Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Differential roles of central and peripheral α-melanocyte stimulating hormone in transient hyperglycemic mice (#195)

Weiyi Chen 1 , Pablo J Enriori 1 , Michael A Cowley 1
  1. Monash University, Clayton, VIC, Australia

Type 1 diabetes represents 10 – 15 % of all cases of diabetes in Australia and it remains a management challenge partly because insulin is lipogenic. Over the years, a number of studies have shown the physiology role of peripheral melanocortin peptides, in particular α-melanocyte stimulating hormone (α-MSH) in lipid metabolism. However, the role of systemic α-MSH in glucose homeostasis has not been evaluated. Here, we explore the central and peripheral effects of α-MSH in transient hyperglycemic mice in vivo.

We were able to induce hyperglycemia (21.9±2.5 mmol/l) in lean mice after 1 day of insulin receptor antagonist (20nmol/kg of S961; NovoNordisk, Denmark) delivery via subcutaneous osmotic (7 days, 0.5μl/h) pumps. Hyperglycemia was further increased and maintained at 27.1±2.7 mmol/l in these mice after 4 days of S961 (20nmol/kg). Interestingly, constant intravenous infusion of α-MSH (1 μg/h) for 2h was able to improve the hyperglycemic condition from 28.4mmol/l to 22.3 mmol/l relative to the control group (29.2mmol/l to 26.7mmol/l), albeit the blood glucose remained elevated. To bolster this finding, systemic α-MSH (1μg/h) delivery during a 2h hyperinsulinemic-euglycemic clamp in lean mice showed a significant increase in glucose infusion rate (Control: 57.3±6.7 mg/kg/min, α-MSH: 70.3±4.7 mg/kg/min, p<0.01) and whole body glucose turnover (Control: 54.2±4.2 mg/kg/min, α-MSH: 63.9±5.2 mg/kg/min, p<0.05). Notably, insulin-mediated glucose disposal rate was no altered showing the additive effect of α-MSH in mediating glucose disposal in skeletal muscle.

A single intracerebroventricular (icv) injection of α-MSH did not alter the glucose tolerance tests in lean mice. Furthermore, hyperglycemia remains unaltered when α-MSH was delivered centrally in S961-treated mice. Collectively, these findings support the notion that peripheral α-MSH is involved in whole body glucose homeostasis independent of insulin. In addition, this study unveils a key role of α-MSH to improve insulin deficiency associated with type 1 diabetes.