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An extracellular domain of the insulin receptor ß-subunit with regulatory function on protein-tyrosine kinase
No full textAnti-insulin receptor monoclonal antibody MA-10 inhibits insulin receptor autophosphorylation of purified rat liver insulin receptors without affecting insulin binding (Cordera, R., Andraghetti, G., Gherzi, R., Adezati, L., Montemurro, A., Lauro, R., Goldfine, I. D., and De Pirro, R. (1987) Endocrinology 121, 2007-2010). The effect of MA-10 on insulin receptor autophosphorylation and on two insulin actions (thymidine incorporation into DNA and receptor down-regulation) was investigated in rat hepatoma Fao cells. MA-10 inhibits insulin-stimulated receptor autophosphorylation, thymidine incorporation into DNA, and insulin-induced receptor down-regulation without affecting insulin receptor binding. We show that MA-10 binds to a site of rat insulin receptors different from the insulin binding site in intact Fao cells. Insulin does not inhibit MA-10 binding, and MA-10 does not inhibit insulin binding to rat Fao cells. Moreover, MA-10 binding to down-regulated cells is reduced to the same extent as insulin binding. In rat insulin receptors the MA-10 binding site has been tentatively localized in the extracellular part of the insulin receptor beta-subunit based on the following evidence: (i) MA-10 binds to insulin receptor in intact rat cells; (ii) MA-10 immunoprecipitates isolated insulin receptor beta-subunits labeled with both [35S]methionine and 32P; (iii) MA-10 reacts with rat insulin receptor beta-subunits by the method of immunoblotting, similar to an antipeptide antibody directed against the carboxyl terminus of the insulin receptor beta-subunit. Moreover, MA-10 inhibits autophosphorylation and protein-tyrosine kinase activity of reduced and purified insulin receptor beta-subunits. The finding that MA-10 inhibits insulin-stimulated receptor autophosphorylation and reduces insulin-stimulated thymidine incorporation into DNA and receptor down-regulation suggests that the extracellular part of the insulin receptor beta-subunit plays a role in the regulation of insulin receptor protein-tyrosine kinase activity
Diabetes increases aging effect on rat collagen linked fluorescence. Prevention with administration of aminoguanidine and rutin.
No full textProducts from the advanced Maillard reaction, which increase during aging and diabetes, may contribute to the development of the typical pathology of aging and diabetes. These compounds are detectable only by their characteristic fluorescence, and few data based on long-term studies are available. For this reason, we studied subcutaneous skin collagen fluorescence in 57 nondiabetic (10- to 110-wk-old) and 74 streptozocin-induced diabetic (10- to 22-wk-old) rats. An exponential increase (r = 0.969, P < 0.001) of collagen-linked fluorescence (excitation at 370 nm, emission at 440 nm) was observed with aging; after a lag, diabetes induced an earlier dramatic elevation of the fluorescence, suggesting a more complicated phenomenon than simle accumulation. To prevent such increases, the effects of 1 g · kg-1 · day-1 aminoguanidine, suggested to be an inhibitor of the advanced glycosylation reaction, and 1 g · kg-1 · day-1 rutin, an aldose reductase inhibitor, in drinking water were tested. Both treatments had a significant lowering effect on collagen fluorescence in diabetic rats. The mechanisms by which aminoguanidine and rutin prevent the accumulation of fluorescence are unknown, but these observations raise the question of whether they could be identical. If fluorescence is a marker for age-related pathologies and diabetic sequelae, aminoguanidine and rutin could have therapeutic effects in their prevention
Water distribution in insulin-dependent diabetes mellitus in various states of metabolic control.
