New molecular pathway controls blood glucose, circumventing insulin resistance.
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.”
Reference: “FGF1 and insulin control lipolysis by convergent pathways” by 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 and Ronald M. Evans, 4 January 2022, Cell Metabolism.
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.
this could be a big deal, i think the agent orange from viet nam which causes adult onset diabetes could be linked to this
I would like more information….on this underline health issue..
I Love this article…very interesting information..
Big money by quadrillions.
I went from 1,500 to 75 in one year and my doctor is very suprised and I have had three shots!
Really wish they would distinguish between Type 2 and Type 1 diabetes in these articles.
Great news, thank God for the update. I wonder how soon the breakthrough to get a complete cure for type-2 diabetes will come over.
I sure hope that it is in the pill form
Great breakthrough by those learned Brothers and Sisters. Keep up!!
Yes they definitely need to distinguish between type 1 and type 2 in these articles It’s a waste of time to read about type 2 when you are a type 1. And then somebody said a cure for type 2 diabetes. Are you kidding me How about a cure for type 1 type 1 is nothing like type 2 Don’t get me started on that. All you type 2’s be thankful that you are a type 2 and not a one In fact we need to be in a class all of our own. Type 2s don’t know how good they’ve got it. Try being in the hospital for the past 3 years 45 times in DKA fighting for your life Three of those times in a coma and your family don’t know if you’re going to make it or not. The doctors are trying their best to control your sugar by an insulin drip while you are in ICU and all of a sudden for no reason your sugar jumps over 500 and then 30 minutes later crashes to 50 How many type 2s have done that. When you are a brittle type 1 and there is nothing you can do to control your sugar It’s tough It’s very tough. Especially when you were diagnosed in 2014 at the age of 28 your whole life changes And everything you knew has turned upside down. Then let’s add gastro paresis and lymphocytic colitis and neuropathy so bad that you cannot stand it and then you lose your eyesight because you have macular edema and the list goes on to kidneys disease heart disease it affects everything. The counter blessings you’re not a type 1