The vascular dysfunction associated with type 2 diabetes is the principal cause of death and disability among the patients. Diabetes mellitus is associated with both microvascular and macrovascular diseases affecting numerous organs, including skeletal muscle, skin, heart, brain, and kidneys¹. Diabetes-associated vascular alterations include anatomic, structural, and functional changes leading to multiorgan dysfunction². One of the major hallmarks of diabetes is the decline in skeletal muscle capillary density, which eventually leads to pronounced decline in skeletal muscle mass³. Such alterations in capillary density in muscle also contribute to the decrease in muscle endurance. Recent studies point to Sirt1, an NAD⁺-dependent protein deacylases, as a key regulator of vascular endothelial homeostasis controlling angiogenesis, vascular tone and endothelial dysfunction⁴. Although Sirt1 has been demonstrated to have beneficial effects on glucose homeostasis and insulin sensitivity in animal models of insulin resistance, it’s role in diabetes-induced vascular dysfunction has yet to be fully elucidated⁵.

In this study we showed that treatment with a NAD⁺ precursor - Nicotinamide Mononucleotide (NMN) - ameliorated diabetes and age-induced decrease in skeletal muscle capillary density and restored muscle endurance capacity in mice. High-fat diet fed mice treated with 2g/L NMN in drinking water demonstrated improved glucose tolerance, insulin secretion and exercise capacity. Mice treated with NMN exhibited higher skeletal muscle capillary density compared to their littermate controls. To address the role of Sirt1 we also created genetically engineered mice that either overexpresses or are deleted of Sirt1 specifically in skeletal muscle capillaries. Loss of endothelial Sirt1 abrogated muscle endurance whereas its overexpression increased muscle endurance in mice. These observations were concomitant with skeletal muscle vascular density. Therefore, we provide evidence that activation of Sirt1 by using NAD⁺ precursor NMN could lead to effective therapy for diabetes mellitus.