Clinical Course of Genetic Diseases of the Insulin Receptor (Type A and Rabson-Mendenhall Syndromes): A 30-Year Prospective

Abstract: The interaction of insulin with its cell surface receptor is the first step in insulin action and the first identified target of insulin resistance. The insulin resistance in several syndromic forms of extreme insulin resistance has been shown to be caused by mutations in the receptor gene. We studied 8 female patients with the type A form of extreme insulin resistance and 3 patients (2 male and 1 female) with the Rabson-Mendenhall syndrome and followed the natural history of these patients for up to 30 years. The 11 patients ranged in age from 7 to 32 years at presentation. All 11 patients had extreme insulin resistance, acanthosis nigricans, and hyperandrogenism in the female patients, and all but 1 were of normal body weight. This phenotype strongly predicts mutations in the insulin receptor: of the 8 patients studied, 7 were found to have mutations. Similar results from the literature are found in other patients with type A and Rabson-Mendenhall syndromes and leprechaunism. The hyperandrogenic state resulting from hyperinsulinemia and insulin resistance in these patients was extreme: 6 of 8 patients had ovarian surgery to correct the polycystic ovarian syndrome and elevation of serum testosterone. By contrast, a larger group of insulin-resistant patients who were obese with hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN syndrome) did not have a high probability of mutations in the insulin receptor. The morbidity and mortality of these patients were high: 3 of 11 died, 9 of 11 were diabetic and 1 had impaired glucose tolerance, and 7 of 9 patients had 1 or more severe complication of diabetes. Our literature review revealed that the mortality of leprechaunism is so high that the term leprechaunism should be restricted to infants or young children under 2 years of age. Analogous to patients with the common forms of type 2 diabetes, these patients had a heterogeneous course. In 2 patients who were able to maintain extremely high endogenous insulin production, the fasting blood glucose remained normal even though post-glucose-challenge levels were elevated. Most patients, however, required large doses of exogenous insulin to ameliorate the severe hyperglycemia. Preliminary results of a recent study suggest that recombinant leptin administration may benefit these patients with severe insulin resistance.

[1]  P. Fernhoff.  Leprechaunism: A euphuism for a rare familial disorder , 2004 .

[2]  P. Gorden,et al.  Efficacy of recombinant methionyl human leptin therapy for the extreme insulin resistance of the Rabson-Mendenhall syndrome. , 2004, The Journal of clinical endocrinology and metabolism.

[3]  E. Tobias,et al.  Identification and functional assessment of novel and known insulin receptor mutations in five patients with syndromes of severe insulin resistance. , 2003, The Journal of clinical endocrinology and metabolism.

[4]  A. Lanzone,et al.  Selective effects of pioglitazone on insulin and androgen abnormalities in normo- and hyperinsulinaemic obese patients with polycystic ovary syndrome. , 2003, Human reproduction.

[5]  Jimmy D Bell,et al.  Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. , 2003, Diabetes.

[6]  B. Carr,et al.  Effects of metformin on body mass index, menstrual cyclicity, and ovulation induction in women with polycystic ovary syndrome. , 2003, Fertility and sterility.

[7]  S. Gammeltoft,et al.  Deletion of V335 from the L2 domain of the insulin receptor results in a conformationally abnormal receptor that is unable to bind insulin and causes Donohue's syndrome in a human subject. , 2003, Endocrinology.

[8]  M. Kasuga,et al.  [Mutations in the insulin receptor gene]. , 2002, Nihon rinsho. Japanese journal of clinical medicine.

[9]  L. Dimeglio,et al.  Genotype-phenotype correlation in inherited severe insulin resistance. , 2002, Human molecular genetics.

[10]  M. Foti,et al.  An arginine to cysteine252 mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events , 2002, Diabetologia.

[11]  Simeon I. Taylor,et al.  Clinical Course of the Syndrome of Autoantibodies to the Insulin Receptor (Type B Insulin Resistance): A 28-Year Perspective , 2002, Medicine.

