Research Digest: autophagy and exercise, cell rejuvenation and keto insight

Camille Bienvenu
By Camille Bienvenu
7th November 2017
In Depth, Opinion
 
4540

Diabetes Awareness Month is an occasion for reflecting on the evolution of diabetes research.

Research right now is moving away from reductionist thinking, and is progressing towards system analysis, where instead of looking at the effect of one variable on a pathway, scientists are looking at the body as a multivariate problem to interpret the big picture and design new treatments.

Major discoveries are made by connecting the dots, thus researchers are mapping out how different environmental, genetic and physiological factors interact in a disease process, both in terms of direction (increasing or decreasing something) and magnitude.

In order to help us all better understand the changing landscape, and impact, of research, we’ve decided to periodically publish a Research Digest that critically analyses recent studies, provides a cumulative view of scientific progress and teases out the implications for our lives.

Without further ado, let’s catch you up with exciting research that recently made the headlines. This first edition of the Research Digest discusses research advances in the prevention and treatment of type 1 and type 2 diabetes, as well as the latest science of ketogenic dieting.
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There has been a great deal of discussion on this important program, called autophagy, which gets activated while fasting and slows cellular aging. There is new evidence that, even without being in a fasted state, exercise can induce a specific type of autophagy that helps to lower insulin resistance to some degree.

Amazing things are also happening in the world of beta cell regeneration. The genetic traits of an insulin-secreting tumour are giving researchers some of the tools they need to encourage cell growth and help people with diabetes make more insulin.

Lastly, low carb followers amongst our readers will be glad to know that yet another advantage to ketone bodies has been uncovered, and this may open up new possibilities for the therapeutic use of very low carb (ketogenic) diets.

Read on, or click on your favourite topics, to read a more detailed account of the findings:

 

How a type of autophagy induced by exercise can improve insulin sensitivity

(Study link)

A new study has found that exercise can induce a type of autophagy which prevents defects in muscle cell mitochondria that are associated with insulin resistance.

Scientists knew that exercise increases the number of receptors (GLUT4) in muscle cells that transport glucose, which is one way insulin sensitivity can improve.

The new research tells us that physical activity may directly affect the resistance that can occur in these transporters (insulin resistance) via the mitochondria – the energy-producing structures in cells.

Certain types of exercise can turn on a cellular cleansing system called mitophagy, a process that takes care of the removal of damaged mitochondria in muscle cells.

Mitophagy is part of this larger important cellular program that is autophagy, which is inducible by fasting. Different mechanisms involved in mitophagy may help to maintain the mitochondria in a “youthful” state.

Keeping mitochondria healthy is thought to help reverse the cell’s declining ability to process energy over time and reduce oxidative stress, all of which contribute to improve insulin sensitivity.

Exercise-induced mitophagy (Laker et al., 2017)

Endurance training is known to be particularly efficient in inducing autophagy in mice, thus researchers at the University of Virginia School of Medicine tested in the current research whether aerobic exercise activated mitophagy.

The team engineered mice to have the mitochondria that the body has decided to recycle glowing red by fluorescence. Then they had the animals run on a small treadmill for 90 minutes and looked at what happened after the exercise ended. Six hours later, they saw signs of ongoing mitophagy ramping up in their skeletal muscle.

Researchers also uncovered how exercise stimulates mitophagy: by stimulating AMP-activated protein kinase (AMPK), a fuel sensor and regulator in muscle. AMPK then switches on a protein known as Ulk1, whose role is to activate other components in the cell to execute the removal of dysfunctional mitochondria.

It isn’t surprising that AMPK mediates mitophagy, as we’re starting to find that the main signals that activate autophagy all involve nutrient sensing.

Putting it all together

These findings indicate that just one bout of moderate-to-intense exercise acts as a “stress test” on muscle mitochondria, which are power generators of cells.

This stress test triggers a process call mitophagy, where the muscle disposes of the damaged or dysfunctional mitochondria, making the muscle healthier and helping to lower insulin resistance.

 

How the DNA of a pancreatic tumour may point the way to new treatments

(Research link)

A discovery about the genetic makeup of rare and benign tumours that are made up of specialised beta cells, called insulinomas, could inform treatment innovations in beta cell regeneration.

