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Oxyntomodulin: Partner to GLP-1?

Oxyntomodulin is a gut peptide released in response to a meal. It is synthesized within specialized enteroendocrine cells called L cells. Oxyntomodulin is released from the intestinal L cells 5-10 minutes after ingestion of food in amounts proportional to calorie intake and levels peak 30 minutes after meals. Oxyntomodulins are thought to act as circulating satiety signals by their effects on the appetite centers such as the hypothalamus and brainstem….

Oxyntomodulin crosses the blood brain barrier and binds to the GLP-1R receptor on neurons in the arcuate nucleus of the hypothalamus and thereby controls appetite. This signaling within the arcuate nucleus is responsible for the effect of oxyntomodulin on the energy homeostasis. Several studies in humans and animals have shown exogenous administration of oxyntomodulin to reduce energy intake, adiposity and body weight. Oxyntomodulin within the gastrointestinal tract is believed to delay gastric emptying and decrease gastric acid secretion. Interestingly, increased levels of oxyntomodulin are observed in patients after undergoing bariatric surgery which is believed to contribute to the loss of weight and appetite in these individuals.

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Oxyntomodulin is a 37 amino acid peptide that contains the 29 amino acid structure of glucagon followed by an octapeptide C terminal extension. Oxyntomodulin is one of the products of the glucagon gene GCG, which is expressed in the intestine, pancreas, and central nervous system.

Glicentin is a proglucagon, within the gut and the brain, broken down to produce oxyntomodulin. Thus oxyntomodulin is a proglucagon derived peptide which is secreted along with GLP-1,and believed to have a glucagon/GLP-1 dual agonist activity. The significance of the effect and the exact mechanism of action of these peptides on blood glucose are not clear. However, several studies in animals noted an increase in secretion of insulin after administration of oxyntomodulin. These beneficial effects justify further research and large scale studies in humans.

The studies currently being conducted in humans to learn the effect of Oxyntomodulin on body weight, appetite control, and energy expenditure show favorable results. A double blind randomized control trial study in overweight and obese subjects showed significant weight loss, decrease in energy intake and changes in the levels of adipose hormones consistent with a loss of adipose tissue in the treatment group. In this study, 14 subjects in the treatment group self administered subcutaneous oxyntomodulin 30 minutes before meals three times daily for a period of 4 weeks.


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These subjects experienced significant weight loss of 2.3 ± 0.4 kg, and a reduced energy intake of over 25%. Also, a study in normal weight subjects showed a reduction in energy intake by 19 ± 6% when oxyntomodulin was administered intravenously before a single study meal. Another study conducted over a 4 day period in 15 healthy overweight or obese subjects resulted in a 26.2 ± 9.9% increase in activity related energy expenditure. Therefore, oxyntomodulin increases energy expenditure while reducing energy intake resulting in negative energy balance. Thus studies support the role of oxyntomodulin as a potential anti-obesity therapy.

Currently there are three drug companies — Zealand Pharma, PROLOR Biotech, Inc., and Wyeth Pharmaceuticals — exploring the benefits of oxyntomodulin. While PROLOR and Wyeth are pursuing oxyntomodulin as a weight loss therapy option, Zealand Pharma in collaboration with Boehringer Ingelheim are pursuing it as a glucagon/GLP-1 dual agonist drug therapy option for diabetic patients.

Farhan Guard, PharmD Candidate
Lake Erie College of Osteopathic Medicine
References

Wynne K, Bloom S. The role of oxyntomodulin and peptide tyrosine-tyrosine (PYY) in appetite control. Nat Clin Pract Endocrinol Metab. 2006;2:612–620

Cohen MA et al. (2003) Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab 88: 4696-4701

Wynne K et al. Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomized controlled trial. Int J Obes [doi: 10.1038/sj.ijo.0803344]

Wynne K et al. (2005) Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes 54: 2390-2395

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