Diabetes Care
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hinke, S. A.
Right arrow Articles by Demuth, H.-U.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hinke, S. A.
Right arrow Articles by Demuth, H.-U.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
Diabetes Care 25:1490-1491, 2002
© 2002 by the American Diabetes Association, Inc.

Letters: Comments and Responses
Letter

On Combination Therapy of Diabetes With Metformin and Dipeptidyl Peptidase IV Inhibitors

Simon A. Hinke, BSC1, Christopher H. S. McIntosh, PHD1, Torsten Hoffmann, PHD2, Kerstin Kühn-Wache, PHD2, Leona Wagner, MSC2, Joachim Bär, MSC2, Susanne Manhart, PHD2, Michael Wermann, MSC2, Raymond A. Pederson, PHD1 and Hans-Ulrich Demuth, PHD2

1 Department of Physiology, University of British Columbia, Vancouver, Canada
2 Probiodrug AG, Halle (Saale), Germany

Recently, data were presented showing that metformin increased plasma active glucagon-like peptide (GLP)-1[7–36NH2] concentrations in obese nondiabetic male patients (1), and it was suggested that metformin was a direct dipeptidyl peptidase (DP) IV inhibitor. Contradiction of this hypothesis is simply found by examining the modes of action of metformin and of the DP IV inhibitors. Although the specific molecular target of metformin is still unknown, biguanides generally act to sensitize peripheral tissues to insulin action (particularly, skeletal muscle) and inhibit hepatic gluconeogenesis and glycogenolysis (2,3,4). In contrast, DP IV inhibitors act to enhance the insulin response to a meal, via preservation of intact bioactive incretins, GLP-1[7–36NH2] and GIP[1–42OH] (5,6,7,8,9,10). Notably, metformin does not improve glucose tolerance via an increase in circulating insulin levels, implicating different antidiabetic mechanisms for metformin and DP IV inhibitors.

Unfortunately, Mannucci et al. (1) did not measure total GLP-1 (GLP-1[7–36NH2] + GLP-1[9–36NH2]) levels in their study. An increase NH2-terminal intact GLP-1 was interpreted as indicating protection from degradation by DP IV, and the possibility of an increase in total GLP-1 levels, yielding a proportional rise in intact GLP-1 concentrations, was not considered. This possibility is consistent with prior studies examining glucagon and GLP-1 levels after metformin treatment (11,12,13). A simplistic interpretation of these findings would be that metformin either enhances the glucose sensitivity of the islet {alpha}-cell and enteroendocrine L-cell, the secretory rate of these cells, or increases transcription/translation of the proglucagon gene, resulting in greater hormone release with metformin treatment. Regardless, we initiated a series of in vitro biochemical studies to test the hypothesis of Mannucci et al., but were unable to duplicate their earlier work or support this hypothesis by other means (13).

Traditional treatment of type 2 diabetes begins with diet control and oral monotherapy (metformin, sulfonylureas, acarbose, or certain glitazones), and as the disease progresses, combinatorial treatment follows, until finally insulin injections are required to achieve glycemic control (3). Considering the different modes of action of DP IV inhibitors (enhancing the postprandial insulin response due to active incretin preservation) and metformin or glitazones (sensitizing peripheral tissue to insulin), we predict that type 2 diabetic patients receiving combinatorial treatment of these therapies will produce an even greater (additive) antidiabetic effect. However, because both DP IV inhibitors and sulfonylureas enhance insulin release, the potential of combination therapy with these agents is doubtful. A corollary to our hypothesis was recently published by Zander et al. (14), who found that subcutaneous infusion of GLP-1 had an additive antidiabetic effect when given in combination with metformin; it was also commented that data were inconsistent with the findings of Mannucci et al. Direct testing using laboratory models of type 2 diabetes and clinical trials will ultimately confirm or refute our prediction on combination therapies.

Footnotes

Address correspondence and reprint requests to Hans-Ulrich Demuth, Probiodrug AG, 22 Weinbergweg, D-06120 Halle (Saale) Germany E-mail: hans-ulrich.demuth{at}probiodrug.de.

