Pilot Study of Mitochondrial Biology in Human Platelets
Condition: Insulin Resistance; Diabetes
MeSH terms: Insulin Resistance
Study type: Observational

Summary: 
      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. Emerging evidence suggests interplay
      between mitochondrial dysfunction and the development of insulin resistance. 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. Although it has been demonstrated that skeletal muscle of
      insulin-resistant individuals has reduced mitochondria and mitochondrial dysfunction, whether
      this disruption of mitochondrial function is more widespread has not been explored. We
      hypothesize that this disruption of mitochondrial function is more systemic and thereby may
      contribute to the development of peripheral insulin resistance and possibly promote the
      myriad of complications associated with diabetes.

      To test these assumptions, we propose an initial proof of concept study to evaluate
      mitochondrial biology in human platelets in normal volunteers, pre-diabetic and diabetic
      subjects to assess whether mitochondrial disruption/dysfunction evolves with the progression
      to type II diabetes. In parallel, proteomic analysis will be performed to evaluate whether
      the development of insulin resistance and diabetes confers a specific modulation in the
      biological signature of human platelets with disease progression. To delineate these
      concepts, we will evaluate study subject's glucose tolerance and insulin sensitivity and draw
      blood in parallel to study their platelets. Biological readouts will include: 1) the
      quantification of the mitochondrial proteome and electron transfer chain content; 2) the
      evaluation of platelet mitochondrial respiratory function and 3) to determine the
      mitochondrial reactive oxygen species capacity and defenses. If this hypothesis is validated,
      this study will show that the mitochondrial disruption/dysfunction is a more generalized
      finding in type II diabetes. Additionally, it would propose the use of platelets as potential
      biomarkers for early detection of mitochondrial function and assessment of disease. Finally,
      this would establish a peripheral blood readout of the modification of mitochondrial function
      as a novel approach to monitor the prevention and/or reversal of insulin resistance and
      diabetes in response to therapeutic strategies.
    

Detailed description: 
      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. Emerging evidence suggests interplay
      between mitochondrial dysfunction and the development of insulin resistance. 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. Although it has been demonstrated that skeletal muscle of
      insulin-resistant individuals has reduced mitochondria and mitochondrial dysfunction, whether
      this disruption of mitochondrial function is more widespread has not been explored. We
      hypothesize that this disruption of mitochondrial function is more systemic and thereby may
      contribute to the development of peripheral insulin resistance and possibly promote the
      myriad of complications associated with diabetes.

      To test these assumptions, we propose an initial proof of concept study to evaluate
      mitochondrial biology in human platelets in normal volunteers, pre-diabetic and diabetic
      subjects to assess whether mitochondrial disruption/dysfunction evolves with the progression
      to type II diabetes. In parallel, proteomic analysis will be performed to evaluate whether
      the development of insulin resistance and diabetes confers a specific modulation in the
      biological signature of human platelets with disease progression. To delineate these
      concepts, we will evaluate study subject's glucose tolerance and insulin sensitivity and draw
      blood in parallel to study their platelets. Biological readouts will include: 1) the
      quantification of the mitochondrial proteome and electron transfer chain content; 2) the
      evaluation of platelet mitochondrial respiratory function and 3) to determine the
      mitochondrial reactive oxygen species capacity and defenses. If this hypothesis is validated,
      this study will show that the mitochondrial disruption/dysfunction is a more generalized
      finding in type II diabetes. Additionally, it would propose the use of platelets as potential
      biomarkers for early detection of mitochondrial function and assessment of disease. Finally,
      this would establish a peripheral blood readout of the modification of mitochondrial function
      as a novel approach to monitor the prevention and/or reversal of insulin resistance and
      diabetes in response to therapeutic strategies.
    

Time perspective: Prospective
Keywords: Mitochondria in Platelets; Mitochondria in Diabetes; Insulin Resistance and Mitochondria; Diabetes; Insulin Resistance