An unexplored protein may curb diabetes

Researchers throughout the world have been trying for years to find a cure for what has been called a runaway and hidden epidemic.

The number of people with diabetes in Denmark has doubled during the past two decades, and this trend will probably continue in the future. The figures primarily reflect an increase in the number of people with type 2 diabetes, which is combatted through lifestyle changes and pharmaceutical treatment. Tablets and injections have been developed, but the most effective remedy is and will be fewer kilos and more exercise.

“Losing weight can really help people, but the vast majority of people have difficulty in keeping the kilos off on their own. Gastric bypass surgery can result in sustained weight loss and can improve a person’s blood glucose levels within a week – well before the weight loss starts. We are therefore interested in determining which proteins can improve a person’s metabolism so substantially, even before they lose weight,” says Lykke Sylow, Associate Professor, Department of Exercise, Nutrition and Sports and head of the Molecular Metabolism in Cancer and Ageing research group, University of Copenhagen.

More muscle mass increases insulin sensitivity

Exercise and a healthier diet can result in gradual weight loss, but there is a more drastic but effective shortcut.

Roux-en-Y gastric bypass surgery constricts the stomach, which reduces the volume of food that can be consumed and thereby limits the uptake of calories. Recent studies have indicated that this surgery has other side-effects. A registry study in Denmark in 2019 concluded that almost two thirds of people with type 2 diabetes were in remission 1 year after undergoing surgery.

Researchers have also showed that bariatric surgery improved the metabolism of severely obese people and lowered their blood glucose in a few weeks. In a new study, they are trying to figure out why.

“We know that gastric bypass surgery leads to quite substantial and sustained weight loss for up to 20 years after surgery. Yet, many of these metabolic changes and improvements occur before the weight loss. There have been several indications that this surgery affects the amount of the protein follistatin. We have previously worked with follistatin and found in mouse experiments that it increases muscle mass quite substantially and improves insulin sensitivity in skeletal muscles,” explains Lykke Sylow.

Increasing muscle mass makes absorbing glucose from the blood easier because it increases the storage space. Combined with follistatin increasing insulin sensitivity this significantly improves metabolic regulation, including lowering blood glucose. One problem people with both type 2 diabetes and overweight have is that their muscles do not absorb as much glucose as those of people with normal weight. Follistatin is therefore an exciting candidate protein for mitigating or perhaps even preventing diabetes.

Follistatin is a police officer

In a previous study, Lykke Sylow and Australian researchers showed that injecting follistatin into the muscles of mice increased their muscle mass by up to 30% and the mice became considerably more insulin sensitive. Other studies have shown that getting follistatin to target the skeletal muscles of the body and not just circulate in the blood can reverse type 2 diabetes in animals.

“We still do not know exactly how follistatin, gastric bypass surgery and insulin sensitivity affect each other. So far, we know that follistatin itself does not directly influence the muscles. Instead, follistatin binds to other proteins that adversely affect muscle mass and insulin sensitivity when they are not bound to follistatin,” says Lykke Sylow.

Follistatin affects myostatin, another protein. Inhibiting or eliminating myostatin produces very muscular cows and dogs. It thus inhibits an inhibitor liberating the muscle mass and insulin sensitivity.

The other protein that follistatin also appears to inhibit is activin A.

“You could say that follistatin is a police officer preventing myostatin and activin A, the criminals, from destroying the house, which in this case are the muscles. Many police officers on the street keep these proteins in check, and follistatin is therefore really important for counteracting activin A and myostatin’s muscle destruction. This especially applies to people with diabetes and obesity, for whom the aim is to upregulate muscle mass and insulin sensitivity,” explains Lykke Sylow.

A protein with potential

In a new study, Lykke Sylow and several colleagues followed 20 people who were obese and were scheduled for gastric bypass surgery at Hvidovre Hospital in Copenhagen. Half of them also had type 2 diabetes. The researchers took blood samples and biopsies from the participants’ muscle and fat tissue and followed up the participants both before and until 1 year after the surgery.

According to the researchers, the results were exciting and partly unexpected.

“The amount of follistatin doubled after 1 week and remained at this level for up to 1 year after the surgery among people who were obese with normal glycaemic regulation. We also expected this to happen among obese people with type 2 diabetes. However, we were surprised that the level of follistatin did not change among people with diabetes despite substantial metabolic changes after surgery in this group,” explains first author Tang Cam Phung Pham, a PhD fellow at the Department of Nutrition, Exercise and Sports, University of Copenhagen.

After 1 week, the concentration of activin A, which inhibits muscle growth, declined by 20% among the overweight people with diabetes and by 27% among the overweight people without diabetes. Most individuals in the first group maintained this decline for up to 1 year after the surgery.

According to the results of the study, the quantity of follistatin in the blood increased among the individuals who were obese but did not have diabetes, and the proportion of activin A declined. More police officers were therefore available to keep track of the criminals, and thus one would expect the muscle mass of that group to remain intact. Among people with diabetes, follistatin levels did not increase after surgery, but the amount of activin A also declined: the same number of police officers for slightly fewer criminals.

“If the surgery-induced benefits are due to the many beneficial effects of follistatin, then the patients without diabetes should be expected to benefit the most. However, that was not the case, since all patients greatly benefitted from surgery. Thus, other mechanisms are implicated that remain to be determined,” says Tang Cam Phung Pham.

A less interventionist treatment for diabetes

The possible benefits of follistatin for people with diabetes have only begun to be examined in recent years, and much remains to be clarified. Two big gaps in knowledge about follistatin are why its concentration can increase after gastric bypass surgery and how it affects the body’s internal organs.

“We are the first researchers to investigate the concentrations of follistatin and activin A and how these affect intracellular signalling in the muscles and in the fat cells. Since the beneficial effects of follistatin on skeletal muscle are well known, we were quite surprised to find that the substantially increased concentration of follistatin in the obese patients without diabetes most strongly affected the fat cells and not the skeletal muscle,” explains Tang Cam Phung Pham.

However, the exact function of this promising protein in fat tissue remains another unresolved question in this relatively unexplored field.

Until researchers obtain more knowledge, type 2 diabetes can primarily be prevented through exercise and a healthy diet. Insulin and tablets remain the way forward for many people who already have type 2 diabetes. The most commonly used drug is metformin, which has side-effects for many people. The most effective remedy is and will be weight loss and exercise, but a really good treatment for the increasing number of people with diabetes is still distant.

“No researchers in the field think that we can find a miracle cure. But some of these hormones and proteins may be able to supplement diet, exercise or the invasive intervention of gastric bypass surgery that often leads to many complications for the individual. Starting with injections of beneficial hormones or proteins at the earlier stages of diabetes may help to postpone surgery or make it completely unnecessary,” says Lykke Sylow.

“But this is incredibly complex, and we are only just beginning to understand the hormonal response to gastric bypass surgery, so we still have a lot to learn,” she concludes.

“Effects of Roux-en-Y gastric bypass on circulating follistatin, activin A, and peripheral ActRIIB signaling in humans with obesity and type 2 diabetes” has been published in the International Journal of Obesity. Lykke Sylow has received grants from the Novo Nordisk Foundation and Independent Research Fund Denmark.