We studied 18 newly diagnosed diabetic patients (8 males and 10 females, aged 18-26 years, within 10-120 days from the onset of symptoms) who were submitted for 15 days to intensive insulin therapy performed via subcutaneous insulin infusion (CSII). We investigated some metabolic and immunological parameters in order to identify a possible marker to predict the selection of patients potentially more responsive to CSII treatment for the remission of type 1 diabetes. In accordance with the International Diabetes Immunology Group we considered clinical remission as being the withdrawal of insulin therapy for at least 3 months. In order to assess beta-cell function a fasting and post-prandial serum C-peptide, blood glucose and HbA1c were performed on all patients before, and 3 days after, the discontinuation of CSII. Islet cell antibodies were determined in all sera by indirect immunofluorescence. Analysis of T-lymphocyte subpopulations was carried out before starting the therapy. The following monoclonal antibodies were used: CD4, CD8, CD57, CD25, HLA-DR. The levels of C3 and C4 and serum IgG, IgA and IgM were also evaluated. After CSII, 11 of 18 patients showed remission. At the beginning of the study we observed no major difference in metabolic parameters between the two groups. Interestingly, the patients who exhibited remission presented a statistically higher percentage of positive cells for CD57, HLA-DR and CD25 surface antigens, significantly lower C4 levels and CD4/CD8 ratio and significantly higher IgG levels compared with patients who did not show any remission. Our study confirms that CSII may prolong beta-cell function and it could suggest that the phenomenon of remission is associated with T-cell activation. The explanation for these findings is still unclear.

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.

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)

The influence of lactate on human adipocytes lipolysis and the possible relationship between lactate-induced metabolic effects and beta-adrenoceptor binding sites were investigated. beta-sites were identified in membranes with (125I)-cyanopindolol and in intact cells with (125I)-cyanopindolol and (3H)-CGP 12177. Lactate reduced isoproterenol-induced lipolysis in a dose-response fashion and such inhibition became significant only at 16 mmol/l lactate. Exposure of human fat cells to 16 mmol/l lactate significantly reduced beta-adrenoceptors density on crude membranes. When the binding assay was performed on intact cells using (125I)-cyanopindolol at 37 degrees C, the radioligand identified the same number of receptors, regardless of the presence of lactate in the preincubation medium. When (3H)-CGP 12177 was used, it bound to about 35% less receptors in lactate pre-treated cells than in control. Seemingly, at 37 degrees C, because of its lipophilicity, (125I)-cyanopindolol can cross the plasma membrane and bind to intracellular sites whereas, (3H)-CGP 1277, due to its hydrophilicity, identifies surface receptors only. Thus, the present in vitro study provides evidence that high levels of lactate, similar to the concentrations usually achieved in overt lactic acidosis, are able per se to inhibit human lipolysis and to redistribute beta-adrenoceptors from cell surface to a domain not accessible to hydrophilic ligands.

We have investigated on eventual relationships existing in men between plasma levels of 17-a-OH-Progesterone (17-a-OH-P) and, plasma levels of Testosterone (T) and on the modifications of these relationships after stimulation of the testicles by HCG (Human Chorionic Gonadotropin). An inverse correlation exists between basal plasma levels of the two steroids and their delta max (%max increase 96 h after the injection of 5000 I.U. of hCG): r = -06, p 0.01. This suggests that the enzymatic steps of the delta -4 steroidogenic pathway are rate-limiting for the synthesis of T. The delta max of the two-steroids are also inversely correlated with the circulating levels of LH (Luteinizing Hormone) (r = -05, -06; p less than 0.01) suggesting that the rate-limiting activity of the delta 4 pathway is under endogenous LH control. A desensitized state of this pathway can be expected in presence of high circulating levels of LH. Similarly to LH also the FSH plasma levels, an index of function of the seminiferous tubules, are inversely correlated with the 17-a-OH-P and T delta max (r = -0.4, -05; p 0.005) indicating close relationships between tubular and interstitial functions. In men with idiopathic oligozoospermia and high circulating levels of FSH we have found increased 17-a-OH-P/T ratios after hCG.

