The discovery of a hormone regulating blood glucose levels independently of insulin could lead to the development of new diabetes therapies and open up promising new avenues in metabolism research, according to a study led by researchers at the Salk Institute for Biological Studies.
Like insulin, the fibroblast growth factor 1 (FGF1) hormone was shown to regulate blood glucose by inhibiting lipolysis. Although the two hormones do so via different mechanisms, the elucidation of these could enable FGF1 to be used to lower blood glucose in patients with insulin resistance (IR).
"We have identified a new player in regulating lipolysis that will help us understand how energy stores are managed in the body," said study co-leader Ronald Evans, professor and director of the Gene Expression Laboratory at the Salk Institute.
"While we have previously shown that FGF1 can lower blood glucose, the mechanism was unknown, with the present study being the first to functionally connect the glucose lowering ability of FGF1 with its suppression of adipose lipolysis," Evans told BioWorld Science.
In patients with IR, glucose is inefficiently removed from the blood and higher lipolysis increases fatty acid levels, accelerating hepatic glucose production and compounding the elevated glucose concentration.
Moreover, fatty acids "are known to accumulate aberrantly in the liver and muscle, contributing to and exacerbating the characteristic IR seen in the progression of diabetes and obesity," said Evans.
Injecting FGF1 had previously been shown to profoundly reduce blood glucose levels in mice, while chronic FGF1 treatment had been shown to relieve IR, albeit via unknown mechanisms.
These mechanisms were investigated in the Salk Institute study, which was reported in the January 4, 2022, edition of Cell Metabolism.
The researchers first demonstrated that, like insulin, FGF1 suppressed lipolysis and regulated the production of glucose in the liver, suggesting that FGF1 and insulin may share the same blood glucose regulatory signaling pathways.
"Using complementary loss-of-function genetic mouse models, we showed that FGF1 injection suppressed lipolysis in adipose tissue explants, lowered circulating free fatty acid levels, and reduced gluconeogenic intermediates in liver," said Evans "In addition, we showed that the ability of FGF1-treated mice to convert pyruvate to glucose in the liver was compromised."
Insulin suppresses lipolysis via the enzyme phosphodiesterase 3B (PDE3B), which initiates a signaling pathway, prompting investigation of PDE3B and similar enzymes.
Surprisingly, the researchers found that FGF1 used a different signaling pathway via PDE4, which is "basically a second loop, with all the advantages of a parallel pathway," said first author Gencer Sancar, a postdoctoral researcher in Evans' lab.
"In IR, insulin signaling is impaired, but with a different signaling cascade; if one is not working, the other can, so you still have control of lipolysis and blood glucose regulation," said Sancar.
This was a surprising finding, because "while the existence of parallel regulatory pathways in biology is not uncommon, a second anti-lipolytic hormone had simply not been expected," noted Evans.
"We propose that the autocrine action of FGF1 in adipose tissue cooperates with the endocrine actions of insulin and, given the importance of lipolysis in maintaining glucose homeostasis, we propose that the parallel signaling pathways provide a more resilient regulatory program."
This is important, "as the elucidation of a second anti-lipolytic pathway will further our understanding of adipose biology, as well as potentially leading to the development of novel approaches to treat diabetes," said Evans.
Indeed, the discovery of the PDE4 pathway opens new opportunities for drug discovery and basic research focused on hyperglycemia and IR.
The Salk Institute scientists are now planning to investigate the possibility of modifying FGF1 to improve PDE4 activity, as well as targeting multiple points prior to PDE4 activation.
"As FGF1 is a short-lived protein, we are exploring mutations/modifications that improve its stability in the circulation and increase its targeting to adipose tissue," said Evans.
"In addition, targeting the kinase/phosphatase that regulates PDE4 phosphorylation may synergize with FGF1 treatment."
"The unique ability of FGF1 to induce sustained glucose lowering in insulin-resistant diabetic mice is a promising therapeutic route for diabetic patients," noted study co-leader Michael Downes, senior staff scientist in Evans' lab.
"We hope that understanding this pathway will lead to better treatments for diabetic patients and, now that we have a new pathway, we can investigate its role in energy homeostasis and how to manipulate it."
"Our study paves the way for new therapeutic routes to treat type 2 diabetes such as FGF1 analogues or PDE4 modulators," noted Evans.
"In addition, the fundamental insights into adipose tissue biology provided by our work may lead to approaches to reduce circulating fatty acid levels by improving adipose storage," he said."We are currently investigating other players involved in FGF1/PDE4 pathway and in future we will explore whether PDE4 is required for the insulin sensitization observed with chronic FGF1 treatment."