Activated T lymphocytes in Type 2 diabetes: implications from in vitro studies

The number of subjects with Type 2 diabetes (DM2) has risen significantly in the last ten years. Obtaining sufficient human tissue to study this disease process as well as many other diseases is generally difficult. T lymphocytes offer a unique opportunity for these studies. Although resting human peripheral T-lymphocytes are devoid of insulin receptors, these receptors emerge upon activation of cells by specific antigens or mitogens. Concomitant with the insulin receptors, two other growth factor receptors (IGF-1 and IL-2) also emerge on the T lymphocyte cell surface along with intracellular signal transduction mechanisms and insulin degrading enzyme (IDE). After binding to its receptor, insulin has been shown to exert its classical effects on carbohydrate metabolism in the stimulated T- cell; thereby, validating the use of activated T-lymphocytes for studying the pathogenesis of metabolic and immune disorders and the mechanism(s) by which insulin exerts its effects. In activated T-lymphocytes, insulin stimulates glucose uptake, glucose oxidation, pyruvate flux and pyruvate dehydrogenase activity, amino acid transport, lipid metabolism and protein synthesis. Through its ability to enhance nutrient uptake and raise the levels of intermediary cellular metabolism, insulin is believed to maintain the allo-activated state of lymphocytes, enhance T-Lymphocyte responsiveness, and support or possibly promote the actions of immuno-derived regulatory growth and differential factors. Since insulin enhances energy requirements and protein synthesis necessary for appropriate T-cell functions, defects in insulin action may lead to inappropriate immunoresponses in various metabolic states such as in diabetes. Studies from our lab have found insulin binding, processing, and responsiveness in phytohemagglutinin(PHA)-activated T-cells are reflective of the donor's glycemic status and ambient insulin levels in subjects with Type 1 and Type 2 diabetes (DM2) and other insulin resistant states. Our studies show that patients with diabetic ketoacidosis and hyperglycemia have increased proinflammatory cytokines and activated CD4+ and CD8+ T lymphocytes. The diabetic state, where effective insulin concentrations are low and both glucose and free fatty acids are high, provides an environment of oxidative stress and activation of the inflammatory pathways. The mechanisms underlying insulin action, in general, or in the CD4+ and CD8+ T-lymphocytes, in particular, have not been clearly elucidated. Due to the accessibility of obtaining these cells from patients, activated T-lymphocytes offer the potential of studying diabetes and other disease in human subjects.