1. Type 1 Diabetes Mellitus: Update on Diagnosis and Management in Children and Adolescents Mark Daniels, MD CHOC/PSF Pediatric Endocrinology February 18, 2009

3. Topics of Discussion The Diagnosis of Diabetes Mellitus Typing Diabetes Mellitus Areas of Research Novel Technological Tools Novel Supplemental Therapies Departures from the Scene

4. Diabetes is out there!!! Approximately one in 300-400 children under the age of 18 has type 1 DM. ~1 million Americans have type 1 DM Over 30 million annual physician visits for DM related services Up to 5% of PICU admissions are for DKA

5. Where Does Insulin Come From?

6. Quiz What is the Latin Root for the word Pancreas? Pan = All Creas= Meat

7. Is it Diabetes? Criteria for the diagnosis of diabetes 1.Fasting Plasma Glucose >= 126 mg/dl OR 2. Symptoms of hyperglycemia and a Casual Plasma Glucose >= 200 mg/dl (Casual is defined as any time of day regardless of last meal.) OR 3. 2-hour plasma glucose >= 200 mg/dl during an OGTT. Test is done using a glucose load containing 75 g anhydrous glucose dissolved in water.* *In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing on a different day Modified from Diabetes Care 32:S62-S67, 2009

8. Could it be “pre-diabetes FASTING CRITERIA: FPG <100 mg/dl = normal fasting glucose; FPG 100–125 mg/dl = IFG (impaired fasting glucose); OGTT CRITERIA: 2-hour postload glucose <140 mg/dl = normal glucose tolerance; 2-hour postload glucose 140–199 mg/dl = IGT (impaired glucose tolerance) Modified from Diabetes Care 32:S62-S67, 2009

9. What Type Is It? “…for the clinician and patient, it is less important to label the particular type of diabetes than it is to understand the pathogenesis of the hyperglycemia and to treat it effectively.” Diabetes Care 32:S62-S67, 2009

10. Type 1? Type 2? Or Something Else? Type 1 Type 2 Genetic-Monogenic Mitochondrial Medication-induced Pancreatic Destruction/Disease –CF –Pancreatitis

11. Type 1 DM Previously known as Juvenile-Onset, or Insulin Dependent Diabetes Mellitus Rapid progression –weeks to months Absolute need for insulin Autoimmunity in 90% (GAD65, ICA, IAA) May present in Diabetic Ketoacidosis Obesity is NOT protective Usually childhood, but ANY age

13. What causes Type 1 DM? It is likely an “Autoimmune” attack on the Beta cells of the pancreas –Both Genetic and Environmental factors –50% concordance in twins –Up to 6% of sibs, and 5% of children of people with DM will also develop diabetes –Environmental trigger---Virus?

14. Type 2 DM Previously known as Adult Onset and Non-insulin dependent DM Usually associated with Obesity Antibodies negative (usually) Insulin and C-Peptide may be inappropriately normal or elevated May be treatable with oral medications, or may require insulin therapy from outset

15. Screening for Type 2 DM Test children 10 years and over who are overweight (BMI >85th percentile for age and sex, weight for height >85th percentile, or weight >120% of ideal for height) and have any TWO of the following risk factors: Family history of type 2 diabetes in first- or second-degree relative Race/ethnicity of Native American, African American, Latino, Asian American, or Pacific Islander Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight) Maternal history of DM or Gestational DM during the child's gestation Testing can be repeated every 3 years. FPG is the preferred test

16. Other Types of Diabetes Genetic Diabetes –MODY 9 defined types presenting after 1 year of life and usually before age 25 Antibody negative Insulinopenia May be treatable with oral medications –Neonatal Diabetes (KCNJ11, IPF1, GCK) Presents in first 6 months, often with DKA May be Transient (18 months) or Permanent May be treatable with oral medications

17. Not type 1, Not type 2

19. Baby Ethan OC Register July 11, 2008 Author: Tom Graves Photos: Jebb Harris

20. What a difference a pill makes...

21. Quiz Who was the first recipient of Injected Insulin?

22. TIME BETA CELL MASS DIABETES “PRE”- DIABETES GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY Natural History of Type 1 Diabetes

23. Beta-Cell Destruction

24. Areas of Research

25. TIME BETA CELL MASS DIABETES “PRE”- DIABETES GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY Prevention:Nutritional Intervention to Prevent (NIP) Type 1 Diabetes CLINICALONSET Intervention Studies – MMF - Abate Natural History of Type 1 Diabetes Prevention: Oral Insulin Trial RESCUE- Transplant TEDDY T1DGC

26. TrialNet is an international network of Diabetes centers that is dedicated to the study, prevention, and early treatment of type 1 diabetes.

