1. Recovery of the β–cell function both in new and long-standing type 2 diabetic patients through long-term treatment with continuous subcutaneous insulin infusion Soo B Choi, Miae Kown, and Yun H noh Department of Internal Medicine and Biochemistry, School of Medicine, Konkuk University, Chungju 380-701, South Korea

2. Diabetes Progressive loss of capacity to maintain glucose homeostasis Treatment Goal –Previous concept To slow diabetic complications To slow the progressive loss of beta cell function –New concept With proper treatment The capacity can be restored or Even Cured Holman RR. Diabetes Res Clin Pract 1998,40 (Suppl),S21

3. Intensive insulin treatment in type 2 diabetes Early insulin: an important therapeutic strategy –Diabetes Care. 2005 Jan;28(1):220-1 Intensive insulin treatment in type 2 diabetes –Diabetes Technol Ther. 2005 Oct;7(5):818-22 Intensive insulin therapy prevents the progression of dia betic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomiz ed prospective 6-year study –Diabetes Res Clin Pract. 1995 May;28(2):103-17 Treating the spectrum of type 2 diabetes: emphasis on insulin pump therapy –Diabetes Educ. 2006 Jan-Feb;32(1 Suppl):39S-46S Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients –Diabetes Care. 2000 Apr;23 Suppl 2:B21-9

4. Induction of Long-term Normoglycemia in Type 2 DM by Intensive Insulin Therapy Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of beta-cell function –Li et al: Diabetes Care. 2004 Nov. Short-term intensive insulin therapy in newly diagnosed type 2 diabetes –Ryan et al: Diabetes Care. 2004 May. Induction of long-term normoglycemia without medication in Korean type 2 diabetes patients after continuous subcutaneous insulin infusion therapy. –Park S, Choi SB: Diabetes Metab Res Rev 2003 May After 2 weeks of CSII treatment FPG 13.6 ± 4.5 mM  6.3 ± 1.3 mM PPG 18.7 ± 6.1 mM  8.6 ± 2.3 mM HbA1c 10.1 ± 2.2 %  8.7 ± 1.9 % After CSII stop only exercise and diet therapy was applied Acute insulin response (AIR), Area under the curve of insulin during IV-GTT, HOMA -B was improved

5. Objectives Report –Cases of DM remission by Long-Term CSII Analyze –Duration of treatment until remission –Change in insulin requirement during CSII –Improvement of insulin resistance and β cell function after long-term CSII

6. Subjects Among the diabetic patients admitted to Diabetes Center at Konkuk University Hospital between 1996- 2005, Patients who achieved fasting and postprandial euglycemia with only diet and exercise therapy

7. Remission Maintenance of normoglycemia Without any pharmaceutical interventions For more than 2 months

8. Overview Sex Age Initial BMI (kg/m 2 ) Therapy before CSII Duration (months) HbA1c (%)FPG (mg/dl)PP2 (mg/dl) before CSII of CSII remiss ion before CSII at present before CSII at present before CSII at present M1625.2None0.14410.44.6360106322128 M40 25.3 NPH 0.12.54115.4 2029357181 M4230.8None0.255126.15.7125101142130 F2120.6None0.256610.86.6115126149126 F5629.7None0.252456.86144107134144 F4920.3OHA181123.85.11898514494 F5629.6OHA9622275.515282251136 M5420.5None12040976.3232144145127 F6123.0OHA13224965.66.3172101189129 M5120.8OHA180603613.86.2416130494144 F6425.5OHA3601898.66.7170113185150

9. HbA1c 8.3 ±2.95.9 ± 0.7 (p <0.05)

11. FPG & PP2 209 ± 96108 ± 19 248 ± 153 126 ± 21 (p<0.05) (mg/dl) FPG PP2 200 126

12. Total Daily Dose of Insulin 58.5 ±40.80 (p <0.001)

13. Duration before CSII Duration of CSII Duration of Remission after CSII Newly Diagnosed Diabetic Patients CSII No Medication No Mx

14. Duration before CSII Duration of CSII Duration of Remission after CSII Long-standing Diabetic Patients OHA CSII OHA No medication No Medication No Mx CSII No Mx No Mx

15. Duration of CSII vs Duration of Diabetes (Months) Duration of Diabetes Duration of CSII R = 0.76 P = <0.01

16. Estimation of Insulin Resistance and β Cell Function Based on C-peptide HOMA-IR = fasting insulin x fasting glucose / 22.5  C-peptide-IR = fasting C-peptide x fasting glucose HOMA- β = 20x insulin / (glucose-3.5)  C-peptide- β = C-peptide / (glucose-3.5)

17. C-peptide-IR (Fasting) 318 ± 169187 ± 50 (p<0.05)

18. C-peptide-β (Fasting) 0.347 ± 0.3400.812 ± 0.333 (p<0.05)

19. C-peptide-β (Post-Prandial) 0.618 ± 0.6071.665 ± 1.382 (p=0.065)

20. BMI (kg/m 2 ) 25 24.9 ±4.224.7 ± 3.5 (p >0.05)

22. Total Daily Insulin Dose and Mean Plasma Glucose M/16: Start CSII 3 days after diagnosis Time(days) (U/day)(mg/ml) 2 nd admission (2002.7.21-8.26) (U/day) (mg/ml) 1 st admission (2002.4.3-5.17) HbA1c (%) FPG (mg/dl) PP2 (mg/dl) C-peptide (ng/ml) FastingPostprandial Before CSII10.43603220.821.27 3 months after CSII Stop 4.61061282.311.3 HbA1c (%) Glucose (mg/dl) C-peptide (ng/ml)

23. Summary Remission of Diabetes –Newly diagnosed diabetic patient (n=5) –Long standing diabetic patient (n=6) With long-term CSII –Insulin resistance is improved –Β cell function is improved Duration of treatment until the remission seemed to be correlated with the duration of diabetes

24. Limitation and Future Plan Retrospective data of remitted cases Cannot estimate –Remission rate –Remission predictive factors → Large Scale of Prospective Cohort Study

25. Indication of CSII Previous concept –T1DM –T2DM Treatment failure with OHA and/or insulin Labile DM Pregnancy After kidney transplantation New concept –T2DM (newly diagnosed and long-standing) Prevention of DM progression and DM complication Improvement of β cell function and insulin resistance CURE of diabetes