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Insulin Internalization into Monocytes Is Decreased in Patients with Type II Diabetes Mellitus^*

Cattedra di Endocrinologia e Clinica Medica III, University of Catania 95123 Catania, Italy
Cell Biology Laboratory and Department of Medicine, Mount Zion Hospital and Medical Center San Franciso, California 94102
Departments of Medicine and Physiology, University of California San Franciso, California 94121

Address requests for reprints to: Dr. Ira Goldfine, Department of Medicine, Cell Biology Laboratory, Mount Zion Hospital and Medical Center, San Francisco, California 94120.

We studied the internalization of [¹²⁵I]insulin into circulating human monocytes, a cell type widely used for insulin binding studies. The internalization of [¹²⁵I]insulin was assessed by both an acid extraction technique, which removes surface-bound insulin but not intracellular insulin, and by a trypsinization technique, which removes cell surface-bound hormone. After 5 h ofincubation at 22 C, over 40% of the total cell-associated [¹²⁵I]insulin was internalized into monocytes of normal subjects. This internalization was temperature dependent; the fraction of internalized hormone was progressively decreased when the incubation with increasing concentrations of 2,4-dinitrophenol also decreased [¹²⁵I] insulin internalization, whereas dansylcadaverine, an inhibitor of transglutaminase, had no effect. Analysis by gel filtrationof the internalized labeled hormone after 4 h of incubation at 22 C indicated that 50–60% of the label was degraded insulin, but detectable intact insulin was still present.

Internalization of insulin was then studied in monocytes from eight obese patients (161% of ideal body weight) with type II diabetes mellitus. After 4 h of incubation at 22 C, the specific total monocyte-associated [¹²⁵I]insulin was decreased compared to that in cells from 7 normal subjects [6.02 ± 0.38% (±SE) vs. 3.91 ± 0.31% of the total; P < 0.001]. Moreover, the percentage of hormone that was internalized was also decreased from 41.4 ± 1.2% of the total to 28.9 + 1.8% (P < 0.001). In 20 nondiabetic obesesubjects, specific cell-associated [¹²⁵I]insulin was reduced to 3.9 ± 0.3% (P < 0.001). However, compared to that in normal subjects, the percentage of hormone that was internalized was not decreased (39.7 ± 3.51% of the total).

The present findings indicate that 1) human circulating monocytes internalize [¹²⁵I]insulin; 2) this process is temperature and energy dependent; and 3) monocytes from obese type II diabetic patients have a significantly decreased ability to internalize insulin. This decreased internalization may play a role in the cellular resistance to insulin that occurs in these patients.

^* This work was supported in part by the Elise Stern Haas Research Fund, Grant AM-26667 from the NIH, and a grant from the Ministero della Pubblica Istruzione,Italy.

Received June 17, 1985.

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