Diabetes Mellitus - The Old and the New

1. Jacalyn Bishop, MD, FAAP 4/17/12 Diabetes Mellitus - The Old and the New

2. The Old • First century AD • Aretaeus coined the term “diabetes” – greek word for “siphon” “...For fluids do not remain in the body, but use the body only as a channel through which they may flow out.” “…For no essential part of the drink is absorbed by the body while great masses of the flesh are liquefied into urine.” Eugene J. Leopold, Aretaeus the Cappodacian

3. 17th century • Dr. Thomas Willis “sampled” urine to determine if a patient had diabetes. Sweet taste equaled diabetes mellitus (mellitus - latin word for ‘honey sweet’) • 17th – 20th century • Low calorie diets used for treatment “Despite physician’s valiant efforts to combat diabetes, their patients remained little more than human guinea pigs.” Melissa Sattley, The History of Diabetes. DiabetesHealth, Dec 17, 2008

4. Insulin is Discovered! • 1921 – Ontario Canada • Frederick Banting and his assistant Charles Best administer canine pancreas extract to a diabetic dog and keep it alive for 70 days. • 1923 • Frederick Banting and J.J. Macleod win the Nobel Prize for Medicine for their discovery of insulin.

5. J. L. Age 3 yrs. Weight 15 lbs, December 15, 1922. Courtesy of Eli Lilly and Company Archives." / "J. L. Weight 29 lbs, February 15, 1923. Courtesy of Eli Lilly and Company Archives

6. 1935 • Roger Hinsworth differentiates type 1 from type 2 diabetes • 1950 • Sulfonylureas developed for type 2 diabetics (Metformin not discovered until 1995). • 1960s • “Urine color wheels” to determine if glucose is in urine – today’s glucose strips • 1961 • Disposable syringe introduced (no more glass syringes or sharpening and boiling needles to sterilize them!)

7. 1969 • Ames Diagnostics releases the first portable glucose meter • 1979 • First insulin pump marketed • First Hba1c test devised

9. Diabetes According to the ADA • Normal fasting blood sugar: 60 – 100 mg/dL • Impaired Glucose Tolerance • Fasting: 101 - 126 mg/dL • OGTT: 2 hour 140 - 199 mg/dL • Hba1c: 5.7-6.4% • Diabetes • Fasting blood glucose >126 mg/dL on two occasions • Random blood glucose >200 mg/dL + symptoms of diabetes • Oral glucose tolerance test: 2hr post glutol blood sugar >200mg/dl • Hba1c: >6.5%

10. Hba1c Interpretation • A1C levels between 5.5% and 6.0% have a 5 year cumulative incidence of diabetes ranging from 12-25%. • A1C levels between 6.0 and 6.5% are at very high risk of developing diabetes • Incidence in this group is greater than 10 times that of people with lower levels. American Diabetes Association. Clinical Practice Recommendations 2012. Diabetes Care. January 2012; 35 (Supplement 1)

11. Diabetes Classification • Type 1 (IDDM) • Primary defect is failure of beta cells resulting in insulin deficiency • Type 2 (NIDDM) • Primary defect is resistance to insulin action and failure of beta cells to compensate – ‘relative’ insulin deficiency • MODY (maturity onset diabetes of youth) • Single gene defect (MODY 1- 6) • Autosomal dominant • Very rare – 70-110 per million • Idiopathic Diabetes • Insulin deficiency without presence of antibodies • Most commonly seen in patients of African or Asian ancestry • Ketoacidosis and Insulin requirement may come and go • Other forms associated with syndromes • Wolfram syndrome (DIDMOAD), Mitochondrial disease

12. Type 1 Diabetes • Still the most common cause of diabetes in children • Incidence increasing – Why? • Current US incidence around 1-2 per 10,000 per year • By 16 years of age, 1 in 330 will have diabetes • Peak incidence is early adolescence (but can occur at ANY age) • More common in Caucasian, less in Asian and African American • Type 1A = autoimmune • Type 1B = non autoimmune – pancreatic disease e.g. cystic fibrosis

