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A1984tu04300001 TM Cc/NUMBER 50 This Week’s Citation Classic DECEMBER 10,1984 Kahn C R, Filer I S, Bar R S, Archer I A, Gorden P, Martin M M & Roth I. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N. Engi. I. Med. 294:739-45, 1976. [Diabetes Branch, Nati. Inst. Arthritis, Metabolism, and Digestive Dis.. NIH, Bethesda, Ml) and Dept. Pediatrics, Georgetown Univ. Sch. Med.. Washington, DCI Six patients are described representing two “As the medical community recognized syndromes of insulin resistance associated our interest in diseases associated with de- with acanthosis nigricans. The Type A pa- fects in insulin action, we were gradually re- I tients are young females with virilization and have insulin resistance due to a de- ferred several patients with syndromes of ex- crease in the number of insulin receptors on treme insulin resistance—some requiring cells. The Type B patients have an autoim- thousands of units of insulin per day. These mune syndrome with autoantibodies to the were clinically challenging cases, but even insulin receptor. [The SCI® indicates that more interestingin that they provided a way this paper has been cited in over 345 publi- to test the importance of the insulin recep- cations since 1976] tor. As we had hoped, when insulin binding to its receptor was measured using circulat- ing monocytes from these patients, there C. Ronald Kahn was a marked decrease. Jeffrey Flier recog- Research Division nized the importance of the immune fea- Joslin Diabetes Center tures in some of these patients and devel- One Joslin Place oped an assay to directly measure anti-re- Boston, MA 02215 ceptor antibodies. “Although the syndromes of insulin resis- August 15, 1984 tance and acanthosis nigricans are quite rare (about 12 cases of the Type A and 30 cases of “Although the concept of specific cellular the Type B syndrome have been identified), receptors for hormones and drugs dates they are now well recognized as discrete back to the turn of the century, direct mea- forms of diabetes. They have also provided surement of the receptor for peptide hor- important insights into insulin action. The mones did not become possible until 1969. Type A patients have been shown to have a When I arrived as a clinical associate at the series of genetic defects in the insulin recep- National Institutes of Health in July 1970, tor molecule or its biosynthesis. The Type B most of the effort of what was then a small patients have provided a source of anti- section on diabetes, under the direction of receptor antibodies that have been valuable Jesse Roth and Phil Gorden, was devoted to probes of receptor structure and function. defining these receptors. A colleague and I Thus, this is another example in which were actually assigned to work on the prob- studies of a rare disease have shed light on lem of ACTH receptors, but this proved im- both normal physiology and the physiology possible to master, moving my interest into of many disease states. the area of insulin receptors and driving my “As a result of this and related studies of colleague into dermatology! insulin receptors, the diabetes section grew “As soon as it became apparent that insu- into a large branch, and many of the fellows lin receptors could be defined by direct involved in these studies now head indepen- binding studies, we turned our attention to dent diabetes clinical and research groups at possible abnormalities in disease states. We several university hospitals. This body of were able to demonstrate defects in insulin work has also been recognized by a number binding to liver membranes from obese of awards given to the investigators in- mice. But for human studies we were re- volved, and the field of insulin receptors has stricted to the study of circulating blood grown to a size large enough for several in- cells, and the significance of insulin recep- ternational13 meetings and many written tors on these cells was uncertain. reviews.” I. Kahn CR. The insulin receptor and insulin. The lock and key to diabetes. Clin. Re:. 31:326-35, 1983. 2. Bar R S, Harrison I. C, Muggeo M, Gorden P Kahn C R & Roth I. Regulation of insulin receptors in normal and abnormal physiology in humans. .4dvan. Internal Med. 24:23-46, 1979. 3. Olefsky J M & Koherman I) C. Mechanisms of insulin resistance in obesity and noninsulin-dependent (Type II) diabetes. Amer. I. Med. 70:151-68, 1981. 24 @1984 byPSI® CURRENT CONTENTS®.
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