Insulin-independent
glucose disposal (referred to as
glucose effectiveness [GE]) is crucial for
glucose homeostasis and, until recently, was thought to be invariable. However, GE is reduced in
type 2 diabetes and markedly decreased in
leptin-deficient ob/ob mice. Strategies aimed at increasing GE should therefore be capable of improving
glucose tolerance in these animals. The gut-derived
hormone FGF19 has previously been shown to exert potent
antidiabetic effects in ob/ob mice. In ob/ob mice, we found that systemic FGF19 administration improved
glucose tolerance through its action in the brain and that a single, low-dose i.c.v. injection of FGF19 dramatically improved
glucose intolerance within 2 hours. Minimal model analysis of
glucose and
insulin data obtained during a frequently sampled i.v.
glucose tolerance test showed that the
antidiabetic effect of i.c.v. FGF19 was solely due to increased GE and not to changes of either insulin secretion or
insulin sensitivity. The mechanism underlying this effect appears to involve increased metabolism of
glucose to
lactate. Together, these findings implicate the brain in the
antidiabetic action of systemic FGF19 and establish the brain’s capacity to rapidly, potently, and selectively increase
insulin-independent
glucose disposal.