[12]  M. Reitman,et al.  Leptin-replacement therapy for lipodystrophy. , 2002, The New England journal of medicine.

[13]  S. Tilghman,et al.  A mutation in the peroxisome proliferator-activated receptor γ-binding site in the gene for the cytosolic form of phosphoenolpyruvate carboxykinase reduces adipose tissue size and fat content in mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  M. Reitman,et al.  Lipoatrophy syndromes: when ‘too little fat’ is a clinical problem , 2000, Pediatric diabetes.

[15]  L. Ibáñez,et al.  Identification of three novel mutations in the insulin receptor gene in type A insulin resistant patients , 2000, Clinical genetics.

[16]  S. O’Rahilly,et al.  Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension , 1999, Nature.

[17]  N. Longo,et al.  Progressive decline in insulin levels in Rabson-Mendenhall syndrome. , 1999, The Journal of clinical endocrinology and metabolism.

[18]  J. Nakae,et al.  Long-term effect of recombinant human insulin-like growth factor I on metabolic and growth control in a patient with leprechaunism. , 1998, The Journal of clinical endocrinology and metabolism.

[19]  A. Dunaif,et al.  Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. , 1997, Endocrine reviews.

[20]  Y. Yazaki,et al.  Four mutant alleles of the insulin receptor gene associated with genetic syndromes of extreme insulin resistance. , 1997, Biochemical and biophysical research communications.

[21]  S. Amselem,et al.  Molecular analysis of the insulin receptor gene for prenatal diagnosis of leprechaunism in two families , 1997, Prenatal diagnosis.

[22]  C. Desbois-Mouthon,et al.  Major Circadian Variations of Glucose Homeostasis in a Patient with Rabson-Mendenhall Syndrome and Primary Insulin Resistance Due to a Mutation(Cys284 → Tyr) in the Insulin Receptor α-Subunit , 1997, Pediatric Research.

[23]  G. Kosztolányi.  Leprechaunism / Donohue syndrome / insulin receptor gene mutations: a syndrome delineation story from clinicopathological description to molecular understanding , 1997, European Journal of Pediatrics.

[24]  T. Okai,et al.  Genotype-stratified treatment for monogenic insulin resistance: a systematic review , 1997, Diabetologia.

[25]  William Clevenger,et al.  Cloning and Characterization of an Alternatively Processed Human Type II Interleukin-1 Receptor mRNA* , 1996, The Journal of Biological Chemistry.

[26]  L. Hart,et al.  An Insulin Receptor Mutant (Asp707 → Ala), Involved in Leprechaunism, Is Processed and Transported to the Cell Surface but Unable to Bind Insulin* , 1996, The Journal of Biological Chemistry.

[27]  C. Desbois-Mouthon,et al.  Deletion of Asn281 in the alpha-subunit of the human insulin receptor causes constitutive activation of the receptor and insulin desensitization. , 1996, The Journal of clinical endocrinology and metabolism.

[28]  L. Elsas,et al.  Two mutations in the insulin receptor gene of a patient with leprechaunism: application to prenatal diagnosis. , 1995, The Journal of clinical endocrinology and metabolism.

[29]  P. Backeljauw,et al.  Effect of Intravenous Insulin-like Growth Factor I in Two Patients with Leprechaunism , 1994, Pediatric Research.

[30]  R. Furlanetto,et al.  Deletion of 3 basepairs resulting in the loss of lysine-121 in the insulin receptor alpha-subunit in a patient with leprechaunism: binding, phosphorylation, and biological activity. , 1994, The Journal of clinical endocrinology and metabolism.

[31]  M. Kasuga,et al.  Insulin receptor disorders in Japan. , 1994, Diabetes research and clinical practice.

[32]  L. Elsas,et al.  Impaired growth in Rabson-Mendenhall syndrome: lack of effect of growth hormone and insulin-like growth factor-I. , 1994, The Journal of clinical endocrinology and metabolism.

