100 years later, scientists have discovered a second blood sugar regulation pathway other than insulin, opening a new door for diabetes treatment

Written | Edited by Wang Cong | Typesetting by Wang Duoyu | Shui Chengwen As early as more than 3,000 years ago, ancient Egypt had records of diabetes
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For thousands of years, human beings have been helpless against diabetes, and once they develop diabetes, they can only sit still
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It was not until the early 20th century that people realized that the urine sugar of diabetic patients was caused by the increase of blood sugar, which was related to the pancreas
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In 1921, Frederick Banting (Frederick Banting) and others discovered insulin (insulin), and in January 1922, insulin was successfully used to treat diabetic patients
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The discovery and use of insulin 100 years ago opened a door to life and hope for millions of people with diabetes
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Since then, insulin, produced in the pancreas, has been considered the mainstay of treatment for diseases characterized by high blood sugar (glucose), such as diabetes
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On January 4, 2022, researchers from the Salk Institute in the United States published a research paper entitled: FGF1 and insulin control lipolysis by convergent pathways in Cell Metabolism, a sub-journal of Cell
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The study found that FGF1, like insulin, rapidly regulates blood sugar levels by inhibiting lipolysis by rapidly lowering hepatic glucose levels, and is the second molecule that rapidly regulates blood sugar
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The discovery could lead to new treatments for diabetes and a new foundation for metabolic research
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At the molecular level, FGF1 acts by activating PDE4D (phosphodiesterase 4D) to inhibit the cAMP-protein kinase A signaling axis, which is different from insulin's mechanism through the PDE3B pathway
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These findings suggest that the FGF1/PDE4 pathway is a second rapid blood glucose regulation pathway in parallel with insulin/PDE3B
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FGF1 works differently than insulin, and this difference may allow FGF1 to safely and effectively lower blood sugar in people with insulin resistance
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Corresponding author of the paper, Professor Ronald Evans, said finding a second hormone other than insulin that inhibits lipolysis and lowers blood sugar levels is a scientific breakthrough
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This study has identified FGF1 as a novel player in fat regulation, which also contributes to our understanding of the body's management of energy storage
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When we eat, energy-rich fats and glucose enter the bloodstream
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Insulin normally delivers these nutrients to cells in muscle and fat tissue, where they can be used immediately or stored for later use
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For those with insulin resistance, glucose cannot be removed from their blood efficiently, and higher lipolysis increases fatty acid levels
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These extra fatty acids speed up the production of glucose in the liver, complicating already high blood sugar levels
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In addition, fatty acid accumulation in organs can exacerbate insulin resistance, which is a hallmark of diabetes and obesity
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Previously, the team had discovered that FGF1 exerts a powerful antidiabetic effect through the adipose FGF receptor 1 (FGFR1)
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Injection of FGF1 significantly reduced blood glucose levels in mice, and FGF1 treatment alleviated insulin resistance
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But exactly how FGF1 works has remained a mystery
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First, the team found that FGF1, like insulin, inhibits fat breakdown and regulates glucose production in the liver
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These similarities led the research team to speculate whether FGF1 and insulin regulate blood sugar through the same pathway
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We know that insulin acts through the PDE3B pathway to inhibit lipolysis
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The research team was surprised to find that FGF1 exerts the same effect through a new signaling pathway, PDE4
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The research team said that insulin and FGF1 can be seen as two parallel pathways, and this parallel pathway is somewhat obvious.
In people with insulin resistance, the insulin pathway is damaged, but the FGF1 pathway can continue to function.
Regulates lipolysis and blood sugar levels
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Insulin and FGF1 are in two parallel pathways that regulate blood sugar.
Image from the Salk Institute.
FGF1 can consistently induce lowering of blood sugar in insulin-resistant diabetic mice.
This unique ability is a very promising approach for the treatment of diabetic patients.
Bringing better treatments to people with diabetes
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Finding the PDE4 pathway opens up new avenues for drug discovery and basic research for the treatment of hyperglycemia and insulin resistance, according to the research team
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Now, on the one hand, it is to improve the activity of PDE4 by modifying FGF1, and on the other hand, it targets and activates the upstream signaling pathway of PDE4
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Paper link: https://doi.
org/10.
1016/j.
cmet.
2021.
12.
004 Open for reprinting, welcome to forward to Moments and WeChat groups