Obesity and related disturbances in the regulation of appetite--and""""""""diabesity"""""""", or the progressive development in many obese adults of overt noninsulin-dependent diabetes mellitus (NIDDM)--will best be effectively treated or prevented as the mechanisms underlying these disorders are discovered. This, our long-term objective, is addressed in the present application, first through the presentation of a unique and valuable nonhuman primate model of obesity and diabetes, with its remarkable similarities to the human condition, and secondly through the identification of specific aims which address the pathophysiology of two of the earliest defects in obesity and NIDDM--insulin resistance and hyperlipidemia. Obesity with or without diabetes develops naturally and spontaneously in some, but not all, adult rhesus monkeys. The proposed studies include cross sectional and longitudinal in vivo analyses of the sequence of physiological defects observable in monkeys progressing from normal lean to obese through variable phases to overt NIDDM, in combination with in vitro determinations of rate-limiting, insulin-sensitive enzymes in muscle, liver and adipose tissue. We hypothesize that """"""""insulin resistance"""""""" is not a singular process which develops uniformly and in parallel in various organs. Rather, our current data indicate that the changes in vivo measurements such as glucose uptake during a euglycemic clamp actually reflect diverse organ-specific defects, such as changes in insulin-stimulated enzyme activity in muscle. We will seek to understand these defects in insulin action at the receptor level, and in the glucose storage and oxidation pathways of liver, muscle, and adipose tissue with studies designed to identify the nature of the defects as well as the onset and sequence of each in the course of the development of obesity and NIDDM. Also, we aim to determine the nature of the earliest defects in vivo lipid and lipoprotein metabolism, and to relate those changes in insulin action in vivo and in adipose tissue, muscle, and liver. Finally, we propose to provide investigators from a wide range of disciplines, with interests in the pathophysiology of obesity and diabetes, the opportunity to study these well-characterized animals,while simultaneously assuring the highest quality of care for each individual animal.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
8R01AG010612-06
Application #
3122522
Study Section
Clinical Trials (CLIN)
Project Start
1986-01-01
Project End
1993-04-30
Budget Start
1991-09-01
Budget End
1993-04-30
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
DeLany, J P; Hansen, B C; Bodkin, N L et al. (1999) Long-term calorie restriction reduces energy expenditure in aging monkeys. J Gerontol A Biol Sci Med Sci 54:B5-11;discussion B12-3
Hotta, K; Gustafson, T A; Ortmeyer, H K et al. (1996) Regulation of obese (ob) mRNA and plasma leptin levels in rhesus monkeys. Effects of insulin, body weight, and non-insulin-dependent diabetes mellitus. J Biol Chem 271:25327-31
Ortmeyer, H K (1996) Dietary myoinositol results in lower urine glucose and in lower postprandial plasma glucose in obese insulin resistant rhesus monkeys. Obes Res 4:569-75
Charge, S B; Esiri, M M; Bethune, C A et al. (1996) Apolipoprotein E is associated with islet amyloid and other amyloidoses: implications for Alzheimer's disease. J Pathol 179:443-7
Huang, Z; Bodkin, N L; Ortmeyer, H K et al. (1996) Altered insulin receptor messenger ribonucleic acid splicing in liver is associated with deterioration of glucose tolerance in the spontaneously obese and diabetic rhesus monkey: analysis of controversy between monkey and human studies. J Clin Endocrinol Metab 81:1552-6
Ortmeyer, H K; Bodkin, N L; Varghese, S S et al. (1996) Glycogen phosphorylase activity and glycogen concentration in muscle of normal to overtly diabetic rhesus monkeys. Int J Obes Relat Metab Disord 20:98-105
Bodkin, N L; Ortmeyer, H K; Hansen, B C (1995) Long-term dietary restriction in older-aged rhesus monkeys: effects on insulin resistance. J Gerontol A Biol Sci Med Sci 50:B142-7
Hansen, B C; Ortmeyer, H K; Bodkin, N L (1995) Prevention of obesity in middle-aged monkeys: food intake during body weight clamp. Obes Res 3 Suppl 2:199s-204s
Ortmeyer, H K; Bodkin, N L; Hansen, B C (1994) Relationship of skeletal muscle glucose 6-phosphate to glucose disposal rate and glycogen synthase activity in insulin-resistant and non-insulin-dependent diabetic rhesus monkeys. Diabetologia 37:127-33
Huang, Z; Bodkin, N L; Ortmeyer, H K et al. (1994) Hyperinsulinemia is associated with altered insulin receptor mRNA splicing in muscle of the spontaneously obese diabetic rhesus monkey. J Clin Invest 94:1289-96

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