Abstract
Skeletal muscle insulin resistance plays a pivotal role in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM), as individuals with this defect are at increased risk of developing the disease later in life. To assess whether the abnormal expression of the structurally distinct human insulin receptor isoforms, HIR-A and HIR-B, which has been found in skeletal muscle of NIDDM patients, is a feature of a prediabetic state, skeletal muscle biopsies from nondiabetic individuals ranging from high insulin sensitivity to insulin resistance were examined. Polymerase chain reaction analysis of mRNA from muscle biopsies detected exclusive or predominant expression of HIR-A in 13 patients with normal insulin sensitivity. In contrast, 7 subjects with various degrees of insulin resistance exhibited abnormally increased HIR-B RNA expression. This association suggests the abnormal expression of receptor isoforms as a characteristic of the prediabetic state and supports the notion of a connection of this aberration with the pathogenesis of NIDDM. Changes in HIR-A/B expression in the skeletal muscle may thus provide a prognostic criterion for the development of NIDDM.
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- Arner P., Pollare T., Lithell H., Livingston J. N. Defective insulin receptor tyrosine kinase in human skeletal muscle in obesity and type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1987 Jun;30(6):437–440. doi: 10.1007/BF00292549. [DOI] [PubMed] [Google Scholar]
- Benecke H., Flier J. S., Moller D. E. Alternatively spliced variants of the insulin receptor protein. Expression in normal and diabetic human tissues. J Clin Invest. 1992 Jun;89(6):2066–2070. doi: 10.1172/JCI115819. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carrascosa J. M., Vogt B., Ullrich A., Häring H. U. Activation of phosphatidylinositol-3-kinase by insulin is mediated by both A and B human insulin receptor types. Biochem Biophys Res Commun. 1991 Jan 15;174(1):123–127. doi: 10.1016/0006-291x(91)90494-r. [DOI] [PubMed] [Google Scholar]
- Coleman T. G., Manning R. D., Jr, Norman R. A., Jr, Guyton A. C. Dynamics of water-isotope distribution. Am J Physiol. 1972 Dec;223(6):1371–1375. doi: 10.1152/ajplegacy.1972.223.6.1371. [DOI] [PubMed] [Google Scholar]
- DeFronzo R. A. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988 Jun;37(6):667–687. doi: 10.2337/diab.37.6.667. [DOI] [PubMed] [Google Scholar]
- DeFronzo R. A., Tobin J. D., Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214–E223. doi: 10.1152/ajpendo.1979.237.3.E214. [DOI] [PubMed] [Google Scholar]
- Ebina Y., Ellis L., Jarnagin K., Edery M., Graf L., Clauser E., Ou J. H., Masiarz F., Kan Y. W., Goldfine I. D. The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell. 1985 Apr;40(4):747–758. doi: 10.1016/0092-8674(85)90334-4. [DOI] [PubMed] [Google Scholar]
- Eriksson J., Franssila-Kallunki A., Ekstrand A., Saloranta C., Widén E., Schalin C., Groop L. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med. 1989 Aug 10;321(6):337–343. doi: 10.1056/NEJM198908103210601. [DOI] [PubMed] [Google Scholar]
- Ferrannini E. The theoretical bases of indirect calorimetry: a review. Metabolism. 1988 Mar;37(3):287–301. doi: 10.1016/0026-0495(88)90110-2. [DOI] [PubMed] [Google Scholar]
- Hultman E. Muscle glycogen in man determined in needle biopsy specimens: method and normal values. Scand J Clin Lab Invest. 1967;19(3):209–217. doi: 10.3109/00365516709090628. [DOI] [PubMed] [Google Scholar]
