Extreme insulin resistance due to anti-insulin receptor antibodies: a direct demonstration of autoantibody secretion by peripheral lymphocytes.

A 59-year-old woman with systemic lupus erythematosus was found to have marked hyperglycemia, extreme insulin resistance and abnormally high plasma immunoreactive insulin. Her circulating erythrocytes displayed a dramatic decrease of 125I-labeled insulin binding. Both the whole serum and purified IgG fraction strongly inhibited the binding of radiolabeled insulin to control erythrocytes. These results suggested, although indirectly, the existence of antibodies to insulin receptors in the serum of the patient. To directly investigate this issue, we used an enzyme-linked solid-phase immunoassay which allows the detection and enumeration of lymphocytes secreting antibodies towards insulin receptors. Peroxidase-conjugated anti-human immunoglobulin is used to reveal the binding of antibodies to insulin receptor-coated dishes. We demonstrated that the patient's mononuclear cells, when briefly incubated in Petri dishes with partially purified insulin receptor, were able to secrete immunoglobulins of G class specifically directed to the antigen. Moreover, only a fraction of the whole population of anti-insulin receptor antibodies was directed towards the insulin binding region of the receptor, seemingly corresponding to the auto-antibodies detected with conventional binding-inhibition assay.

Beta-adrenoceptors desensitization may modulate catecholamine induced insulin resistance in human pheochromocytoma.

Catecholamines acutely exert a pronounced insulin-antagonistic effect, which is mediated by beta-adrenergic receptors stimulation. Nevertheless, several patients with pheochromocytoma fail to exhibit an overt diabetic syndrome, in spite of steadily elevated plasma levels of catecholamines. This prompted us to investigate a 16 years old male patient, bearing an extra-adrenal pheochromocytoma, who displayed a slightly impaired glucose tolerance to oral glucose tolerance test, whereas fasting and post-prandial blood glucose, as well as glycaemic response to intravenous glucagon, were in the normal range. Peripheral insulin sensitivity, as evaluated by intravenous insulin tolerance test, was slightly decreased. Supine norepinephrine plasma levels were steadily upon 9 ng/ml; plasma insulin, both fasting and post-prandial, was within the normal range. beta-adrenergic receptors density of peripheral mononuclear cells was strongly reduced when compared to controls (0.97 +/- 0.08 vs 2.82 +/- 0.37 fmol/10(6) cells), without any concomitant change of affinity. Insulin binding to circulating monocytes was reduced as well (2.38 +/- 0.27 vs 5.1 +/- 0.4%/10(7) monocytes); insulin receptor affinity was quite normal (1.7 ng/ml) and total receptor number was 9,200 sites/cell. In desensitization experiments, 1 microM isoproterenol caused only a 20% decrease of beta-adrenergic receptors density in the patient's cells (70% decrease in controls). Six months after surgery, all the above modifications of receptor binding, as well as the mild glucose intolerance, were almost completely reversed. Thus, high levels of norepinephrine were able to induce a decrease of both beta-adrenoceptor and insulin receptor binding, together with a marked reduction of in vitro agonist-induced redistribution of beta-adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatomedin-C (SM-C). Study in diabetic patients with and without retinopathy.

In the present study we evaluated somatomedin-C (Sm-C) plasma levels in diabetic patients, with and without retinopathy. One hundred and thirty four diabetic patients (65 type I and 69 type II) and 90 controls, strictly matched for age and sex, were enrolled in the study. Ophthalmoscopy and fluorescein angiography allowed to distinguish: 49 patients without retinopathy, 45 patients with background retinopathy, and 40 with proliferative retinopathy. Growth hormone (GH) and Sm-C plasma levels were measured using a pool of 20-24 blood samples over 24h. Sm-C levels in type I (0.62 +/- 0.11 U/ml) and type II (0.56 +/- 0.09 U/ml) patients were significantly decreased (p less than 0.01) when compared to controls (0.89 +/- 0.30 U/ml). The mean daily secretion of GH was significantly (p less than 0.01) greater in diabetic patients (7.8 +/- 2.6 ng/ml) than in controls (4.1 +/- 1.5 ng/ml), but no correlation was found between Sm-C and GH (r = 0.15; p = n.s.). Our findings did not show any correlation between Sm-C plasma levels and either the existence of retinopathy, regardless of the degree of microvascular damage, or duration of the disease, or degree of metabolic control, as evaluated by HbA1c.

Plasmatic levels of fibronectin in diabetics with and without retinopathy. Correlation with some hormonal and metabolic parameters.

Fibronectin is a high molecular weight alpha-2-glycoprotein. Its peculiar role in the structure of connective tissue, together with its wide involvement in coagulative dynamics, justified the increasing interest for fibronectin in the pathogenesis of diabetic disease and its vascular sequelae. In the present work, we evaluated the levels of plasma fibronectin (PF) in diabetics with and without retinopathy, and studied the possible correlation between the glycoprotein and some hormonal and metabolic parameters, expression of glycometabolic balance. We examined 26 type I and 24 type II diabetics, further divided into retinopathics and not retinopathics, and 43 normal subjects. We did not find any significant difference in PF levels either between normals and diabetics, or between type I and type II patients, or between retinopathics and not retinopathics. PF was significantly correlated to age, both in normals and in diabetics. Diabetic patients showed a significant positive correlation of PF to total cholesterol (r = 0.56; p less than 0.05) and triglycerides (r = 0.36; p less than 0.05). This seems to suggest, although indirectly, the existence of a relationship between the levels of PF and the degree of large vessel involvement. No significant correlation was found with HbA1c, beta-OH, AcAc, lactate, pyruvate, C-peptide, total and free insulin or GH. We further indicated an inverse correlation between PF and plasma glucagon (IRG). Very low levels of PF are commonly associated with high IRG plasma values during acute energy deprivation such as prolonged fasting and ketoacidotic coma. Therefore, PF levels might represent an index of latent to overt energy depletion.