Insulin resistance is a major defect underlying the development of type 2 diabetes and is a central component of the metabolic syndrome. It is characterized by complex interactions among genetic determinants, nutritional factors, and lifestyle. Multiple biochemical, metabolic, and signal transduction pathways contribute to insulin resistance. As the incidence of obesity and insulin resistance continues to rise in adolescents and adults at staggering levels, new approaches to tackling this world-wide epidemic are warranted. The overall focus of our laboratory is to explore the new mechanisms involved in induction of insulin resistance, and to identify and develop new molecules to counteract insulin resistance for the treatment of type 2 diabetes and associated secondary complications. We are investigating the role of innate immune components in inflammation-mediated insulin resistance. Simultaneously we are exploring the input of dietary fructose, with specific reference to extra hepatic metabolism, in induction of insulin resistance. At the same time we are involved in the discovery, development and validation of novel antidiabetic agents from natural as well as synthetic sources, using various in vitro and in vivo model systems.
Role of innate immune components in inflammation-induced insulin resistance
The innate immune system provides the first line of defense against microbial pathogens and is imperative for the survival of all multicellular organisms. A critical step in the innate immune response is the identification of common motifs from invading organisms as foreign. This discrimination relies on a family of evolutionary conserved pattern recognition receptors (PRRs) that recognize a limited, but highly conserved, set of molecular structures inherent to microbial pathogens, which upon detection mediate inflammatory responses. Emerging evidences indicate that in addition to invading pathogens, PRRs can also be activated by endogenous molecules of non-microbial origin and may also participate in the induction of sterile inflammation. Both infection-induced inflammation and sterile inflammation can lead to chronic inflammation, which is now considered as one of the key etiological conditions leading to the development of many chronic diseases, including atherosclerosis, insulin resistance and cancer. Inflammation-mediated insulin resistance has been linked to macrophage and adipose tissue cross talk, which ultimately may impair insulin action in skeletal muscle and/or the liver leading to whole body insulin resistance. Since, the components of the innate immune system are ubiquitous expressed, a cell autonomous response is possible to external stimuli to induce inflammatory response. We are exploring the role of PRRs in the pathogenesis of tissue specific insulin resistance. We have shown the involvement of cytoplasmic PRRs, the Nucleotide Oligomerization Domain Protein 1/2 (NOD1 and NOD2) in inflammation-induced insulin resistance. Metabolic tissues harbor these components of the innate immune system and their activation though specific ligands confer insulin resistance in skeletal muscle cells in a cell autonomous manner (Endocrinology, 2010). We have identified the involvement of NOD proteins in diet-induced inflammation and insulin intolerance. Mice deficient in NOD1/2 were protected against high fat diet induced inflammation, lipid accumulation and peripheral insulin resistance, and acute activation of NOD proteins caused whole-body insulin resistance (Diabetes, 2011). We have further demonstrated the implication of oxidative stress in the development of mitochondrial dysfunction and insulin resistance in response to NOD2 activation in skeletal muscle cells (Free Redic Biol Med, 2015). Activation of innate immunity provides a new model for the pathogenesis of type-2 diabetes and the metabolic syndrome, which may explain some of these features, and points to research directions that might result in new therapeutic approaches for managing and predicting type-2 diabetes and its complications.
View More..