1. دکتر رحیم وکیلی استاد غدد ومتابولیسم کودکان دانشگاه علوم پزشکی مشهد INSULIN THERAY IN TYPE 1 DIABETES

2. Goals of management Manage symptoms Manage symptoms Prevent acute and late complications Prevent acute and late complications Improve quality of life Improve quality of life Avoid premature diabetes-associated death Avoid premature diabetes-associated death An individualised approach An individualised approach Management Glycaemic control BP Lipids Patient education Lifestyle (e.g. diet & exercise) Foot care Eye care Microalbuminuria & kidneys

3. Diabetes Management Principles An effective insulin regimen An effective insulin regimen Monitoring of glucose Monitoring of glucose As flexible with food and activity as possible As flexible with food and activity as possible Must remember Must remember Young children need routine and rules Young children need routine and rules Young children need to develop autonomy Young children need to develop autonomy Young children need to explore and experience Young children need to explore and experience Young children need to begin to make decisions Young children need to begin to make decisions

4. Question What are the glycemic targets for young children?

5. Glycemic Targets Glucose values are plasma (mg/mL) AgePre-Meal BGHS/Night BGHbA1c 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% Diabetes Care 28:186-212, 2005

6. *Levels recommended for adults shown in square brackets; † AM fasting or pre-prandial; DCCT=Diabetes Control and Complications Trial SMBG=self-monitored blood glucose; BG=blood glucose; PPBG=post-prandial blood glucose Parameter Ideal (non-diabetic)OptimalSuboptimal High risk (action required) HbA 1c (%) (DCCT stand.) <6.0<7.5 [<7.0]* 7.5–9.0>9.0 SMBG values, mmol/L † 3.6–5.65.0–8.0 [5.0–7.2]* >8.0>9.0 BG, mmol/L PPBG4.5–7.05–10 [<10.0]* 10–14>14 Bedtime BG4.0–5.66.7–10.0<6.7 or 10–11 11.0 Nocturnal BG3.6–5.64.5–9.0 9.0 11.0 ISPAD guidelines: Target indicators of glycaemic control for children & adolescents Rewers M, et al. Pediatr Diabetes 2007;8:408–18.

7. Question Can Intensive Management Be Done Safely in Young Children?

8. Owens DR, et al. Lancet 2001;358:739−46. The ideal insulin therapy should mimic endogenous insulin secretion Insulin (U/l) 0.08 0.04 0 Glucose homeostasis 08.0013.0019.0016.00 Time (hours) Plasma glucose (mmol/L) 8642086420 Plasma glucose profilesEndogenous insulin secretion

9. Insulin management Fixed dose regimens: Fixed dose regimens: requires scheduled meals and snacks and is not flexible enough for most young children requires scheduled meals and snacks and is not flexible enough for most young children Basal: bolus regimens: Basal: bolus regimens: MDI MDI useful only if child is willing to take frequent injections useful only if child is willing to take frequent injections Insulin pumps Insulin pumps child must be willing to wear the pump child must be willing to wear the pump

10. Insulin Terminology Basal insulin Basal insulin Long-acting, all Type 1 and most Type 2 DM patients should have basal insulin whether they are eating or not (insulin glargine, insulin detemir, or NPH) Long-acting, all Type 1 and most Type 2 DM patients should have basal insulin whether they are eating or not (insulin glargine, insulin detemir, or NPH) Nutritional or pre-meal / prandial insulin Nutritional or pre-meal / prandial insulin Short-acting insulin given with meals in anticipation of carbohydrate load glycemic spike (scheduled insulin aspart, insulin lispro, insulin glulisine, regular insulin) Short-acting insulin given with meals in anticipation of carbohydrate load glycemic spike (scheduled insulin aspart, insulin lispro, insulin glulisine, regular insulin) Correction or supplemental insulin Correction or supplemental insulin Short-acting insulin given to cover high glucose; if substantial use, it should drive adjustment of basal and nutritional insulins Short-acting insulin given to cover high glucose; if substantial use, it should drive adjustment of basal and nutritional insulins

