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

58 Evaluation Physical examination Weight Height BMI Waist circumference
Blood pressure

59 Evaluation Physical examination Dysmorphic features
Acanthosis nigricans Striae Plethora Body hair (hirsutism) External genitalia

60 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

61 Work-ups Hormonal assays when indicated Chromosomal analysis
TSH, T4 LH, FSH Others like testosterone, SHBG, cortisol Chromosomal analysis CT scan /MRI Head – craniopharyngioma Abdomen- adrenal tumor

62 Obesity-related complications
This is not puppy fat that will go away. Obesity is not benign. It is dangerous. Besides the social issues and problems with depression, obese children are at immediate risk of serious health problems that include high blood pressure, lipid abnormalities, metabolic syndrome, and sleep apnea. Tibia vara Psychosocial problems: Depression Poor self esteem

63 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)

64 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

65 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 Definitions Clinical overweight: BMI ≥85th centileClinical obesity: BMI > 95th centile on national charts Epidemiological or international studies: IOTF cutoffsPreventive strategies Action is required antenatally, in schools, community facilities, marketing, government and regulatory agencies. [ii]ScreeningPopulation screening is required to identify overweight children with BMI >85th centileAssessmentLaboratory assessment of children > 95th centile should include:a) Thyroid and liver function tests, fasting glucose, insulin and lipid profile.b) Children at increased 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.TreatmentChildren with BMI ≥85th centile should receive regular lifestyle counseling.Children with BMI >95th centile require specialist pediatric care.Service developmentChildren 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. [ii] 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 [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

66 Summary of treatment proposals based on the consensus development conference (March 2004) [i]
Assessment Laboratory assessment of children >95th P: Thyroid and liver function tests, fasting glucose, insulin and lipid profile. Children at ↑ risk for the metabolic syndrome require periodic oral glucose tolerance tests from age 10. Screening for other comorbidities: e.g., hypertension, sleep apnea, orthopedic problems, etc. AssessmentLaboratory assessment of children > 95th centile should include:a) Thyroid and liver function tests, fasting glucose, insulin and lipid profile.b) Children at increased 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.TreatmentChildren with BMI ≥85th centile should receive regular lifestyle counseling.Children with BMI >95th centile require specialist pediatric care.Service developmentChildren 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.

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

68

69 Treatment Weight Management Diet Physical Activity
Behavioral modification Pharmacotherapy Multidisciplinary interventions Diet A balanced reduced calorie diet (focusing on eating fewer energy dense foods) given in line with dietary guidelines was more effective than no diet. for example, Epstein's "traffic light" diet, which divides foods into "colored" groups according to whether they can be consumed freely (green) with discretion (yellow) should be strictly limited (red

70 Treatment Treatment of obesity-related medical conditions
Hypertension Dyslipidemia Treatment of specific disease Adrenal tumor – excision Craniopharyngioma – surgery/ radiotherapy

71 Childhood Obesity Overweight / obesity Prevalence is rising
Genetic and environmental factors Exogenous obesity and endocrine causes Obesity related conditions/ morbidities Treatment and prevention

72 Diabetes Mellitus in Children

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

74 Diabetes Mellitus in the Pediatric Population
Diagnosis Types and Pathophysiology Clinical Presentation Management Acute complication DKA Hypoglycemia Diagnose diabetes mellitus in the children and adolescents Provide diabetes care of children and diabetes Manage acute complications (I) – diabetic ketoacidosisManage acute complications (II) – hypoglycemia “ The incidence of Type 1 diabetes in children age 0-14 years old in our country in 1998 is 0.41/100,000 population “ Prevalence of Type 1 DM in Childhood And Adolescent in Metro Manila, Philippines; Diabetes Watch; July-December 2000

