New route for regulating blood sugar levels independent of insulin
New molecular pathway controls blood glucose, circumventing insulin
resistance

Date:
January 4, 2022
Source:
Salk Institute
Summary:
The discovery of insulin 100 years ago opened a door that would
lead to life and hope for millions of people with diabetes. Ever
since then, insulin, produced in the pancreas, has been considered
the primary means of treating conditions characterized by high
blood sugar (glucose), such as diabetes. Now, scientists have
discovered a second molecule, produced in fat tissue, that, like
insulin, also potently and rapidly regulates blood glucose. Their
finding could lead to the development of new therapies for treating
diabetes, and also lays the foundation for promising new avenues
in metabolism research.



FULL STORY ==========================================================================
The discovery of insulin 100 years ago opened a door that would lead
to life and hope for millions of people with diabetes. Ever since then, insulin, produced in the pancreas, has been considered the primary means
of treating conditions characterized by high blood sugar (glucose), such
as diabetes. Now, Salk scientists have discovered a second molecule,
produced in fat tissue, that, like insulin, also potently and rapidly
regulates blood glucose. Their finding could lead to the development of
new therapies for treating diabetes, and also lays the foundation for
promising new avenues in metabolism research.


==========================================================================
The study, which was published in Cell Metabolism on January 4, 2022,
shows that a hormone called FGF1 regulates blood glucose by inhibiting
fat breakdown (lipolysis). Like insulin, FGF1 controls blood glucose
by inhibiting lipolysis, but the two hormones do so in different
ways. Importantly, this difference could enable FGF1 to be used to
safely and successfully lower blood glucose in people who suffer from
insulin resistance.

"Finding a second hormone that suppresses lipolysis and lowers glucose
is a scientific breakthrough," says co-senior author and Professor Ronald Evans, holder of the March of Dimes Chair in Molecular and Developmental Biology. "We have identified a new player in regulating fat lipolysis
that will help us understand how energy stores are managed in the body."
When we eat, energy-rich fats and glucose enter the bloodstream. Insulin normally shuttles these nutrients to cells in muscles and fat tissue,
where they are either used immediately or stored for later use. In people
with insulin resistance, glucose is not efficiently removed from the
blood, and higher lipolysis increases the fatty acid levels. These extra
fatty acids accelerate glucose production from the liver, compounding the already high glucose levels. Moreover, fatty acids accumulate in organs, exacerbating the insulin resistance -- characteristics of diabetes
and obesity.

Previously, the lab showed that injecting FGF1 dramatically lowered
blood glucose in mice and that chronic FGF1 treatment relieved insulin resistance.

But how it worked remained a mystery.

In the current work, the team investigated the mechanisms behind
these phenomena and how they were linked. First, they showed that
FGF1 suppresses lipolysis, as insulin does. Then they showed that FGF1 regulates the production of glucose in the liver, as insulin does. These similarities led the group to wonder if FGF1 and insulin use the same
signaling (communication) pathways to regulate blood glucose.

It was already known that insulin suppresses lipolysis through PDE3B,
an enzyme that initiates a signaling pathway, so the team tested a full
array of similar enzymes, with PDE3B at the top of their list. They were surprised to find that FGF1 uses a different pathway -- PDE4.

"This mechanism is basically a second loop, with all the advantages of
a parallel pathway. In insulin resistance, insulin signaling is impaired.

However, with a different signaling cascade, if one is not working, the
other can. That way you still have the control of lipolysis and blood
glucose regulation," says first author Gencer Sancar, a postdoctoral
researcher in the Evans lab.

Finding the PDE4 pathway opens new opportunities for drug discovery
and basic research focused on high blood glucose (hyperglycemia) and
insulin resistance.

The scientists are eager to investigate the possibility of modifying FGF1
to improve PDE4 activity. Another route is targeting multiple points in
the signaling pathway before PDE4 is activated.

"The unique ability of FGF1 to induce sustained glucose lowering in
insulin- resistant diabetic mice is a promising therapeutic route for
diabetic patients.

We hope that understanding this pathway will lead to better treatments
for diabetic patients," says co-senior author Michael Downes, a senior
staff scientist in the Evans lab. "Now that we've got a new pathway,
we can figure out its role in energy homeostasis in the body and how
to manipulate it." Other authors included Sihao Liu, Emanuel Gasser, Jacqueline G. Alvarez, Christopher Moutos, Kyeongkyu Kim, Yuhao Wang,
Timothy F. Huddy, Brittany Ross, Yang Dai, David Zepeda, Brett Collins,
Emma Tilley, Matthew J. Kolar, Ruth T.

Yu, Annette R. Atkins and Alan Saghatelian of Salk; Tim van Zutphen,
Theo H.

van Dijk and Johan W. Jonker of the University of Groningen, in the Netherlands.

The research was supported by the National Institutes of Health, the Nomis Foundation, the March of Dimes, Deutsche Forschungsgemeinschaft (DFG), Netherlands Organization for Scientific Research, the European Foundation
for the Study of Diabetes and the Swiss National Science Foundation.

========================================================================== Story Source: Materials provided by Salk_Institute. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Gencer Sancar, Sihao Liu, Emanuel Gasser, Jacqueline G. Alvarez,
Christopher Moutos, Kyeongkyu Kim, Tim van Zutphen, Yuhao Wang,
Timothy F. Huddy, Brittany Ross, Yang Dai, David Zepeda, Brett
Collins, Emma Tilley, Matthew J. Kolar, Ruth T. Yu, Annette
R. Atkins, Theo H. van Dijk, Alan Saghatelian, Johan W. Jonker,
Michael Downes, Ronald M. Evans.

FGF1 and insulin control lipolysis by convergent pathways. Cell
Metabolism, 2022; 34 (1): 171 DOI: 10.1016/j.cmet.2021.12.004 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220104112231.htm
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