1. Diabetes in Young Women Francine R. Kaufman, M.D. Professor of Pediatrics The Keck School of Medicine of USC Head, Center for Diabetes and Endocrinology Childrens Hospital Los Angeles

2. Life Goes on …. Diabetes does not have to stop you Diabetes does not have to stop you That can only happen if you face your diabetes That can only happen if you face your diabetes 24/7 24/7 Just do it Just do it If people react negatively If people react negatively They are uninformed – you need to educate them They are uninformed – you need to educate them If they cannot be enlightened – you dont need them If they cannot be enlightened – you dont need them Make it a positive – or at least a neutral Make it a positive – or at least a neutral

3. Points of Discussion Practical Strategies for Managing Diabetes Practical Strategies for Managing Diabetes Leaving Home – Taking Risks Leaving Home – Taking Risks Colleges Life and Employment Colleges Life and Employment Dating - Marriage Dating - Marriage Pregnancy Pregnancy Avoiding Complications Avoiding Complications

4. Question What are the Targets?

5. Glycemic Targets Glucose values are plasma (mg/mL) Age Pre-Meal BG HS/Night BG HbA1c Toddler (0-5 yrs) 100-180110-200 7.5 & 8.5% School-age (6-11 yrs) 90-180100-180<8% Adolescent (12-19 yrs) 90-13090-150<7.5% Adults <7%

6. HbA1c Statistics for CHLA 2003 Type 1: Diabetes > 1 year, followed > 1 year Enrolled in Long-term study – total n 1800 n Average ± SD All patients 1181 8.2 ± 1.6 Males579 Females602 < 5 51 7.8 ± 1.3 5-10 5-10355 7.9 ± 1.3 11-16 11-16489 8.4 ± 1.8 17-19>20157127 8.3 ± 1.5 7.4 + 1.3

7. Question Strategies for Diabetes Management?

8. Managing Diabetes In DCCT, intensively treated adolescents (13-17 yrs of age) manifested a greater absolute rate of severe hypoglycemia and higher mean HbA1 c levels. In DCCT, intensively treated adolescents (13-17 yrs of age) manifested a greater absolute rate of severe hypoglycemia and higher mean HbA1 c levels. Why? Why? Adolescents are faced with rapid physiological and psychological modifications with the onset of puberty which may destabilize glycemic control. Adolescents are faced with rapid physiological and psychological modifications with the onset of puberty which may destabilize glycemic control.

9. DCCT Results: Comparison of Adults Versus Adolescents Adults Adolescents Intensive Therapy Intensive Therapy Glycemia Mean BG (mg/dL) 155 ± 30 171 ± 31 HbA1c (%)7.12 ± 0.03 8.06 ± 0.03 Change in HbA1c1.7 ± 0.1 1.7 ± 0.2 Risk Reduction Retinopathy 63% 61% Microalbuminuria 54% 35% Hypoglycemia Episodes/100 pt-yrs 61.2 85.7 Relative Risk 3.3 2.8

10. Insulin management Fixed dose regimens: Fixed dose regimens: requires scheduled meals and snacks and is not flexible enough for most lifestyles requires scheduled meals and snacks and is not flexible enough for most lifestyles Basal: bolus regimens: Basal: bolus regimens: Long-acting relatively peak free analogue with pre- food injection of rapid acting analogue useful only if child is willing to take frequent injections Long-acting relatively peak free analogue with pre- food injection of rapid acting analogue useful only if child is willing to take frequent injections Insulin pumps being increasingly used in all age groups but child must be willing to wear the device Insulin pumps being increasingly used in all age groups but child must be willing to wear the device

11. Relationship Between Number of Blood Glucose Determinations and A1C 0 1 2 3 4 5 6 7 8 >10/day8-10/day6-8/day4-6/day<4/day <5% 5%-6% 6%-7% 7%-8% >8% Number of Blood Glucose Levels per Day A1C (%)

12. Question Does Good Diabetes Control Interfere with My Life?

13. Metabolic Control and Quality of Life The study involved 20 centres in 17 countries in Europe, Japan and North America. The study involved 20 centres in 17 countries in Europe, Japan and North America. Adolescents aged 10-18 yrs at each study centre were invited to participate. Adolescents aged 10-18 yrs at each study centre were invited to participate. 2,101 adolescents were enrolled. 2,101 adolescents were enrolled. Samples and information from 79% of all patients registered at the centres were obtained. Samples and information from 79% of all patients registered at the centres were obtained.