75 Diabetes Mellitus (DM)
A heterogeneous group of disorders Insulin production and/or insulin action  hyperglycemia

76 Diagnosis of DM Diseases of abnormal carbohydrate metabolism
FPG 126 mg/dl (7.0 mmol/l) RBS 200 mg/dl (11.1 mmol/l) & symptoms of DM 2-h plasma glucose 200 mg/dl (11.1mmol/l) during an OGTT The FPG is the preferred test to diagnose diabetes in children and nonpregnant adults. The American Diabetes Association (ADA) The diagnosis is based on one of three abnormalities: fasting plasma glucose, random elevated glucose with symptoms, or abnormal oral glucose tolerance test (OGTT) The 2003 criteria lowered the fasting plasma glucose level used to define impaired fasting glucose (IFG) from the 1997 criteria but maintained the same definitions for diabetes and for impaired glucose tolerance (IGT) as measured by an oral glucose tolerance test Patients with IFG and/or IGT are now referred to as having "pre-diabetes" indicating the relatively high risk for development of diabetes in these patients FPG AND OGTT AS PREDICTORS OF DIABETES — Although the natural history of IFG and IGT is variable, approximately 25 percent of subjects with either will progress to diabetes over three to five years. Subjects with additional diabetes risk factors, including obesity and family history, are more likely to develop diabetes.

77 Classification and Pathophysiology
TYPE PATHOPHYSIOLOGY Insulin 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 T1DM is generally seen in lean children with pancreatic autoimmunity. T2DM is generally seen in obese children with insulin resistance Monogenic DM generally have a strong family history of diabetes affecting multiple generations, a classically normal weight, and do not have features of insulin resistance or evidence of pancreatic autoimmunity Secondary DM: Medication-induced DM is diagnosed when hyperglycemia develops following the initiation of a known diabetogenic medication

78 T1DM Triggering factors Genes DIABETES islet-cell (ICA)
specific autoimmunity islet-cell (ICA) glutamic acid decarboxylase (anti-GAD) Insulin (IAA) tyrosine phosphatase IA-2 Autoantigen Susceptibility Triggering factors Genes Viruses Toxins Diet DIABETES

79 T1 DM Local study (Metro Manila, 1998-1999) 99 children (1-14 yr)
Sy RA, Chan-Cua S, 1999 Local study (Metro Manila, ) 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 In Asia, the incidence of type 1 diabetes is extremely low: China 0.1 per (3), Japan 2.4 per 100,000 (42);

80 Age Distribution of Diabetic Children and Adolescents in PGH, 2010
2 4 6 8 10 12 14 <1 1 3 5 7 9 11 13 15 16 17 18 Age in year Percent Male Female Pre-school age Pubertal age

81 Type 2 diabetes incidence (per 100,000 per year)
Pediatric T2DM and Obesity in Japan 8 7 Type 2 diabetes 6 9 Type 2 diabetes incidence (per 100,000 per year) 5 8 4 Obesity (%) 3 7 Pediatric type 2 diabetes and obesity in Japan Further data from Japan illustrate the importance of obesity as a risk factor for the development of paediatric type 2 diabetes. The 25-year screening programme in Japanese schoolchildren provides an elegant illustration of the simultaneous development of obesity and type 2 diabetes in this population. Kitagawa T, Owada M, Urakami T, Yamauchi K. Increased incidence of non-insulin dependent diabetes mellitus among Japanese schoolchildren correlates with an increased intake of animal protein and fat. Clin Pediatr (Phila) 1998; 37: 2 6 Obesity 1 5 1975 1980 1985 1990 1995 Year Kitigawa T et al. Clin Pediatr (Phila) 1998; 37:

82 Insulin resistance and beta-cell function
Normal glycaemia Glucose intolerance Type 2 diabetes Insulin resistance Beta-cell function Insulin resistance and beta-cell dysfunction As in adult type 2 diabetes, insulin resistance develops for a period of time, most strongly from puberty onwards, before a decline in beta-cell function precipitates the onset of clinical type 2 diabetes. Age Puberty

83 T2DM Characterized 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)  Unraveling non-type 1 diabetes mellitus in childhood Shazhan Amed, MD, The Hospital for Sick Children Heather Dean, MD, Winnipeg Children’s Hospital Jill Hamilton, MD, The Hospital for Sick Children In the normoglycemic, insulin sensitive individual, there is a precise balance between insulin secretion and insulin sensitivity. Data on the pathophysiology of T2DM in children are sparse.