Diabetic MedicineVolume 5, Issue 5 p. 501-502 Responses to Chickling Vetch and Bread Meals in Normal and Type 2 Non-insulin-dependent Diabetic Subjects M. Cignarelli, M. Cignarelli Clinica Medica Generale RR E Terapia Medica, Universita Degli Studi Di Bari, Bari, ItalySearch for more papers by this authorM. R. Cospite, M. R. Cospite Clinica Medica Generale RR E Terapia Medica, Universita Degli Studi Di Bari, Bari, ItalySearch for more papers by this authorM. Rosco, M. Rosco Clinica Medica Generale RR E Terapia Medica, Universita Degli Studi Di Bari, Bari, ItalySearch for more papers by this authorG. Garruti, G. Garruti Clinica Medica Generale RR E Terapia Medica, Universita Degli Studi Di Bari, Bari, ItalySearch for more papers by this authorG. M. Nardelli, G. M. Nardelli Clinica Medica Generale RR E Terapia Medica, Universita Degli Studi Di Bari, Bari, ItalySearch for more papers by this authorG. de Pergola, G. de Pergola Clinica Medica Generale RR E Terapia Medica, Universita Degli Studi Di Bari, Bari, ItalySearch for more papers by this authorR. Giorgino, R. Giorgino Clinica Medica Generale RR E Terapia Medica, Universita Degli Studi Di Bari, Bari, ItalySearch for more papers by this author M. Cignarelli, M. Cignarelli Clinica Medica Generale RR E Terapia Medica, Universita Degli Studi Di Bari, Bari, ItalySearch for more papers by this authorM. R. Cospite, M. R. Cospite Clinica Medica Generale RR E Terapia Medica, Universita Degli Studi Di Bari, Bari, ItalySearch for more papers by this authorM. Rosco, M. Rosco Clinica Medica Generale RR E Terapia Medica, Universita Degli Studi Di Bari, Bari, ItalySearch for more papers by this authorG. Garruti, G. Garruti Clinica Medica Generale RR E Terapia Medica, Universita Degli Studi Di Bari, Bari, ItalySearch for more papers by this authorG. M. Nardelli, G. M. Nardelli Clinica Medica Generale RR E Terapia Medica, Universita Degli Studi Di Bari, Bari, ItalySearch for more papers by this authorG. de Pergola, G. de Pergola Clinica Medica Generale RR E Terapia Medica, Universita Degli Studi Di Bari, Bari, ItalySearch for more papers by this authorR. Giorgino, R. Giorgino Clinica Medica Generale RR E Terapia Medica, Universita Degli Studi Di Bari, Bari, ItalySearch for more papers by this author First published: July/August 1988 https://doi.org/10.1111/j.1464-5491.1988.tb01041.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume5, Issue5July/August 1988Pages 501-502 RelatedInformation

In order to evaluate factors influencing the duration of residual B-cell function in maturityonset diabetics we investigated 104 patients (age 60±11 years) with a mean duration of disease of 11.3±8.7 years by measuring fasting C-peptide (FCP) and fasting blood glucose levels (FBG), C-peptide increment after a standardized breakfast and both mean diurnal plasma glucose (MBG) and mean diurnal C-peptide levels (MCP). C-peptide levels were found to be reciprocally dependent on both the age at onset (positively) and, conversely, on the duration of diabetes (y=0.75+0.026x1−0.049x2; R=0.52, t1=2.76, t2=−4.08). In particular, the present B-cell secretory capacity appears to be lower the younger the patients were at onset, thus suggesting that inherent impairment of B-cell capacity may play a crucial role in determining age at onset of type II diabetes and thus the duration of their residual B-cell function. Moreover, by analyzing separately the data from patients treated with insulin and oral agents respectively, we found that the influence of the duration of the disease on the rate on B-cell exhaustion is unrelated to the mode of treatment even though B-cell capacity at onset appears to be more severely reduced in insulin-treated subjects who, apart from anything else, were younger at onset. In addition, no significant difference was found in FCP levels between patients showing MBG values above or below 160 mg/dl (1.76±0.66vs 1.57±0.68 ng/ml), whereas MCP values were lower in patients with MBG above 160 mg/dl (2.14±0.92vs 2.55±0.88 ng/ml; p<0.05) who, on the other hand, showed significant reduction in the C-peptide response to breakfast. These data suggest that prolonged metabolic derangement may impair the physiological response of B-cells and eventually lead, via B-cell overstimulation, or via a gap between synthesis and release of insulin, or through other as yet poorly understood mechanisms, to earlier insulin dependence in maturity-onset diabetic patients.

