Insulin receptors and insulin actions in the nervous system.

Insulin receptors are widely distributed in the brain. They are also present in peripheral nerve. Insulin signaling through its receptors in the brain is responsible for the hormone's effects on the regulation of food intake, body weight, and reproduction. Signaling through the insulin receptor also appears to influence higher cognitive functions. In peripheral nerve, insulin signaling may play a role in the maintenance and repair of myelinated fibers. Future studies should determine the extent to which a defective insulin signal may be linked to the pathogenesis of diabetic neuropathies and neurodegenerative disorders such as Alzheimer's disease.

[Macroprolactinemia, a variety of hyperprolactinemia. Apropos of 5 cases]. / Macroprolactinémie, une variété d'hyperprolactinémie. A propos de cinq observations.

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.

[Preoperative localization in primary hyperparathyroidism: value of Tc-99m-MIBI scintigraphy]. / Localisation préopératoire dans I'hyperparathyroïdie primitive: valeur de la scintigraphie au 99mTc-MIBI.

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.

[Insulin resistance: lessons from animal models of obesity]. / Résistance à l'insuline: les enseignements de modèles animaux d'obésité.

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.

Abnormalities suggestive of cardiomyopathy in patients with type 2 diabetes of relatively short duration.

OBJECTIVE: The aim was to assess the presence of cardiomyopathic features in asymptomatic patients with Type 1 and Type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: Fifty-two (27 Type 1; mean duration: 10.2 +/- 7.4 yr; 25 Type 2, mean duration: 6.5 +/- 4.4 yr) diabetic patients with no signs of ischaemic heart disease or high blood pressure were studied by noninvasive techniques: Holter ECG; Filtered-Amplified ECG (FAECG); Exercise ECG; Echocardiography (BD, TM) and Doppler evaluation of diastolic parameters. Twenty-four healthy subjects matched for age were studied as controls. RESULTS: Holter ECG did not detect rhythm disturbances or features of silent ischaemia in either group of patients. With FAECG, at least one criterion of late ventricular potentials was found in 28% of Type 2 patients, vs 11% of Type 1 patients and 8.3% of control subjects. With exercise ECG, maximum oxygen uptake, anaerobic threshold, and workload performance were all significantly lower in Type 2 patients compared to control subjects. Echocardiography depicted a greater end diastolic interventricular septum thickness in Type 2 patients than in control subjects, with a trend toward left ventricular hypertrophy in 28% of Type 2 and 7.4% of Type 1 patients. Doppler echocardiography revealed a significant decrease in early diastolic peak filling rates (E) in diabetic patients as a whole group (Type 1 + Type 2) compared to controls. Late diastolic peak filling rates (A) were significantly higher in Type 2 patients than in their controls. The E/A ratio was significantly lower in diabetic patients (as a whole group) than in control subjects; this was accounted for mainly by a significant decrease of E/A in Type 2 patients compared to their controls. CONCLUSIONS: Our major finding rests on the disclosure of abnormalities suggestive of cardiomyopathy in Type 2 diabetic patients with a relatively short duration of the known disease, while these alterations appeared in our study less prominent in Type 1 patients despite a longer duration of the disease. Among the various noninvasive techniques, FAECG and Doppler echocardiography used to detect late ventricular potentials and to assess left ventricular diastolic dysfunction, respectively, appear to be suitable tools.

Type 1 diabetes mellitus and homocyst(e)ine.

High Homocyst(e)ine levels (H) have been recently recognized as a risk factor for atherosclerosis. Patients with Diabetes Mellitus (DM) are prone to atherosclerosis. Therefore, this study was designed to search for the effect of DM on H and their relationship. Forty-one Type 1 diabetic subjects (DS, age 34.8 +/- 12 yr, DM duration: 10.7 +/- 11.1 yr) were compared to 40 age-matched control subject (CS, age 34.2 +/- 9.1 yr). H (measured by ion-exchange chromatography, units: mumol/l) and several parameters (creatininemia; triglycerides; total, HDL, LDL cholesterol; Lp(a); HbA1c; vitamins B9 and B12) were determined after an overnight fast. H were significantly (p = 0.0001) lower in DS (6.8 +/- 2.2) than in CS (9.5 +/- 2.9). This difference was still apparent in male and female subgroups compared to matched CS (p = 0.003 for each). No correlation was found between H and: lipids, vitamins, renal or retinal status. But H seemed to increase with age, especially in women (p = 0.03; r = 0.32). While there is, at this time, no explanation for the lower H observed in DS, it appears that H cannot directly account for accelerated atherosclerosis in DM. Nevertheless, it remains to be established if high, or even normal, H could identify a subgroup of DS at higher risk of precocious and severe atherosclerosis.

Mycobacterium avium intracellulare suppurative thyroiditis in a patient with Hashimoto's thyroiditis.

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.

[Lithium therapy and hyperthyroidism: disease caused or facilitated by lithium? Review of the literature apropos of a case of hyperthyroidism preceded by transient hypothyroidism]. / Thérapeutique par lithium et hyperthyroïdie: pathologie causée ou facilitée par le lithium? Revue de la littérature à propos d'un cas où l'hyperthyroïdie a été précédée d'une hypothyroïdie transitoire.

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.

Toxic hepatitis induced by antithyroid drugs: four cases including one with cross-reactivity between carbimazole and benzylthiouracil.

OBJECTIVE: This study was conducted to assess the occurrence of hepatic adverse effects encountered with antithyroid drugs. METHODS: Retrospective review of medical records of 236 patients with hyperthyroidism admitted in our department (in- or out-patients) from 1986 to 1992. RESULTS: Four patients (1.7%) were identified with toxic hepatitis which could reasonably be attributed to the use of antithyroid agent. Two patients had a cholestatic hepatitis induced by carbimazole (Néomercazole). Two others had a mixed (cholestatic and cytolytic) hepatitis following carbimazole. One of the latter two patients further experienced a cytolytic hepatitis which appeared after Benzylthiouracil (Basdène) had replaced carbimazole. Biological features of hepatitis disappeared in all cases after cessation of the incriminated drug, while biliary, viral and immunological searches were negative. Only 2 patients of our retrospective study experienced a mild or severe neutropenia. CONCLUSION: Toxic hepatitis is a potential adverse effect of antithyroid drugs which warrants, as for haematological disturbances, a pre-therapeutic determination and a careful follow-up of relevant biological markers. Moreover, hepatotoxicity may not be restricted to one class of antithyroid agents.

[Cardiac tamponade in severe hypothyroidism. A rare cause]. / Tamponnade cardiaque au cours d'une hypothyroïde sévère. Une cause rare.

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.

[Insulin receptors: structure and physiology]. / Récepteurs de l'insuline: structure et physiologie.

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.

Malignant pancreatic oncocytoma. An unusual cause of organic hypoglycemia.

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.

Invasive mixed growth hormone/prolactin secreting pituitary tumour: complete shrinking by octreotide and bromocriptine, and lack of tumour growth relapse 20 months after octreotide withdrawal.

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.