A brief history of insulin resistance: from the first insulin radioimmunoassay to selectively targeting protein kinase C pathways

Abstract

The first description of insulin resistance goes, historically, back to 1960, shortly after the development of radioimmunoassays made the quantification of insulin in the serum possible and subsequently demonstrated that individuals with late-onset diabetes mellitus had high insulin levels [ 1 Yalow R.S. Berson S.A. Immunoassay of endogenous plasma insulin in man. J Clin Invest. 1960; 39: 1157-1175 Crossref PubMed Scopus (1803) Google Scholar , 2 Yalow R.S. Berson S.A. Plasma insulin concentrations in nondiabetic and early diabetic subjects. Determinations by a new sensitive immuno-assay technic. Diabetes. 1960; 9: 254-260 Crossref PubMed Scopus (170) Google Scholar ]. Drs Yalow and Berson [ 1 Yalow R.S. Berson S.A. Immunoassay of endogenous plasma insulin in man. J Clin Invest. 1960; 39: 1157-1175 Crossref PubMed Scopus (1803) Google Scholar , 2 Yalow R.S. Berson S.A. Plasma insulin concentrations in nondiabetic and early diabetic subjects. Determinations by a new sensitive immuno-assay technic. Diabetes. 1960; 9: 254-260 Crossref PubMed Scopus (170) Google Scholar ] defined insulin resistance as “a state in which a greater than normal amount of insulin is required to elicit a quantitatively normal response.” The next landmark discovery in the history of insulin resistance was the discovery of the insulin receptor and the observation that hyperinsulinemia, secondary to insulin resistance, was associated with abnormal binding of insulin to its receptor in rodent models [ 3 Kahn C.R. Neville Jr., D.M. Roth J. Insulin-receptor interaction in the obese-hyperglycemic mouse. A model of insulin resistance. J Biol Chem. 1973; 248: 244-250 Abstract Full Text PDF PubMed Google Scholar , 4 Goldfine I.D. Kahn C.R. Neville Jr., D.M. Roth J. Garrison M.M. Bates R.W. Decreased binding of insulin to its receptors in rats with hormone induced insulin resistance. Biochem Biophys Res Commun. 1973; 53: 852-857 Crossref PubMed Scopus (64) Google Scholar ]. It was not until 1976 when the first evidence, that insulin receptor defects could be associated with insulin resistance in humans, provided translational evidence for the importance of insulin resistance in human pathophysiology [ [5] Kahn C.R. Flier J.S. Bar R.S. Archer J.A. Gorden P. Martin M.M. et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976; 294: 739-745 Crossref PubMed Scopus (832) Google Scholar ]. Kahn et al [ [5] Kahn C.R. Flier J.S. Bar R.S. Archer J.A. Gorden P. Martin M.M. et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976; 294: 739-745 Crossref PubMed Scopus (832) Google Scholar ] described 2 syndromes that where characterized by acanthosis nigricans, virilization, anovulation, hirsutism, acne, and defective binding of insulin on insulin receptor of circulating lymphocytes. The first syndrome was characterized as type A insulin resistance when the latter occurred in the absence of anti-insulin antibodies and the defect of the insulin receptor was primary, whereas it was characterized as type B when it was associated with clinical features of autoimmune diseases and it occurred in the presence of neutralizing anti-insulin antibodies [ [5] Kahn C.R. Flier J.S. Bar R.S. Archer J.A. Gorden P. Martin M.M. et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976; 294: 739-745 Crossref PubMed Scopus (832) Google Scholar ]. The description of type A and type B syndrome was followed by the description of the hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome; the Rabson-Mendenhall syndrome; leprechaunism; and lipodystrophy, all representing rare syndromes of extreme insulin resistance [ 6 Mantzoros C.S. Flier J.S. Insulin resistance: the clinical spectrum. Adv Endocrinol Metab. 1995; 6: 193-232 PubMed Google Scholar , 7 Tritos N.A. Mantzoros C.S. Clinical review 97: syndromes of severe insulin resistance. J Clin Endocrinol Metab. 1998; 83: 3025-3030 PubMed Scopus (0) Google Scholar , 8 Fiorenza C.G. Chou S.H. Mantzoros C.S. Lipodystrophy: pathophysiology and advances in treatment. Nat Rev Endocrinol. 2011; 7: 137-150 Crossref PubMed Scopus (164) Google Scholar ]. The description and subsequently the molecular understanding of these extremely rare syndromes not only played a vital role in our understanding of the mechanisms involved in insulin resistance but importantly opened the road for a better understanding of disease states associated with insulin resistance through the study of the molecular mechanisms underlying insulin resistance in these disease states.