Diabetes damages the heart; a peptide protects it

Peptides are in the spotlight. One peptide, semaglutide, is the active ingredient of weight-loss drugs Ozempic and Wegovy. Others, yet to pass clinical trials, appear in small vials touted by influencers on social media – colourless liquids that, when injected, purportedly build muscle, erase wrinkles, or improve sleep.

Questionable claims aside, peptides contain a lot of medical potential. Made up of a string of amino acids, peptides are like proteins – just smaller. The reason they can allegedly do so much is that they act as messengers in the body, each one giving different signals or instructions to the cells.

Auckland Bioengineering Institute senior researcher Dr Toan Pham has been studying one which may improve the diabetic body’s ability to produce energy – and it looks like it also has the helpful side effect of preventing heart disease.

Diabetes disrupts the body’s energy production system, meaning that extreme fatigue is a hallmark of the disease. In a healthy body, cells take glucose out of the bloodstream and turn it into energy, but diabetic cells do this inefficiently. The result: too much glucose in the bloodstream, not enough being used as fuel. Hence the tiredness.

The problem is magnified in the heart, which has among the highest energy demands of any part of the body – its single muscle needs plenty of oomph for the nonstop task of pumping blood around all your organs and limbs. When heart cells can’t get enough energy from glucose, they compensate by using more of their other main fuel source, fatty acids.

Fatty acids are great at making energy, but they use more oxygen in doing so, which places the heart under stress. Worse, if the balance between glucose and fatty acids is out of kilter, fatty acids leave behind a harmful residue in the heart – like gunk clogging up an engine. “So, gradually the body’s heart muscle cells are getting weaker,” says Pham.

Pham began studying diabetes as a master’s student at the School of Biological Sciences and returned to the disease as a postdoc at the Auckland Bioengineering Institute, investigating how diabetic heart cells use energy.

In 2019, he noticed a paper in Cell Metabolism that identified a new peptide, MOTS-c, which reduced obesity and insulin resistance in mice. Insulin resistance is a precursor to diabetes: it’s where cells first stop responding to messages from insulin (another peptide) to absorb glucose. Pham took note: no one was looking at whether MOTS-c might help diabetes, even though it seemed like the logical next step.

MOTS-c is naturally produced in the body by mitochondria, tiny structures in each cell which generate energy. Mitochondria make MOTS-c in order to communicate with the rest of the cell when the body exerts itself – anything from getting up off the couch, to feeling stressed, to going to the gym. When that happens, MOTS-c travels from the mitochondria to the nucleus, the cell’s brain, and tells the nucleus to respond to the body’s energy demands.

“In normal life, that communication is very strong,” says Pham, “but in disease, that communication gets weaker and weaker.”

Pham began work on MOTS-c in 2020 with a small study looking at the peptide’s impact on human skeletal muscle cells. He found mitochondria functioned more efficiently after only two days of an extra dose of MOTS-c.

“That inspired me to say, ‘Wow, this is really cool, I think MOTS-c has huge potential to treat metabolic diseases,’” he says.

Current treatments for diabetes don’t tackle the underlying mechanism of the disease – the energy-production issues – but rather aim to control levels of blood glucose, Pham says. MOTS-c was a chance to address the source of the problem.

Pham started looking at heart cells, and his preliminary data found diabetic heart cells make less MOTS-c than healthy heart cells. In other words, he’s right: the cells lack a messaging system.

More research showed that adding MOTS-c helps: last year, he showed giving diabetic rats a top-up of MOTS-c improved the heart cells’ ability to produce energy from glucose, and reduced inflammation and oxidative stress. In addition, the rats’ blood glucose levels, which had been elevated at the start of the study, returned to normal.

That means fixing the cells’ messaging system could make people with diabetes feel less tired and potentially prevent them from developing heart disease. So far, it looks as though MOTS-c can make diabetic cells function almost as effectively as healthy cells, Pham says. “It’s really promising.”

For Pham’s latest research, he bought a high-resolution respirometer for the Auckland Bioengineering Institute, a machine the size of an air fryer that he describes as his “baby”. Give it a slice of muscle tissue and it measures how well mitochondria are functioning, how quickly energy is produced and used, and how much gunk is generated as a side effect.

He has been able to combine results from the respirometer with information from a custom-made cardiac-muscle-measuring instrument – the ‘work-loop calorimeter’ – designed and built by Auckland Bioengineering Institute colleagues. It allows him to link the amount of energy used by heart muscles to the amount supplied by mitochondria.

He reckons the Auckland Bioengineering Institute is the only research group in the world that can do both – and that’s allowed him to identify that the diabetic heart’s mitochondria aren’t working properly.

“From my understanding, mitochondria are the key to this disorder,” he says.

Pham's research shows the power of combining biology and engineering to tackle a major health problem, linking processes from the smallest scale of the cell’s mitochondria through to whole-heart function in diabetes, says Auckland Bioengineering Institute director Professor Merryn Tawhai.

"This is innovative bioengineering research with real potential to inform new therapeutic strategies."

Meanwhile, Pham’s respirometer is being used by others around the institute and the university. He is currently working with gastrointestinal health researchers to look at mitochondria in different parts of the stomach and small intestine to help them solve other health issues.

“Now I not only focus on the heart, but I also focus on other organs: how new treatments or how new diseases affect mitochondrial function.”

Late last year Pham and three other senior ABI academics published a new literature review on MOTS-c and Type 2 diabetes in the journal Life Sciences.

Meanwhile, Pham is waiting for news about whether he’ll receive funding to take his research on MOTS-c to the next level: combining it with existing medications to see if those enhance the peptide’s effects, as well as figuring out the optimal dose and the method for delivering it to the body.

There’s a long road ahead: MOTS-c would need to pass through the multiple rounds of clinical trials necessary for figuring out whether a drug is safe and effective before it could become a medication.

Still, Pham has seen YouTube videos of people injecting themselves with MOTS-c, claiming it improves energy. “MOTS-c is not an FDA-approved drug,” he cautions. It’s also a banned substance in sporting events in case it gives competitors an unfair advantage.

He wants to make sure not only that MOTS-c is safe, but find a better way of delivering it to the cells. He doesn’t want people to have to inject it.

“That’s my real, final goal,” he says. “To make a pill.”

Article written by Rebekah White.