0021 -972X/78/4703-0620$02.0O/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1978 by The Endocrine Society
Vol. 47, No. 3 Printed in U.S.A.
Insulin Resistance, Acanthosis Nigricans, and Normal Insulin Receptors in a Young Woman: Evidence for a Postreceptor Defect ROBERT S. BAR, MICHELE MUGGEO, JESSE ROTH, C. RONALD KAHN, JANA HAVRANKOVA, AND JULIANNE I M P E R A T O - M C G I N L E Y Diabetes Branch, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20014 when stimulated. Proinsulin was less than 10% of the total immunoassayable insulin. In distinct contrast to the type A patients, insulin receptors on cells from this patient were entirely normal on the basis of specificity, negative cooperativity, affinity, concentration, and interaction with antiinsulin receptor antibodies. These findings suggest the presence of an intracellular defect as the cause of the observed insulin resistance. (J Clin Endocrinol Metab 47: 620, 1978)
ABSTRACT. We have previously described a group of young females with virilization, acanthosis nigricans, insulin resistance, and markedly decreased binding of insulin to its receptor (syndrome of insulin resistance and acanthosis nigricans type A). The present report concerns a 15-yr-old female with clinical features indistinguishable from the type A patients, including virilization, acanthosis nigricans, and extreme resistance to endogenous and exogenous insulin. Insulin levels were 400-650 /iU/ml while fasting and were over 2200 /iU/ml
W
E HAVE previously described six patients with insulin resistance, acanthosis nigricans, and decreased binding of insulin to its membrane receptors (the syndrome of insulin resistance and acanthosis nigricans) (1, 2). These patients were further subdivided into two distinct syndromes: type A and type B patients. Type A patients were younger females with virilization and polycystic ovaries. Type B patients were older females with signs of autoimmune disease. In both type A and B patients, the pathogenesis of insulin resistance seemed to be related to alterations in the binding of insulin to its membrane receptor; in the type B patients, this was due to circulating antibodies to the insulin receptor. In the present report, we describe a 15-yrold female with acanthosis nigricans, severe insulin resistance, and other clinical features indistinguishable from the type A patients. However, in contrast to the type A patients, insulin receptors on cells from this patient
Received December 5, 1977. Address requests for reprints to: Dr. Robert S. Bar, Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242.
were entirely normal. Other potential causes of insulin resistance, including abnormal or inactive circulating forms of insulin and circulating antiinsulin antibodies, were not present. These findings suggest that the insulin resistance in this patient was due to a postreceptor or intracellular defect.
Case History This 15-yr-old female was the product of a normal pregnancy and delivery. Pubic and axillary hair appeared at age 11 and breast tissue was present by age 12. At age 13, skin hyperpigmentation and diffuse hirsutism were first noted and have gradually increased in the last 2 yr. The patient has never menstruated. There was no history of galactorrhea, diabetes mellitus, hypertension, or thyroid disease. The mother and a younger sister underwent menarche at approximately age 13. A paternal grandmother had diabetes mellitus. There was no family history of acanthosis nigricans, hirsutism,, or polycystic ovarian disease. Physical exam revealed a well developed, bearded female. Height was 156 cm, weight was 61 kg, blood pressure was 110/70 (supine and erect), pulse was 84, and temperature was 37 C. Diffuse hyperpigmented lesions of acanthosis ni-
620
INSULIN RESISTANCE, ACANTHOSIS NIGRICANS gricans were present. There was a full facial beard, masculine escutcheon, and mild facial and trunkal acne. Breasts were small (Tanner stage 5) with hyperpigmentation of the nipples and areolae. Galactorrhea was not present. Pelvic examination showed clitoromegaly and a normal cervix and uterus; the ovaries were not palpated. Plasma level of testosterone was 245 ng/dl (normal,
Vol. 47, No. 3 Printed in U.S.A.
Insulin Resistance, Acanthosis Nigricans, and Normal Insulin Receptors in a Young Woman: Evidence for a Postreceptor Defect ROBERT S. BAR, MICHELE MUGGEO, JESSE ROTH, C. RONALD KAHN, JANA HAVRANKOVA, AND JULIANNE I M P E R A T O - M C G I N L E Y Diabetes Branch, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20014 when stimulated. Proinsulin was less than 10% of the total immunoassayable insulin. In distinct contrast to the type A patients, insulin receptors on cells from this patient were entirely normal on the basis of specificity, negative cooperativity, affinity, concentration, and interaction with antiinsulin receptor antibodies. These findings suggest the presence of an intracellular defect as the cause of the observed insulin resistance. (J Clin Endocrinol Metab 47: 620, 1978)
ABSTRACT. We have previously described a group of young females with virilization, acanthosis nigricans, insulin resistance, and markedly decreased binding of insulin to its receptor (syndrome of insulin resistance and acanthosis nigricans type A). The present report concerns a 15-yr-old female with clinical features indistinguishable from the type A patients, including virilization, acanthosis nigricans, and extreme resistance to endogenous and exogenous insulin. Insulin levels were 400-650 /iU/ml while fasting and were over 2200 /iU/ml
W
E HAVE previously described six patients with insulin resistance, acanthosis nigricans, and decreased binding of insulin to its membrane receptors (the syndrome of insulin resistance and acanthosis nigricans) (1, 2). These patients were further subdivided into two distinct syndromes: type A and type B patients. Type A patients were younger females with virilization and polycystic ovaries. Type B patients were older females with signs of autoimmune disease. In both type A and B patients, the pathogenesis of insulin resistance seemed to be related to alterations in the binding of insulin to its membrane receptor; in the type B patients, this was due to circulating antibodies to the insulin receptor. In the present report, we describe a 15-yrold female with acanthosis nigricans, severe insulin resistance, and other clinical features indistinguishable from the type A patients. However, in contrast to the type A patients, insulin receptors on cells from this patient
Received December 5, 1977. Address requests for reprints to: Dr. Robert S. Bar, Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242.
were entirely normal. Other potential causes of insulin resistance, including abnormal or inactive circulating forms of insulin and circulating antiinsulin antibodies, were not present. These findings suggest that the insulin resistance in this patient was due to a postreceptor or intracellular defect.
Case History This 15-yr-old female was the product of a normal pregnancy and delivery. Pubic and axillary hair appeared at age 11 and breast tissue was present by age 12. At age 13, skin hyperpigmentation and diffuse hirsutism were first noted and have gradually increased in the last 2 yr. The patient has never menstruated. There was no history of galactorrhea, diabetes mellitus, hypertension, or thyroid disease. The mother and a younger sister underwent menarche at approximately age 13. A paternal grandmother had diabetes mellitus. There was no family history of acanthosis nigricans, hirsutism,, or polycystic ovarian disease. Physical exam revealed a well developed, bearded female. Height was 156 cm, weight was 61 kg, blood pressure was 110/70 (supine and erect), pulse was 84, and temperature was 37 C. Diffuse hyperpigmented lesions of acanthosis ni-
620
INSULIN RESISTANCE, ACANTHOSIS NIGRICANS gricans were present. There was a full facial beard, masculine escutcheon, and mild facial and trunkal acne. Breasts were small (Tanner stage 5) with hyperpigmentation of the nipples and areolae. Galactorrhea was not present. Pelvic examination showed clitoromegaly and a normal cervix and uterus; the ovaries were not palpated. Plasma level of testosterone was 245 ng/dl (normal,