No full textAlterations in water compartments have been described in insulin-dependent diabetes mellitus (IDDM). Both insulin and lack of natriuretic counteracting response lead to water expansion, while hyperglycemica-induced osmotic diuresis leads to water depletion. Both total body water and water distribution in the extra-intracellular space, as well as their relationships to metabolic control, were investigated in 15 controls (30.1 +/- 1.4 years) and in 26 IDDM patients (31.3 +/- 1.6, diabetes duration 11.3 +/- 1.4 years) who were neither hypertensive nor proteinuric. The amounts of total body water (TBW) and extracellular water (ECW) were predicted by impedance measurements at 100 KHz and at 1 KHz. The amount of intracellular water (ICW) was computed as the difference between the two. Water distribution was estimated by measuring the ratio between low- and high-frequency impedance and by computing the ratio between ECW and ICW. The IDDM patients were divided into four groups on the basis of reference HbA(lc) mean and SD: A < or = mean + 2 SD < B < or = mean + 4 SD < C < or = mean +6SD < D. The groups were comparable with sodium intake, insulin dosage, fasting glycemia and laboratory hydration markers. As compared to controls, impedance values at 1, 5, 10, 50 and 100KHz were significantly lower in diabetic patients and the difference within group D increased as the frequency increased: -3.9% at 1 KHz, -10.1% at 100 KHz. As compared to controls, groups A, B and C showed higher TBW, ECW and ICW while water distribution was normal, and group D showed higher TBW and ICW but normal ECW and a different water distribution. In all IDDM patients, HbA(lc) correlated with ECW (r = -0.49) and distribution ratios (r = 0.42, impedance; r = 0.40, ECW/ICW ratio). These observations suggest that good or moderate long-term control IDDM patients have proportionately normal distributions of ECW and ICW excess. However, water excess in poor control IDDM patients was only found in the ICW space
Malondialdehyde (MDA) level in diabetic patients. Relationship with blood glucose and glycosylated hemoglobin.
No full textThe relationship between plasma malondialdehyde (MDA) and metabolic parameters in type I and II diabetic subjects have been studied at different levels of glycemic control. In 67 diabetics (20 type I, 47 type II, aged 53 ± 1.2) and 40 healthy subjects (aged 47 ± 1.75), triglycerides (TG), total cholesterol (CT) and C-HDL, fasting blood glucose (FBG), glycosylated hemoglobin (GHb) and MDA were measured. Diabetic population as a whole showed higher MDA plasma levels compared to controls, together with higher FBG, TG, GHb. MDA showed a significant correlation with both FBG and GHb, but was not correlated to plasma lipids. The patients with a poor metabolic control showed the highest plasma MDA concentrations, significantly different from the group with a better control: GHb 10% = MDA 4.22 ± 0.39 nmol/ml (z = 2.10, α 150 mg/dl = MDA 4.15 ± 0.37 nmol/ml (z = 2.22, α < 0.02). Glycemic equilibrium seemed to influence plasma MDA, increasing free radical production. This phenomenon probably occurred either because of enhanced glycosylation and platelet aggregation, or impairment of cellular antioxidant protective systems. The increased free radical production may play a role in the pathogenesis of metabolic vasculopathy
Indipendence of morphological and functional aspects of pseudoislets from gel collagen matrix. cell
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An instrument for real-time spectral estimation of heart rate variability signals.
No full textA Digital Signal Processor (DSP)-based instrument is proposed for estimating and displaying the Heart Rate Variability (HRV) spectrum in real-time. It consists of an intelligent module which is properly interfaced to an IBM PC and whose operations are independent from the computer's other tasks. In this way, the simultaneous recording of the ECG sequence, needed for the more complete off-line analysis, can be performed by the same host. The employed hybrid spectral estimator (in which a classical FFT analysis follows the autoregressive extrapolation of data) appears to be the most apt for the present fixed point arithmetics implementation. The reliability of the instrument and its accuracy are checked both with suitable test signals and by comparison with the results obtained through off-line analysis of the same ECG tracks. The instrument is presently used for cardiovascular investigations, in particular for quickly picking patients with cardiac autonomic neuropathy (CAN) out of a population of diabetic subjects
Exploration of the early insulin response by two small successive loads of I.V. glucose in normal and obese subjects.
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