[The Maurice Dérot 2002 award. 1971-2002: a story on the insulin receptor].
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Biomedical subjects
Publications and source records attributed to P Freychet.
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Macroprolactinemia, due to increased circulating levels of large molecular weight forms of prolactin, results in elevated level of immuno-reactive prolactin. The big variants have only weak biological activity; thus macroprolactinemia appears as a case of hyperprolactinemia without clinical significance as demonstrated by the five patients described. The diagnosis is based upon chromatography which separates the hormone and its variants. This disorder produces a pitfall in the diagnostic evaluation of hyperprolactinemia.
In order to assess the value of scanning with 99mTc-MIBI before surgery in primary hyperparathyroidism (PHP), we performed this procedure in 30 patients with PHP. MIBI imaging findings were: 24 true positive results, three false positive, three false negative (sensitivity: 89%). The 24 true positive results comprised 21 solitary adenomas (one of which was ectopic), one cancer, and two parathyroid hyperplasias. Thus 99mTc-MIBI scanning seems to be useful for the preoperative localization, and for preparing the surgeon to unusual features that could generate surgical failure.
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The insulin resistance of animal models of obesity (the gold thioglucose obese mouse and the o b/o b mouse) is characterized by several abnormalities. At the receptor step, both the binding function (decreased number of sites) and the enzymatic, tyrosine kinase function (decreased insulin activation) are altered. At postreceptor steps, phosphatidylinositol 3-kinase (PI3-K) plays an important role in insulin signalling, particularly for the stimulation of glucose transport in muscle and adipocyte. Insulin activation of PI3-K is markedly diminished in obese mice; starving the obese animals restores normal responses of PI3-K, glucose transport, and glycogen synthesis, to insulin. These observations emphasize the multi-site, and largely reversible, nature of insulin resistance in these animal models of obesity. Similar alterations have been reported in the literature with regard to the sites of insulin resistance in human obesity and non insulin-dependent diabetes.
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A case of suppurative thyroiditis occurring in a 72-year-old woman is reported. The clinical history of this woman, treated by tianeptine for mild exogenous affective disorder and by conventional insulin therapy for long-standing insulin-dependent diabetes, was remarkable for the pseudotumoral signs which led to the simultaneous diagnosis of hypothyroidism due to Hashimoto's thyroiditis and of mycobacterium avium intracellulare suppurative thyroiditis. To our knowledge, this is the second reported case of mycobacterium avium intracellulare thyroiditis. This case is also exemplary, given its occurrence in the absence of severe immunodepression, setting apart the mild impact on the immune system of affective disorder and of long duration's insulin-dependent diabetes.
A case of hyperthyroidism occurring in a 68 year old man receiving lithium carbonate (1 g/day) for 5 years is reported. The clinical history of the patient, treated for bipolar affective disorder, was remarkable for transient hypothyroidism followed several months later by tremor, increased free thyroxine and triiodothyronine, and decreased TSH levels which led to lithium withdrawal. Two months later, clinical and biological signs were unchanged, Tc99m-scan displayed a homogeneous and increased isotope uptake. In this setting, high levels of autoantibodies against TSH-receptor, and grade I exophthalmos and slightly ocular muscle enlargement at CT-scan favored the diagnosis of Graves' disease (perhaps facilitated by lithium therapy). Carbimazole treatment was effective in controlling hyperthyroidism. Review of the literature disclosed 44 cases of hyperthyroidism occurring in lithium-treated patients. Most of these cases concerned specific thyroid diseases, particularly with an autoimmune mechanism. There is also evidence for an actual role of lithium in increasing intrathyroid iodide pool and for an impact of lithium on the immune system. Thus, the hypothesis that lithium may trigger the development of an autoimmune thyroid disease in predisposed patients deserves further investigation.
