Metformin is expected to become a safe and reliable new weight loss drug

Metformin is a drug for the treatment of type 2 diabetes. As an oral hypoglycemic drug that has entered thousands of households, it has a history of more than 60 years of clinical application since its introduction in 1957. Today, about 150 million people around the world are taking metformin, which is currently one of the most widely used oral hypoglycemic drugs.

**With the continuous in-depth research on metformin in recent years, many scholars have found that in addition to its blood sugar-lowering effect, it can also reduce the weight of diabetic patients. **However, for decades, the mechanism by which metformin can reduce weight has not been confirmed by relevant research.

The latest research published in Nature Metabolism recently revealed a new mechanism of action of metformin for weight loss. Nature Metabolism also published a special review article, pointing out that exploring the downstream signaling pathways of metformin may lead to safer and more reliable weight loss therapies.

Although metformin has been used for hypoglycemic treatment as early as the 1950s, new functions are constantly being discovered as scientists continue to conduct in-depth research. In addition to the well-known hypoglycemic function, it also has cardiovascular protection, weight loss, improved blood lipid metabolism, reduced the risk of some cancers, and anti-aging effects. Therefore, it is also called a "miracle drug."

The weight loss effect of metformin can be said to be an additional benefit for diabetic patients after improving their metabolism. In peripheral tissues, it can improve insulin sensitivity, increase glucose uptake and utilization; inhibit hepatic gluconeogenesis and decomposition, and reduce hepatic glucose output; it can also inhibit intestinal absorption of glucose and increase glucagon-like peptide-1 levels; by reducing the source of blood sugar and increasing the way out of blood sugar, it can achieve the purpose of lowering blood sugar. When the energy consumed by the human body is greater than the energy taken in for a long time, the body weight will be reduced.

The U.S. Diabetes Prevention Program study enrolled 3,234 obese patients with prediabetes and randomly divided them into a lifestyle intervention group, a placebo group, and a metformin group. After 2.8 years of follow-up, the average weight of the three groups of patients decreased by 5.6, 0.1, and 2.1 kg, respectively (P<0.001), which shows that metformin can safely and effectively improve insulin resistance and has a certain effect on weight control in obese and overweight patients with type 2 diabetes.

Previous studies have shown that metformin's weight loss effect mainly comes from suppressing appetite, but how it achieves this effect has been debated by scientists for decades.

In the latest study published in Nature Metabolism, a research team led by Dr. Jonathan Z. Long of Stanford University found that metformin can promote intestinal cells to produce a metabolite called Lac-Phe in the intestines of humans and animals. Previous research by Dr. Long's team showed that Lac-Phe is a metabolic molecule synthesized based on lactate and phenylalanine. Intense exercise in humans can lead to increased lactate levels in the blood, and the level of Lac-Phe also increases. Lac-Phe has the effect of reducing appetite. Long-term use of Lac-Phe in mouse models can reduce adipose tissue levels and body weight and improve glucose homeostasis.

To further confirm whether the weight loss effect of metformin depends on the Lac-Phe-mediated signaling pathway, the researchers used a mouse model in which the key enzyme CNDP2 for synthesizing Lac-Phe is not expressed in the cells of this mouse, so Lac-Phe cannot be produced. Both CNDP2 knockout mice and wild-type mice gain weight significantly after 8 weeks of high-fat diet. Taking metformin causes wild-type mice to have a decreased appetite and slower weight gain, while in CNDP2 knockout mice, metformin has almost no effect.

Figure 1 Comparison of body weight between mice and wild mice

In CNDP2 knockout mice, the weight loss effect of metformin was greatly weakened. Further studies have found that metformin can stimulate the production of Lac-Phe in the intestine by inhibiting the electron transport chain complex 1 of intestinal epithelial cells expressing CNDP2, thereby increasing the level of lactate flowing into cells. So far, scientists have built a complete signaling pathway for metformin weight loss. Oral metformin stimulates intestinal epithelial cells expressing CNDP2 to produce Lac-Phe in the intestine, and Lac-Phe suppresses appetite by acting on the brain-gut axis to achieve a weight loss effect.

So, for ordinary people who want to lose weight all day long but do not have diabetes or insulin resistance, can they use metformin to lose weight?

The answer is no.

Metformin has clear indications, and it is clearly stated in the drug instructions that it is only a blood sugar-lowering drug, not a weight-loss drug.

The "weight loss" effect of metformin is an additional benefit for overweight and obese diabetic patients to restore their normal weight after improving their sugar metabolism, which can be said to be an "unexpected gain". For those who are simply obese, metformin does not have a definite weight loss effect, and blind use may bring adverse consequences, so doctors must remind patients to pay attention.

References:

TeSlaa T. Metformin induces a Lac-Phe gut-brain signaling axis. Nat Metab. 2024 Mar 18.