O R I G I N A L
A R T I C L E
E
xtreme resistance to endogenous and exogenous insulin is a rare disorder due to impairment of insulinreceptor function. This condition may be recognized at birth or in early childhood (1,2) or it may become manifest later in life in young girls or women (3). In the last few years, several defects of the insulin-receptor molecule have been described in patients suffering from this disorder (4-8) and in some cases the molecular defects have been identified PAOLO G. GERUNDINI, MD NlCOLETTA DOZIO, MD either in the insulin binding or in the PlERO MlCOSSI, MD FERRUCCIO FAZIO, MD GIUSEPPE CHIUMELLO, MD GABRIELLA GALJMBERTI, MD kinase domain or in regions of the molLUIGI GARGANTINI, MD STEFANO SARTORI, MD ecule interfering with the correct prore• FRANCHISE SODOYEZ-GOFFAUX, MD GUIDO POZZA, MD ceptor processing or with its transport to JEAN-CLAUDE SODOYEZ, MD FlAVlAND DOSIO, MD the membrane (9-24). Although the reANNARITA SAVI, MSC cent progresses in cell biology have greatly increased our knowledge of insulin-receptor function at the molecular OBJECTIVE — Insulin-receptor function in humans is usually studied in vitro on level, few methodological approaches are readily available cells, e.g., erythrocytes and fibroblasts. Although these cells are not available to study directly insulin recepmetabolically important targets for insulin action, information derived from them are tors in vivo in humans. Insulin-receptor often taken as representative of other tissues. The aim of this study was to investigate abnormalities are usually not demoninsulin receptors in vitro on erythrocytes and in vivo on one of the main insulin- strated in the liver or in other metabolically important targets of the hormone. target organs, the liver. Because of the difficult accessibility of these organs, more readily available cells RESEARCH DESIGN AND METHODS— A 16-yr-old girl affected by severe such as erythrocytes or fibroblasts are insulin resistance was identified. Insulin receptor binding was measured on the chosen for in vitro studies, which are erythrocytes of the patient and of 6 nondiabetic volunteers. The biodistribution of considered as representative of other cell 123 I-labeled insulin was studied in vivo by scintigraphic scanning in the insulin- types. Herein, we describe the in vivo resistant patient and in 10 nondiabetic volunteers. study of 123I-labeled insulin biodistribution in a patient with insulin resistance in whom an insulin binding defect was deRESULTS — Erythrocytes of this patient displayed a markedly reduced [125I]insulin monstrable in vitro on erythrocytes. binding. In vivo 123I-insulin biodistribution was characterized by lack of hormone uptake by the liver (4 vs. 21% of the injected dose in control subjects) contrasting RESEARCH DESIGN AND with intense accumulation of radioactivity in the kidneys. METHODS
In Vivo Demonstration of Insulin-Receptor Defect With 123 I-Labeled Insulin and Scintigraphic Scanning in Severe Insulin Resistance
CONCLUSIONS — Our studies show that defects of insulin binding can be di- Case report rectly demonstrated in vivo on liver receptors with a noninvasive technique with low The patient a white daughter of nonconradiotoxicity. sanguineous parents, was 16-yr-old at the time of the study. Her early medical history has been previously reported (25). Clinical features included low birth FROM THE DEPARTMENTS OF INTERNAL MEDICINE, NUCLEAR MEDICINE, AND PEDIATRICS, SAN RAFFAELE weight, failure to thrive, hypertrichosis, SCIENTIFIC INSTITUTE, UNIVERSITY OF MILAN, MILAN, ITALY; AND THE DEPARTMENT OF EXPERIMENTAL hypertrophy of the clitoris, sparse subNUCLEAR MEDICINE, UNIVERSITY OF LIEGE, LIEGE, BELGIUM. cutaneous fat stores, and unusual facial ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO PIERO MICOSSI, MD, SCIENTIFIC INSTITUTE H SAN appearance with widely spaced eyes, flarRAFFAELE, VIA OLGETTINA, 60, 20132 MILAN, ITALY. ing nostrils, thick lips, large low-set ears, RECEIVED FOR PUBLICATION 19 FEBRUARY 1991 AND ACCEPTED IN REVISED FORM 30 OCTOBER 1991. and short neck. Glucose intolerance and
DIABETES CARE, VOLUME 15, NUMBER 5, MAY 1992
651
f
I]insulin biodistribution and insulin-receptor defect
acanthosis nigricans were first observed at the age of 4 yr, and a defect of insulin binding to its receptors was recognized at the age of 6 yr. Initial breast development and pubic hair appeared at 11 and 12 yr, respectively; however, no further progression was observed or menarche, despite the presence of echographically normal ovaries. At the age of 16 yr, the patient was severely growth retarded. Her height at complete skeletal maturation was 129 cm, and her weight was 23 kg. At the time of the study, blood glucose ranged from 11 to 25 mM, HbA: ranged from 10 to 12% (normal