381 glucose intake normal curves were studied according to the Diabetes Data Group new classification in healthy persons between 10 and 80 years in order to assess the influence of the age upon the normal glucose tolerance. Such an influence, which was evident in all the subjects, turned out to be more important in women with respect to me. In fact, males showed an increase, per decade, of about 1 mg/dl in fasting glycemic levels, of about 6 mg/dl at 60', of 4 mg/dl at 120', while in females there was an increase of about 2 mg/dl in fasting glicemic values, of about 6 mg/dl at 60' and of about 5 mg/dl at 120'. No meaningful correlation between age and insulinemic values was found at all considered points, either in males or in females. The reasons of the decreased glucose tolerance with aging and of its different behavior in the two sexes are discussed.

The influence of plasma lipid disorders on red blood cell (RBC) lipid pattern and some related erythrocyte membrane functions, such as glycerol (GLT50) permeability and erythrocyte deformability was studied in diabetes mellitus. Significantly higher red blood cell cholesterol content, GLT50 and erythrocyte filtration time values were found in diabetics. GLT50 values were found closely related to both RBC cholesterol content (r = 0.84, p less than 0.001) and filtration time (r = 0.60, p less than 0.001). Interestingly, six diabetics with retinopathy showed GLT50 values above 60 sec. The RBC Cholesterol/Phospholipids molar ratio was significantly higher in diabetics. The most notable changes of plasma lipid pattern in diabetics were a decrease of both plasma HDL cholesterol, phospholipids and Apolipoprotein A levels with an increase of HDL free cholesterol/phospholipids molar ratio. RBC cholesterol content was found to be inversely related to HDL esterified/free cholesterol molar ratio (r = -0.56, p less than 0.001), while RBC cholesterol/phospholipids molar ratio was significantly related to both HDL free cholesterol/phospholipids (r = 0.51, p. 0.001) and to LDL total cholesterol/phospholipids (r = 0.25, p less than 0.05). Lastly, HDL cholesterol levels were found to inversely relate to glycosylated haemoglobin values (r = -0.54, p less than 0.01).

Pyruvate-dehydrogenase, an enzymatic mitochondrial complex, exists in both inactive and active forms, insulin being the regulating factor of the transformation of a latter into the former. The basal (PDHb) and total (PDHt) activity of this enzyme in adipose tissue mitochondria from obese hyperinsulinemic humans has been found equal to 1014 +/- 459 SD mU respectively. These values are 250% higher than those found in normal subjects (403 +/- 76 SD and 575 +/- 142 SD respectively). Both in normal and obese subjects the PDHb/PDHt percent ratio was equal to about 70. These results show that insulin, undoubtedly hyperactive in obesity, by activating PDH can induce a major synthesis of fat, a high caloric density tissue.

The effect of PEBG on respiration and oxidative phosphorilation (succinate as substrate) has been studied in liver mitochondria of rat treated with glucagon. The results obtained indicate that, while glucagon, as reported by others, induce a significant increase of respiration rate in state 3 (+ ADP), PEBG, at pharmachological dose, antagonizes this effect. The conclusion is that PEBG exertes its hypoglycemic activity by inhibiting the gluconeogenic reactions promoted by glucagon. This is strongly evident in diabetic or starwed conditions.