Glucagon-like peptide 1 (GLP-1) in the treatment of Diabetes
Clinical Diabetes, April 2005 vol. 23 no. 2 56-62
Figure 1.Multiple sites of action for GLP-1. Image courtesy: American Diabetes Association and Dr. John. Buse MD, PhD.
GLP-1 and GLP-2 stimulate intestinal growth and upregulate villus height in the gastrointestinal tract. The primary site of action of GLP-2 starts in the stomach and ends in the colon. It has an essential function in nutrient homeostasis (5) by an increased stimulus in the gastrointestinal track which leads to an increment in nutrient assimilation. The Pharmaceutical industry has developed drugs that mimic the GLP-1 targeting control of glucose levels in type-2 diabetes. Weight loss contributes in increasing the GLP-1 levels leading to improved glucose control in Type-2 Diabetes. Lower levels of GLP-1 in the body lead to obesity, feeling of hunger and empty stomach making the individual eat more.
Incretin based GLP-1 therapies have additional effects, e.g. the reduction of glucagon, the slow down of gastric emptying, and inducing the sense of satiety. In clinical practice these therapies are associated with significant reductions in glycated hemoglobin (HbA1c) weight loss and a low risk of hypoglycemia. Few of the incretin GLP-1 receptor agonist based therapies are mentioned below:
Exenatide (exendin-4) is a reptilian hormone isolated from the saliva of the Gila monster (Heloderma suspectum) which acts as a GLP-1 mimic. The 39 amino acid-containing peptide has been approved as a monotherapy for the treatment of type-2 diabetes.
Exenatide is marketed under the trade name of Byetta® by AstraZeneca. It enhances insulin production and has 53% sequence identity to GLP-1. Because of its shorter half-life of 2.4 hours exenatide has twice-a-day dosing regimen taken with metformin ± sulfonylurea. Exenatide was well tolerated in patients and rates of hypoglycemia were relative low in these studies.
Oral glucose stimulates the release of the endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin-releasing polypeptide (GIP). These stimulate insulin release and inhibit glucagon release resulting in lower blood glucose. They are rapidly inactivated by dipeptidyl peptidase-4 (DPP-4). The DPP-4 inhibitors prolong the action of endogenous incretins, enhancing the first-phase insulin response. (Image courtesy: Dr.Fisher Miles).
Liraglutide is a GLP-1 analog which has 97% sequence -similarity towards GLP-1. It is marketed under the trade name Victoza® by Novo Nordisk. The fatty acid side chain enables the heptamer formation thus increasing the stability and the binding to albumin. The drug was generally well tolerated and rates of hypoglycemia seemed to be low in these trials; however frequency of hypoglycemia increased with the combined use of other anti-diabetic drugs (metformin and sulfonylurea drugs). It was reported that in direct comparison between exenatide twice daily and liraglutide once a day, liraglutide was significantly more effective in controlling the glycemic index when compared to exenatide. The weight and fasting plasma glucose was significantly reduced by liraglutide treatment.
Exenatide LAR from Amylin/ AstraZeneca: A once-weekly injection of exenatide has been approved as of January 27, 2012 under the trademark Bydureon®. Exenatide once a week dose was more effective when compared to twice a day dose of exenatide.
|Drug Name||Developer/Manufacturer||Dosage||Plasma Half life||Approval year/Countries|
|Exenatide||AstraZeneca||5-10 mcg SC route||2.4 hrs||2005 USA|
|Liraglutide||Novo Nordisk||1.2-1.8 mg once SC||11-15 hrs||2009 USA|
|Lixisenatide||Sanofi-Aventis||20 mcg daily||2.7-4.3 hrs||EU, Mexico, Australia, Japan|
Table showing the list of GLP-1 Receptor Agonist: Adapted with permission from J. Med. Chem., Article ASAP. DOI: 10.1021/jm500810s.Publication Date (Web): October 28, 2014 Courtesy: copyright 2014; American chemical society.
In hypoglycemia, GLP-1 reduces the brain glucose concentration. Further effects are an increase of the net blood brain clearance and the brain metabolism, but it is not known whether they depend on the prevailing plasma glucose (PG) (6). GLP-1 peptide is a post- translational product of preglucagon which is a precursor of many glucagon related peptides. They are two equipotent forms of GLP-1, GLP-1 (7-36)-NH2 and GLP-1 (7-37), the first one being more abundant, which bind to and activate the GLP-1 receptor. The GLP-1 receptor or GLP-1R belongs to the class B family of G-protein coupled receptors (GPCRs) and carries out its regulatory functions. GLP-1R is found in many organs like pancreas, kidney, GI tract and brain, but is highly expressed in pancreas.
In summary it is projected that GLP-1 agonist peptides against type-2 diabetes are promising targets for patients with poor Hb1Ac control.
1. Anon., Lancet 1998, 352, 837.
2. Stephen Bloom et.al; Imperial College London Society of Endocrinology; BES 2013.
3. J. J. Holst, Physiol Rev 2007, 87, 1409.
4. S. Runge, B. S. Wulff, K. Madsen, H. Brauner-Osborne, L. B. Knudsen, Br J Pharmacol 2003, 138, 787.
5. C. X. Dong, P. L. Brubaker, Nat Rev Gastroenterol Hepatol 2012, 9, 705.
6. M. Gejl, S. Lerche, L. Egefjord, B. Brock, N. Moller, K. Vang, A. B. Rodell, B. M. Bibby, J. J. Holst, J. Rungby, A. Gjedde, Front Neuroenergetics 2013, 5, 2.
What is your official job title at Bachem?
How long have you been with Bachem? Where did you work before Bachem?
I was with American Peptide Company (APC) from 2013. Bachem acquired APC earlier this year. Prior to that I was working as Research Scientist at drug delivery company designing prodrugs to make them more bioavailable and less toxic. Working as bench scientist I gained knowledge about different disease areas, drugs that treat them and their mechanism of action on diseases. I am the inventor of new chemical entities and hold of many patents to my credit.
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At Bachem I take care of marketing activities like scientific writings, market research, newsletter content, Ad words/SEO and integration for Bachem and American Peptide Company.
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I have masters in medicinal organic chemistry and I am certificate holder in Regulatory Affairs from UCSC extension.
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I am trained classical dancer and love to dance with good music. I also like travelling around the world with my family.
What makes a perfect day for you?
Day should start with right dose of caffeine, when I finish my tasks in a way that makes me stand apart from the rest.
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The best part in this job is scientific writing and market search that keeps me in touch with scientific discoveries and development. I feel proud to be part of Bachem team and its contribution towards bringing better medicines into the market.
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Hiking with my family including my dog, good music and cooking.
Do you like to communicate any key message to the reader?
Do your Best in this innovative field.
What is your preferred peptide?
I feel RGD and CPPs might play big role in bringing new technologies into healthcare industry.
Thank you Archana!