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      A Novel Long-Acting Glucagon-Like Peptide-1 Agonist with Improved Efficacy in Insulin Secretion and β-Cell Growth

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          Abstract

          Background

          Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced by cleavage of proglucagon in intestinal L-cells. In the pancreas, GLP-1 stimulates post-prandial insulin secretion, promotes insulin biosynthesis, and improves insulin sensitivity. Because of its insulinotropic activity, GLP-1 has been considered a good candidate drug for treatment of diabetes mellitus. However, clinical use of GLP-1 has been limited by its short half-life, as a result of rapid degradation by dipeptidyl peptidase-IV (DPP-IV).

          Methods

          We designed a novel GLP-1 analog, Xenopus GLP-1 (xGLP)-E4. The Ala residue in the second position of xGLP was replaced with a Ser residue to increase the half-life in the body. The C-terminal tail of exendin-4 was added to enhance the binding affinity for the GLP-1 receptor (GLP1R). The potency of GLP-1 and its analogs was determined by luciferase assay. The stability of GLP1R agonists was evaluated by determining the activity of agonists that had been preincubated in the presence of fetal bovine serum, which contains innate DPP-IV activity. The effects of xGLP-E4 on insulin secretion and β-cell growth were investigated using insulin enzyme-linked immunosorbent assay and cell counting.

          Results

          xGLP-E4 exhibited improved stability against DPP-IV activity and increased potency to GLP1R, compared with GLP-1. An increase in glucose-dependent insulin secretion was observed in xGLP-E4-treated pancreatic β-cells. The effect of xGLP-E4 on β-cell growth was greater than that of GLP-1.

          Conclusion

          We developed a novel GLP-1 analog, xGLP-E4, that shows prolonged longevity and improved efficacy. This analog is a potential candidate for treatment of type 2 diabetes.

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          Most cited references38

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          Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV.

          T. Kieffer, C McIntosh, R. A. Pederson (1995)
          The combined actions of glucose-dependent insulinotropic polypeptide (GIP) and truncated glucagon-like peptide-1 (tGLP-1) may fully account for the incretin effect. These hormones are released from the small intestine in response to oral glucose and stimulate insulin release. Recently, evidence has been provided demonstrating the degradation of GIP-(1-42) and GLP-1-(7-36)NH2 by the serum enzyme dipeptidyl peptidase IV (DPP IV) into the biologically inactive products GIP-(3-42) and GLP-1-(9-36)NH2. The objective of the current investigation was to develop a method to monitor the degradation of these hormones in vivo. Synthetic peptides were radiolabeled and purified by HPLC. Subsequent degradation of the peptides under various conditions was then monitored by further HPLC analysis. Incubation of [125I]GIP-(1-42) or [125I]GLP-1-(7-36)NH2 with Wistar rat serum or purified DPP IV resulted in the major N-terminal-truncated products [125I]GIP-(3-42) and [125I]GLP-1-(9-36)NH2. These products were significantly reduced when the specific DPP IV inhibitor diprotin A was included in the incubation mixture and were absent when serum from DPP IV-deficient rats was used. When the labeled peptides were infused into rats at hormone levels within the physiological range, over 50% was metabolized to the truncated forms within 2 min. These products were absent when the tracers were infused into DPP IV-deficient animals. It is concluded that DPP IV may be a primary inactivating enzyme of both GIP and tGLP-1 in vivo. As the N-terminal-truncated products of the DPP IV cleavage may not be distinguished from the biologically active hormone by currently employed assays, reports of circulating hormone levels should be reconsidered. The method described in this manuscript may be useful for investigating the durations of action of GIP and tGLP-1 in normal and pathophysiological conditions.
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            Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea.