Pericardial effusion frequently occurs in patients with hypothyroidism, and this fully justifies the use of echocardiography at the time of diagnosis and during the follow-up of hypothyroidism. Signs indicating that the pericardial effusion is poorly tolerated are rare, and the development of pericardial tamponade is exceptionally reported. A case of tamponade in an elderly woman with severe hypothyroidism is described here. Some physiopathological particularities are emphasized, together with the value of echocardiography for the diagnosis and that of pericardial drainage for the treatment.
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Insulin receptor is a transmembrane glycoprotein. It is synthetized, in endoplasmic reticulum, as a proreceptor which is processed (glycosylation, proteolytic cleavage) and transported to the cell surface. The receptor is a hetero-tetramer comprising 4 subunits: the two alpha-subunits are extracellular; they are held, through disulfide bonds, to the beta-subunits. These are located across the membrane; their intracellular domain possesses a tyrosine-kinase activity. Insulin receptor gene has been located on chromosome 19 and its nucleotide sequence is known. The first functional property of the receptor is to recognize the hormone. Specific and high affinity binding site is supported by the alpha subunit. Shortly after insulin binding, the tyrosine-kinase is activated, resulting in autophosphorylation and phosphorylation of various substrates. Current research focuses on these nature of there substrates which activate intracellular putative mediators of insulin action. Insulin-resistant states are associated with functional alteration of the receptor. But only a few cases are directly related to nucleotide mutations at the level of the gene resulting in structurally abnormal receptor.
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A case of malignant islet-cell tumor with oncocytic features occurring in a 54-year-old woman with symptoms of organic hypoglycemia is reported. The tumor was composed of ribbons of cells arranged in an endocrine pattern. The cytoplasm of these cells was eosinophilic and finely granular. Ultrastructurally, the cells contained numerous mitochondria and dense-core neurosecretory granules. Tumor cells were focally immunoreactive for neuron-specific enolase, insulin, glucagon and VIP. Capillaries invasion and metastases to lymph nodes argued in favor of malignancy but there was no subsequent malignant involvement during a 3-year follow-up after surgery. Such insulinomas with oncocytic features have not been previously described. Endocrine features in oncocytomas of the pancreas and of other locations are discussed.
Octreotide and bromocriptine were used to treat an acromegalic patient harbouring an invasive pituitary tumour secreting growth hormone and prolactin. Octreotide (100 micrograms, subcutaneously, three times daily) and bromocriptine (15 mg orally, daily) rapidly improved clinical signs and symptoms, including diabetes that initially required insulin. Complete control of growth hormone and prolactin secretion was obtained and maintained by this treatment protocol for 12 months without affecting the other pituitary functions. A major tumour shrinkage was apparent by magnetic resonance imaging after six months, and was considered to be complete after 12 months of treatment. Octreotide was then discontinued without any relapse in either growth hormone secretion or tumour growth over a 20-month period following withdrawal. Attempts were made to discontinue bromocriptine, but a maintenance therapy (2.5 mg daily) was required to control rebounds of prolactin hypersecretion. Two months after octreotide withdrawal, acute pancreatitis secondary to cholelithiasis required surgery; this complication was attributed to octreotide (pre-treatment ultrasonography was normal). These findings suggest that combination therapy with octreotide and bromocriptine may be considered in pituitary macroadenomas secreting growth hormone and prolactin. They also emphasize the need for a close monitoring of cholelithiasis, not only during octreotide therapy but also after the drug's withdrawal.
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To determine whether autoantibodies to the insulin receptor may represent markers of Type 1 (insulin-dependent) diabetes, the prevalence of such antibodies was investigated in sera of 60 newly diagnosed untreated Type 1 diabetic patients. A sensitive assay, based on enzyme linked immunosorbent assay has been set up which detects antibodies to the insulin receptor irrespective of their potentially inhibiting effect on insulin binding. Moreover, this method allows easy determination of the immunoglobulin class involved in the anti-receptor activity. Among the 60 sera examined, only one was found to contain anti-insulin receptor autoantibodies (IgG class). In view of our data, we conclude that autoantibodies to the insulin receptor are infrequent findings in Type 1 diabetes of recent onset.