Since both genotype and environmental risk factors for diabetes, including obesity and inactivity, converge to influence cellular function at the level of gene and protein expression, we hypothesize that alterations in gene expression in nondiabetic individuals at high risk for developing diabetes (""""""""prediabetes"""""""") mediate this risk. In our recent array studies of differential gene expression in skeletal muscle from Mexican-American subjects, we identified a pattern of coordinate reduction in expression of multiple nuclear respiratory factor (NRF)-regulated genes of oxidative metabolism and mitochondrial function in insulin resistant and diabetic subjects. We have now identified a potential molecular mechanism for these changes: decreased expression of PGC-1, a coactivator of both NRF and PPARgamma-dependent transcription linked to mitochondrial biogenesis and function. Quantitative RT-PCR demonstrates that PGC-1 expression is reduced in insulin resistant and diabetic subjects and correlates with obesity, insulin resistance, and free fatty acid levels. Taken together, these data form the basis of our hypothesis that reductions in PGC-1 and NRF-dependent metabolic gene transcription play an important role in metabolic changes characteristic of insulin resistance and diabetes progression, including inabililty to modulate lipid oxidation, intramuscular lipid accumulation, and further insulin resistance. We will test this hypothesis in 2 additional populations at high risk for diabetes: subjects with a family history of diabetes and African-American ethnicity. Moreover, we will test the specific hypotheses that obesity and inactivity mediate risk in prediabetes via reduction in PGC-1 and NRF-dependent gene expression, and evaluate whether weight loss and physical training can increase PGC-1 expression and reverse abnormal patterns of metabolic gene expression in parallel with improved insulin sensitivity. Finally, since it is difficult to dissect the contribution of individual metabolic risk factors to reductions in PGC-1 expression in humans, we will utilize cultured cells to test whether nutrient excess and/or insulin resistance can directly reduce PGC-1 expression, and determine whether experimental reductions in PGC-1 expression can directly induce intracellular triglyceride accumulation and/or insulin resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062948-03
Application #
6924535
Study Section
Endocrinology Study Section (END)
Program Officer
Mckeon, Catherine T
Project Start
2003-09-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$319,824
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
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