11. Approximate pharmacokinetic profiles of human insulin and insulin analogues Hirsch IB. N Engl J Med 2005; 352: 174-83 N.B. Duration of action will vary widely between and within people NPH = neutal protamine hagedorn/isophane insulin

12. Rationale for basal-bolus therapy Basal-bolus should be the regimen of choice for maintaining overall glycaemic control 1 Basal-bolus should be the regimen of choice for maintaining overall glycaemic control 1 An ideal basal insulin An ideal basal insulin Peakless profile, prolonged duration of action Peakless profile, prolonged duration of action Flexible dosing Flexible dosing Suppresses hepatic glucose production between meals and overnight 1 Suppresses hepatic glucose production between meals and overnight 1 An ideal bolus insulin (a bolus with every meal) An ideal bolus insulin (a bolus with every meal) Rapid onset and short duration of action Rapid onset and short duration of action Limits postmeal hyperglycaemia 1 Limits postmeal hyperglycaemia 1 Prevents post-prandial hypoglycaemia 2 Prevents post-prandial hypoglycaemia 2 1. Rosenstock J. Clin Cornerstone 2001;4:50–64. 2. Dave JA, Delport SV. S Afr Family Practice 2006;48:30–6.

13. Commonly used insulin regimens Basal-bolus insulin regimens Basal-bolus insulin regimens 1 long-acting basal + mealtime insulin injections or 2 intermediate-acting basal + mealtime insulin injections 1,2 1 long-acting basal + mealtime insulin injections or 2 intermediate-acting basal + mealtime insulin injections 1,2 Pre-mixed insulin regimens Pre-mixed insulin regimens 2 or more pre-mixed insulin injections 2 2 or more pre-mixed insulin injections 2 Continuous subcutaneous insulin infusion (CSII) Continuous subcutaneous insulin infusion (CSII) Continuous (rapid-acting) insulin infusion to meet basal insulin needs + 3 or more mealtime doses 2 Continuous (rapid-acting) insulin infusion to meet basal insulin needs + 3 or more mealtime doses 2 1. DeWitt DE, Hirsch IB. JAMA 2003;289:2254–64. 2. Rosenstock J. Clin Cornerstone 2001;4:50–64.

14. Action profile of different basal insulins Lepore M, et al. Diabetes 2000;49:2142−8. Glucose infusion rate (mg/kg/min) 0 2 4 Time (hours) 1 3 Ultralente CSII Insulin lispro NPH Insulin glargine Peak 4–6 hours Rates of glucose infusion needed to maintain plasma glucose at 130 mg/dL (7.2 mmol/L) after s.c. injection in patients with T1DM (n=20) 0 4 8 20 16 12 24 Flat action profile lasting for 24 hours s.c. injection 0.3 IU/kg or CSII 0.3 IU/kg/24h

15. Activity profiles of glargine and detemir diverge after 12 hours in T1DM patients Bock G, et al. Diabetologia 2008;51(Suppl. 1):S390. Detemir Glargine 300510152025 Time (h) 0 2 4 6 8 10 12 BG (mmol/L) 0 0.4 0.8 1.2 1.6 2.0 GIR (mg/kg/min) 051015202530 BG (steady state)GIR (steady state) Time (h) GIR = glucose infusion rate Activity profile of insulin glargine allows once-daily dosing, whereas most patients require twice-daily dosing with detemir – particularly T1DM patients

16. Type 1 Diabetes: Serum Insulin Concentrations Following Subcutaneous Injection of Insulin Lispro or Human Regular Time (minutes) Serum Insulin Conc. (ng/mL) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Insulin Lispro (n=10) Human Regular (n=10) 0.2 mU/min/kg insulin infusion -600 Meal 60120180240300360420480 Heinemann et al. Diabetic Medicine,13:625-629, 1996 Injection Mean + SE

17. Rapid-acting insulin analogues reduce risk of PP hyperglycaemia and late hypoglycaemia Normal post-prandial values Insulin lispro, insulin aspart, or insulin glulisine Lower risk of late post-prandial hypoglycaemia Plasma-free insulin (µU/mL) Time after insulin injection or meal ingestion (hours) Regular human insulin (RHI) 80 60 40 20 0 Meal 024681012 Subcutaneous insulin Better PPBG control PPBG=post-prandial blood glucose Bolli GB. Av Diabetol 2007;23:326–32.

18. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Glargine or Detemir Plasma insulin Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs LisproLisproLispro Glulysene Glulysine Glulysine AspartAspartAspart

19. Owens DR, et al. Lancet 2001;358:739−46. The ideal insulin therapy should mimic endogenous insulin secretion Insulin (U/l) 0.08 0.04 0 Glucose homeostasis 08.0013.0019.0016.00 Time (hours) Plasma glucose (mmol/L) 8642086420 Plasma glucose profilesEndogenous insulin secretion

20. Effectiveness of Postprandial Humalog in Toddlers Rutledge, Chase, Klingensmith et al Pediatrics 100:968,97 Determine if postprandial rapid-acting insulin effective Determine if postprandial rapid-acting insulin effective Subjects < 5 years old Subjects < 5 years old Results: 2-hour glucose excursions lower with postprandial Humalog compared to preprandial regular Results: 2-hour glucose excursions lower with postprandial Humalog compared to preprandial regular Similar to preprandial Humalog Similar to preprandial Humalog

21. Outcomes of Pump Therapy Kaufman, et al, Diabetes Metabolism and Reviews,2000 6 month data 130 subjects PREPOSTP value HbA1c % 8.4 + 1.87.8 + 1.20.01 BMI22.8 + 423.2 + 5NS Hypo- glycemia events/pt/y 0.060.030.05 DKA events/pt/y 0.150.090.05

22. Results of Insulin Pump Therapy In Young Children Kaufman, et al, Diabetes Spectrum, 2001 PrePostP Value HbA1c8.5+1.87.4+1.10.01 Mean BG157+ 6492 + 310.03 Hypo-glycemia 0.180.09ND Quality of Life Family Cohesion 82 + 690 + 50.009

23. Question Why About the Risk of Hypoglycemia From Intensive Regimens?

24. Adverse Events in Intensively Treated Children and Adolescents with Type 1 Nordfeldt, Ludvigsson Acta Pediatr 88:1184,99 139 Subjects, ages 1-18 yrs on MDI 139 Subjects, ages 1-18 yrs on MDI Mean HbA1c 6.9% Mean HbA1c 6.9% Severe Hypoglycemia - 0.17 events/pt/yr Severe Hypoglycemia - 0.17 events/pt/yr Decreased from 1-2 injections Decreased from 1-2 injections Correlated with previous severe hypoglycemia r=.38,p<0.0001 Correlated with previous severe hypoglycemia r=.38,p<0.0001 DKA rate 0.015 events/pt/yr DKA rate 0.015 events/pt/yr MDI effective and safe MDI effective and safe

25. Conclusion Ultimate Goals Of Diabetes Treatment Sustained Normal Blood Glucose Control Lowest Possible Incidence of Hypoglycemia No Long-Term Diabetes Complications No Acute Diabetes Complications = = Best Quality of Life with Diabetes For the child and your family

26. Summary Basal-bolus therapy is the treatment of choice Basal-bolus therapy is the treatment of choice Separate FBG and PPBG control Separate FBG and PPBG control Flexible dosing and timing of injections Flexible dosing and timing of injections Insulin glargine and insulin glulisine are an effective combination for basal-bolus therapy Insulin glargine and insulin glulisine are an effective combination for basal-bolus therapy Glargine: peakless 24 hour coverage Glargine: peakless 24 hour coverage Glulisine: fast onset of action and effective PPBG control Glulisine: fast onset of action and effective PPBG control As effective in children and adolescents as adults As effective in children and adolescents as adults Adding glulisine to basal insulin provided more effective glycaemic control than adding lispro in children and adolescents T1DM patients Adding glulisine to basal insulin provided more effective glycaemic control than adding lispro in children and adolescents T1DM patients Particularly in adolescents aged 13–17 years Particularly in adolescents aged 13–17 years The particularities of adolescents need to be considered when treating T1DM The particularities of adolescents need to be considered when treating T1DM