Inhibition by aldosterone of insulin receptor mRNA levels and insulin binding in U-937 human promonocytic cells

ABSTRACT Corticosteroids have profound effects on bone metabolism, though the underlying mechanisms remain unclear. They are also known to alter glucose metabolism, in part by induction of insulin resistance. To determine whether corticosteroids impair glucose metabolism in bone cells, we have examined the actions of dexamethasone (DEX) on glucose transport and insulin receptor expression using osteoblast-like UMR 106-01 cells. DEX was shown to inhibit basal 2-deoxyglucose uptake by up to 30% in a time- and dose-dependent manner. It inhibited insulin-stimulated glucose transport by 13%. By Northern and Western blot analysis, DEX was shown to stimulate insulin receptor mRNA and protein by up to 5·6-fold, but it had no effect on expression of the glucose transporter GLUT 1 mRNA or protein under basal conditions. However, DEX augmented insulin-stimulated GLUT 1 mRNA and protein levels. By Scatchard analysis of labelled insulin binding, DEX increased insulin receptor number per cell by 54%. Subcellular fractionation and Western blot analysis demonstrated that DEX caused a redistribution of immunoreactive GLUT 1 from plasma membrane to intracellular microsomes, resulting in a 21% decrease in GLUT 1 at the plasma membrane. These data suggest that (i) DEX impairs basal glucose transport by post-translational mechanisms in UMR 106-01 cells, (ii) DEX increases insulin receptor mRNA, protein and insulin binding and (iii) the inhibition of glucose transport by DEX dominates its effects on the insulin receptor. It is possible that DEX inhibition of glucose transport in osteoblasts may contribute to steroid-induced osteoporosis.

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In-frame exon 2 deletion in insulin receptor RNA in a family with extreme insulin resistance in association with defective insulin binding: a case report

Acta Endocrinologica ◽

10.1530/eje.0.1350357 ◽

1996 ◽

Vol 135 (3) ◽

pp. 357-363 ◽

Cited By ~ 3

Author(s):

Wolfgang Moritz ◽

Marianne Böni-Schnetzler ◽

Wayne Stevens ◽

E Rudolf Froesch ◽

James R Levy

Keyword(s):

Insulin Resistance ◽

Insulin Receptor ◽

Receptor Binding ◽

Type A ◽

Insulin Binding ◽

Exon 2 ◽

Receptor Mrna ◽

Mrna Transcripts ◽

Extreme Insulin Resistance ◽

Type A Insulin Resistance

Moritz W, Böni-Schnetzler M, Stevens W, Froesch ER, Levy JR. In-frame exon 2 deletion in insulin receptor RNA in a family with extreme insulin resistance in association with defective insulin binding. Eur J Endocrinol 1996;135:357–63. ISSN 0804–4643 The phenotype and allelic expression of the insulin receptor gene is presented in a family with a patient with type A insulin resistance. Compared to controls, insulin receptor binding in transformed lymphocytes was 100%, 33% and 13% in the father, mother and proband, respectively. Reduced insulin receptor binding co-segregated with altered insulin receptor mRNA expression; the mother and daughter expressed eight insulin receptor mRNA species, including a set of four normal sized and a set of four shorter mRNA transcripts. In the proband the levels of the normal sized mRNA transcripts were suppressed relative to the shorter transcripts. Reverse polymerase chain reaction (PCR) revealed that the shorter transcripts contained an in-frame deletion of exon 2. Sequencing of the entire insulin receptor coding region revealed a paternally inherited A to T substitution in nucleotide 3205, converting isoleucine 996 to phenylalanine. which does not co-segregate with reduced binding. Therefore, we hypothesize that two findings are necessary for the presentation of type A insulin resistance in this patient: an in-frame deletion of the insulin receptor exon 2 that codes for amino acids crucial for insulin binding; and an inhibition of expression of the paternal insulin receptor allele. Marianne Böni-Schnetzler, Division of Endocrinology and Metabolism, Department of Internal Medicine, University Hospital, 8091 Zurich, Switzerland

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