[33]  D. Accili,et al.  Homozygosity for a new mutation (Ile1"9--Met) in the insulin receptor gene in five sibs with familial insulin resistance , 2022 .

[34]  D. Accili,et al.  A Novel Human Insulin Receptor Gene Mutation Uniquely Inhibits Insulin Binding Without Impairing Posttranslational Processing , 1994, Diabetes.

[35]  S. O’Rahilly,et al.  Molecular Scanning of the Insulin Receptor Gene in Syndromes of Insulin Resistance , 1994, Diabetes.

[36]  T. Imamura,et al.  Ala1048→Asp Mutation in the Kinase Domain of Insulin Receptor Causes Defective Kinase Activity and Insulin Resistance , 1993, Diabetes.

[37]  E. Seemanová,et al.  An in-frame insertion in exon 3 and a nonsense mutation in exon 2 of the insulin receptor gene associated with severe insulin resistance in a patient with Rabson-Mendenhall syndrome , 1993, Diabetologia.

[38]  Ş. Ozsoylu,et al.  Leprechaunism (Donohue's syndrome): a case report. , 1993, Turkish Journal of Pediatrics.

[39]  S. O’Rahilly,et al.  Homozygous nonsense mutation in the insulin receptor gene in infant with leprechaunism , 1993, The Lancet.

[40]  L. Al-Gazali,et al.  A syndrome of insulin resistance resembling leprechaunism in five sibs of consanguineous parents. , 1993, Journal of medical genetics.

[41]  T. Imamura,et al.  A mutation (Trp1193→Leu1193) in the tyrosine kinase domain of the insulin receptor associated with type A syndrome of insulin resistance , 1993, Diabetologia.

[42]  Simeon I. Taylor,et al.  Lilly Lecture: Molecular Mechanisms of Insulin Resistance: Lessons From Patients With Mutations in the Insulin-Receptor Gene , 1992, Diabetes.

[43]  B. Burguera,et al.  Treatment of Insulin-Resistant Diabetic Ketoacidosis with Insulin-like Growth Factor I in an Adolescent with Insulin-Dependent Diabetes , 1992 .

[44]  E. Bonora,et al.  Detection of Mutations in Insulin Receptor Gene by Denaturing Gradient Gel Electrophoresis , 1992, Diabetes.

[45]  Y. Yazaki,et al.  Detection of mutations in the insulin receptor gene in patients with insulin resistance by analysis of single-stranded conformational polymorphisms , 1992, Diabetologia.

[46]  D. Lindhout,et al.  An Arg for Gly substitution at position 31 in the insulin receptor, linked to insulin resistance, inhibits receptor processing and transport. , 1992, The Journal of biological chemistry.

[47]  W. Möller,et al.  A leucine to proline mutation at position 233 in the insulin receptor inhibits cleavage of the proreceptor and transport to the cell surface. , 1991, Biochemistry.

[48]  M. de la Luz Sierra,et al.  A mutation in the tyrosine kinase domain of the insulin receptor associated with insulin resistance in an obese woman. , 1991, The Journal of clinical endocrinology and metabolism.

[49]  Simeon I. Taylor,et al.  Two Patients With Insulin Resistance Due to Decreased Levels of Insulin-Receptor mRNA , 1991, Diabetes.

[50]  Simeon I. Taylor,et al.  Mutagenesis of lysine 460 in the human insulin receptor. Effects upon receptor recycling and cooperative interactions among binding sites. , 1990, The Journal of biological chemistry.

[51]  A. Maccuish,et al.  Acute response to recombinant insulin-like growth factor I in a patient with Mendenhall's syndrome. , 1990, The New England journal of medicine.

[52]  J. Flier,et al.  A naturally occurring mutation of insulin receptor alanine 1134 impairs tyrosine kinase function and is associated with dominantly inherited insulin resistance. , 1990, The Journal of biological chemistry.

[53]  Simeon I. Taylor,et al.  Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance. , 1990, The Journal of clinical investigation.