The most distinctive feature that insulinomas have is their ability to secrete insulin in excessive amounts, thus researchers are trying to understand how the DNA of beta cells they are derived from is organised.

A team of researchers at the Icahn School of Medicine has performed analyses on 90 insulinomas so far and provided the “genetic maps” of 38 of them in the current study.

They identified a number of genetic particularities, such as mutations, variations and differences in expression of genes that make insulinoma cells distinctly different from normal beta cells and/or are enabling them to proliferate.

Then they found many pathways (30) in which genes of interest are involved. One of those pathways was actually uncovered in their earlier work and a drug called harmine acting on it led to beta cell regeneration in mice.

Genetic maps for making insulin (Wang et al., 2017)

Researchers are now looking to modulate these pathways so as to increase the number of beta cells and help them to make insulin more efficiently.

The challenge for researchers resides in using these pathways to develop treatments while eliminating side effects. For example, at certain doses, harmine can produce unwanted hallucinogenic effects.

There is also the concern that a drug engineered from insulinomas could cause the body to produce too much insulin and blood glucose would fall to dangerously low levels.

Researchers want to avoid replicating the lack of control of an insulinoma too. The symptoms of this type of tumour range from mild confusion to abnormal behaviours and decreased consciousness.

In order to circumvent some of these issues, researchers will need to find ways to switch these pathways on and off, and deliver drugs that target them specifically to beta cells at the right dosage.

Implications for further research

These findings help further our understanding of what’s happening with beta cells and scientists can take those lessons to build out new therapies.

A therapy developed from these pathways would likely be for people with type 2 diabetes first. People with type 1 diabetes have the added issue of the autoimmune attack, which could destroy any newly made cells.

In this case, some sort of immune system suppression might be necessary, though it is possible that repeated treatments might keep enough beta cells alive to be effective.

 

How a ketone body can help neutralise the harmful effects of sugar on the body

(Review link)

Scientists have found a new biological function of ketone bodies. Ketones are produced from fatty acids by the liver during fasting or nutritional ketosis, when eating a very low carb diet.

This state of nutritional ketosis has been linked to several metabolic advantages including weight management and improvements in blood glucose control and blood lipids.

New research has now uncovered a new benefit of ketone production: protecting against a damaging metabolite of glucose metabolism (glycolysis).

This metabolite is methylglyoxal (MG) and is known to be involved in diabetes-related diseases. It is a major inducer of advanced glycation end-products (AGEs), which result from the bonding of sugar to proteins during hyperglycemia.

In diabetes, AGEs form more rapidly and accumulate in certain tissues where they cause damage leading to complications such as retinopathy or neuropathies. AGEs are also associated with aging and neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s.

Here, scientists at Aarhus University, in Denmark, have found evidence that the ketone body acetoacetate can miminise the amount of harmful MG in the body and consequently reduce the rate of formation of AGEs.

Ketone Body neutralises dangerous metabolite of glucose metabolism (Salomon et al., 2017)

In normal conditions, the body has a system (the glyoxalase system) that is constantly at work to keep MG levels in check. During ketosis, the ketone body acetoacetate may play a similar role.

According to the findings, acetoacetate reacts with MG in the blood and forms a new compound called 3-hydroxyhexane-2,5-dione (3-HHD), which is then broken down to less harmful metabolites than MG by blood cells.

When researchers analysed the blood of people with diabetes taken off insulin and who fasted the night before, they saw an increase in the levels of 3-HDD. They also had increased amounts of the ketone body beta-hydroxybutyrate.

In a separate experiment, researchers put healthy individuals on a ketogenic diet. They found that acetoacetate generated during nutritional ketosis also reacted with MG and formed 3-HHD.

This suggests that the clearance of MG via 3-HHD takes place simultaneously with fat metabolism in the cells and that ketone bodies might do a lot more than merely acting as alternative fuel sources.

What this means for you

Although the impact of ketosis and 3-HHD on MG levels is still questionable, these findings suggest that the ketone body acetoacetate may play a major role in the cellular defence against AGEs.

Levels of MG are elevated in people with type 2 diabetes as well. These observations suggest that being in a state of nutritional ketosis, achieved when following diets that restrict carbs, may help lower the level of MG which may benefit long-term health.

What do you think?