- Kellerer M., Lammers R., Ermel B., Tippmer S., Vogt B., Obermaier-Kusser B., Ullrich A., Häring H. U. Distinct alpha-subunit structures of human insulin receptor A and B variants determine differences in tyrosine kinase activities. Biochemistry. 1992 May 19;31(19):4588–4596. doi: 10.1021/bi00134a008. [DOI] [PubMed] [Google Scholar]
- McClain D. A. Different ligand affinities of the two human insulin receptor splice variants are reflected in parallel changes in sensitivity for insulin action. Mol Endocrinol. 1991 May;5(5):734–739. doi: 10.1210/mend-5-5-734. [DOI] [PubMed] [Google Scholar]
- Moller D. E., Yokota A., Caro J. F., Flier J. S. Tissue-specific expression of two alternatively spliced insulin receptor mRNAs in man. Mol Endocrinol. 1989 Aug;3(8):1263–1269. doi: 10.1210/mend-3-8-1263. [DOI] [PubMed] [Google Scholar]
- Moller D. E., Yokota A., Flier J. S. Normal insulin-receptor cDNA sequence in Pima Indians with NIDDM. Diabetes. 1989 Nov;38(11):1496–1500. doi: 10.2337/diab.38.11.1496. [DOI] [PubMed] [Google Scholar]
- Mosthaf L., Grako K., Dull T. J., Coussens L., Ullrich A., McClain D. A. Functionally distinct insulin receptors generated by tissue-specific alternative splicing. EMBO J. 1990 Aug;9(8):2409–2413. doi: 10.1002/j.1460-2075.1990.tb07416.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mosthaf L., Vogt B., Häring H. U., Ullrich A. Altered expression of insulin receptor types A and B in the skeletal muscle of non-insulin-dependent diabetes mellitus patients. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4728–4730. doi: 10.1073/pnas.88.11.4728. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Obermaier-Kusser B., White M. F., Pongratz D. E., Su Z., Ermel B., Muhlbacher C., Haring H. U. A defective intramolecular autoactivation cascade may cause the reduced kinase activity of the skeletal muscle insulin receptor from patients with non-insulin-dependent diabetes mellitus. J Biol Chem. 1989 Jun 5;264(16):9497–9504. [PubMed] [Google Scholar]
- Reaven G. M., Bernstein R., Davis B., Olefsky J. M. Nonketotic diabetes mellitus: insulin deficiency or insulin resistance? Am J Med. 1976 Jan;60(1):80–88. doi: 10.1016/0002-9343(76)90536-2. [DOI] [PubMed] [Google Scholar]
- Reaven G. M. Insulin resistance in noninsulin-dependent diabetes mellitus. Does it exist and can it be measured? Am J Med. 1983 Jan 17;74(1A):3–17. doi: 10.1016/0002-9343(83)90650-2. [DOI] [PubMed] [Google Scholar]
- Seino S., Bell G. I. Alternative splicing of human insulin receptor messenger RNA. Biochem Biophys Res Commun. 1989 Feb 28;159(1):312–316. doi: 10.1016/0006-291x(89)92439-x. [DOI] [PubMed] [Google Scholar]
- Ullrich A., Bell J. R., Chen E. Y., Herrera R., Petruzzelli L. M., Dull T. J., Gray A., Coussens L., Liao Y. C., Tsubokawa M. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. 1985 Feb 28-Mar 6Nature. 313(6005):756–761. doi: 10.1038/313756a0. [DOI] [PubMed] [Google Scholar]
- Warram J. H., Martin B. C., Krolewski A. S., Soeldner J. S., Kahn C. R. Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med. 1990 Dec 15;113(12):909–915. doi: 10.7326/0003-4819-113-12-909. [DOI] [PubMed] [Google Scholar]
- Yamaguchi Y., Flier J. S., Yokota A., Benecke H., Backer J. M., Moller D. E. Functional properties of two naturally occurring isoforms of the human insulin receptor in Chinese hamster ovary cells. Endocrinology. 1991 Oct;129(4):2058–2066. doi: 10.1210/endo-129-4-2058. [DOI] [PubMed] [Google Scholar]
- Yarden Y., Ullrich A. Growth factor receptor tyrosine kinases. Annu Rev Biochem. 1988;57:443–478. doi: 10.1146/annurev.bi.57.070188.002303. [DOI] [PubMed] [Google Scholar]