The effect of GLP-1/glucagon 'dual agonists' on amino acid metabolism: potential side effects and solutions

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Oxyntomodulin (OXM) is a natural hormone released from the gut following eating. We know that OXM can reduce weight and improve blood sugar levels in people with diabetes. This is because OXM combines the effects of two other hormones, glucagon-like peptide-1 (GLP-1) and glucagon, leading to: 1. A reduction in the amount of food eaten, leading to weight loss. 2. Improved release of insulin by the pancreas and lower sugar levels. 3. Increased energy expenditure by the body which helps with weight loss. Drug companies are currently developing medications based on OXM to help patients with diabetes and obesity. These are the GLP-1/glucagon 'dual agonists'. However, the research on these dual agonists has concentrated on their effects on body weight and blood glucose levels and has neglected other equally important components of the body such as the muscles, which contain most of the protein in our bodies. We know that glucagon leads to a breakdown of the building blocks of proteins (amino acids). Where glucagon occurs in excess, patients lose a great deal of muscle and become weaker. Our own research shows that OXM has a similar effect because of its glucagon-like effects, leading to breakdown of amino acids. This may cause loss of muscle protein to restore circulating amino acids. If OXM and 'dual agonists' lead to breakdown of amino acids and muscle loss this could cause serious health problems, particularly as we know that diabetic patients already have a lower level of muscle relative to fat in their bodies. Therefore, this project aims to investigate the effect of dual agonists, asking the following questions: - Does the GLP-1/glucagon dual agonist cause the body to break down amino acids, resulting in loss of muscle? - Is this effect associated with the increase in energy expenditure? - Can the muscle loss be reversed by a high-protein diet? Knowing the answer to these questions is important to establishing the safety of these new 'dual agonists' prior to their widespread use in patients and may also allow us to prevent problems with a simple dietary change.