27. Natural History Screen 100,000 relatives of people with type 1 Diabetes Mellitus with 2 goals: 1 – Understand the blood markers (antibodies) and risk factors that predict who will progress to Diabetes Mellitus, and 2 – Identify subjects who may be eligible for prevention/early intervention studies

28. NIP Nearlyborns and Newborns who have a family member with Type 1 Diabetes Mellitus are eligible Offered a common Dietary Supplement, DHA (an Omega-3 fatty acid) in hopes of “resetting” the immune system and preventing self-attack

29. Oral Insulin Previous Study (DPT-1) suggested that diabetes could be delayed or prevented in certain high risk individuals with an Insulin Pill This study will look at this group specifically. Insulin pill does not lower blood glucose, but may change immune system attack

30. Diabetes Vaccinations Under Investigation Diamyd –GAD 65 injection –Leads to tolerance/immunomodulation BCG (bacille Calmette-Guerin) –Induces Tumor Necrosis Factor (TNF) –TNF selectively destroys Autoreactive T-cells, decreasing the autoimmune attack

32. Islet Transplants - Edmonton

33. In its 2006 annual report, the Collaborative Islet Transplant Registry –225 patients received islet transplants between 1999 and 2005. –approx two-thirds of recipients achieved “insulin independence”—defined as being able to stop insulin injections for at least 14 days. At 2-year follow-up, about one-third of recipients were still insulin free.

34. Islet Transplants – Side Effects Mouth sores Stomach upset/Diarrhea. Increased blood cholesterol levels, hypertension, anemia, fatigue, decreased white blood cell counts, decreased kidney function, and increased susceptibility to bacterial and viral infections. Increased risk of tumors and cancer.

36. The Brazil Experience The researchers enrolled 15 patients aged 14 to 31 (mean 19.2) between November 2003 and July 2006. All patients had been diagnosed with type 1 diabetes mellitus within the prior six weeks. All patients were first given an immune ablative conditioning regimen (Cyclophosphamide and Antithymocyte globulin)

37. Results from Brazil At time of publication (2007), 13 of 14 patients were off insulin, at a mean of 16 months (range 1 -35 months) 1 patient went back on insulin at ~ 1 year.

38. The Brazil Experience Concerns Cyclophosphamide – toxic to gonads 1 patient had Bilateral pneumonia – resolved –Could there be worse side effects –worth it? Not placebo controlled –Good honeymoon? Final Results REMAIN TO BE SEEN

39. Quiz 3 What is the Root meaning of Diabetes Mellitus? Diabetes = Siphon Mellitus = Honey-Like

40. Natural History of Type 1 Diabetes

41. New and Old Insulins X X

42. Quiz 4 What is the Root meaning of the word Insulin? From Insula or Island

43. Pumps

44. Features of Pumps Continuous insulin infusion at variable rates (Basal) On-board calculators for determining insulin bolus dose for correction of hyperglycemia and coverage of carbohydrate intake Integration with Glucose meter and/or Continuous Sensor Allows for flexibility compared to injections

45. Meters and Downloads

46. Sensors/CGMS Embedded in Pump –Medtronic Stand Alone –Medtronic Guardian RT –DexCom –FreeStyle Navigator

49. Glucose Trend DexCom

51. Caveats of Sensor Use It only works if you wear it!!! Overreacting is as dangerous as underreacting Data Fatigue is common It is NOT a replacement for testing Sleep deprivation is a problem We are seeing things we didn’t want to know about.

52. Quiz 6 Exenatide (Byetta) was modeled after a digestive enzyme from what animal? The Gila Monster

53. Pramlintide (Symlin) Amylin is a naturally occurring hormone substance made in the pancreas. It works in three areas: –Controls hunger/satiety in the brain –Slows the transit of food in the stomach –Decreases release of glucose from the liver

54. Pramlintide (Symlin)

55. Pramlintide

56. Quiz 5 After Insulin was discovered by Banting and Best, for how much was the patent sold? $1

57. Complications and Monitoring Associated Autoimmunity –Annual TSH levels (consider Thyroid Ab’s) –Celiac Sprue Screen at Dx, then as needed –Addison’s Screening as needed Blood Pressure – each visit Kidney Effects –Urine Microalbumin for children over 10 and 5 years post-Dx, then annually. Ophthalmology –Dilated Exam at 5 years post-Dx, then annually Lipids –Initial screen, then every 5 years

58. Departures Exubera Inhaled Insulin Glucowatch Pork Insulin Lente and Ultralente Human Insulin

59. Summary The Diagnostic Criteria for Diabetes Mellitus and Pre-Diabetes Monogenic Diabetes New Research Areas and Advances Meter, Pump and Sensor Technologies Monitoring of Complications Novel Non-insulin supplemental medications to improve glycemic control

60. It’s All About the Kids Courtesy PADRE

61. Resources for Practioners and Families www.t1diabetes.nih.gov www.diabetestrialnet.gov www.childrenwithdiabetes.com www.jdrf.org www.diabetes.org