A R T I C L E
E
xtreme resistance to endogenous and exogenous insulin is a rare disorder due to impairment of insulinreceptor function. This condition may be recognized at birth or in early childhood (1,2) or it may become manifest later in life in young girls or women (3). In the last few years, several defects of the insulin-receptor molecule have been described in patients suffering from this disorder (4-8) and in some cases the molecular defects have been identified PAOLO G. GERUNDINI, MD NlCOLETTA DOZIO, MD either in the insulin binding or in the PlERO MlCOSSI, MD FERRUCCIO FAZIO, MD GIUSEPPE CHIUMELLO, MD GABRIELLA GALJMBERTI, MD kinase domain or in regions of the molLUIGI GARGANTINI, MD STEFANO SARTORI, MD ecule interfering with the correct prore• FRANCHISE SODOYEZ-GOFFAUX, MD GUIDO POZZA, MD ceptor processing or with its transport to JEAN-CLAUDE SODOYEZ, MD FlAVlAND DOSIO, MD the membrane (9-24). Although the reANNARITA SAVI, MSC cent progresses in cell biology have greatly increased our knowledge of insulin-receptor function at the molecular OBJECTIVE — Insulin-receptor function in humans is usually studied in vitro on level, few methodological approaches are readily available cells, e.g., erythrocytes and fibroblasts. Although these cells are not available to study directly insulin recepmetabolically important targets for insulin action, information derived from them are tors in vivo in humans. Insulin-receptor often taken as representative of other tissues. The aim of this study was to investigate abnormalities are usually not demoninsulin receptors in vitro on erythrocytes and in vivo on one of the main insulin- strated in the liver or in other metabolically important targets of the hormone. target organs, the liver. Because of the difficult accessibility of these organs, more readily available cells RESEARCH DESIGN AND METHODS— A 16-yr-old girl affected by severe such as erythrocytes or fibroblasts are insulin resistance was identified. Insulin receptor binding was measured on the chosen for in vitro studies, which are erythrocytes of the patient and of 6 nondiabetic volunteers. The biodistribution of considered as representative of other cell 123 I-labeled insulin was studied in vivo by scintigraphic scanning in the insulin- types. Herein, we describe the in vivo resistant patient and in 10 nondiabetic volunteers. study of 123I-labeled insulin biodistribution in a patient with insulin resistance in whom an insulin binding defect was deRESULTS — Erythrocytes of this patient displayed a markedly reduced [125I]insulin monstrable in vitro on erythrocytes. binding. In vivo 123I-insulin biodistribution was characterized by lack of hormone uptake by the liver (4 vs. 21% of the injected dose in control subjects) contrasting RESEARCH DESIGN AND with intense accumulation of radioactivity in the kidneys. METHODS
In Vivo Demonstration of Insulin-Receptor Defect With 123 I-Labeled Insulin and Scintigraphic Scanning in Severe Insulin Resistance
CONCLUSIONS — Our studies show that defects of insulin binding can be di- Case report rectly demonstrated in vivo on liver receptors with a noninvasive technique with low The patient a white daughter of nonconradiotoxicity. sanguineous parents, was 16-yr-old at the time of the study. Her early medical history has been previously reported (25). Clinical features included low birth FROM THE DEPARTMENTS OF INTERNAL MEDICINE, NUCLEAR MEDICINE, AND PEDIATRICS, SAN RAFFAELE weight, failure to thrive, hypertrichosis, SCIENTIFIC INSTITUTE, UNIVERSITY OF MILAN, MILAN, ITALY; AND THE DEPARTMENT OF EXPERIMENTAL hypertrophy of the clitoris, sparse subNUCLEAR MEDICINE, UNIVERSITY OF LIEGE, LIEGE, BELGIUM. cutaneous fat stores, and unusual facial ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO PIERO MICOSSI, MD, SCIENTIFIC INSTITUTE H SAN appearance with widely spaced eyes, flarRAFFAELE, VIA OLGETTINA, 60, 20132 MILAN, ITALY. ing nostrils, thick lips, large low-set ears, RECEIVED FOR PUBLICATION 19 FEBRUARY 1991 AND ACCEPTED IN REVISED FORM 30 OCTOBER 1991. and short neck. Glucose intolerance and
DIABETES CARE, VOLUME 15, NUMBER 5, MAY 1992
651
f
I]insulin biodistribution and insulin-receptor defect
acanthosis nigricans were first observed at the age of 4 yr, and a defect of insulin binding to its receptors was recognized at the age of 6 yr. Initial breast development and pubic hair appeared at 11 and 12 yr, respectively; however, no further progression was observed or menarche, despite the presence of echographically normal ovaries. At the age of 16 yr, the patient was severely growth retarded. Her height at complete skeletal maturation was 129 cm, and her weight was 23 kg. At the time of the study, blood glucose ranged from 11 to 25 mM, HbA: ranged from 10 to 12% (normal
