Incretins in Diabetes: Physiology,

Pharmacology and Mythology

David D’Alessio, MD
University of Cincinnati
 The Incretin Effect in T2DM
Control Type 2 DM
Glucose (mmol/L)
Venous Plasma

15 15

10 10

5 5

0 0
O1 D2 50 120 150 O1 D2 50 120 150
Time (min) Time (min)

(nmol/L)
30 30
IR-C-peptide
(nmol/L)

20 20
*
* * * * *
10 * 10
*
0 0
O1 D2 50 120 150 O1 D2 50 120 150
Time (min) Time (min)
=oral glucose
Nauck M, et al. Diabetologia. 1986;29:46-52. Copyright © 1986 Springer-Verlag.
=IV glucose
 Effectiveness of Incretins to Stimulate Insulin
Secretion in Patients With T2DM
Hyperglycemic Clamp
Saline or GIP or GLP-1

GLP-1
GIP
Saline

-15 -10 0 5 10 15 20 30 45 60 75 90 105 120 150

Data from Vilsboll T, et al. Diabetologia. 2002;45:1111-1119.

 Release of GLP-1 Is Impaired in Patients
With T2DM
20

* * * * * NGT
15 * IGT
GLP-1 (pmol/L)

* T2DM
*P < .05 vs T2DM
10

*
5

0
0 60 120 180 240
Time (min)

Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001

The “original” incretin effect in Diabetes

M Perley, D Kipnis, JCI 1967

β-cell sensitivity to GLP-1 in T2DM and non-DM

L Kjems et al, Diabetes 2003

β-Cell sensitivity to GIP in T2DM and non-DM

J Meier et al, Diabetes 2004

Improved responsiveness to incretins following
improved glycemic control in T2DM

P Hojberg et al, Diabetologia, 2008

Incretin secretion in T2DM revisited

K Vollmer et al, Diabetes, 2008

Incretin secretion in states of abnormal glucose
metabolism

1.  T2DM: decreased, normal, increased

2.  IGT: Normal, decreased
3.  GDM: Normal
4.  First degree relatives of DM: Normal
5.  Men with hx of LBW: Normal
6.  Chronic pancreatitis: Normal
 The incretins in T2DM

1.  Diabetes is not likely to be an incretin deficiency

state.
2.  The insulin response to incretins is reduced, but it is
unclear whether this is a defect specific to GIP and
GLP-1, or simply a function of general β-cell
dysfunction.
3.  The incretin effect may be related to hyperglycemia
- mild DM with normal response
- correction of hyperglycemia improves the
responses to GIP and GLP-1
 Effect of GLP-1 on Fasting Hyperglycemia in
Patients With T2DM
Glucose (mg/dL) C-Peptide (nmol/L) Glucagon (pmol/L)

GLP-1 GLP-1 GLP-1

*
* * * ** *
* * * * **
* * * *
GLP-1 *
**
Saline

Adapted from Nauck MA, et al. Diabetologia. 1993;36:741-744. *P<0.05

 Normalization of Fasting and Postprandial
Glucose With IV GLP-1 in T2DM
Glucose (mmol/L) Glucose (mmol/L) 16
A 14
12
10
8
6
4
2 Breakfast Lunch Snack IV Saline
0 IV GLP-1
Nondiabetics
16
B 14
12
10
8
6
4 Breakfast Lunch Snack
2 Discontinuation of GLP-1
0
22.00 24.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00
Clock Time (h)
Rachman J, et.al. Diabetologia. 1997;40:205-211. Copyright © 1997 Springer-Verlag.
 Exendin-4 Remains in the Circulation
Longer Than GLP-1
50 nmol
5 nmol
0.5 nmol

Exendin-4 GLP-1
Log Mean (SE) Plasma Exendin-4 (pM)

Log Mean (SE) Plasma GLP-1 (pM)

100000 100000

10000 10000

1000 1000

100 100

10 10

10 10
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Time After sc Bolus (h) Time After sc Bolus (h)

N = 4-7 (rats).
P < .05. Adapted from Parkes D, et al. Drug Dev Res. 2001;53:260-267.
 Acute Exenatide Infusion Restored
First-Phase Insulin Response

30 Healthy Subjects, Placebo

Type 2 Diabetes, Placebo
(pmol • kg-1 • min-1)
25
Insulin Secretion

Type 2 Diabetes, Exenatide

20
15
10
5
0
– 180 0 10 20 30 60 90 120
Time (min)
First- (0-10 min) and second- (10-120 min) phase insulin increased in exenatide-treated patients
compared with placebo-treated T2DM, P < .0002.
Second-phase insulin increased in exenatide-treated patients compared with healthy
controls, P < .0029.
Values are mean (SE).
N = 25. Fehse F, et al. J Clin Endocrinol Metab. 2005;90:5991-5997.
 Pharmacologic effects of GLP-1r agonists
in T2DM

1.  Stimulation of glucose-stimulated insulin secretion

2.  Suppression of glucagon
3.  Delayed gastric emptying
4.  Reduced food intake and weight loss
Effect of DPP-IV inhibition of plasma GLP-1 levels

Sitagliptin Vildagliptin

Time (min)

G Herman, et al, JCEM, 2006 Ahren B, et al. J Clin Endocrinol Metab. 2004
Effects of DPP-4 Inhibition on glucose
metabolism in T2DM

1.  Improved insulin secretion

2.  Inhibition of glucagon release
3.  Improved meal tolerance
4.  Reduced HbA1c
 Stimulation of Islet Growth With a GLP-1
Analogue in Mice

Islet Area (Arbitrary Units x 104)

3

0
Saline Ex-4
Stoffers DA, et al. Diabetes. 2000;49:741-748. Copyright © 2000 The American Diabetes Association.
Reprinted with permission from the American Diabetes Association.
 GLP-1 Preserves Human Islet
Morphology In Vitro
Control GLP-1
•  Pancreatic islets cultured
in the absence of GLP-1
lost organization after
5 days Day 1

•  By Day 5, 45% of islets in

control cultures had lost
their 3-D structure
Day 3

•  Only 15% of GLP-1–

treated islets lost their 3-D
structure in 5 days (P < .01
Day 5
vs control)
Farilla L, et al. Endocrinology. 2003;144:5149-5158.
Evidence that Type 2 DM is Associated with a
Significant Decrease in β-cell Mass

Butler AE, et al. Diabetes. 2003;52:2304-2314.

Durability as a new index of drugs for T2DM

Kahn SE et al, NEJM, 2006

 Summary

1.  The incretin effect may be defective in T2DM.

2.  Incretin secretion is not a major abnormality in
T2DM but diabetic β-cells have reduced
sensitivity to GIP and GLP-1.
3.  Pharmacologic levels of GLP-1r agonists
reduce blood glucose and cause weight loss.
4.  DPP-4 inhibition reduces blood glucose but
the mechanism of action is not clear.
5.  The full extent to which the GLP-1 system can
be utilized to treat human disease is not yet
complete.