IIT Mandi Researchers Identify Protein That Links Fatty Liver Disease And Diabetes Type 2

About 40 per cent of adult Indians suffer from this non-alcoholic fatty liver disease (NAFLD). Nearly 50 million adults in India are living with both NAFLD and type 2 diabetes.

Researchers at the Indian Institute of Technology Mandi have discovered the biochemical link between fatty liver disease and Type 2 diabetes mellitus. This finding is important because scientists can use it to develop newer techniques to diagnose the risk of diabetes among people with non-alcoholic fatty liver disease (NAFLD). With the help of this discovery, scientists can find new therapeutic ways to control or reverse fatty-liver induced diabetes. 

NAFLD is a condition in which fat builds up in the liver, and is an umbrella term for a range of liver conditions affecting people who drink little to no alcohol. The main characteristic of NAFLD is that too much fat is stored in the liver cells. 

According to the United States National Institutes of Health (NIH), non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) are types of NAFLD. If a person suffers from NASH, he or she has inflammation and liver damage, along with fat in the liver.

What Is Type 2 Diabetes?

Type 2 diabetes is a condition in which the way the body regulates and uses glucose as a fuel is impaired. Due to this chronic condition, too much sugar starts circulating in the bloodstream. 

Type 2 diabetes is mainly a lifestyle-related condition and develops over time. It happens when the body is not able to make enough insulin or the insulin produced does not work properly. 

Factors such as weight and ethnicity put a person at risk for type 2 diabetes. The symptoms of type 2 diabetes appear slowly. 

While type 1 diabetes is an autoimmune condition, type 2 diabetes occurs when the body does not make enough insulin, or the insulin does not work properly. This mechanism is known as insulin resistance. Type 2 diabetes is also known as adult-onset diabetes.

The number of cases of NAFLD in India is increasing. According to recent surveys, 40 per cent of adult Indians suffer from this condition. The disease is often associated with type 2 diabetes. Nearly 50 million adults in India are living with both NAFLD and type 2 diabetes.

NAFLD is considered an independent predictor of systemic insulin resistance and type 2 diabetes. 

How Was The Study Conducted?

The findings made by the IIT Mandi team were recently published in the journal Diabetes. In order to conduct the study, the researchers analysed blood samples extracted from fat-fed mice and human NAFLD patients. In both the samples, high amounts of a calcium-binding protein, known as S100A6, were found. 

How Does The Protein Serve As A Link Between Fatty Liver And Type 2 Diabetes?

When one is suffering from fatty liver, the protein is released. The protein serves as a communication link between the liver and the pancreas. However, the protein adversely affects the ability of the beta cells to secrete insulin. The cells in the pancreas making insulin are known as beta cells.

Since S100A6 affects the ability of beta cells to secrete insulin, this may result in type 2 diabetes. Also, the protein may exacerbate existing type 2 diabetes. 

“Based on our observations, S100A6 suppresses cAMP synthesis and mitochondrial ATP synthesis. Both are essential for insulin release,” Dr. Prosenjit Mondal, IIT Mandi, told ABP Live via email. 

The protein was observed to activate the receptor for advanced glycation end product (RAGE) on pancreatic beta cells. This resulted in the inhibition of insulin secretion. RAGE is a multi-ligand receptor that regulates immune responses and has been linked to diabetes. 

Importance Of The Study

The new study is important because it presents the molecular and cellular events associated with S100A6 secretion in those with fatty liver, and the adverse impact of the secretion of this protein on the release of insulin by beta cells. 

This implies that increased levels of S100A6 in the blood may serve as a biomarker to identify risks of type 2 diabetes mellitus among NAFLD patients. 

The research is important at a therapeutic level because it shows that removing the circulating S100A6 from blood can help in preserving the function of beta cells. Researchers now understand the biochemical pathway through which S100A6 acts on beta cells. Therefore, they can use RAGE antagonist molecules to restore the function of the beta cells in NAFLD patients.

“In our preclinical study we used shRNA ( short hairpin RNA).  Neutralizing antibody and/or antagonizing RAGE- S100A6 axis can be other alternatives to stop S100A6 effects,” Dr Mondal said. 

S100A6 inhibits glucose-stimulated insulin secretion from beta cells by activating RAGE and curtailing mitochondrial respiration. 

Therefore, the study proposes neutralisation of the protein as a novel therapeutic technique to restore the function of beta cells in those suffering from NAFLD.

“NASH patients with increased serum S100A6 also have diminished beta cell function (can be diabetic eventually),” Dr Mondal said. 

He added that currently, the IIT Mandi team is working on designing a neutralising S100A6 antibody as therapy in restoring insulin secretion in a NASH preclinical model.