Exploring the Role of the Insulin and Insulin-like Growth Factor Receptors in Vascular Regeneration and Aging

Insulin resistance is a key independent risk factor for cardiovascular disease. Our group has previously shown that the insulin-like growth factor-1 receptor (IGF-1R) is a negative regulator of insulin receptor (IR) signalling, by sequestering IR subunits in insulin resistant IR:IGF1R ‘hybrid receptors’. By crossing IR haploinsufficient (IRKO) mice with IGF-1R haploinsufficient (IGF1Rko) mice (producing “double knockout” or DKO mice), our group has previously demonstrated rescue of the endothelial dysfunction caused by insulin resistance. Whether this is associated with wider benefits in vascular biology or aging is unclear. Our hypothesis was that reduced expression of the IGF-1R in whole body insulin resistance would improve vascular repair and regeneration and prolong healthspan. Metabolic assessment included measurement of weight gain and glucose and insulin tolerance testing. We studied vascular repair and regeneration with in vivo models, complementing these studies with mechanistic work in vitro. 15 animals per group were aged until they met healthspan endpoints, with monitoring of metabolic status throughout. Glucose and insulin tolerance tests were similar in young DKO and IRKO mice, with DKO and IRKO having improved glucose tolerance and insulin sensitivity compared with WT and IGF1Rko when tested at ≥80 weeks of age. Body weight was significantly lower in young DKO than IRKO, with IRKO and DKO remaining lighter than WT and IGF-1Rko littermates as they aged. DKO had superior recovery after induction of hind-limb ischemia versus both IRKO and WT. Re- endothelialisation after denuding femoral artery wire injury was improved in the DKO group compared with IRKO. Healthspan was significantly prolonged in DKO versus WT. In conclusion, reduced IGF-1R expression improves vascular repair and regeneration in the context of whole-body insulin resistance, and also appears to promote healthy aging. Further work will aim to elucidate the possible mechanisms for these observations.