14. Etiology of Autoimmune Diabetes • Genetic susceptibility • Lifetime risk in general population: 0.4% • Up to 50% concordance in monozygotic twins • Sibling risk: 5%, Father to child risk: 6-12%, Mother to child risk: 4% if <25 years at delivery and 1% if >25 years (Risk doubles if parent/sibling was younger than 11 at diagnosis.) • Associated with HLA DR3/DR4 genes • Environmental trigger • Incidence more common in fall and winter - viral infection trigger? • Possibly multiple potential triggers in early infancy: viruses, cows milk, toxins • Auto-antibodies: 1 or more present in 85-90% at diagnosis: • GAD 65, islet cell, insulin and tyrosine phosphatases (IA-2 & IA-2B) antibodies • GAD 65 (glutamic acid decarboxylase) most common: protein found in the beta cell which shares sequence homology with some viruses

16. Case Study • 12 year old girl, brought to her PCPs office. Complaining of heart racing and generally feeling unwell. Mother is concerned that she has started wetting the bed, having been dry at night since 4 years of age. • What pertinent questions do you want to ask the family? • Weight loss (amount, duration) • Energy level • Behavior changes • Appetite changes (early stages increased, then decreased) • Vomiting • Presence of fever or intercurrent viral illness • Vaginal yeast infection • Medications • Family history of diabetes and/or autoimmune disease

17. Case Study • 12 year old girl, brought to her PCPs office. Complaining of heart racing and generally feeling unwell. Mother is concerned that she has started wetting the bed, having been dry at night since 4 years of age. • What should you look for on your physical exam? • Physical exam often NORMAL in early type 1 diabetes • Presence of obesity and/or acanthosis nigricans • Presence, degree of dehydration • Ketone breath • Respiratory rate and effort (Kussmaul respirations?) • Infection (girls: candidal vulvovaginitis common) • Thyromegaly (coexisting autoimmune thyroiditis common)

18. Case Study • 12 year old girl, brought to her PCPs office. Complaining of heart racing and generally feeling unwell. Mother is concerned that she has started wetting the bed, having been dry at night since 4 years of age. • What laboratory tests do you want to order? • If patient is well with no signs/symptoms suggestive of ketoacidosis: • Capillary blood glucose, confirmed by serum glucose • Urinalysis for glucose and ketones • If patient is unwell, needs evaluation and prompt treatment of ketoacidosis: • Above PLUS • Serum electrolytes including bicarbonate • Venous pH • CBC

19. Case Study - Findings • 12 year old girl, brought to her PCPs office. Complaining of heart racing and generally feeling unwell. Mother is concerned that she has started wetting the bed, having been dry at night since 4 years of age. • History positive for 12 lbs. weight loss over past 4 months, despite a good appetite. Drinking a lot during the day and waking at night to drink. Also having trouble concentrating at school. A maternal grandmother developed diabetes at 73 years and does not require insulin. • Physical exam: height 25th percentile, weight 10th percentile. Well- looking girl with no acanthosis or thyromegaly, vital signs and respirations normal, no signs of dehydration • CBG 310, confirmed by serum blood glucose • Urinalysis: heavy glucosuria, ketones moderate • Diagnosis?

20. Case Study - Diagnosis TYPE 1 DIABETES, without ketoacidosis • Further investigations?

21. Case Study - Investigations • 12 year old girl, brought to her PCPs office. Complaining of heart racing and generally feeling unwell. Mother is concerned that she has started wetting the bed, having been dry at night since 4 years of age. • Diagnosis? • TYPE 1 DIABETES, without ketoacidosis • Further investigations? • HbA1c • Free T4 and TSH • Celiac screen (?) • (Insulin, C-peptide, autoantibodies only necessary when diagnostic uncertainty about type 1 vs. type 2 diabetes)

22. Management of Newly Diagnosed Diabetes • Admit child to hospital for education / insulin or, if patient stable, establish immediate follow-up care with pediatric endocrinologist as outpatient • Treat DKA if necessary • Establish insulin regimen – typically MDI • Education – diabetes educator and dietician • Typical education lasts 4-5 hours over 2 days if not in DKA

23. Goals of Management • Devise a schedule which allows minimum disruption to daily life of the child and family • Educate parents and caregivers • Balance the risk of long term complications 2° to chronic high blood sugars vs. the risk of severe hypoglycemia

24. Home Glucose Monitoring • Check blood sugars 4 times/day: before breakfast, lunch, dinner, and bedtime with occasional checks in the middle of the night • Goal = 80%-90% of the readings within the “ target range” • Parents or older teens review the values every 3-7 days and adjust insulin as necessary • Lipohypertrophy at shot sites may cause erratic blood sugars

25. HbA1c, How is it helpful in following patients with diabetes • Can’t be altered by the patient • Compliments home glucose monitoring, equivalent blood sugar equals HbA1C X 30 – 60. • Goals: • Type 1 <6 years 7.5-8.5% 6-12 years <8% 13-19 years <7.5% Adults < 7% • Type 2 : <7%

