Manipal University: Biomolecules promoting complications in Diabetes discovered

Bangalore : In an effort to identify the chemicals in the body responsible for preventing the healing of foot infections in diabetic patients and vascular diseases, researchers at the Manipal University School of Life Sciences, interrogated specialized sentinel cells called neutrophils in the blood that fight infections.The investigators describe how chemicals and proteins present inappropriately in diabetic individuals disable short lived cells such as neutrophils, making them ineffective to fight infections and may promote diabetes associated complications.

"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, PhD, Assistant Professor and lead author of the manuscript of School of Life Sciences, Manipal University, Manipal, India. He further continues, "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 is called 'NETosis'. In healthy individuals, this process is 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. NETs in diabetes appear to be the culprit by two ways 1) ineffective NETs fail to fight against pathogens such as those associated with foot infections and 2) accumulation of excess NETs might lead to delayed wound healing and promoting cardiovascular diseases." These new findings were published recently in Nature Publishing Group's (NPG) journal 'Scientific Reports' entitled 'Elevated homocysteine levels in type 2 diabetes induce constitutive neutrophil extracellular traps'.

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 undergoes amputation and is a significant public health problem. Manipal University team first demonstrated in 2013 that neutrophils from diabetic individuals are constitutively weak to respond to cues and produce extracellular traps (nets) due to high levels of glucose which could be partially recovered by inhibiting the glucose transport inside the neutrophils. "We 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. We show this from battery of experiments to conclude that this very effect may have implication to complications associated with diabetes such as cardiovascular diseases and stroke. Elevation of homocysteine can be due to several reasons including vitamin deficiency," mentions Dr. K. Satyamoorthy, a lead scientist who led the group. This work was undertaken under the active collaboration with medical doctors, Dr. Lingadakai Ramachandra and Dr. Kaniyoor Nagri Shivashankara from Kasturba Medical College, Manipal.

Due to compromised immune function of the individuals with diabetes, they become susceptible to infections and are unable to combat them. While antibiotics are increasingly becoming ineffective due to drug resistance, another way to combat infectious bacteria is to boost the innate immune function of the body and neutrophils which form about 50-70% 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.

Understanding how microbes thrive in the host taking advantage of weak defense mechanisms while the body is in a compromised state within the diabetic foot ulcers and beyond is the priority area of research at Manipal University. Scientists at the School of Life Sciences and other departments are investigating antibiotic resistance and associated several diseases. "This important finding was possible at Manipal University because of the environment created to execute multidisciplinary research bringing together clinical practitioners and basic scientists," says Vice Chancellor Dr. Vinod Bhat. Dr. H.S. Ballal, Pro-Chancellor for Manipal University continues, "We have been striving for societal benefit through our network or hospitals, education institutions with special emphasis on research and developmental activities. The work being carried out at School of Life Sciences is critical to manage chronic diseases such as diabetes and may lead to better clinical practices in future." Diabetes and associated complications such as nephropathy, neuropathy and cardiovascular diseases are the major problems worldwide and grave public health problems. Diabetes accounts for about 5 million deaths worldwide annually and globally more 350 million suffer from the disease. Diabetes and its precursor conditions would encompass 7% of the world population by 2030.