            Nicole C. Riddle, Michael Baron, Anthony D. Kendall … (2005)
            This study evaluated the effects of exenatide, a novel incretin mimetic, in hyperglycemic patients with type 2 diabetes unable to achieve glycemic control with metformin-sulfonylurea combination therapy. A 30-week, double-blind, placebo-controlled study was performed in 733 subjects (aged 55 +/- 10 years, BMI 33.6 +/- 5.7 kg/m(2), A1C 8.5 +/- 1.0%; means +/- SD) randomized to 5 microg subcutaneous exenatide b.i.d. (arms A and B) or placebo for 4 weeks. Thereafter, arm A remained at 5 microg b.i.d. and arm B escalated to 10 microg b.i.d. Subjects continued taking their dose of metformin and were randomized to either maximally effective (MAX) or minimum recommended (MIN) doses of sulfonylurea. Week 30 A1C changes from baseline (+/-SE) were -0.8 +/- 0.1% (10 microg), -0.6 +/- 0.1% (5 microg), and +0.2 +/- 0.1% (placebo; adjusted P < 0.0001 vs. placebo), yielding placebo-adjusted reductions of -1.0% (10 microg) and -0.8% (5 microg). In the evaluable population, exenatide-treated subjects were more likely to achieve A1C < or =7% than placebo-treated subjects (34% [10 microg], 27% [5 microg], and 9% [placebo]; P < 0.0001). Both exenatide arms demonstrated significant weight loss (-1.6 +/- 0.2 kg from baseline each exenatide arm, -0.9 +/- 0.2 kg placebo; P < or = 0.01 vs. placebo). Mild or moderate nausea was the most frequent adverse event. The incidence of mild/moderate hypoglycemia was 28% (10 microg), 19% (5 microg), and 13% (placebo) and appeared lower with MIN than with MAX sulfonylurea treatment. Exenatide significantly reduced A1C in patients with type 2 diabetes unable to achieve adequate glycemic control with maximally effective doses of combined metformin-sulfonylurea therapy. This improvement in glycemic control was associated with no weight gain and was generally well tolerated.
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              Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes.

              , D. Kim, Michael Baron … (2004)
              This study evaluated the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy. This was a triple-blind, placebo-controlled, 30-week study conducted at 101 sites in the U.S. After a 4-week, single-blind, placebo lead-in period, 377 subjects were randomized (60% men, age 55 +/- 11 years, BMI 33 +/- 6 kg/m(2), HbA(1c) 8.6 +/- 1.2% [+/-SD]) and began 4 weeks at 5 microg subcutaneous exenatide twice daily (before breakfast and dinner; arms A and B) or placebo. Subsequently, subjects in arm B were escalated to 10 microg b.i.d. exenatide. All subjects continued sulfonylurea therapy. At week 30, HbA(1c) changes from baseline were -0.86 +/- 0.11, -0.46 +/- 0.12, and 0.12 +/- 0.09% (+/-SE) in the 10-microg, 5-microg, and placebo arms, respectively (adjusted P 7% (n = 237), 41% (10 microg), 33% (5 microg), and 9% (placebo) achieved HbA(1c)
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                Author and article information

                Journal
                Journal ID (nlm-ta): Endocrinol Metab (Seoul)
                Journal ID (iso-abbrev): Endocrinol Metab (Seoul)
                Journal ID (publisher-id): ENM
                Title: Endocrinology and Metabolism
                Publisher: Korean Endocrine Society
                ISSN (Print): 2093-596X
                ISSN (Electronic): 2093-5978
                Publication date (Print): September 2014
                Publication date (Electronic): 25 September 2014
                Volume: 29
                Issue: 3
                Pages: 320-327
                Affiliations
                [1 ]Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
                [2 ]Korea University Graduate School of Medicine, Seoul, Korea.
                Author notes
                Corresponding author: Mi Jin Moon. Korea University Graduate School of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 136-705, Korea. Tel: +82-2-2286-1092, Fax: +82-2-921-4355, mmj34@ 123456korea.ac.kr
                Article
                DOI: 10.3803/EnM.2014.29.3.320
                PMC ID: 4192806
                SO-VID: 99286d83-f16e-4ecd-8de3-db73a43d4716
                Copyright © Copyright © 2014 Korean Endocrine Society
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 17 October 2013
                Date revision received : 04 December 2013
                Date accepted : 06 December 2013
                Funding
                Funded by: National Research Foundation of Korea
                Award ID: 2011-0019205
                Award ID: 2013R1A1A2010481
                Categories
                Subject: Original Article
                Subject: Endocrine Research

                Keywords: glucagon-like peptide 1,exenatide,xglp-e4,analog,diabetes
                Data availability:
                Keywords: glucagon-like peptide 1, exenatide, xglp-e4, analog, diabetes

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