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Pilot Study of Mitochondrial Biology in Human Platelets

30 juni 2017 uppdaterad av: National Heart, Lung, and Blood Institute (NHLBI)

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.

Studieöversikt

Status

Avslutad

Betingelser

Detaljerad beskrivning

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.

Studietyp

Observationell

Inskrivning (Faktisk)

18

Kontakter och platser

Det här avsnittet innehåller kontaktuppgifter för dem som genomför studien och information om var denna studie genomförs.

Studieorter

  • Förenta staterna
    • Maryland
      • Bethesda, Maryland, Förenta staterna, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Deltagandekriterier

Forskare letar efter personer som passar en viss beskrivning, så kallade behörighetskriterier. Några exempel på dessa kriterier är en persons allmänna hälsotillstånd eller tidigare behandlingar.

Urvalskriterier

Åldrar som är berättigade till studier

21 år till 60 år (Vuxen)

Tar emot friska volontärer

Nej

Kön som är behöriga för studier

Allt

Beskrivning

  • ELIGIBILITY CRITERIA:

Inclusion Criteria (young control group):

  1. Adults older than 21 years and less than 40 years.
  2. Insulin sensitivity with a fasting glucose less than 100 mg/dl and a 2-hour post oral glucose tolerance test blood glucose less than 140 mg/dl.
  3. Subject understands protocol and provides written, informed consent.

Inclusion Criteria (young insulin-resistant group):

  1. Adults older than 21 years and less than 40 years.
  2. Insulin resistance as defined by a fasting blood sugar of greater than or equal to 100mg/dl but less than 125 mg/dl and/or a 2-hour post oral glucose tolerance test blood glucose greater than 140 mg/dl and less than 200 mg/dl.
  3. Subject understands protocol and provides written, informed consent.

Inclusion Criteria (middle age control group):

  1. Adults greater than or equal to 40 years and less than or equal to 60 years.
  2. Insulin sensitivity with a fasting blood glucose less than 100 mg/dl and a 2-hour post oral glucose tolerance test blood glucose less than 140 mg/dl.
  3. Subject understands protocol and provides written, informed consent.

Inclusion Criteria (middle age insulin-resistant group):

  1. Adults greater than or equal to 40 years and less than or equal to 60 years.
  2. Insulin resistance as defined by a fasting blood sugar of greater than or equal to 100mg/dl but less than 125 mg/dl and/or a 2-hour post oral glucose tolerance test blood glucose greater than 140 mg/dl and less than 200 mg/dl.
  3. Subject understands protocol and provides written, informed consent.

Inclusion Criteria (middle age type II diabetes group):

  1. Adults greater than or equal to 40 years and less than or equal to 60 years.
  2. Type II diabetes as defined by a fasting blood sugar of greater than 125 mg/dl and/or a 2-hour post oral glucose tolerance test blood glucose greater than 200 mg/dl if untreated and/or if subjects are on oral hypoglycemic agent therapy where the HbA1c is greater than 6.7 percent.
  3. Subject understands protocol and provides written, informed consent.

Exclusion Criteria (all study subjects) :

  1. Uncontrolled hypertension, heart failure, unstable coronary artery disease or symptomatic peripheral arterial disease requiring changes in medication or medical intervention in the preceding 3 months.
  2. Insulin-dependant diabetes mellitus or current use of thiazolidinediones.
  3. Women of childbearing age unless recent pregnancy test is negative and are not breast feeding.
  4. Serum creatinine greater than 2.5 mg/dl.
  5. Liver transaminase levels greater than 2.5 times upper limit of normal.
  6. History of cancer treated with chemotherapy or irradiation in the last 5 years.
  7. Active inflammatory disease, or infection, or abnormal white blood cell differential.
  8. Enrollment in any drug studies within the last 30 days.
  9. BMI greater than 35 for the middle age groups and greater than 30 for the younger subjects.
  10. Age greater than 60 years.
  11. Another member of a potential study subject's immediate family has been recruited/participated in this study.
  12. The use of anticoagulation therapy, thiazide diuretics, corticosteroids, or some psychiatric drugs that cannot be stopped for medical reasons for a few days for study participation.

Studieplan

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Hur är studien utformad?

Designdetaljer

Samarbetspartners och utredare

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Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

Publikationer och användbara länkar

Den som ansvarar för att lägga in information om studien tillhandahåller frivilligt dessa publikationer. Dessa kan handla om allt som har med studien att göra.

Allmänna publikationer

Studieavstämningsdatum

Dessa datum spårar framstegen för inlämningar av studieposter och sammanfattande resultat till ClinicalTrials.gov. Studieposter och rapporterade resultat granskas av National Library of Medicine (NLM) för att säkerställa att de uppfyller specifika kvalitetskontrollstandarder innan de publiceras på den offentliga webbplatsen.

Studera stora datum

Studiestart

27 januari 2009

Avslutad studie

24 oktober 2011

Studieregistreringsdatum

Först inskickad

30 januari 2009

Först inskickad som uppfyllde QC-kriterierna

30 januari 2009

Första postat (Uppskatta)

2 februari 2009

Uppdateringar av studier

Senaste uppdatering publicerad (Faktisk)

2 juli 2017

Senaste inskickade uppdateringen som uppfyllde QC-kriterierna

30 juni 2017

Senast verifierad

24 oktober 2011

Mer information

Termer relaterade till denna studie

Nyckelord

Ytterligare relevanta MeSH-villkor

Andra studie-ID-nummer

  • 090068
  • 09-H-0068

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