Exagerrated postprandial glucose excursions and extended time spent in hyperglycaemia drive the development of diabetes complications which in turn have severe and life-threatening consequences for patients.
Patients with Type 1 Diabetes and decompensated Type 2 diabetes require life-long treatment with insulin. While insulin therapy is effective in lessening the extent and impact of excursions it can come with significant side-effects especially when used intensively. Hypoglycaemia and excessive weight gain are both of sequelae of intensive insulin therapy and may detract from its therapeutic benefit.
Adjunct drugs that facilitate insulin action could provide for insulin sparing benefits in the treatment of diabetes. Some drugs in this category are in clinical use but can also be associated with undesirable effects such as weight gain. We have generated important pre-clinical evidence implicatiing pituitary derived alpha melanocyte stimulatory hormone (alpha-MSH) as a physiological player in postprandial glycaemic control. Furthermore we have demonstrated that in the experimental setting in rodents and sheep, exogenous alpha-MSH improves glucose tolerance by increasing skeletal muscle uptake and glycolytic disposal of glucose.
The current application seeks to extend and translate these findings by characterising the glucose tolerising effects of alpha-MSH in humans and defining the specific role of priming of skeletal muscle glucose uptake and utilisation in this effect. We will furthermore seek to elucidate whether alpha-MSH action in humans can be explained by optimisation of skeletal muscle insulin sensitivity and/or the activation of complimentary insulin independent disposal pathways.
The work proposed in the current application will provide critical insight into the role of alpha-MSH as a mediator of post-prandial glycaemic control in humans. Moreover it will assess the potential of skeletal muscle MCR-5 receptor agonism to serve as a new therpaeutic approach in the treatment of diabetes.
