Peripheral mechanisms mediating the sustained antidiabetic action of FGF1 in the brain

Jarrad M. Scarlett, Kenjiro Muta, Jenny M. Brown, Jennifer M. Rojas, Miles E. Matsen, Nikhil K. Acharya, Anna Secher, Camilla Ingvorsen, Rasmus Jorgensen, Thomas Høeg-Jensen, Darko Stefanovski, Richard N. Bergman, Francesca Piccinini, Karl J. Kaiyala, Masakazu Shiota, Gregory J. Morton, Michael W. Schwartz

Research output: Contribution to journalJournal articleResearchpeer-review

39 Citations (Scopus)

Abstract

We recently reported that in rodent models of type 2 diabetes (T2D), a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces remission of hyperglycemia that is sustained for weeks. To clarify the peripheral mechanisms underlying this effect, we used the Zucker diabetic fatty fa/fa rat model of T2D, which, like human T2D, is characterized by progressive deterioration of pancreatic b-cell function after hyperglycemia onset. We report that although icv FGF1 injection delays the onset of b-cell dysfunction in these animals, it has no effect on either glucose-induced insulin secretion or insulin sensitivity. These observations suggest that FGF1 acts in the brain to stimulate insulin-independent glucose clearance. On the basis of our finding that icv FGF1 treatment increases hepatic glucokinase gene expression, we considered the possibility that increased hepatic glucose uptake (HGU) contributes to the insulin-independent glucose-lowering effect of icv FGF1. Consistent with this possibility, we report that icv FGF1 injection increases liver glucokinase activity by approximately twofold. We conclude that sustained remission of hyperglycemia induced by the central action of FGF1 involves both preservation of b-cell function and stimulation of HGU through increased hepatic glucokinase activity.
Original languageEnglish
JournalDiabetes
Volume68
Issue number3
Pages (from-to)654-664
Number of pages11
ISSN0012-1797
DOIs
Publication statusPublished - 1 Mar 2019
Externally publishedYes

Cite this