INS and Hyperinsulinemia: Since the PACAP/VIP system has been associated with modulating IR in the hyperinsulinemia environment, possibly by sensitizing neurons to insulin [121], it is possible that metformin increased the expression of PACAP and VIP in an attempt to regain homeostatic control of brain glucose metabolism, noting that metformin is known to sensitize neuronal cell lines to insulin under hyperinsulinemic insults [119].