There is growing evidence that the development of Type 2 diabetes is precipitated by alterations in the partitioning of fat between the adipose tissue vs. muscle, liver and pancreas. Intracellular accumulation of triglyceride and fatty acid metabolites leads to acquired insulin signaling defect and insulin resistance. One can, therefore, hypothesize that the inability of the adipose organ to expand to accommodate excess calories results in adipose tissue hypertrophy and Type 2 diabetes in predisposed obese subject. Such a hypothesis is now clearly supported by the following data: 1) Pima Indians with larger abdominal fat cells are more likely to develop diabetes than obesity-matched subjects with smaller fat cells; 2) thiazolidinediones improve insulin sensitivity by inducing adipocyte differentiation; 3) subjects with acquired total lipodystrophy (like fatless mice) are severely diabetic; 4) insulin sensitivity is inversely proportional to the triglyceride content of the muscle. In this application, we want to test the following hypotheses: 1) muscle lipid content correlates positively with abdominal subcutaneous adipocyte size in Type 2 diabetics and obesity-, sex-, and age-matched nondiabetics; 2) larger adipocytes are associated with greater weight loss and better improvement in insulin sensitivity after one year of intensive lifestyle treatment; 3) expression of genes involved in adipocyte proliferation and differentiation correlates negatively with adipocyte size in Type 2 diabetic and obesity matched non-diabetics. In response to weight loss, the expression of these genes will increase. To test these hypotheses we will perform the following studies: 1) determine the relationship between abdominal subcutaneous fat cell size (biopsy) and muscle fat infiltration (CT scan) in 100 subjects from Look AHEAD Trial and 50 non-diabetic matched for sex, race, age and BMI; 2) identify the effect of abdominal fat cell size on weight loss and improvement in insulin sensitivity (hyperglycemic clamp) after one year of intensive lifestyle treatment in the 100 subjects from the Look AHEAD Trial; 3) quantify in subcutaneous abdominal adipose tissue the expression of genes involved in adipocyte proliferation/differentiation in 100 Type 2 diabetic subjects and 50 non-diabetic subjects. Gene expression will also be measured in Type 2 diabetics after one year of intensive lifestyle changes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060412-04
Application #
6786590
Study Section
Special Emphasis Panel (ZDK1-GRB-1 (M1))
Program Officer
Harrison, Barbara
Project Start
2001-09-30
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
4
Fiscal Year
2004
Total Cost
$571,061
Indirect Cost
Name
Lsu Pennington Biomedical Research Center
Department
Type
Organized Research Units
DUNS #
611012324
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
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Toledo, Frederico G S; Johannsen, Darcy L; Covington, Jeffrey D et al. (2018) Impact of prolonged overfeeding on skeletal muscle mitochondria in healthy individuals. Diabetologia 61:466-475
Peterson, C M; Zhang, B; Johannsen, D L et al. (2017) Eight weeks of overfeeding alters substrate partitioning without affecting metabolic flexibility in men. Int J Obes (Lond) 41:887-893
Peterson, Courtney M; Orooji, Mahdi; Johnson, Deanna N et al. (2017) Brown adipose tissue does not seem to mediate metabolic adaptation to overfeeding in men. Obesity (Silver Spring) 25:502-505
Covington, Jeffrey D; Johannsen, Darcy L; Coen, Paul M et al. (2017) Intramyocellular Lipid Droplet Size Rather Than Total Lipid Content is Related to Insulin Sensitivity After 8 Weeks of Overfeeding. Obesity (Silver Spring) 25:2079-2087
Covington, Jeffrey D; Tam, Charmaine S; Bajpeyi, Sudip et al. (2016) Myokine Expression in Muscle and Myotubes in Response to Exercise Stimulation. Med Sci Sports Exerc 48:384-90
Gilmore, L Anne; Butte, Nancy F; Ravussin, Eric et al. (2016) Energy Intake and Energy Expenditure for Determining Excess Weight Gain in Pregnant Women. Obstet Gynecol 127:884-92
Covington, J D; Bray, G A; Redman, L M et al. (2015) Eight weeks of dietary overfeeding increases renal filtration rates in humans: implications for the pathogenesis of diabetic hyperfiltration. J Intern Med 278:396-400
Covington, Jeffrey D; Noland, Robert C; Hebert, R Caitlin et al. (2015) Perilipin 3 Differentially Regulates Skeletal Muscle Lipid Oxidation in Active, Sedentary, and Type 2 Diabetic Males. J Clin Endocrinol Metab 100:3683-92
Johannsen, Darcy L; Tchoukalova, Yourka; Tam, Charmaine S et al. (2014) Effect of 8 weeks of overfeeding on ectopic fat deposition and insulin sensitivity: testing the ""adipose tissue expandability"" hypothesis. Diabetes Care 37:2789-97

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