The objectives of this grant proposal are to study the clinical significance of pro-insulin, pro-insulin intermediates and C-peptide and to expand investigations of families with structurally abnormal proinsulin and insulin molecules. Specific antisera will be raised to human proinsulin in guinea pigs and rabbits and characterized in terms of their cross reactivity with insulin, C-peptide, proinsulin and its intermediates. Monoclonal antibodies will be raised and characterized similarly. These immunoassays will be used in conjunction with high pressure liquid chromatography (HPLC) to separate and identify serum proinsulin, its intermediates, C-peptide and insulin. In addition urinary C-peptide and its potential degradation products in dogs and man will be separated by a similar combination of techniques. The availability of human proinsulin and C-peptide will permit studies on their biological activity and metabolism. The potential use of human proinsulin for therapeutic purposes in Type I diabetics will be assessed. In these experiments, the possible in-vivo conversion of proinsulin to its intermediates will be evaluated using HPLC. The C-peptide will be used to study its metabolic clearance rate in man, as well as its urinary excretion. These studies should provide data relevant to accurately measuring insulin secretion in man. Several patients with mutant (pro)insulins have been identified. These patients and their families will undergo clinical evaluation in terms of their carbohydrate homeostasis. In addition their serum (pro)insulins will be characterized and the structural abnormality identified at both the protein and gene level. Studies in dogs will be carried out to quantify the metabolism of the abnormal insulin mutants and relate the results to the findings in the affected patients and their families.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK013941-20
Application #
3225179
Study Section
Metabolism Study Section (MET)
Project Start
1974-11-01
Project End
1990-11-30
Budget Start
1988-12-01
Budget End
1990-11-30
Support Year
20
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
O'Meara, N M; Sturis, J; Herold, K C et al. (1995) Alterations in the patterns of insulin secretion before and after diagnosis of IDDM. Diabetes Care 18:568-71
O'Meara, N M; Sturis, J; Blackman, J D et al. (1993) Analytical problems in detecting rapid insulin secretory pulses in normal humans. Am J Physiol 264:E231-8
O'Meara, N M; Sturis, J; Blackman, J D et al. (1993) Oscillatory insulin secretion after pancreas transplant. Diabetes 42:855-61
O'Meara, N M; Blackman, J D; Sturis, J et al. (1993) Alterations in the kinetics of C-peptide and insulin secretion in hyperthyroidism. J Clin Endocrinol Metab 76:79-84
O'Meara, N M; Blackman, J D; Ehrmann, D A et al. (1993) Defects in beta-cell function in functional ovarian hyperandrogenism. J Clin Endocrinol Metab 76:1241-7
O'Meara, N M; Sturis, J; Van Cauter, E et al. (1993) Lack of control by glucose of ultradian insulin secretory oscillations in impaired glucose tolerance and in non-insulin-dependent diabetes mellitus. J Clin Invest 92:262-71
Oohashi, H; Ohgawara, H; Nanjo, K et al. (1993) Familial hyperproinsulinemia associated with NIDDM. A case study. Diabetes Care 16:1340-6
O'Meara, N M; Lewis, G F; Cabana, V G et al. (1992) Role of basal triglyceride and high density lipoprotein in determination of postprandial lipid and lipoprotein responses. J Clin Endocrinol Metab 75:465-71
Blackman, J D; Polonsky, K S; Jaspan, J B et al. (1992) Insulin secretory profiles and C-peptide clearance kinetics at 6 months and 2 years after kidney-pancreas transplantation. Diabetes 41:1346-54
Blackman, J D; Towle, V L; Sturis, J et al. (1992) Hypoglycemic thresholds for cognitive dysfunction in IDDM. Diabetes 41:392-9

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