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Diabetes and Polycystic Ovary Syndrome
Published in Jack L. Leahy, Nathaniel G. Clark, William T. Cefalu, Medical Management of Diabetes Mellitus, 2000
Carolyn H. Kreinsen, Andrea Dunaif
Insulin resistance, independent of obesity, is a unique feature of PCOS but not of hyperandrogenic states in general. Obesity is a common cause of insulin resistance and hyperinsulinemia; it also occurs more frequently in PCOS women than in age- and sex-matched control women in the general population. Obesity has a major synergistic negative effect with PCOS on insulin resistance, such that obese PCOS women are at greater risk for glucose intolerance and dyslipidemia. There also appears to be a direct relation between the chronically anovulatory state and insulin resistance. Therapies that improve insulin sensitivity may restore ovulation in PCOS women. Although hyperandrogenemia may contribute somewhat to the insulin resistance, there is an intrinsic defect in insulin action in PCOS. Several rare disorders have been identified in which extreme insulin resistant diabetes mellitus in females has been found in conjunction with hyperandro- genism. These include the type A syndrome in adolescent women and the type B syndrome in pre- and postmenopausal women, associated with anti-insulin receptor antibodies. Other studies noted insulin receptor gene mutations as the cause of leprechaunism, Rabson-Mendenhall syndrome, and some cases of type A syndrome. All of these disorders have insulin-resistant diabetes mellitus, acanthosis nigricans, and hyperandrogenism in common.
Genetics of Endocrine Disorders and Diabetes Mellitus
Published in George H. Gass, Harold M. Kaplan, Handbook of Endocrinology, 2020
Bess Adkins Marshall, Abby Solomon Hollander
A relatively large number of defects have been described in the insulin receptor gene in patients with three rare syndromes: the syndrome of Type A severe insulin resistance, characterized by marked hyperinsulinemia and insulin resistance, acanthosis nigricans, and hyperandrogenism of ovarian origin;39 leprechaunism, characterized by severe primordial dwarfism, hyperinsulinism, and fasting hypoglycemia;40 and Rabson-Mendenhall syndrome, characterized by insulin resistance, abnormal dentition, and thickened nails.41 Some of these mutations are outlined in Table 2. In many cases defects in the binding of insulin,42–46 the kinase activity of the receptor,43,47-55 mRNA abundance,56,57 or the posttranslational processing or trafficking of the receptor43,45,58–60 have been found in these mutant receptors. One mutation appeared to cause constitutive activation of receptor autophosphorylation, kinase activity, and glucose transport.61 Some of the mutations act in a “dominant-negative” fashion, causing severe insulin resistance in the heterozygous state despite the presence of a normal receptor allele.49,51,52,55 One functionally silent mutation,62,63 Val985 to Met, has been found in patients with Type A insulin resistance, NIDDM, and in normal subjects.62–65 It is not clear why defects in the receptor present with varying clinical syndromes. Insulin receptor defects appear thus far to be the cause of all cases of leprechaunism and the Rabson-Mendenhall syndrome, both of which are extremely rare. However, insulin receptor defects may be only a minor cause of the more common Type A severe insulin resistance syndrome. In a study of 22 women with this syndrome, only one had a detectable defect in the insulin receptor.64
Arg1201Gln mutation of insulin receptor impairs tyrosine kinase activity and causes insulin resistance: a case report
Published in Gynecological Endocrinology, 2020
The heterozygous mutation was also present in her mother but was absent in her father, indicating an autosomal dominant pattern of inheritance. In addition, the genetic trait of TAIRS can also be transmitted in an autosomal recessive pattern [24]. In general, missense mutations in the tyrosine kinase domain of the INSR are frequently inherited in a dominant form [15]. Although homozygous or compound-heterozygous mutations in the INSR are frequently associated with leprechaunism and Rabson-Mendenhall syndrome, they can also be detected in patients with TAIRS [10,24–26]. To clarify, the majority of individuals affected with TAIRS do not have mutation in INSR gene [7]. What’s more, Jacques Young et al. reported a case of a woman with TAIRS associated with a heterozygous missense mutation in the lamin A/C gene rather than INSR gene [27]. These lend support to the genetic heterogeneity of TAIRS.
HCV treatment with direct acting antivirals improves the insulin sensitivity
Published in Expert Review of Anti-infective Therapy, 2019
Ayman Alsebaey, Mostafa Elhelbawy, Wael Abdel-Razek, Mohammed Hashim, Hassan Elshenawy, Imam Waked
IR is a subnormal glucose response to a given concentration of insulin. IR may be an inherited disease as in Rabson-Mendenhall syndrome or secondary to other diseases, such as obesity, metabolic syndrome, DM, stress, infection, pregnancy, immune-mediated conditions (anti-insulin antibodies), polycystic ovary, starvation, and uremia [17].