26. Factors Affecting Weight in Diabetes Weight gain Abnormal weight loss Too many lows Developing insulin resistance Poor control Celiac Disease Graves’ Disease Addison’s Disease Eating Disorders

27. Organ Specific Autoimmune Disorders Associated with Diabetes • Hypothyroidism • free T4 and TSH at diagnosis and every 1-2 years and if poor growth or other symptoms • Celiac disease • Tissue transglutaminase Ab (TTg Ab) with serum IgA if symptoms like diarrhea, FTT, slow growth, abdominal pain/bloating, unusually low insulin dose, distended abdomen, erratic blood sugars (many lows) • Addison’s disease • ACTH stimulation test if unusually low insulin dose, lots of hypoglycemia, poor growth, excessive tan, low energy

28. Type 2 Diabetes Who’s at risk???

30. Percentage of U.S. Children and Adolescents Who Were Overweight* 12.1% * >95th percentile for BMI by age and sex based on 2000 CDC BMI-for-age growth charts **Data are from 1963-65 for children 6-11 years of age and from 1966-70 for adolescents 12-17 years of age Source: National Center for Health Statistics

32. Boys vs. Girls

33. The Facts • Obesity in adolescents has increased by 18% over the last 30 years • There has been a 33% increase in prevalence of type 2 diabetes in childhood over the last 15 years • Type 2 diabetes now accounts for 20% of diabetes in children aged 10-19 years

35. Type 2 Diabetes • More common in non-whites (African American, Native American) • Remains unusual in preadolescent children (consider MODY, particularly if not obese) • Stronger (poly)genetic basis than type 1 • Almost 100% concordance in monozygotic twins • Often a positive family history of type 2 diabetes

36. Etiology & Diagnosis of Type 2 DM • Etiology: Long standing hyperinsulinemia with normal glucose levels, “insulin resistance” with eventual beta cell failure and decline in insulin levels leading to hyperglycemia. • Most typical presentation is mild hyperglycemia, with negative urine ketones. May be asymptomatic. • May need oral glucose tolerance test to diagnose • Ketoacidosis can occur (glucose toxicity to beta cell) - a more common presentation of type 2 diabetes in adolescence than in adulthood

38. Screening Guidelines • Criteria to begin screening Patient overweight or at risk for overweight plus Any 2 of the following: Family history of type 2 DM in 1st or 2nd degree relative Ethnicity: American Indian, black, Hispanic/Latino, Asian American, Pacific islander Signs of, or conditions associated with, insulin resistance American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care 2000;23:386

39. When and How to Screen • Screen every 2 years, starting at age 10 or at onset of puberty if this occurs 1st • Perform a fasting plasma glucose • Normal = less than 100mg/dL • Pre diabetes = 100-125mg/dL • Diabetes = >126mg/dL (repeat on subsequent day to confirm) American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care 2000;23:386

40. Initial Type 2 Diabetes Management • At diagnosis: Hba1c lipid profile (if normal, repeat every 3-5yrs) opthalmologic exam diabetes education psychosocial assessment nutrition therapy review goals of care and treatment plan

41. Treatment - After acute management • Insulin? • Diet and exercise (of course!) but only effective in 10% of youths • Next up – Metformin (Glucophage) • approved down to the age of 12 • takes 4 weeks to become effective • Start at low doses and increase gradually to avoid GI upset • Metformin XR in same doses causes less GI upset • Blood sugar checks 1-2x/day

42. Ongoing Diabetes Management (for all types!) • Quarterly: • Assess injection site – if applicable • Assess psychosocial adjustment, self-management skills, dietary needs and physical activity level • Discuss tobacco, drug and alcohol use • Measure a1c • Review blood glucose records • Annually: • Flu vaccine • Physical to address comorbidities including PCOS, fatty liver, foot lesions, etc… • Measure urine microalbumin/creatinine ratio (normal <30) • Ophthalmologic exam (if over 10 years and diabetes for more than 3 years

43. Now for the New… • 2009 • Medtronic released Paradigm Veo pump with low-glucose suspend feature. Awaiting US FDA approval… • Jan 2012 • FDA issued guidance for work toward approved artificial pancreas • Feb. 2012 • FDA approved MySentry Remote Glucose Monitor: glucose monitor that can be used in another room to monitor Medtronic sensor/pump data

45. More New Technology