Received 12 March 2002.

S.A.H., C.H.S.M., and R.A.P. have received honoraria from Probiodrug, which synthesizes inhibitors of DP IV as potential therapeutic agents in human disease. H.-U. D. holds stock in Probiodrug.

References

  1. Mannucci E, Ognibene A, Cremasco F, Bardini G, Mencucci A, Pierazzuoli E, Ciani S, Messeri G, Rotella CM: Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care 24:489–494, 2001[Abstract/Free Full Text]
  2. Zhang BB, Moller DE: New approaches in the treatment of type 2 diabetes. Curr Opin Chem Biol 4:461–467, 2000[Medline]
  3. DeFronzo RA: Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 131:281–303, 1999[Abstract/Free Full Text]
  4. Bailey CJ, Turner RC: Metformin. N Engl J Med 334:574–579, 1996[Free Full Text]
  5. Pauly RP, Demuth H-U, Rosche F, Schmidt J, White HA, McIntosh CHS, Pederson RA: Inhibition of dipeptidyl peptidase IV (DP IV) in rat results in improved glucose tolerance (Abstract). Regul Pept 64:148, 1996
  6. Kieffer TJ, McIntosh CHS, Pederson RA: Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136:3585–3596, 1995[Abstract]
  7. Pauly RP, Rosche F, Wermann M, McIntosh CHS, Pederson RA, Demuth H-U: Investigation of GIP1–42 and GLP-1 7–36 degradation in vitro by dipeptidyl peptidase IV (DP IV) using Matrix-Assisted Laser Desorption/Ionization - Time of Flight Mass Spectometry (MALDI-TOF MS): a novel kinetic approach. J Biol Chem 271:23222–23229, 1996[Abstract/Free Full Text]
  8. Pauly RP, Demuth H-U, Rosche F, Schmidt J, White HA, Lynn F, McIntosh CHS, Pederson RA: Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD26) inhibitor ile-thiazolidide. Metabolism 48:385–389, 1999[Medline]
  9. Pederson RA, White HA, Schlenzig D, Pauly RP, McIntosh CHS, Demuth H-U: Improved glucose tolerance in zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide. Diabetes 47:1253–1258, 1998[Abstract]
  10. Holst JJ, Deacon CF: Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes 47:1663–1670, 1998[Abstract]
  11. Lugari R, Dell’Anna C, Sarti L, Coppi S, Verlato CA, Sbordone P, Bianco M, Gnudi A, Zandomeneghi R: Effects of metformin on intestinal and pancreatic endocrine secretion in type 2 (non-insulin-dependent) diabetes: In Molecular and Cell Biology of Type 2 Diabetes and Its Complications. Vol. 14. F Belfiore, M Lorenzi, GM Molinatti, M Porta, Eds. Karger, Basel, 1998, p.161–163
  12. Molloy AM, Ardill J, Tomkin GH: The effect of metformin treatment on gastric acid secretion and gastrointestinal hormone levels in normal subjects. Diabetologia 19:93–96, 1980[Medline]
  13. Hinke SA, Kühn-Wache K, Hoffmann T, Pederson RA, McIntosh CHS, Demuth H-U: Metformin effects on dipeptidyl peptidase IV degradation of glucagon-like pepide-1. Biochem Biophys Res Commun 291:1302–1308, 2002[Medline]
  14. Zander M, Taskiran M, Toft-Nielsen M-B, Madsbad S, Holst JJ: Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes. Diabetes Care 24:720–725, 2001[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
N. Yasuda, T. Inoue, T. Nagakura, K. Yamazaki, K. Kira, T. Saeki, and I. Tanaka
Metformin Causes Reduction of Food Intake and Body Weight Gain and Improvement of Glucose Intolerance in Combination with Dipeptidyl Peptidase IV Inhibitor in Zucker fa/fa Rats
J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 614 - 619.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hinke, S. A.
Right arrow Articles by Demuth, H.-U.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hinke, S. A.
Right arrow Articles by Demuth, H.-U.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum