Science in Society Archive

Treating Diabetes with a Glucagon-like Peptide

Looks promising for some Prof. Joe Cummins

Insulin and glucagon regulate blood glucose

Peter Saunders summarized fundamentals of diabetes and explained how blood glucose is regulated in the body by two hormones [1] (Diabetes, New Cures from Old Foods, SiS 52): when there is too much, the beta cells in the pancreas secrete more insulin, which stimulates fat cells in the body to take up glucose; when there is too little, the alpha cells in the pancreas secrete more glucagon, and this stimulates the liver to release more glucose into the blood. As he explained, the difference between type 1 insulin- dependent and type 2 (insulin-resistant) diabetes is that the latter usually appears as we mature; and can be treated successfully by a programme of diet and exercise.  If that fails, pharmaceutical drugs are needed to control blood glucose. Following years of satisfactory use, however, the drugs often grow less effective.  Currently, new drugs are being developed to cope with a worldwide epidemic of type 2 diabetes [2] (see Global Diabetes Epidemic Rages On, SiS 52).

New glucagon-like drugs

Among the newly developed pharmaceuticals, the recombinant proteins (biologicals) appear to be having a huge impact. In particular a glucagon-like peptide, liraglutide (Victoza) is proving useful in treating type 2 diabetes.  Liraglutide is currently being marketed worldwide, but is undergoing further clinical trials called a phase IV trial, also known as postmarketing  surveillance trial, at least partly due to concerns over thyroid cancer risk raised by studies in mice and rats (see [3] New Diabetes Drug and Cancer Risk, SiS 52), though not in primates [4].

Phase IV trials involve safety surveillance and continuing technical support for a drug after it receives marketing permission. The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials required for commercial release. Participation in the trial involves taking a single daily  injection of the drug and recording blood sugar levels over a period of one or two years, and monitoring and reporting of any adverse reactions. The use of the liraglutide injection is accompanied by the continued use of the pills that have grown ineffective in controlling blood sugar.

Liraglutide, is a long acting analogue of the human glucagon like peptide-1 (GLP-1(7-37)) with 97 percent homology and a lipophilic substituent to prolong its half life. The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells.

Liraglutide is produced as the polypeptide precursor in genetically modified Saccharomyces cerevisiae strain YES2085, and is a fragment of the naturally occurring human glucagon-like peptide-1 sequence position 7-37 (GLP-1[7-37]) with one amino acid substitution and with addition of a fatty acid chain [5].

Numerous benefits

Laboratory studies have revealed many potential benefits from liraglutide treatment [3] although its mechanism of action is not completely understood. Plasma concentrations of adiponectin, a newly discovered adipose-specific protein with  anti-atherogenic and anti-inflammatory effects, was found to be decreased in individuals with obesity, type 2 diabetes, and cardiovascular disease, conditions commonly associated with insulin resistance. Hypo-adiponectinaemia (low levels of adiponectin) was associated with high fat diet induced insulin-resistance. Mice made insulin-resistant, in which hypo-adiponectinaemia was induced by RNAi treatment in addition to a high fat diet, were given liraglutide treatment twice a day [6]. The treatment prevented the hypo-adiponectinemia-induced deterioration in peripheral and hepatic insulin sensitivity and alterations in key regulatory factors of glucose and lipid metabolism, suggesting that liraglutide may rescue insulin resistance induced by hypoadiponectinemia and high fat diet.

Liraglutide not only controlled blood sugar levels, but also improved cardiovascular risk factors. It lowers body weight, glycated haemoglobin, blood pressure, triglycerides and C-reactive protein (a measure of inflammation) in diabetic patients [7].  Liraglutide was found to be cost-effective compared with other drugs such as sulphonylurea or sitagliptin in combination with metformin for treating type 2 diabetes [8]. Liraglutide has been noted as a treatment for overweight patients on account of its effect in lowering body weight [9].

Several glucagon like peptides with long half-life are completing phase III clinical trials.  These peptides are all similar to liraglutide but engineered in such a manner that they require weekly rather than daily injections [9]. Such long-lasting injections will be welcomed by people with type 2 diabetes.

My own experience with liraglutide is that it is has so far provided over seven months of excellent blood sugar control with no obvious detrimental side effect. 

Article first published 26/10/11


References

  1. Saunders P. Diabetes new cures from old foods. Science in Society 52.
  2. Ho MW. Global diabetes epidemic rages on. Science in Society 52.
  3. Ho MW. New diabetes drug & cancer. Science in Society 52.
  4. European Medicines Agency ASSESSMENT REPORT FOR Victoza International Nonproprietary Name: liraglutide Procedure No. EMEA/H/C/001026Evaluation of Medicines for Human Use ea.europa.eu http://www.emea.europa.eu   © European Medicines Agency, 2009.  Doc.Ref.: EMEA/379172/2009
  5. Li L, Miao Z, Liu R, Yang M, Liu H, Yang G. Liraglutide Prevents Hypoadiponectinemia-Induced Insulin Resistance and Alterations of Gene Expression Involved in Glucose and Lipid Metabolism Mol Med. 2011 Jul 11. doi: 10.2119/molmed.2011.00051. [Epub ahead of print]
  6. Varanasi A, Patel P, Makdissi A, Dhindsa S, Chaudhuri A, Dandona P. Clinical Use of Liraglutide in Type 2 Diabetes, and Its Effects on Cardiovascular Risk Factors. Endocr Pract. 2011 Aug 19:1-13. [Epub ahead of print]
  7. Davies MJ, Chubb BD, Smith IC, Valentine WJ Cost-utility analysis of liraglutide compared with sulphonylurea or sitagliptin, all as add-on to metformin monotherapy in Type 2 diabetes mellitus. Diabet Med. 2011 Aug 29. doi: 10.1111/j.1464-5491.2011.03429.x. [Epub ahead of print]
  8. Meneghini LF, Orozco-Beltran D, Khunti K, Caputo S, Damçi T, Liebl A, Ross SA. Weight Beneficial Treatments for Type 2 Diabetes.J Clin Endocrinol Metab. 2011 Sep 7. [Epub ahead of print]
  9. Lund A, Knop FK, Vilsbøll T. Expert Opin Emerg Drugs. 2011 Sep 9. [Epub ahead of print] PMID: 21905764  [PubMed - as supplied by publisher]

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There are 3 comments on this article so far. Add your comment above.

Arden Andersen Comment left 30th October 2011 11:11:01
Hi Dr. Ho, I am wondering if there has been any investigation into the possible harmful consequences of all these recombinant protein drugs manufactured via genetically engineered organisms? You have written yourself about the adverse consequences related to the GE crops, esp. the Cry1Ac protein. I am concerned that we are going to see some disasterous effects in the future from all these GE drugs just like we do with the crops. Your comments?

Sandra Comment left 5th January 2012 07:07:52
I just read that adiponectin increase is linked to greater risk of Alzhiemers and other dementia in women.This srticle appeared 1/3/2012 in HealthDay News. This would be bad news for those of us who use Victoza for the long term.

Norman Stanley Comment left 23rd August 2014 15:03:36
I had no idea that peptides had any affect on diabetes. I thought they were used only for bodybuilding purposes.

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