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Burning More Fat and Less Glucose Leads To Diabetes

Burning More Fat and Less Glucose Leads To DiabetesBurning more amount of fat and less amount of glucose can increase the chances for diabetes, says a recent study done by researchers from Baylor College of Medicine and other institutions.

The muscles of mice use glucose as an energy source when they are active and awake; while they are asleep, they depend on fat. The team of researchers found that disturbing this natural cycle can result to diabetes but unexpectedly can also increase endurance for exercising. The switch is managed by a molecule called histone deacetylase 3, or HDAC3. This result opens the chance of selecting the right time to exercise for reducing body fat and also increases the concern of using HDAC inhibitors as doping drugs for exercise endurance.

Internal circadian clock regulates the usage of glucose by muscle and it waits for the level of its activity during the day and at night, explained senior author Dr. Zheng Sun, assistant professor at Baylor. “The circadian clock functions by keeping certain genes on and off while the 24-hour cycle progresses. HDAC3 is a main connection between the circadian clock and gene expression. Our earlier work demonstrated that HDAC3 facilitates the liver alternation between making glucose and producing lipid. In this work, we analyzed how HDAC3 manages the use of various fuels in skeletal muscle.”

Skeletal muscles, which are voluntary muscles, are essential in the management of blood glucose in the body. They utilize most glucose, and if people have insulin resistance and are not able to metabolize glucose, then diabetes will develop. To find the role of HDAC3 in mouse skeletal muscle, Sun and colleagues genetically engineered laboratory mice to reduce HDAC3 in the skeletal muscles. Then they compared these knocked out mice with normal mice as to how their muscles burn fuel.

Surprising results

When normal mice eat, their blood glucose level increases and insulin is secreted, which induces muscles to use glucose as fuel. While the knocked out mice ate, their blood glucose level increased and insulin was released as expected, but their muscles refused to consume and utilize glucose,” mentioned Sun. “Lack of HDAC3 made mice insulin-resistant, which made them develop diabetes.”

However, while the HDAC3-knocked out mice did activities like running on a treadmill, they developed higher endurance, “which was fascinating since diabetes is commonly linked with poor muscle performance,” described Sun. “Glucose is the key fuel of muscle, so if a condition restricts the use of glucose, low performance in endurance exercises is anticipated. That’s the surprise.”

The researchers then analyzed what fueled the HDAC3-knocked out mice's superior performance using metabolomics methods and discovered that their muscles break down more amino acids. This altered the muscles’ choice from glucose to lipids and let them to burn lipid very effectively. This gives superior endurance, since the body carries a much bigger energy reservoir in the form of lipids than carbohydrates.

The result challenged the widely-used carbohydrate-loading (carbo-loading) approach for enhancing endurance performance. “Carbo-loading didn’t make evolutionary sense prior to the agriculture invented,” noted Sun. “Changing muscles from using carbohydrates to lipids might enhance exercise endurance, particularly for low-intensity exercise.” The study proposes that HDAC inhibitors, a class of small molecule drugs now being tested for treating several diseases, could likely be used to control such fuel switch in muscles and consequently raises concerns of doping.

Connection to the body’s internal clock

The team conducted a number of functional genomics studies that proved the connection between HDAC3 and the circadian clock. “In normal mice, while the mouse is awake, the biological clock in the muscle expects a feeding cycle and utilizes HDAC3 to turn off various metabolic genes. This makes the muscles utilize more amount of carbohydrates,” said Sun. “When the mice is about to go to sleep and expects a fasting cycle, the clock eliminates HDAC3. This makes the muscles use more lipids.”

Even though these studies were performed in mice, the researchers considered that human muscles most likely will have the same cycle. The study opens the opportunity of promoting body fat burning by enhancing exercise activity during the periods in which muscles use lipid, which occurs at night among people. “Burning body fat would be easier by exercising gently and fasting at night,” said Sun. “Thus the study reveals that it’s not bad to go for a walk after dinner.”

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