Prevention of insulin-induced lipohypertrophy by coadministration of a low dose of high-affinity PI3K inhibitors

Abstract

Background

Insulin-induced lipohypertrophy (ILH) is the most frequent injection site side effect of insulin therapy. ILH consists of local adipose tissue overgrowth at the insulin injection site that eventually progresses to lipoma-like masses of a relatively large size, causing discomfort and disfiguration. Insulin injection into ILH areas delays insulin delivery, and the presence of ILH is associated with poor glycemic control and more frequent hypoglycemic events. Although, in principle, the development of ILH can be minimized by avoiding injecting insulin in the same spot, in practice, ILH remains highly prevalent. So far, no molecular mechanism for ILH has been proposed.

Methods

We screened a panel of PI3K inhibitors with different specificities for their capacity to reduce insulin signaling and growth of human primary adipocytes exposed to pharmacological doses of insulin. The two most effective inhibitors from the screening above were investigated in an in-vivo model of ILH.

Results

We identified PI3K inhibitors capable of reducing the hypertrophic (enlargement of lipid droplets) and hyperplastic (adipocyte differentiation) growth of primary human adipocytes exposed to pharmacological doses of insulin. Since preventing ILH development requires only a localized inhibition of PI3K activity, using a low dose of high-affinity PI3K inhibitors, we could prevent the development of ILH in a mouse model without inhibiting the systemic effects of insulin on blood glucose and without causing any apparent adverse reaction.

Conclusion

We now show evidence indicating that ILH is caused by pathological PI3K activation at insulin injection sites and that ILH can be prevented by local inhibition of PI3K activity at the injection site.