Relation of White Blood Cell Function to Diabetes

Type II diabetes mellitus is rapidly becoming a global pandemic with a deleterious impact on cardiovascular morbidity and mortality. Understanding its pathophysiology is important for the development of future therapeutic interventions. Interestingly, mitochondrial dysfunction in skeletal muscle and adipose tissue are early events in the development of type II diabetes mellitus and are proposed to play a role in exacerbating insulin resistance. The genetic disruption of macrophage mitochondrial biology in preclinical studies results in the development of insulin resistance and concurrent mitochondrial dysfunction in peripheral tissue including skeletal muscle and the liver. Whether this disruption of mitochondrial function is evident in human mononuclear cells is unknown. We propose that the disruption of mitochondrial function in circulating cells may contribute to not only peripheral insulin resistance but may also evoke the myriad of vascular complications associated with diabetes.

To test these assumptions, we propose an initial proof of concept study to evaluate mitochondrial biology in circulating monocytes in normal volunteers, pre-diabetic and diabetic subjects to assess whether mitochondrial disruption/dysfunction evolves with the progression to type II diabetes. In parallel, gene expression and proteomic analysis will be performed to evaluate whether the development of insulin resistance and diabetes confers a specific modulation in the biological signature of monocytes with disease progression. To delineate these concepts we will evaluate study subjects' glucose tolerance and insulin sensitivity and draw blood to examine peripheral monocytes. Biological readouts will include: 1) the quantification of the mitochondrial genomic and electron transfer chain content; 2) the determination of mitochondrial reactive oxygen species capacity and defenses; 3) the pattern of monocyte differentiation and 4) the unbiased assessment of monocyte gene expression and proteome.

If the mitochondrial hypothesis is operational, this study will show that the mitochondrial disruption/dysfunction is a more generalized finding in type II diabetes. This would establish targeting the modification of mitochondrial function in various tissue/cell types as a novel strategy in the prevention and/or reversal of insulin resistance and diabetes.