84 T1 & T2 DM in children and adolescents
Type 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

85 Monogenic diabetes - MODY
Maturity onset diabetes of the young (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 Genetic defects of beta-cell function — Approximately two to five percent of patients with type 2 diabetes present at a young age, have mild disease, and autosomal dominant transmission. This condition was formerly called maturity-onset diabetes of the young MODY [14] . These patients are quite heterogeneous and clinical characteristics are not reliable in predicting the underlying pathogenesis [15,16 UpToDate] . Six different genetic abnormalities have been identified with types 3 and 2 accounting for 65 and 15 percent of cases, respectively [16] . Some members of a family have the genetic defect but do not develop diabetes; the reason for this is unclear. In the new classification, the MODY subtypes have been eliminated, and replaced by specific descriptions of the known genetic defects. It is anticipated that other subtypes of type 1 and type 2 diabetes will become more clearly defined in the future. References 1. Weiss R, Taksali SE, Tamborlane WV, Burgert TS, Savoye M, Caprio S. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care 2005;28(4):902-9. 2. Ho J, Pacaud D. Secondary diabetes in children. Can J Diabetes 2004;28(4):400-5. 3. Lindenmayer JP, Nathan AM, Smith RC. Hyperglycemia associated with the use of atypical antipsychotics. J Clin Psychiatry 2001;62 Suppl 23:30-8. 4. Verrotti A, Basciani F, De Simone M, Trotta D, Morgese G, Chiarelli F. Insulin resistance in epileptic girls who gain weight after therapy with valproic acid. J Child Neurol 2002;17(4): 5. 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. 7. 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): 8. Sellers EA, Triggs-Raine B, Rockman-Greenberg C, Dean HJ. The prevalence of the HNF-1alpha G319S mutation in Canadian aboriginal youth with type 2 diabetes. Diabetes Care 2002;25(12): 9. Canadian Diabetes Association 2003 Clinical Practise Guidelines for the Prevention and Management of Diabetes in Canada: Definition, Classification and Diagnosis of Diabetes and Other Dysglycemic Categories. Can J Diabetes 2003;27(supplement 2):S7-S9. 10. Sellers EA, Dean HJ. Diabetic ketoacidosis: a complication of type 2 diabetes in Canadian aboriginal youth. Diabetes Care 2000;23(8): 11. Hathout EH, Thomas W, El-Shahawy M, Nahab F, Mace JW. Diabetic autoimmune markers in children and adolescents with type 2 diabetes. Pediatrics 2001;107(6):E102.

