The kidney is a major site of insulin metabolism removing the hormone from the circulation by means of glomerular filtration and by extraction from the postglomerular peritubular circulation. Insulin removed binds to specific receptors in the apical and basolateral tubular membranes. Filtered insulin is internalized by endocytosis and degraded completely. However the role of receptors in mediating endocytosis, the intracellular pathway for insulin, and the contributin of lysosomal and extralysosomal compartments to the degradative process are poorly defined. Basolateral uptake form the peritubular circulation is also followed by degradation but it is not known whether internalization is a prerequisite. Indeed in contrast to the apical side of the cell, basolateral endocytosis is a minor process.
The aim of this study are; 1) To evaluate the role of insulin receptors in mediating the renal uptake and degradation of insulin. 2) To characterize the intracellular pathways involved in the apical and basolateral uptake and degradation of insulin. 3) To characterize the products of insulin degradation and thereby to further our understanding of renal epithelial insulin metabolism. Studies will be conducted with kidneys from rats, and with cultured opossum kidney cell line and primary rabbit proximal tubular epithelial cells. Methodology includes subcellular fractionation, electron microscopic autoradiography, cell culture and high pressure liquid chromatography. These studies are particularly significant because of the major role played by the kidney in insulin metabolism. New information will be generated that should achieve our objectives of enhancing the understanding of renal insulin metabolism. In the long term, knowledge gained from this study should contribute significantly to our understanding of the physiology of insulin metabolism in general and in particular will form the basis of elucidating the pathophysiology of alterations of renal insulin metabolism that may occur in disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK032342-08
Application #
3230787
Study Section
Special Emphasis Panel (SSS (G))
Project Start
1982-09-01
Project End
1993-06-30
Budget Start
1991-09-30
Budget End
1992-06-30
Support Year
8
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Rabkin, R; Hamik, A; Yagil, C et al. (1996) Processing of 125I-insulin by polarized cultured kidney cells. Exp Cell Res 224:136-42
Rabkin, R; Fervenza, F C (1996) Renal hypertrophy and kidney disease in diabetes. Diabetes Metab Rev 12:217-41
Rabkin, R; Brody, M; Lu, L H et al. (1995) Expression of the genes encoding the rat renal insulin-like growth factor-I system. J Am Soc Nephrol 6:1511-8
Fawcett, J; Rabkin, R (1995) Sequential processing of insulin by cultured kidney cells. Endocrinology 136:39-45
Fawcett, J; Rabkin, R (1995) The processing of insulin-like growth factor-I (IGF-I) by a cultured kidney cell line is altered by IGF-binding protein-3. Endocrinology 136:1340-7
Tsao, T; Wang, J; Fervenza, F C et al. (1995) Renal growth hormone--insulin-like growth factor-I system in acute renal failure. Kidney Int 47:1658-68
Clark, R; Mortensen, D; Rabkin, R (1994) Recovery from acute ischaemic renal failure is accelerated by des-(1-3)-insulin-like growth factor-1. Clin Sci (Lond) 86:709-14
Fawcett, J; Rabkin, R (1993) Endosomes degrade insulin. Contrib Nephrol 101:61-5
Rabkin, R; Tsao, T; Elliot, S J et al. (1993) Insulin uptake and processing by cultured mouse glomerular endothelial cells. Am J Physiol 265:C453-9
Fawcett, J; Rabkin, R (1993) Degradation of insulin by isolated rat renal cortical endosomes. Endocrinology 133:1539-47

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