Metformin is an unassuming hero of modern medicine. For more than 60 years, this humble pill has been a mainstay of diabetes care, helping millions of people manage their blood sugar. It lowers blood sugar, improves cholesterol, modestly reduces weight and is so safe it’s prescribed to millions worldwide. And yet, for decades, scientists haven’t fully understood how it works.
The standard explanation has long been that metformin works in the liver, reducing how much sugar it sends into the bloodstream. It also helps muscles and fat cells respond more effectively to insulin.
More recent research added other suspects: the gut, which can tweak hormones and the microbiome, and a cellular pathway called mTOR, a major regulator of metabolism and longevity. But a new study published in Science Advances suggests that part of metformin’s magic might be happening somewhere unexpected: in the brain.
• The Blood Sugar Command Center
Researchers turned their attention to a protein called Rap1, found in a small pocket of the brain known as the ventromedial hypothalamus (VMH). This area is a metabolic mission control, coordinating hunger, energy use and glucose balance.
When scientists switched off Rap1 in this brain region in mice, blood sugar levels fell, even without metformin. But when they kept Rap1 switched on, metformin lost its blood-sugar-lowering power. The results hint that, at the doses typically prescribed, metformin may partly work by silencing Rap1’s activity in the brain, not just by acting on the liver or gut.
Most of us think of blood sugar control as the domain of the pancreas, liver and muscles. Yet the brain is deeply involved. The VMH works like an air traffic controller, taking in information from across the body and sending out signals to adjust glucose production and use. Metformin, it seems, may be tapping into this high-level control system. By dialing down Rap1 activity, the drug might trigger a cascade of neural instructions that ripple out to the rest of the body, improving how tissues handle sugar.
• Beyond Diabetes
The discovery of the brain-Rap1 link opens new possibilities. Could this same circuit be part of metformin’s longevity effects? If so, drugs that target Rap1 or its related pathways might someday offer more precise ways to improve metabolism or promote healthy aging, perhaps without some of metformin’s side effects.
• When Old Drugs Tell New Tales
This does not mean discarding what is already known about metformin’s effects on the liver, muscles and gut. Those mechanisms are still in play. But at everyday doses, the brain may have a starring role in how the drug works. At much higher doses, peripheral mechanisms can take over, but in real-world clinical use, the brain’s contribution could be key.
From www.medscape.com
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https://www.science.org/doi/10.1126/sciadv.adu3700
Low-dose metformin requires brain Rap1 for its antidiabetic action
Hsiao-Yun Lin et al
Abstract
Metformin is the most commonly prescribed antidiabetes drug, yet its precise mechanism of action remains controversial. Previous studies have suggested that metformin acts peripherally by reducing hepatic glucose output and altering gut functions.
Here, we report a neural mechanism via the small guanosine triphosphatase Ras-related protein 1 (Rap1). Mice with forebrain-specific Rap1 knockout exhibited resistance to the antidiabetic effects of low-dose metformin while remaining sensitive to other antidiabetic agents. Centrally administered metformin inhibited brain Rap1 and reduced hyperglycemia. Conversely, forced activation of brain Rap1 increased glycemia and abolished the glycemic effect of metformin. Metformin activated a specific subset of neurons in the ventromedial hypothalamic nucleus (VMH) that requires Rap1. Both loss-of-function and gain-of-function studies suggest that VMH Rap1 is indispensable for the antidiabetic effects of metformin. These findings highlight the VMH Rap1 pathway as a critical mediator of metformin action.
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