86 Monogenic Diabetes - MODY
Genetic defects of β-cell function MODY 1 MODY 2 MODY 3 MODY 4 MODY 5 MODY 6 Gene 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 Chromosome 20 7 12 13 17 2 Hepatocyte nuclear factor-4-alpha — Mutations in the (HNF-4-alpha) gene on chromosome 20 cause the condition formerly called MODY1 [17] . HNF-4-alpha is expressed both in the liver and in pancreatic beta cells. One of its functions is to regulate positively the activity of HNF-1-alpha, the affected gene in the previously labeled MODY3 syndrome. The precise mechanism by which a defect in HNF-4-alpha causes hyperglycemia is not clear, but it has been associated with a reduced insulin secretory response to glucose, suggesting a primary genetic defect in insulin secretion [18-20] . Although HNF-4-alpha plays a central role in the hepatic synthesis of lipoprotein and coagulation proteins, these functions are largely maintained in HNF-4-alpha diabetes, suggesting that this disorder is primarily one of impaired pancreatic beta-cell function [19] . Glucokinase gene — Over a dozen mutations in the glucokinase gene on chromosome 7 have been described, and were formerly called MODY2 [21] . Defects in the expression of glucokinase, which phosphorylates glucose to glucose-6-phosphate and probably acts as a glucose sensor, result in deficient insulin secretion. On occasion, the expressed enzyme functions but is unstable, again leading to an insulin secretory deficit [22] . (See "Insulin secretion and pancreatic beta-cell function"). Markers in the glucokinase locus have been linked to type 2 diabetes in American blacks [23] and some other ethnic groups, but not in whites. The resulting hyperglycemia is often mild and is not associated with the vascular complications that are so common in other types of diabetes mellitus [24] . Hepatocyte nuclear factor-1-alpha — One of several mutations in the HNF-1-alpha gene on chromosome 12 was formerly called MODY3 [25] . This form of diabetes is more common among European patients [26,27] . HNF-1-alpha is a weak transactivator of the insulin gene in beta cells. Mutations of HNF-1-alpha can lead to abnormal insulin secretion; whether this or some other action is defective enough to cause diabetes mellitus is unclear [27] . Prior to onset of diabetes, mutation carriers have detectable glycosuria provoked by glucose loading [28] . Testing for glycosuria two hours after a glucose load could be used to screen children of mutation carriers and guide the need for further evaluation. Patients with HNF-1-alpha diabetes have increased insulin sensitivity and marked sensitivity to the hypoglycemic effects of sulfonylureas compared to metformin (fall in FPG 85 versus 16 mg/dL [4.7 versus 0.9 mmol/L]) and compared to patients with type 2 diabetes (3.9 fold greater reduction in FPG) [29] . Insulin promoter factor 1 — Mutations in the insulin promoter factor 1 (IPF-1) gene can lead to what was called MODY4 by reduced binding of the protein to the insulin gene promoter [30,31] and perhaps by altering fibroblast growth factor signaling in beta cells [32] . Less severe mutations in IPF-1 may predispose to late onset type 2 diabetes [31,33] . In addition, nondiabetic carriers have higher blood glucose concentrations and lower insulin-to-glucose ratios than nondiabetic family members without a mutation [34] . Hepatocyte nuclear factor-1-beta — Mutations in the HNF-1-beta gene produce a syndrome that was formerly called MODY5 [35-38] . Affected patients can develop a variety of manifestations in addition to early onset diabetes. These include pancreatic atrophy (on CT scan), abnormal renal development (renal dysplasia that can be detected on ultrasonography in the fetus, single or multiple renal cysts, glomerulocystic disease, oligomeganephronia), slowly progressive renal insufficiency, elevated serum aminotransferases, and genital abnormalities (epididymal cysts, atresia of vas deferens, and bicornuate uterus) [36] . (See "Renal cystic diseases in children" section on Cortical cystic diseases). In addition, some patients have a phenotype consistent with familial juvenile hyperuricemic nephropathy [39] . (See "Uric acid renal diseases", section on Familial juvenile hyperuricemic nephropathy). One of the functions of HNF-1-beta is the regulation of tissue-specific gene expression. In the kidney, the proximal promoter of the Pkhd1 gene has a binding site for HNF-1-beta. Mutations in HNF-1-beta inhibit the expression of Pkhd1 and lead to cyst formation [38] . This is not surprising since mutations in Pkhd1 are responsible for the autosomal recessive form of polycystic kidney disease. (See "Autosomal recessive and dominant polycystic kidney disease in children", section on Pathogenesis). Neurogenic differentiation factor-1 — Mutations in the gene for neurogenic differentiation factor-1 (also called NEUROD1 or BETA2) can lead to what was called MODY6 [40,41] . NEUROD1 normally functions as a regulatory switch for endocrine pancreatic development. References 1. Weiss R, Taksali SE, Tamborlane WV, Burgert TS, Savoye M, Caprio S. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care 2005;28(4):902-9. 2. Ho J, Pacaud D. Secondary diabetes in children. Can J Diabetes 2004;28(4):400-5. 3. Lindenmayer JP, Nathan AM, Smith RC. Hyperglycemia associated with the use of atypical antipsychotics. J Clin Psychiatry 2001;62 Suppl 23:30-8. 4. Verrotti A, Basciani F, De Simone M, Trotta D, Morgese G, Chiarelli F. Insulin resistance in epileptic girls who gain weight after therapy with valproic acid. J Child Neurol 2002;17(4): 5. 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. 7. 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): 8. Sellers EA, Triggs-Raine B, Rockman-Greenberg C, Dean HJ. The prevalence of the HNF-1alpha G319S mutation in Canadian aboriginal youth with type 2 diabetes. Diabetes Care 2002;25(12): 9. Canadian Diabetes Association 2003 Clinical Practise Guidelines for the Prevention and Management of Diabetes in Canada: Definition, Classification and Diagnosis of Diabetes and Other Dysglycemic Categories. Can J Diabetes 2003;27(supplement 2):S7-S9. 10. Sellers EA, Dean HJ. Diabetic ketoacidosis: a complication of type 2 diabetes in Canadian aboriginal youth. Diabetes Care 2000;23(8): 11. Hathout EH, Thomas W, El-Shahawy M, Nahab F, Mace JW. Diabetic autoimmune markers in children and adolescents with type 2 diabetes. Pediatrics 2001;107(6):E102. Confirmed diagnosis by genetic testing 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

