Insulin resistance precedes and predicts the development of type 2 diabetes mellitus (T2D). Adipose tissue has an important role in the development of insulin resistance. Failure to develop adequate adipose tissue mass (known as ‘lipodystrophy’) results in severe insulin resistance and non-obese diabetes. This is thought to be due to the increased levels of circulating fatty acids and lipid accumulation in non-adipose tissues such as liver and muscles. This situation is improved by PPAR-γ ligands, which promote fatty acids storage in fat depots and regulate the expression of genes that impact on glucose and lipid metabolism. Recently, increasing evidence demonstrated that hexarelin, a growth hormone secretagogue (GHS), promoted PPAR-γ activation in macrophages and adipocytes that might impact the overall metabolic activity of lipid storage and mobilization by adipocytes1. However, the effects of GHS receptor (GHS-R) agonists and antagonists in diabetes are still not clear2. This work studied the effects of GHS-R agonist (hexarelin) and antagonist ((D-Lys3)-GHRP-6) in lean T2D MKR mice. MKR mouse model provides a good comparative model of human non-obese T2D, which is chracterized by hyperinsulinaemia, hypertriglyceridaemia and impared adipose tissue lipogenesis. Our data demonstrated that chronic treatment with hexarelin for 2 weeks restored glucose and insulin tolerance to normal levels in MKR mice. This could be attributed to the improvement of fatty acid oxidation as measured by indirect calorimetry. Histological examination of gonadal adipose tissues showed increased adipocytes proliferation in hexarelin treated group comared to saline and (D-Lys3)-GHRP-6 treated groups. Treatment with (D-Lys3)-GHRP-6) had no effect on glucose, insulin tolerance and showed an unexpected increase in food intake in MKR-treated mice. In conclusion, these results demonstrate that hexarelin improved the diabetic state of non-obese diabetic MKR mice by potentiation of fatty acid oxidation and adipocytes proliferation, suggesting a potential therapeutic role for hexarelin in non-obese diabetes.