14. Daily insulin regimen 1 injection 2 injections 3 injections 4 or more injections Premixed insulin, n (%) Insulin dose (U/kg/day) Boys (n=1085) 8 472 295 307 445 (41) 0.94 ± 0.32 Girls (n=1016) 10 380 287 339 407 (40) 1.01 ± 0.32 Results as means ± SD # Adjusted for center, age and duration of diabetes. P-value <0.05 0.66 <0.0001# Patient characteristics on insulin management

15. Worries about diabetes in adolescents by age, gender and HbA 1C

16. Metabolic Control and Quality of Life Key messages Key messages First large international study evaluating the relationship between metabolic control and QOL in 2,101 adolescents with diabetes First large international study evaluating the relationship between metabolic control and QOL in 2,101 adolescents with diabetes Lower HbA 1c associated with better QOL of adolescents and lesser perceived family burden Lower HbA 1c associated with better QOL of adolescents and lesser perceived family burden

17. Question Leaving Home? Taking Risks

18. Adolescent Issues Desire for peer acceptance Desire for peer acceptance Rebellion against authority Rebellion against authority Expectations of increasing responsibilities outside of home Expectations of increasing responsibilities outside of home

19. Taking Risks Alcohol Alcohol Drugs Drugs Driving Driving Hiding diabetes – impacts on it all Hiding diabetes – impacts on it all

20. Question College Life

21. Fun Fun Food Food Friends Friends Fraternity Fraternity Focus Focus

22. Keeping in Touch Stay with health care provider who knows you versus changing at college or before you go Stay with health care provider who knows you versus changing at college or before you go Email program Email program Less frequent visits Less frequent visits Stressors and stress reduction Stressors and stress reduction

23. Question Dating and Marriage

24. Dating When to tell about diabetes When to tell about diabetes What to tell What to tell Where to find information Where to find information How do you handle different responses How do you handle different responses MARRIAGE MARRIAGE

25. Question Pregnancy

27. Prevalence of Diabetes in Pregnancy in the United States of America More than 135,000 GDM + 200,000 T2DM + More than 135,000 GDM + 200,000 T2DM + 6,000 T1DM pregnancies annually 6,000 T1DM pregnancies annually Diabetes 8% Non-diabetes 92% American Diabetes Association. Diabetes Care. 1998;21(Suppl. 2).

28. Glucos e Glucos e Insulin MotherFetus Placenta Fetal Hyperglycemia Fetal Hyperinsulinemia Stimulates fetal pancreas

29. Data At CHLA 225 Teens at Risk 5-6 pregnancies / year 5-6 pregnancies / year >50% interrupted or SAB >50% interrupted or SAB 2-3 Live Births / year 2-3 Live Births / year 1/3 Require Prolonged Hospitalization 1/3 Require Prolonged Hospitalization Last 3 years – no anomalies Last 3 years – no anomalies Overall increased rate of anomalies 6-12% compared to 2-3% - a 2-5 fold increase But this can be modified by pre-conception planning and meticulous diabetes control

30. Question How To Avoid Complications

31. DCCT Results: Comparison of Adults Versus Adolescents Adults Adolescents Intensive Therapy Intensive Therapy Glycemia Mean BG (mg/dL) 155 ± 30 171 ± 31 HbA1c (%)7.12 ± 0.038.06 ± 0.03 Change in HbA1c1.7 ± 0.11.7 ± 0.2 Risk Reduction Retinopathy 63% 61% Microalbuminuria 54% 35% Hypoglycemia Episodes/100 pt-yrs 61.2 85.7 Relative Risk 3.3 2.8

32. RELATIVE RISK HbA 1c Relative Risk of Progression of Diabetic Complications by Mean HbA1c Based on DCCT Data

33. *Not statistically significant due to small number of events. Showed statistical significance in subsequent epidemiologic analysis. DCCT Research Group. N Engl J Med. 1993;329:977-986; Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117; UKPDS 33: Lancet. 1998;352: 837-853; Stratton IM, et al. Brit Med J. 2000;321:405-412. Intensive Therapy for Diabetes: Reduction in Incidence of Complications T1DMDCCTT2DMKumamotoT2DMUKPDS A1C 9% 7% 8% 7% Retinopathy63%69% 17%–21% Nephropathy54%70% 24%–33% Neuropathy60%58%– Cardiovascular disease 41%*52* 16%* 16%* T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

34. Recommendations For Treatment Of Retinopathy Annual screening should be done when the child is 10 years old and has diabetes for 3-5 years Annual screening should be done when the child is 10 years old and has diabetes for 3-5 yearsQuestions: Is this early enough for a child with poorly controlled diabetes for longer than 3-5 years? Is this early enough for a child with poorly controlled diabetes for longer than 3-5 years?

