Glucose can cure as well as lead to lifestyle diseases: Study

A recent study led by the Tata Institute of Fundamental Research (TIFR), Colaba, has revealed that glucose acts both as a hero and villain in controlling and causing lifestyle disorders and age-related diseases.

A 10-member team – including researchers from the Pune-based Indian Institute of Science Education and Research – has shown that glucose can bind itself to a longevity gene – Sirtuin1 (SIRT1) – in the liver and modify the gene’s functions. While in moderation this can lead to balancing blood sugar levels, in excess it can result in metabolic diseases. What this means, said researchers, is that SIRT1 modification by glucose can cause diabetes and hyper-inflammation, while excessive modification is associated with accelerated aging and obesity.

The primary drivers of metabolic diseases are our feeding habits or diet. The study findings are important because the body’s metabolic balance is largely controlled by the liver, which manages the production/accumulation of fat, sugar breakdown, etc. The liver has to, therefore, properly respond to feeding and fasting cycles, or else the body ends up with an imbalanced metabolism.

“Global efforts are underway to uncover molecular mechanisms within liver cells to distinguish between a fed state, calorie-restricted state, and high-fed state; and also to regulate the activity of SIRT1,” said Ullas Kolthur, lead investigator and professor at the department of biological sciences, TIFR.

SIRT1 has been long thought to be beneficial in mitigating diseases such as diabetes, cardiovascular dysfunctions, neurodegeneration, cancer, and aging.

“Our study shows that while there are efforts to find therapeutic activators for SIRT1, both over-activation and under-activation of this longevity factor could lead to diseases,” Kolthur said.The study was published earlier this week in the Proceedings of National Academy of Sciences of the United States of America, an international peer-reviewed multidisciplinary scientific journal.

Scientists not involved in the study described the findings as an “excellent advance”, with direct implications for the development of better treatment for metabolic disorders like diabetes and fatty liver disease.

“The glycosylation modification on SIRT1 [attachment of glucose or sugar molecules to SIRT1] is carried out by specific enzymes, which are all ‘druggable’,” said Sunil Laxman, scientist, Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bengaluru.

“There is value in having both inhibitors and activators of these enzymes that can either increase or decrease SIRT1 activity. These can be potential second-line drugs, beyond just diet control and exercise,” said Laxman.

The study used mice as experimental models since they closely resemble humans in terms of genes, biology and behaviour traits. Researchers found that SIRT1 in healthy individuals was high in the fasting state and decreased in a fed state.

Arnab Mukhopadhyay, scientist at the Delhi-based National Institute of Immunology, who was not involved in the study, said feeding and fasting are regular events in our lives.

“How they impact our physiology at the molecular and biochemical levels is an active area of research. This is important to comprehend as diseases of metabolism like type II diabetes can be understood better if we know how our body reacts to food and why it fails to do so under diseased conditions,” said Mukhopadhyay. “While there are many studies on modifications on SIRT1, Dr Kolthur’s study has shown how a physiologically relevant process, the fed-fast cycle, controls metabolism by modifying the protein and has important implications to our understanding of liver function and diabetes,” he said.

“For healthy individuals, giving a gap between feeding-fasting cycle along with reduced calorie intake is better because it helps SIRT1 to be active for a longer period. This is because glucose neither acts as a bad factor nor is the protein being active unnecessarily,” said Kolthur.