Insulin resistance and glucose intolerance have classically been associated with aging in humans. Recent studies, however, suggest that lifestyle, as opposed to aging per se, might be responsible for the development of insulin resistance in older individuals. Insulin resistance and the resultant hyperinsulinemia are risk factors for non-insulin-dependent diabetes mellitus and atherosclerosis. More recently, insulin resistance has been implicated as a major factor in a metabolic syndrome consisting of hyperinsulinemia, hypertension, obesity, hypertriglyceridemia and increased blood clotting, all risk factors for atherosclerosis. The long-term objectives of this continuation proposal are to better understand the mechanisms involved in regulating glucose transport in skeletal muscle, the major insulin-responsive tissue in the body. Using the Fischer 344 rat, the investigators have previously shown that insulin resistance does not develop when rats are raised on a low-fat, high-complex-carbohydrate (LFCC) diet. However, when rats were raised on a high-fat, refined sugar (HFS) diet, insulin resistance was well developed at 2 yr of age. In addition, the HFS rats become obese, hypertensive, hypertriglyceridemic and had increased blood clotting compared to the LFCC rats.
The specific aims of this proposal are to investigate the mechanisms by which the HFS diet induces skeletal muscle insulin resistance and how the resultant hyperinsulinemia induces obesity and hypertension. Fischer 344 rats will be raised for up to 2 years on either the HFS or LFCC diet. Studies on insulin resistance in skeletal muscle will focus on insulin receptor autophosphorylation and tyrosine kinase activity. Studies on obesity will focus on the effects of hyperinsulinemia on lipoprotein and hormone- sensitive lipase in fat cells as well as hypothalamic regulation of food intake. Studies on hypertension will focus on the role that insulin exerts via the autonomic nervous system. The results of this project should provide important insight into the role that diet plays in the induction of insulin resistance, obesity and hypertension, all major health problems in this country.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG007592-07
Application #
2049815
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1989-01-01
Project End
1998-02-28
Budget Start
1995-03-01
Budget End
1996-02-29
Support Year
7
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Youngren, J F; Paik, J; Barnard, R J (2001) Impaired insulin-receptor autophosphorylation is an early defect in fat-fed, insulin-resistant rats. J Appl Physiol 91:2240-7
Roberts, C K; Barnard, R J; Jasman, A et al. (1999) Acute exercise increases nitric oxide synthase activity in skeletal muscle. Am J Physiol 277:E390-4
Berger, J J; Barnard, R J (1999) Effect of diet on fat cell size and hormone-sensitive lipase activity. J Appl Physiol 87:227-32
Barnard, R J; Roberts, C K; Varon, S M et al. (1998) Diet-induced insulin resistance precedes other aspects of the metabolic syndrome. J Appl Physiol 84:1311-5
Roberts, C K; Barnard, R J; Scheck, S H et al. (1997) Exercise-stimulated glucose transport in skeletal muscle is nitric oxide dependent. Am J Physiol 273:E220-5
Youngren, J F; Barnard, R J (1995) Effects of acute and chronic exercise on skeletal muscle glucose transport in aged rats. J Appl Physiol 78:1750-6
Zernicke, R F; Salem, G J; Barnard, R J et al. (1995) Long-term, high-fat-sucrose diet alters rat femoral neck and vertebral morphology, bone mineral content, and mechanical properties. Bone 16:25-31
Barnard, R J; Faria, D J; Menges, J E et al. (1993) Effects of a high-fat, sucrose diet on serum insulin and related atherosclerotic risk factors in rats. Atherosclerosis 100:229-36
Barnard, R J; Lawani, L O; Martin, D A et al. (1992) Effects of maturation and aging on the skeletal muscle glucose transport system. Am J Physiol 262:E619-26
Barnard, R J; Ugianskis, E J; Martin, D A et al. (1992) Role of diet and exercise in the management of hyperinsulinemia and associated atherosclerotic risk factors. Am J Cardiol 69:440-4

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