87 Monogenic Diabetes - MODY
Resembles T2DM Relatively mild May need no insulin (-) antibodies Different from T2DM not obese not insulin resistant

88 Monogenic diabetes - NDM
Neonatal Diabetes Mellitus (NDM): β-cell dysfunction 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

89 NDM - Wolcott-Rallison syndrome (WRS)
Mutations of EIF2AK3 gene – pancreatic eukaryotic initiation factor 2 kinase (2p12) AR Neonatal onset / < 6 months Multiple epiphyseal dysplasia Convulsions Retarded development Short stature Liver disease Nephropathy Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3, the pancreatic eukaryotic initiation factor 2 (eIF2) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably, the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with other patients (<6 months). The patient with no EIF2AK3 involvement did not have any of the other variable clinical manifestations associated with WRS, which supports the idea that the genetic heterogeneity between this variant form of WRS and EIF2AK3 WRS correlates with some clinical heterogeneity. Diabetes 53:1876–1883, 2004 TD Manna. J Pediatr (Rio J). 2007;83(5 Suppl):S Valerie Senee, et al.Diabetes 53:1876–1883, 2004

90 Genetic Defects/ Syndromes
Genetic defects in insulin action Type A insulin resistance Leprechaunism Rabson-Mendenhall syndrome Lipoatrophic diabetes Genetic Syndromes Down syndrome Klinefelter syndrome Turner syndrome Prader-Willi syndrome Wolfram syndrome (DIDMOAD) DI, DM, optic nerve atrophy, sensorineural deafness Wolfram syndrome (DIDMOAD) is characterized by the presence of diabetes insipidus, DM, atrophy of the optic nerve and sensorineural deafness and has autosomal recessive inheritance associated with non-immunological degeneration of pancreatic beta cells. The WSF-1 gene linked to the syndrome is located on chromosome 4.17 Clinical manifestations include: - DM (mean age 8.2 years); - Atrophy of the optic nerve (mean age 13.1 years); - Diabetes insipidus (mean age 14.1 years); - Sensorineural deafness (mean age 15 years); - Neurological degeneration (atrophy of the central nervous system seen on magnetic resonance imaging); - Psychiatric disorders; - Death (mean age 28 years).

91 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. References 1. Weiss R, Taksali SE, Tamborlane WV, Burgert TS, Savoye M, Caprio S. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care 2005;28(4):902-9. 2. Ho J, Pacaud D. Secondary diabetes in children. Can J Diabetes 2004;28(4):400-5. 3. Lindenmayer JP, Nathan AM, Smith RC. Hyperglycemia associated with the use of atypical antipsychotics. J Clin Psychiatry 2001;62 Suppl 23:30-8. 4. Verrotti A, Basciani F, De Simone M, Trotta D, Morgese G, Chiarelli F. Insulin resistance in epileptic girls who gain weight after therapy with valproic acid. J Child Neurol 2002;17(4): 5. 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. 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): 7. 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): 8. Sellers EA, Triggs-Raine B, Rockman-Greenberg C, Dean HJ. The prevalence of the HNF-1alpha G319S mutation in Canadian aboriginal youth with type 2 diabetes. Diabetes Care 2002;25(12): 9. Canadian Diabetes Association 2003 Clinical Practise Guidelines for the Prevention and Management of Diabetes in Canada: Definition, Classification and Diagnosis of Diabetes and Other Dysglycemic Categories. Can J Diabetes 2003;27(supplement 2):S7-S9. 10. Sellers EA, Dean HJ. Diabetic ketoacidosis: a complication of type 2 diabetes in Canadian aboriginal youth. Diabetes Care 2000;23(8): 11. Hathout EH, Thomas W, El-Shahawy M, Nahab F, Mace JW. Diabetic autoimmune markers in children and adolescents with type 2 diabetes. Pediatrics 2001;107(6):E102.

