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 nohDepartment of Internal Medicine and Biochemistry, School of Medicine, Konkuk University,

Chungju 380-701, South Korea

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 conceptWith proper treatment• The capacity can be restored or• Even Cured

Holman RR. Diabetes Res Clin Pract 1998,40 (Suppl),S21

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 diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized 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

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 appliedAcute insulin response (AIR), Area under the curve of insulin during IV-GTT, HOMA -B was improved

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 f

unction after long-term CSII

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

Remission

• Maintenance of normoglycemia

• Without any pharmaceutical interventions

• For more than 2 months

Overview

SexAge

Initial BMI

(kg/m2)

Therapybefore CSII

Duration (months) HbA1c (%) FPG (mg/dl) PP2 (mg/dl)

before CSII

of CSII

remission

before CSII

at present

before CSII

at present

before CSII

at present

M16 25.2 None 0.1 4 4 10.4 4.6 360 106 322 128

M40 25.3 NPH 0.1 2.5 4 11 5.4 202 93 571 81

M42 30.8 None 0.25 5 12 6.1 5.7 125 101 142 130

F21 20.6 None 0.25 6 6 10.8 6.6 115 126 149 126

F56 29.7 None 0.25 24 5 6.8 6 144 107 134 144

F49 20.3 OHA 18 11 2 3.8 5.1 189 85 144 94

F56 29.6 OHA 96 22 2 7 5.5 152 82 251 136

M54 20.5 None 120 40 9 7 6.3 232 144 145 127

F61 23.0 OHA 132 24 96 5.6 6.3 172 101 189 129

M51 20.8 OHA 180 60 36 13.8 6.2 416 130 494 144

F64 25.5 OHA 360 18 9 8.6 6.7 170 113 185 150

HbA1c

2

4

6

8

10

12

14

16

Before Tx At present

8.3 ±2.9 5.9 ± 0.7 (p <0.05)

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FPG & PP2

209 ± 96 108 ± 19 248 ± 153 126 ± 21(p<0.05) (p<0.05)

0

100

200

300

400

500

600

before at present

0

100

200

300

400

500

600

before at present

(mg/dl)

FPG PP2

200

126

Total Daily Dose of Insulin

Before Tx At present0

20

40

60

80

100

120

140

160

58.5 ±40.8 0 (p <0.001)

Duration before CSIIDuration of CSII

Duration of Remission after CSIINewly Diagnosed Diabetic Patients

0 5 10 15 20 25 30 35

1

2

3

4

5

Duration before CSII Duration of CSII Duration of remission after CSII

CSII

CSII

CSII

CSII

CSII

No Medication

No Mx

No Mx

No Mx

No Mx

Duration before CSIIDuration of CSII

Duration of Remission after CSIILong-standing Diabetic Patients

0 50 100 150 200 250 300 350 400 450

1

2

3

4

5

6

Duration before CSII Duration of CSII Duration of remission after CSII

OHA

OHA

OHA

OHA

CSII

CSII

CSII

CSII

CSII

OHA

No medication

No Medication

No Mx

CSII

NoMx

NoMx

Duration of CSII vsDuration of Diabetes

0

10

20

30

40

50

60

70

0 100 200 300 400

(Months)

(Months)Duration of Diabetes

Du

ration

of

CS

II

R = 0.76

P = <0.01

Estimation of Insulin Resistance andβ 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)

C-peptide-IR (Fasting)

0

100

200

300

400

500

600

Before Tx At present

318 ± 169 187 ± 50(p<0.05)

C-peptide-β (Fasting)

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Before Tx At present

0.347 ± 0.340 0.812 ± 0.333(p<0.05)

C-peptide-β (Post-Prandial)

0

1

2

3

4

5

Before Tx At present

0.618 ± 0.607 1.665 ± 1.382(p=0.065)

BMI

Before Tx At present18

20

22

24

26

28

30

32(kg/m2)

25

24.9 ±4.2 24.7 ± 3.5 (p >0.05)

http://www.konkuk.ac.kr/index.php

Total Daily Insulin Dose and Mean Plasma Glucose

• M/16: Start CSII 3 days after diagnosis Time(days)

70 80 90 100 110 1200

20

40

60

80

100

120

140

160

Glu

cose

0

100

200

300

400

500(U/day) (mg/ml)

2nd admission (2002.7.21-8.26)

0 10 20 30 40 50

Insu

lin

0

20

40

60

80

100

120

140

160

0

100

200

300

400

500(U/day) (mg/ml)

1st admission (2002.4.3-5.17)

HbA1c (%)

FPG (mg/dl)

PP2 (mg/dl)

C-peptide (ng/ml)

Fasting Postprandial

Before CSII 10.4 360 322 0.82 1.27

3 months after CSII Stop

4.6 106 128 2.3 11.3

Insulin Glucose

0

2

4

6

8

10

12

Before CSII 3 months after CSII

HbA1c(%)

050

100150200250300350400

Before CSII 3 months after CSII

Fasting PostprandialGlucose(mg/dl)

0

2

4

6

8

10

12

Before CSII 3 months after CSII

Fasting PostprandialC-peptide

(ng/ml)

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

Limitation and Future Plan

• Retrospective data of remitted cases

• Cannot estimate– Remission rate– Remission predictive factors

→ Large Scale of Prospective Cohort Study

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