35. Recommendations For Microalbuminuria Testing Annual screening for urinary albumin should begin when Annual screening for urinary albumin should begin when Child is 10 yrs old Child is 10 yrs old DM of 5 years duration DM of 5 years duration If urine albumin: creat ratio on spot urine is abnormal (30-299 mg/gm creatinine) If urine albumin: creat ratio on spot urine is abnormal (30-299 mg/gm creatinine) Confirm with 2 additional urine specimens Confirm with 2 additional urine specimens Obtain up: down urine specimen to rule out orthostatic proteinuria Obtain up: down urine specimen to rule out orthostatic proteinuria

36. Recommendations For Microalbuminuria Treatment ACE Inhibitors may reverse microalbuminuria or delay rate of progression to macro-albuminuria ACE Inhibitors may reverse microalbuminuria or delay rate of progression to macro-albuminuria Treat BP aggressively Treat BP aggressively Questions: Questions: Should these children all be referred to a nephrologist for evaluation and treatment? Should these children all be referred to a nephrologist for evaluation and treatment? Should children with poorly controlled DM be evaluated sooner? Should children with poorly controlled DM be evaluated sooner? Should children with HTN be evaluated sooner? Should children with HTN be evaluated sooner?

37. BP Recommendations Repeat with child sitting and relaxed on 2 more occasions Repeat with child sitting and relaxed on 2 more occasions HTN defined as BP 95% for age, sex and height measured on at least 3 separate days HTN defined as BP 95% for age, sex and height measured on at least 3 separate days High normal BP is 90% but < 95% High normal BP is 90% but < 95% Rule out non-diabetes causes Rule out non-diabetes causes

38. BP: When to Treat High normal BP High normal BP Diet (limit salt) and exercise for 3-6 months Diet (limit salt) and exercise for 3-6 months If still high normal, treat with ACE inhibitor If still high normal, treat with ACE inhibitor Consider adding ARBs if 90% on maximal doses Consider adding ARBs if 90% on maximal doses Hypertension (confirmed) Hypertension (confirmed) Treat with ACEI to achieve BP< 90% Treat with ACEI to achieve BP< 90% Questions Remaining: At what age to treat? At what level to treat?

39. Children with diabetes have increased muscle thickness & stiffness Carotid artery intima media thickness is significantly increased in youth with diabetes compared to controls matched for age and gender Carotid artery intima media thickness is significantly increased in youth with diabetes compared to controls matched for age and gender -correlated with LDL-C levels -correlated with LDL-C levels Brachial artery reactivity is decreased in children with diabetes compared to matched controls Brachial artery reactivity is decreased in children with diabetes compared to matched controls Radial artery tonometry stiffer vessels in children with diabetes compared to BMI, age, sex matched controls Radial artery tonometry stiffer vessels in children with diabetes compared to BMI, age, sex matched controls

40. Cardiovascular Disease Risk Factors in Adolescents with Type 1 Diabetes Mellitus M.V. Karantza, S. Bababeygy, H.N. Hodis, W.J. Mack, C.-R. Liu, C.-H. Liu, and F.R. Kaufman and F.R. Kaufman Division of Endocrinology, Diabetes, and Metabolism, Childrens Hospital Los Angeles Supported by ADA Clinical Research Award 1-01-CR-06

41. Background Atherosclerosis is a Major Cause of Morbidity and Mortality in Patients with T1DM May be initiated early May be initiated early Accelerated by traditional CVD factors Accelerated by traditional CVD factors Hig blood pressure, dyslipidemia, cigarette smoking, obesity Hig blood pressure, dyslipidemia, cigarette smoking, obesity Inflammatory and prothrombotic factors Inflammatory and prothrombotic factors

42. Background Previous Investigations Atherosclerosis assessed by IMT measurement Atherosclerosis assessed by IMT measurement 142 subjects with T1DM 142 subjects with T1DM Mean age 16.0 ± 2.6 yr, mean T1DM duration 6.6 ± 7.9 yr Mean age 16.0 ± 2.6 yr, mean T1DM duration 6.6 ± 7.9 yr 87 matched healthy subjects 87 matched healthy subjects Results: Results: Adolescents with T1DM had increased atherosclerosis compared to controls Adolescents with T1DM had increased atherosclerosis compared to controls Risk factors for increased IMT included diabetic complications, and HDL and LDL/HDL ratio Risk factors for increased IMT included diabetic complications, and HDL and LDL/HDL ratio Krantz JS, et al, J Pediatr 2004;145: 452-457 Krantz JS, et al, J Pediatr 2004;145: 452-457