92 Mostly ↑ counter-regulatory hormone effects
Endocrine Diosorders Mostly ↑ counter-regulatory hormone effects Acromegaly Cushing's syndrome Glucagonoma Pheochromocytoma ↓ glucose uptake/ ↑gluconeogenesis ↓ glucose uptake ↑ gluconeogenesis/ ↑ glycogenolysis ↓ glucose uptake/ ↑ glycogenolysis

93

94 DM Children differ from adults
Insulin sensitivity related to sexual maturity Physical growth Ability to provide self-care Neurologic vulnerability to hypoglycemia

95 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

96 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. When extremely low insulin levels are reached, keto acids accumulate. At this point, the child quickly deteriorates. Keto acids produce abdominal discomfort, nausea, and emesis, preventing oral replacement of urinary water losses. Dehydration accelerates, causing weakness or orthostasis—but polyuria persists. As in any hyperosmotic state, the degree of dehydration may be clinically underestimated because intravascular volume is conserved at the expense of intracellular volume. Ketoacidosis exacerbates prior symptoms and leads to Kussmaul respirations (deep, heavy, rapid breathing), fruity breath odor (acetone), diminished neurocognitive function, and possible coma. About 20–40% of children with new-onset diabetes progress to DKA before diagnosis.

97 Absolute insulin deficiency
↑counter-regulatory hormones Stress, infection or insufficient insulin intake ↑Proteolysis ↓Protein synthesis ↑ Lipolysis ↓Glucose utilization ↑Glycogenolysis ↑Gluconeogenesis ↑Ketogenesis Hyperglycemia Acidosis 2006 American Diabetes Association. From Diabetes Care, Vol. 29, 2006; 1150–1159.

98 Management of Diabetes Mellitus
Monitoring Nutrition Exercise Medication Multidisciplinary team of specialists Child & Family

99 Insulin Types and Action Profiles
Rapid- acting Short-acting Intermediate –acting (NPH) Intermediate-acting (Lente) Long-acting Premixed (75/25) Premixed (70/30) Premixed (50/50) Make a choice Combination Teach injection How Where Dosage 0.5-1 U/ kg / day

100 Primary Mechanism of Action
Oral Hypoglycemic Agents Actions of Oral Hypoglycemic Agents Address Different Defects of Type 2 Diabetes Class Primary Site of Action Primary Mechanism of Action Pancreas Oral sulfonylurea Increase insulin secretion Liver Reduce basal hepatic glucose production Biguanide Enhance insulin-stimulated Glucose uptake Thiazolidinedione Muscle Table— Summary of antidiabetic interventions as monotherapy Interventions Expected decrease in A1C (%)AdvantagesDisadvantagesStep 1: initial    Lifestyle to decrease weight     and increase activity1–2Low cost, many benefitsFails for most in 1st year    Metformin1.5Weight neutral, inexpensiveGI side effects, rare lactic acidosisStep 2: additional therapy    Insulin1.5–2.5No dose limit, inexpensive, improved lipid profileInjections, monitoring, hypoglycemia, weight gain    Sulfonylureas1.5InexpensiveWeight gain, hypoglycemia*    TZDs0.5–1.4Improved lipid profileFluid retention, weight gain, expensiveOther drugs     -Glucosidase inhibitors0.5–0.8Weight neutralFrequent GI side effects, three times/day dosing, expensive    Exenatide0.5–1.0Weight lossInjections, frequent GI side effects, expensive, little experience    Glinides1–1.5 Short durationThree times/day dosing, expensive    Pramlintide0.5–1.0Weight lossInjections, three times/day dosing, frequent GI side effects, expensive, little experience * Severe hypoglycemia is relatively infrequent with sulfonylurea therapy. The longer-acting agents (e.g. chlorpropamide, glyburide [glibenclamide], and sustained-release glipizide) are more likely to cause hypoglycemia than glipizide, glimepiride, and gliclazide. Repaglinide is more effective at lowering A1C than nateglinide. GI, gastrointestinal. Sulfonylureas. Sulfonylureas lower glycemia by enhancing insulin secretion. They appear to have an effect similar to metformin, and they lower A1C by 1.5 percentage points (26). The major adverse side effect is hypoglycemia, but severe episodes, characterized by need for assistance, coma, or seizure, are infrequent. However, such episodes are more frequent in the elderly. Episodes can be both prolonged and life threatening, although these are very rare. Several of the newer sulfonylureas have a relatively lower risk for hypoglycemia (Table 1) (45,46). In addition, weight gain of 2 kg is common with the initiation of sulfonylurea therapy. This may have an adverse impact on CVD risk, although it has not been established. Finally, sulfonylurea therapy was implicated as a potential cause of increased CVD mortality in the University Group Diabetes Program (47). Concerns raised by the University Group Diabetes Program study that sulfonylurea therapy may increase CVD mortality in type 2 diabetes were not substantiated by the UKPDS (6). Alpha-glucosidase inhibitor Intestine Decrease gastrointestinal absorption of glucose DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999; 131; Felig 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: Saltiel AR: Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes. 1996;45:

