Central and Peripheral Administration of Fibroblast Growth Factor 1 Improves Pancreatic Islet Insulin Secretion in Diabetic Mouse Models

Abstract

Fibroblast growth factor 1 (FGF1) has been shown to reverse hyperglycemia in diabetic rodent models through peripheral and central administration routes. Previous studies demonstrated that insulin is required for central and peripheral FGF1 metabolic improvements; however, it is unknown if FGF1 targets insulin secretion at the islet level. Here we show for the first time that FGF1 increases islet insulin secretion in diabetic mouse models. FGF1 was administered via a single intracerebroventricular or multiple subcutaneous injections to leptin receptor-deficient (db/db), diet-induced obese, and control mice; pancreatic islets were isolated 7 days later for analysis of insulin secretion. Central and peripheral FGF1 significantly lowered blood glucose in vivo and increased ex vivo islet insulin secretion from diabetic, but not control, mice. FGF1 injections to the cisterna magna mimicked intracerebroventricular outcomes, pointing to a novel therapeutic potential. Central effects of FGF1 appeared dependent on reductions in food intake, whereas peripheral FGF1 had acute actions on islet function prior to significant changes in food intake or blood glucose. Additionally, peripheral, but not central, FGF1 increased islet β-cell density, suggesting that peripheral FGF1 may induce long-term changes in islet structure and function that are not present with central treatment.

Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission

“…To estimate which subpopulations were most affected one day after icv FGF1 injection, differentially expressed genes (DEGs) were identified with a repeated downsampling approach to control for both cell number and between-sample variation 19 . In line with previous evidence that both tanycytes and astrocytes are highly responsive to FGF1 4,5,11 , robust transcriptomic responses were observed in tanycytes, ependymal cells, and, to a lesser degree, astrocytes (false discovery rate (FDR) < 0.1; Fig. 1e).…”

“…That a single icv injection of FGF1 is sufficient to re-set the defended level of glycemia to normal in rodent models of T2D 4,5,11 is a finding of substantial therapeutic relevance. Ongoing efforts to bridge the gap between diverse cellular responses to FGF1 and the associated normalization of glycemia may ultimately uncover novel strategies for achieving sustained diabetes remission.…”

“…While this finding is in line with accumulating evidence supporting a key role for the hypothalamus in glucose homeostasis, our current understanding of glucoregulatory neurocircuitry is limited 6 , 7 . Most of this work is focused on hypothalamic neurons with glucose-sensing properties 8 , but many glial cell types are also potential targets for the hypothalamic action of FGF1, since tanycytes and astrocytes are implicated in glucose homeostasis 9 , 10 and since glial cell responsiveness to FGF ligands is well documented 5 , 11 , 12 . Moreover, glia–neuron interactions can modify neuronal activity and remodel neurocircuit structure 13 – 15 , effects of interest for understanding the long-lived nature of the FGF1 effect.…”

Leptin modulates pancreatic β-cell membrane potential through Src kinase–mediated phosphorylation of NMDA receptors

“…Mice were purchased from The Jackson Laboratory (Bar Harbor, ME): control (C57BL/6J) and db/db [B6.BKS(D)-Lepr db /J]. Pancreatic islets were isolated from the mice as described previously (75) and were performed in compliance with institutional guidelines and approved by the Oregon Health and Science University Animal Care and Use Committee. Following isolation islets were cultured overnight in FBS supplemented RPMI 1640 media at 37 o C and 5% CO2.…”

Rethinking the role of the brain in glucose homeostasis and diabetes pathogenesis

“…This model of T2D pathogenesis predicts that correcting the underlying defect should normalize glycemia in diabetic animals. Notable in this regard is the sustained antidiabetic action induced by central administration of FGF1 (19)(20)(21)(22). In rodent models of T2D, remission of hyperglycemia can be sustained for weeks or months following a single intracerebroventricular injection of FGF1.…”