1/15. Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective.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.- - - - - - - - - - ranking = 1keywords = acanthosis nigricans, nigricans, acanthosis (Clic here for more details about this article) |
2/15. Rabson-Mendenhall syndrome.Rabson-Mendenhall syndrome is characterized by growth retardation, dysmorphisms, lack of subcutaneous fat, acanthosis nigricans, enlarged genitalia, hirsutism, premature and dysplastic dentition, coarse facial features, paradoxical fasting hypoglycemia and post-prandial hyperglycemia, extreme hyperinsulinemia and pineal hyperplasia. We describe a six-month-old female child with physical features suggestive of the Rabson-Mendenhall syndrome. The child also had medullary nephrocalcinosis.- - - - - - - - - - ranking = 0.5keywords = acanthosis nigricans, nigricans, acanthosis (Clic here for more details about this article) |
3/15. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man.In six patients with acanthosis nigricans variable degrees of glucose intolerance, hyperinsulinemia and marked resistance to exogenous insulin were found. Studies of insulin receptors on circulating monocytes suggest that the insulin resistance in these patients was due to a marked decrease in insulin binding to its membrane receptors. When these patients were fasted, there was a fall in plasma insulin but no increase in insulin binding, suggesting that the receptor defect was not secondary to the hyperinsulinemia. The clinical features shared by these cases and several similar ones previously reported may be divided into two unique clinical syndromes: Type A, a syndrome in younger females with signs of virilization or accelerated growth, in whom the receptor defect may be primary, and Type B, a syndrome in older females with signs of an immunologic disease, in whom circulating antibodies to the insulin receptor are found.- - - - - - - - - - ranking = 2.5keywords = acanthosis nigricans, nigricans, acanthosis (Clic here for more details about this article) |
4/15. Medical therapy for the syndrome of familial virilization, insulin resistance, and acanthosis nigricans.In the syndrome of familial virilization, insulin resistance, and acanthosis nigricans, the interrelationships are not understood. Twin sisters were studied, along with a lesser affected sister and mother. They manifested amenorrhea, hirsutism, masculinization, hypertension, hyperinsulinemia, hypertriglyceridemia, and hyperprolactinemia. Medical therapy with a gonadotropin-releasing hormone agonist plus an antiandrogen resulted in reversal of the hirsutism, yet with preservation of potential fertility. In response to luteinizing hormone (LH) and follicle-stimulating hormone suppression, there was normalization of the serum androgens, but not of the hyperinsulinemia, hypertriglyceridemia, hyperprolactinemia, hypertension, or acanthosis nigricans. Conclusions: (1) This syndrome may be familial. (2) Medical therapy for the virilization is successful. (3) The hyperandrogenemia is primarily LH dependent and not primarily insulin dependent, although insulin may have an amplification effect. (4) Hyperinsulinemia, hypertriglyceridemia, hyperprolactinemia, and the hypertension are not androgen dependent.- - - - - - - - - - ranking = 3keywords = acanthosis nigricans, nigricans, acanthosis (Clic here for more details about this article) |
5/15. Familial type C syndrome of insulin resistance and short stature with possible autosomal dominant transmission.We describe a 17-yr-old girl with insulin resistant diabetes, acanthosis nigricans, hirsutism and short stature. At the age of 14 she was found to have glycosuria and diagnosed as diabetes mellitus. No endocrinological abnormality except transient amenorrhea and exaggerated LH response to LHRH was found. insulin resistance was demonstrated by fasting hyperinsulinemia, insulin tolerance test and euglycemic glucose clamp test, and large doses of insulin with CSII were not effective in controlling blood glucose. Insulin binding to erythrocytes was normal, suggesting a postbinding defect. The same phenotype of insulin resistant diabetes and short stature was found in her mother who was diagnosed as diabetes mellitus at the age of 31 and died of diabetic nephropathy at the age of 41. Her maternal grandfather and uncle were reportedly affected with the same phenotype. Her father had impaired glucose tolerance, but no hyperinsulinemia. Two sisters had essentially normal glucose tolerance. Insulin binding to erythrocytes of her father and mother was also in the normal range. These results suggest that the present case may be a rare syndrome present together with type C syndrome of insulin resistance, and with short stature which was inherited autosomal dominantly.- - - - - - - - - - ranking = 0.5keywords = acanthosis nigricans, nigricans, acanthosis (Clic here for more details about this article) |