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

102 Diabetes Mellitus in the Pediatric Population
Acute Complications DKA

103 Decreased Glucose Utilization &
Islets of Langerhans b-cell destruction Insulin Deficiency Epi,Cortisol GH Decreased Glucose Utilization & Increased Production Stress Glucagon Muscle Liver Increased Protein Catabolism Adipocytes Increased Ketogenesis Gluconeogenesis, Glycogenolysis Increased Lipolysis Polyuria Volume Depletion Ketonuria Threshold 180 mg/dl Hyperglycemia Ketoacidosis HyperTG

104 DKA DKA Hyperglycemia (BG >11 mmol/L = 200 mg/dL) Venous pH <7.3
Bicarbonate <15 mmol/L Ketonemia and ketonuria HbA1c CBC an ↑ WBC count in response to stress is characteristic of DKA and is not indicative of infection DKA

105 DKA The 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 The 3 most useful signs for assessing dehydration in young children and predicting at least 5% dehydration and acidosis are: s prolonged capillary refill time (normal capillary refill is 1.5–2 s) s abnormal skin turgor (tenting’ or inelastic skin) s abnormal respiratory pattern (hyperpnea) Other useful signs in assessing degree of dehydration include dry mucus membranes, sunken eyes, absent tears, weak pulses, and cool extremities.

106 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 Correct dehydration Correct acidosis and reverse ketosis Restore blood glucose to near normal Avoid complications of therapy Identify and treat any precipitating event

107 DKA Shock ↓ consciousness Dehydration >5%, acidotic, not in shock
Mild dehydration, Tolerating oral fluid total body deficit of K

108 DKA Hourly blood glucose monitoring Hourly fluid input & output
Neurological status at least hourly Repeat electrolytes after start of IV Monitor ECG for T-wave changes

109 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.

110 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

111 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 Management Give mannitol g/kg Restrict IV fluids by one-third Call senior staff Move to ICU Consider cranial imaging only after patient stabilised Warning signs and symptoms of cerebral edema include: Headache & slowing of heart rate Change in neurological status (restlessness, irritability, increased drowsiness, incontinence) Specific neurological signs (e.g., cranial nerve palsies) Rising blood pressure Decreased O2 saturation

112 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

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

114 Management of complications: Hypoglycemia
Immediate source of glucose Juice Milk Glucagon Dextrose infusion

115 Diabetes Mellitus in the Pediatric Population
SUMMARY Diagnosis Types and Pathophysiology Clinical Presentation Management Acute complication DKA Hypoglycemia Diagnose diabetes mellitus in the children and adolescents Provide diabetes care of children and diabetes Manage acute complications (I) – diabetic ketoacidosisManage acute complications (II) – hypoglycemia “ The incidence of Type 1 diabetes in children age 0-14 years old in our country in 1998 is 0.41/100,000 population “ Prevalence of Type 1 DM in Childhood And Adolescent in Metro Manila, Philippines; Diabetes Watch; July-December 2000


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