The etiology of insulin resistance during diabetic ketoacidosis is still poorly understood. Changes in insulin receptor binding and the existence of postreceptor alterations have been proposed. In an attempt to clarify the role of low pH and ketone bodies in the insulin resistance, we examined the effectiveness of insulin during and after 48 h of exposure of cultured 3T3-L1 adipocytes to low pH and ketoacids. In the “acute” stage, lowering of physiologic pH (pH 7.4) to pH 6.9 induced a decrease in insulin binding (50%), which was due to a decrease in the rate of association. Concomitantly, the insulin sensitivity was decreased (ninefold). The basal hexose uptake and insulin responsiveness were only slightly decreased at low pH. Beta-hydroxybutyrate partially counteracted the effect of low pH on insulin binding and sensitivity in a dose-dependent fashion (ED50: 10 mM). The binding-enhancing effect of ketoacids was more pronounced at low pH than at physiologic pH and absent at optimum pH (pH 8.0). After 48 h of exposure of the cells to pH 6.9, insulin binding and insulin sensitivity (measured at physiologic pH) were similar as in cells cultured at pH 7.4. The insulin response, however, was substantially impaired (40%), due to an increase in basal hexose uptake as well as a decrease in maximal insulin-stimulated uptake. These postbinding alterations induced by low pH could be reversed by culturing the cells at physiologic pH for another 48 h. Prolonged exposure to ketoacids did not affect the insulin effectiveness. Our data suggest that the insulin resistance accompanying ketoacidosis is due to low pH-induced insulin receptor binding as well as postbinding alterations. Ketoacids do not seem to contribute to the insulin resistance.
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Original contribution|
August 01 1985
Low pH and Ketoacids Induce Insulin Receptor Binding and Postbinding Alterations in Cultured 3T3 Adipocytes
J P M Van Putten;
J P M Van Putten
Laboratory for Diabetes Research, Department of Endocrinology and Metabolic Diseases, University Hospital
2333 AA Leiden, The Netherlands
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Tj Wieringa;
Tj Wieringa
Laboratory for Diabetes Research, Department of Endocrinology and Metabolic Diseases, University Hospital
2333 AA Leiden, The Netherlands
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H M J Krans
H M J Krans
Laboratory for Diabetes Research, Department of Endocrinology and Metabolic Diseases, University Hospital
2333 AA Leiden, The Netherlands
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Address reprint requests to Prof. Dr. H. M. J. Krans, Department of Endocrinology and Metabolic Diseases, University Hospital, Bldg. 30, 2333 AA Leiden, The Netherlands.
Diabetes 1985;34(8):744–750
Article history
Received:
February 10 1984
Revision Received:
December 30 1984
PubMed:
3926564
Citation
J P M Van Putten, Tj Wieringa, H M J Krans; Low pH and Ketoacids Induce Insulin Receptor Binding and Postbinding Alterations in Cultured 3T3 Adipocytes. Diabetes 1 August 1985; 34 (8): 744–750. https://doi.org/10.2337/diab.34.8.744
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