6/15. Defective processing of insulin-receptor precursor in cultured lymphocytes from a patient with extreme insulin resistance.We have studied a patient with extreme insulin resistance, acanthosis nigricans, and decreased erythrocyte insulin binding. EBV-transformed lymphocytes from this patient exhibited markedly reduced binding of 125I-insulin. Radioiodination of cell surface receptors followed by immunoprecipitation with anti-receptor antibodies revealed the presence of increased amounts of a 210-kD protein but no detectable alpha or beta subunits. Continuous labeling with 2-[3H]mannose revealed the synthesis of a 190-kD precursor and a 210-kD protein. The 210-kD protein was phosphorylated in an insulin-dependent manner at high insulin concentrations. These results suggest that in this patient the biosynthesis of 190-kD receptor precursor, its terminal glycosylation, and intracellular transport to the cell surface proceed normally, while proteolytic maturation to alpha and beta subunits does not occur. We postulate that this defect either results from mutation(s) within the insulin-receptor gene, which render the precursor resistant to cleavage, or from a defect in the receptor processing enzyme.- - - - - - - - - - ranking = 0.5keywords = acanthosis nigricans, nigricans, acanthosis (Clic here for more details about this article) |
7/15. Prolonged suppression of hirsutism with combination therapy in an adolescent with insulin resistance and acanthosis nigricans.spironolactone and oral contraceptives have been used separately with some success in the treatment of hirsutism. hirsutism associated with the Kahn type-A syndrome of insulin resistance, acanthosis nigricans, and polycystic ovaries may be severe and refractory to conventional treatment. In view of their different sites and mechanisms of action, spironolactone and an oral contraceptive were used in combination to treat severe hirsutism in a 13-year-old girl with features of this syndrome. The two therapeutic agents, apparently acting together, resulted in a marked reduction in facial hair and serum androgen concentrations, which persisted during 18 months of treatment. testosterone and androstenedione levels fell from 100 ng/dl and 628 ng/dl, respectively, to 47 ng/dl and 230 ng/dl by six months and to 35 ng/dl and 156 ng/dl by 18 months. This result suggests that combination therapy may be an effective treatment for severe hirsutism.- - - - - - - - - - ranking = 2.5keywords = acanthosis nigricans, nigricans, acanthosis (Clic here for more details about this article) |
8/15. insulin resistance with acanthosis nigricans and acral hypertrophy.Two patients are described with obesity, acanthosis nigricans, acral hypertrophy, basal hyperinsulinism and exaggerated insulin responses to oral glucose. One patient, a diabetic female showed features of virilisation due to polycystic ovarian disease and underwent gonadectomy with some resolution of her androgenisation and acanthosis nigricans. Binding of labelled insulin to erythrocytes was significantly decreased in both patients compared with normal or obese control subjects. In contrast, the receptor concentration in adipose tissue obtained from the patient undergoing gonadectomy was higher than seen in obese control subjects. Thus, somatic growth may be stimulated by insulin in some tissues in these hyperinsulinaemic patients due to relative preservation of receptor numbers.- - - - - - - - - - ranking = 3keywords = acanthosis nigricans, nigricans, acanthosis (Clic here for more details about this article) |
9/15. acanthosis nigricans, hirsutism, insulin resistance and insulin receptor defect.A 24-year-old negress with the triad of acanthosis nigricans, hirsutism associated with polycystic ovaries and insulin resistance is reported. Metabolic studies were done 3 years after a bilateral ovarian wedge resection. Partial remission of the hirsutism and return of menstrual cycles occurred after surgery. Extreme resistance to endogenous and exogenous insulin was observed. Three studies of insulin receptors on circulating red blood cells (RBC) showed abnormal inhibition-competition curves, characterized by increased percentage insulin binding at higher unlabelled insulin levels. Scatchard plots suggested an apparent increase in the number of low affinity receptors. Despite the changes in receptor-insulin interaction, the defect does not seem to explain the insulin resistance since binding of insulin to a target tissue (RBC) appeared to be quantitatively normal at physiological insulin levels, suggesting a simultaneous post receptor defect.- - - - - - - - - - ranking = 0.80012388885935keywords = acanthosis nigricans, nigricans, acanthosis (Clic here for more details about this article) |
10/15. Primary amenorrhea associated with hirsutism, acanthosis nigricans, dermoid cysts of the ovaries and a new type of insulin resistance.We describe a 15 1/2 year old presenting with primary amenorrhea, hirsutism, acanthosis nigricans and insulin resistance. Ovarian vein catheterization studies revealed bilateral excess plasma testosterone and androstenedione secretion, and at surgery multiple dermoid cysts of both ovaries were found in association with polycystic ovaries. The suggestion that the dermoid cysts may be causative in the evolution of the polycystic ovarian disease has been made. The mechanism of the insulin resistance appears to be at the post receptor level. The acanthosis nigricans diminished following surgery with normalization of the plasma androgens.- - - - - - - - - - ranking = 3keywords = acanthosis nigricans, nigricans, acanthosis (Clic here for more details about this article) |
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