[54]  Y. Ebina,et al.  Insulin-resistant diabetes associated with partial deletion of insulin-receptor gene , 1990, The Lancet.

[55]  D. Accili,et al.  Mutations in Insulin-Receptor Gene in Insulin-Resistant Patients , 1990, Diabetes Care.

[56]  D. Lipman,et al.  National Center for Biotechnology Information , 2019, Springer Reference Medizin.

[57]  T. Sasaoka,et al.  Unprocessed insulin proreceptor in cultured fibroblasts from a patient with extreme insulin resistance. , 1989, Metabolism: clinical and experimental.

[58]  C A Stuart,et al.  Prevalence of acanthosis nigricans in an unselected population. , 1989, The American journal of medicine.

[59]  E. Lander,et al.  A mutation in the insulin receptor gene that impairs transport of the receptor to the plasma membrane and causes insulin‐resistant diabetes. , 1989, The EMBO journal.

[60]  L. Sandkuyl,et al.  A leucine‐to‐proline mutation in the insulin receptor in a family with insulin resistance. , 1989, The EMBO journal.

[61]  K. Kriauciunas,et al.  Molecular defects in the insulin receptor in patients with leprechaunism and in their parents. , 1989, The Journal of laboratory and clinical medicine.

[62]  L. Elsas,et al.  Increased glucose transport by human fibroblasts with a heritable defect in insulin binding. , 1989, Metabolism: clinical and experimental.

[63]  C. Kahn,et al.  Insulin-Receptor Gene and Its Expression in Patients With Insulin Resistance , 1989, Diabetes.

[64]  A. Kosaki,et al.  Defective processing of insulin-receptor precursor in cultured lymphocytes from a patient with extreme insulin resistance. , 1988, The Journal of clinical investigation.

[65]  Simeon I. Taylor,et al.  Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance. , 1988, Science.

[66]  A. Kosaki,et al.  Insulin-resistant diabetes due to a point mutation that prevents insulin proreceptor processing. , 1988, Science.

[67]  T. Sasaoka,et al.  Insulin Resistance by Uncleaved Insulin Proreceptor: Emergence of Binding Site by Trypsin , 1988, Diabetes.

[68]  A. Dunaif,et al.  Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. , 1987, The Journal of clinical endocrinology and metabolism.

[69]  Simeon I. Taylor,et al.  Insulin-Receptor Biosynthesis in Cultured Lymphocytes From an Insulin-Resistant Patient (Rabson-Mendenhall Syndrome): Evidence for Defect Before Insertion of Receptor Into Plasma Membrane , 1986, Diabetes.

[70]  C. Kahn,et al.  Characterization of Binding and Phosphorylation Defects of Erythrocyte Insulin Receptors in the Type A Syndrome of Insulin Resistance , 1986, Diabetes.

[71]  E. Smith,et al.  Obesity, acanthosis nigricans, insulin resistance, and hyperandrogenemia: pediatric perspective and natural history. , 1985, The Journal of pediatrics.

[72]  K. Minaker,et al.  Acanthosis nigricans in Obese Women with Hyperandrogenism: Characterization of an Insulin-Resistant State Distinct from the Type A and B Syndromes , 1985, Diabetes.

[73]  G. Grunberger,et al.  Tyrosine kinase activity of the insulin receptor of patients with type A extreme insulin resistance: studies with circulating mononuclear cells and cultured lymphocytes. , 1984, The Journal of clinical endocrinology and metabolism.

[74]  G. Grunberger,et al.  Defect in phosphorylation of insulin receptors in cells from an insulin-resistant patient with normal insulin binding. , 1984, Science.

[75]  R. Barbieri,et al.  Hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features. , 1983, American journal of obstetrics and gynecology.

[76]  G. Grunberger,et al.  11 Insulin receptors in normal and disease states , 1983 .

[77]  M. Kasuga,et al.  Extreme insulin resistance in association with abnormally high binding affinity of insulin receptors from a patient with leprechaunism: evidence for a defect intrinsic to the receptor. , 1982, The Journal of clinical endocrinology and metabolism.

