Relation of White Blood Cell Function to Diabetes
Maneno muhimu
Kikemikali
Maelezo
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.
Tarehe
| Imethibitishwa Mwisho: | 10/18/2009 |
| Iliyowasilishwa Kwanza: | 12/06/2007 |
| Uandikishaji uliokadiriwa Uliwasilishwa: | 12/06/2007 |
| Iliyotumwa Kwanza: | 12/09/2007 |
| Sasisho la Mwisho Liliwasilishwa: | 06/29/2017 |
| Sasisho la Mwisho Lilichapishwa: | 07/01/2017 |
| Tarehe halisi ya kuanza kwa masomo: | 11/26/2007 |
| Tarehe ya Kukamilisha Msingi iliyokadiriwa: | 10/18/2009 |
Hali au ugonjwa
Awamu
Vigezo vya Kustahiki
| Zama zinazostahiki Kujifunza | 21 Years Kwa 21 Years |
| Jinsia Inastahiki Kujifunza | All |
| Hupokea Wajitolea wa Afya | Ndio |
| Vigezo | - INCLUSION CRITERIA (young groups) Adults older than 21 years and less than 40 years Subjects must either have: 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 or 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. Subject understands protocol and provides written, informed consent. INCLUSION CRITERIA (middle age groups) Adults greater than or equal to 40 years and less than or equal to 60 years Subjects must either have: 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 or 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. or 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. Subject understands protocol and provides written, informed consent. EXCLUSION CRITERIA (all study volunteers and subjects) Uncontrolled hypertension or therapy with a Beta-blocker History of heart failure (or ejection fraction less than 55 percent by echocardiogram), unstable coronary artery disease or symptomatic peripheral arterial disease requiring changes in medication or medical intervention in the preceding 3 months. Insulin-dependant diabetes mellitus or current use of thiazolidinediones Women of childbearing age unless recent pregnancy test is negative and you are not breast feeding. Serum creatinine greater than 2.5 mg/dl Liver transaminase levels greater than 2.5 times upper limit of normal History of cancer in the last 5 years Active inflammatory disease, or infection, or abnormal white blood cell differential Enrollment in any drug studies within the last 30 days BMI greater than 35 for the middle age group and greater than 30 for the younger subjects |