43. .5.55.6.65.7.75 IMT mm 68101214 HbA1c (%) P<0.05, r=0.34 IMT vs HbA1c

44. .4.5.6.7.8 No Tobacco Exposure Tobacco Exposure IMT and Tobacco Exposure in Males with T1DM IMT mm P=0.02 0.575 ±.048 0.624 ±.042

45. IMT vs Lipids in T1DM In males, IMT is significantly associated with Total Cholesterol (r=0.32, p<0.05) Total Cholesterol (r=0.32, p<0.05) Apolipoprotein B (r=0.41, p<0.05) Apolipoprotein B (r=0.41, p<0.05) In females, IMT is negatively correlated with HDL (r=-0.30, p<0.05 ) HDL (r=-0.30, p<0.05 )

46. The Continuum Of Vascular Damage in T1DM Conventional CVD risk factors result in increased IMT and probably cause the initial endothelial dysfunction in our cohort of youth with T1DM Conventional CVD risk factors result in increased IMT and probably cause the initial endothelial dysfunction in our cohort of youth with T1DM The subsequent loss of normal endothelial homeostatic properties leading to a proinflammatory, proadhesive, and procoagulant endothelial surface is not yet present in our cohort The subsequent loss of normal endothelial homeostatic properties leading to a proinflammatory, proadhesive, and procoagulant endothelial surface is not yet present in our cohort Early treatment of modifiable risk factors could avert the chronic inflammatory process which, if unabated, will result in the advanced atherosclerotic plaque formation Early treatment of modifiable risk factors could avert the chronic inflammatory process which, if unabated, will result in the advanced atherosclerotic plaque formation

47. Recommendations For Lipid Management When to test When to test Pre-pubertal children >2 years old should have Pre-pubertal children >2 years old should have Fasting lipids at diagnosis if there is positive FH of increased lipids or early cv event (<50 males, < 60 females) Fasting lipids at diagnosis if there is positive FH of increased lipids or early cv event (<50 males, < 60 females) If initial LDL-c < 100 mg/dl, repeat every 5 years If initial LDL-c < 100 mg/dl, repeat every 5 years If initial LDL-c > 100 mg/dl, begin therapeutic lifestyle change (TLC) If initial LDL-c > 100 mg/dl, begin therapeutic lifestyle change (TLC) Fasting lipids at puberty or at age 12 yrs if FH normal Fasting lipids at puberty or at age 12 yrs if FH normal Pubertal children or > 12 years old should have fasting lipid profile done at time of diagnosis after BG control established Pubertal children or > 12 years old should have fasting lipid profile done at time of diagnosis after BG control established

48. Recommendations For Lipid Management LDL-c > 100 mg/dl LDL-c > 100 mg/dl Step 2 diet (< 7% saturated fat, < 200 mg/d chol) Step 2 diet (< 7% saturated fat, < 200 mg/d chol) Exercise 60 minutes daily Exercise 60 minutes daily Intensify efforts to normalize BG Intensify efforts to normalize BG Repeat 3-6 months Repeat 3-6 months LDL-c >130 mg/dl & 160 mg/dl after 3-6 mos LDL-c >130 mg/dl & 160 mg/dl after 3-6 mos Consider treatment Consider treatment LDL-c > 160 mg/dl after 3-6 months LDL-c > 160 mg/dl after 3-6 months Treat Treat

49. Pittsburgh Epidemiology of Diabetes Complications Study 10 year follow up of patients with Type 1 diabetes diagnosed before age 17 10 year follow up of patients with Type 1 diabetes diagnosed before age 17 Showed that increased LDL is an independent factor of microvascular disease, macrovascular disease, and mortality Showed that increased LDL is an independent factor of microvascular disease, macrovascular disease, and mortality LDL 100-129 RR 5.3 LDL 130-159 RR 5.6 LDL >160 RR 12.1 (p 160 RR 12.1 (p<0.01 in all)

50. Unanswered Questions At what age should we begin medication to decrease lipids? At what age should we begin medication to decrease lipids? Should we wait until glycemic control is achieved before initiation of lipid lowering medications Should we wait until glycemic control is achieved before initiation of lipid lowering medications At what level of LDL-c should we treat? At what level of LDL-c should we treat? Should we be monitoring hsCRP? Should we be monitoring hsCRP? What drugs should we use? What drugs should we use?

51. Life Goes on …. Diabetes does not have to stop you Diabetes does not have to stop you That can only happen if you face your diabetes That can only happen if you face your diabetes 24/7 24/7 Just do it Just do it If people react negatively If people react negatively They are uninformed – you need to educate them They are uninformed – you need to educate them If they cannot be enlightened – you dont need them If they cannot be enlightened – you dont need them Make it a positive – or at least a neutral Make it a positive – or at least a neutral