[78]  M. Kasuga,et al.  Decreased insulin binding in cultured lymphocytes from two patients with extreme insulin resistance. , 1982, The Journal of clinical endocrinology and metabolism.

[79]  C. Kahn,et al.  Cell culture studies on patients with extreme insulin resistance. I. Receptor defects on cultured fibroblasts. , 1982, The Journal of clinical endocrinology and metabolism.

[80]  J. Olefsky,et al.  Cutaneous manifestations of leprechaunism. , 1981, Archives of dermatology.

[81]  J. Leonard,et al.  Familial insulin resistance with pineal hyperplasia: metabolic studies and effect of hypophysectomy. , 1980, Archives of disease in childhood.

[82]  C. Kahn,et al.  Demonstration of a primary (? genetic) defect in insulin receptors in fibroblasts from a patient with the syndrome of insulin resistance and acanthosis nigricans type A. , 1980, The Journal of clinical endocrinology and metabolism.

[83]  C. Kahn,et al.  Characterization of insulin receptors in patients with the syndromes of insulin resistance and acanthosis nigricans , 1980, Diabetologia.

[84]  M. Rechler,et al.  A case of leprechaunism with severe hyperinsulinemia. , 1980, American journal of diseases of children.

[85]  C. Kahn,et al.  Insulin resistance, acanthosis nigricans, and normal insulin receptors in a young woman: evidence for a postreceptor defect. , 1978, The Journal of clinical endocrinology and metabolism.

[86]  J. Olefsky,et al.  Insulin resistance due to a defect distal to the insulin receptor: demonstration in a patient with leprechaunism. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[87]  C. Kahn,et al.  The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. , 1976, The New England journal of medicine.

[88]  S. Najjar,et al.  Leprechaunism. A report of two new cases. , 1971, American journal of diseases of children.

[89]  D. Haskin,et al.  Redbook's young mother. , 1970, Pediatrics.

[90]  R. Summitt,et al.  Leprechaunism (Donohue's syndrome): a case report. , 1969, The Journal of pediatrics.

[91]  J. H. Patterson,et al.  Leprechaunism in a male infant. , 1962, The Journal of pediatrics.

[92]  S. Rabson,et al.  Familial hypertrophy of pineal body, hyperplasia of adrenal cortex and diabetes mellitus; report of 3 cases. , 1956, American journal of clinical pathology.

[93]  J. Pickup,et al.  Continuous subcutaneous insulin infusion: A developing tool in diabetes research , 2005, Diabetologia.

[94]  D. Accili,et al.  Human diabetes associated with defects in nuclear regulatory proteins for the insulin receptor gene. , 1996, The Journal of clinical investigation.

[95]  D. Accili,et al.  Homozygosity for a null allele of the insulin receptor gene in a patient with leprechaunism , 1995, Human mutation.

[96]  K. Morooka.  [Leprechaunism (Donohue's syndrome)]. , 1995, Ryoikibetsu shokogun shirizu.

[97]  Y. Ebina,et al.  Human diabetes associated with a deletion of the tyrosine kinase domain of the insulin receptor. , 1989, Science.

[98]  al. et,et al.  Human diabetes associated with a mutation in the tyrosine kinase domain of the insulin receptor. , 1989, Science.

[99]  S. Taylor.  Insulin action and inaction. , 1987, Clinical research.

[100]  G. Grunberger,et al.  Structure of the insulin receptor and post-receptor events in cells from a type A insulin-resistant patient with normal alpha-subunit but defective function of the beta-subunit of the insulin receptor. , 1985, Transactions of the Association of American Physicians.

[101]  S. Taylor.  Receptor defects in patients with extreme insulin resistance. , 1985, Diabetes/metabolism reviews.

[102]  G. Grunberger,et al.  Insulin receptors in normal and disease states. , 1983, Clinics in endocrinology and metabolism.