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Manipal scientists find cause for diabetic complications

Manipal, Nov 23, 2016, DHNS Researchers at Manipal University’s School of Life Sciences have discovered biomolecules that impede surveillance against infection and promotes complications in diabetes.

The researchers have identified the chemicals in the body responsible for preventing healing of foot infections in diabetic patients and vascular diseases.

They have examined specialised sentinel cells called neutrophils in the blood that fight infections. The researchers described how chemicals and proteins present inappropriately in diabetic individuals disable short lived cells such as neutrophils, make them ineffective to fight infections and may promote diabetes- associated complications. The new findings were published recently in Nature Publishing Groups (NPG) journal ‘Scientific Reports’ entitled ‘Elevated Homocysteine Levels in type 2 Diabetes Induce Constitutive Neutrophil Extracellular Traps.’

“Of the various ways in which neutrophils fight infection, the process called ‘NETosis’ is key to trap the bacteria and eliminate them in the body,” explains Manjunath B Joshi, Assistant Professor and lead author of the manuscript of School of Life Sciences, Manipal University.

“Neutrophils constitute a major part of blood cells and are actively involved in fighting against pathogens. During infection, neutrophils release their DNA along with few proteins to trap bacteria and fungi and kill them. This happens similar to fishermen who throw the net to trap the fish! These structures are known as Neutrophil Extracellular Traps (NETs) and the process NETosis,” he said.

In healthy individuals, these processes are very efficient to guard the body from harmful bacteria while in diabetic individuals, the very process is ineffective due to excessive inflammatory proteins and biomolecules such as glucose and homocysteine.

Infections of foot ulcers in diabetic individuals are difficult to manage due to drug- resistant bacteria and inability of the host to fight infection. Approximately 15% of all diabetic foot ulcers undergo amputation and is a significant public health problem. The university team first demonstrated in 2013 that neutrophils from diabetic individuals are constitutively weak to respond to cues to produce extracellular traps (nets) due to high levels of glucose which could be partially recovered by inhibiting the glucose transport inside the neutrophils.

“The team had previously identified inflammatory proteins such as interleukin-6 and high levels of glucose which is found in diabetic individuals make the neutrophils ineffective to respond to bacterial infections. We now show that higher levels of homocysteine, which is a risk factor for several human diseases including diabetes, also robustly produces nets from neutrophils which in turn can activate platelets, cells which play role in clot formation. From the battery of experiments, we concluded that this very effect may have implication to complications associated with diabetes such as cardiovascular diseases and stroke. The elevation of homocysteine can be due to several reasons including vitamin deficiency,” mentioned Dr K Satyamoorthy who is the lead scientist of the group.

The work was undertaken in collaboration with Dr Lingadakai Ramachandra and Dr Kaniyoor Nagri Shivashankara from Kasturba Medical College. Due to compromised immune function in the individuals with diabetes, they become susceptible to infections and unable to combat them. While antibiotics are increasingly becoming ineffective due to drug resistance, other way to combat infectious bacteria is to boost the innate immune function of the body and neutrophils which form about 50% to 70% of all the cells in the blood can hold the key. Understanding the mechanisms of how neutrophils can be reinforced under immune compromised diseases may be beneficial to develop diagnostic and therapeutic strategies.