Nicola Passariello

Improved Insulin Response and Action by Chronic Magnesium Administration in Aged NIDDM Subjects

In eight aged non-insulin-dependent diabetes mellitus (NIDDM) subjects, insulin response and action were studied before and after chronic magnesium supplementation (2 g/day) to diet. Chronic magnesium supplementation to diet versus placebo produced 7) a significant increase in plasma (0.83 ± 0.05 vs. 0.78 ± 0.06 mM, P < .05) and erythrocyte (2.03 ± 0.06 vs. 1.88 ± 0.09 mM, P < .01) magnesium levels, 2) an increase in acute insulin response (AIR) (4.0 ± 0.6 vs. - 1 .6 ± 0.6 mU/L, P < .05) to glucose pulse, and 3) an increase in glucose infusion rate (GIR) (3.6 ± 0.6 vs. 2.9 ± 0.5 mg kg∼1 min−1 P < .025) calculated in the last 60 min of a euglycemic-hyperinsulinemic (100U m2 · min−1 during 180 min) glucose clamp. Net increase in AIR, glucose disappearance rate after glucose pulse, and GIR were significantly and positively correlated to the net increase in erythrocyte magnesium content calculated after chronic magnesium supplementation to diet. In conclusion, our data suggest that NIDDM subjects may benefit from therapeutic chronic administration of magnesium salts.

Insulin induces opposite changes in plasma and erythrocyte magnesium concentrations in normal man.

SummaryPlasma and erythrocyte magnesium levels were measured by atomic absorption spectrophotometry in 10 healthy volunteers during an oral glucose tolerance test and during an euglycaemic hyperinsulinaemic glucose clamp. At min 180 and 210 of the oral glucose tolerance test, a significant decline in plasma magnesium levels (p < 0.01 andp < 0.05 respectively) and a significant increase in erythrocyte magnesium levels (p < 0.01 andp < 0.05 respectively) were observed. Similar changes were seen during the second hour of the glucose clamp, during which euglycaemia (4.1 ± 0.4 mmol/1) was maintained despite hyperinsulinaemia (110–130 mU/1). During in vitro incubations, glucose (5 mmol/1) did not modify erythrocyte magnesium levels. In contrast, erythrocyte magnesium levels were significantly increased (p < 0.01) by insulin (100 mU/1), an effect entirely abolished by ouabain (5 .10−4 mol/1). These results suggest that insulin induces a shift of magnesium from the plasma to the erythrocytes both in vivo and in vitro. These data may help to interprete the abnormalities in magnesium circulating levels frequently reported in diabetic patients.

Greater Efficacy of Pulsatile Insulin in Type I Diabetics Critically Depends on Plasma Glucagon Levels

The aim of this study was to investigate the role of plasma glucagon levels on the blood glucose response to intravenous insulin administered continuously or in a pulsatile manner. Six type I diabetic patients proven to have no residual insulin secretion were investigated. Endogenous glucagon secretion was inhibited by a continuous intravenous infusion of somatostatin (100 micrograms/h) and replaced by exogenous infusions of the hormone at three different rates (7.5, 4.5, and 2.5 micrograms/h), resulting in three different plasma glucagon steady-state levels (i.e., approximately equal to 200, approximately equal to 130, and approximately equal to 75 pg/ml, respectively). Each subject, in random order and on different days, was infused intravenously with regular human insulin either continuously (0.17 mU X kg-1 X min-1) or with the same amount of insulin infused in a pulsatile manner (0.85 mU X kg-1 X min-1 during 2 min followed by 8 min during which no insulin was infused). At plasma glucagon levels approximately equal to 200 pg/ml, blood glucose rose from approximately 10 to approximately 13 mM without any difference between the two modalities of insulin infusion. For plasma glucagon levels approximately equal to 130 pg/ml, plasma glucose remained steady throughout the experiments, but during the last 40 min, plasma glucose levels were significantly lower when insulin was administered intermittently. This greater blood glucose-lowering effect of pulsatile insulin occurred earlier and was more pronounced for plasma glucagon levels averaging 75 pg/ml. We conclude that the greater hypoglycemic effect of insulin administered intravenously in a pulsatile manner in type I diabetics critically depends on plasma glucagon circulating levels.

Pharmacological Doses of Oxytocin Affect Plasma Hormone Levels Modulating Glucose Homeostasis in Normal Man

Pharmacological doses of oxytocin administered in basal conditions evoked a rapid surge in plasma glucose and glucagon levels followed by a later increase in plasma insulin and adrenaline levels. The effects of oxytocin on plasma glucagon and adrenaline levels were potentiated by hypoglycemia. When the endogenous pancreas secretion was suppressed by cyclic somatostatin (150 micrograms/h) and exogenous glucagon (3.5 micrograms/h) and insulin (0.2 mU/kg.min) were both replaced, oxytocin (0.2 U/min) evoked a transient but significant increase in plasma glucose levels suppressing the glucose infusion rate (GIR) in the first 60 min. On the contrary at higher insulin infusion rate (0.6 mU/kg.min) plasma glucose levels and GIR remained unaffected throughout the study. Oxytocin seems also to potentiate glucose-induced insulin secretion as evidenced by hyperglycemic glucose clamp. In conclusion, pharmacological doses of oxytocin seem to exert a prevalent hyperglycemic effect by a combined action at the liver site (as glycogenolytic agent) and at the endocrine pancreas (as a stimulatory agent of A cell secretion).

Metabolic Control May Alter Antithrombin III Activity but Not Its Plasma Concentration in Diabetes: A Possible Role for Nonenzymatic Glycosylation

The effects of metabolic control on both antithrombin III (AT III) activity and AT III plasma concentration in 20 insulin-treated diabetic subjects have been evaluated. Basal AT III activity was significantly lower in diabetic subjects versus healthy controls (P < 0.001), whereas no difference was found in AT III concentration. A good correlation was found between AT III activity and AT III concentration (r = 0.81; P < 0.001) in healthy controls, but this correlation was not significant in diabetic subjects (r = 0.12; P = NS). In those subjects a linear inverse correlation was found to exist between AT III activity and level of glycosylated proteins (r = −0.43; P < 0.05). Diabetic subjects were also examined after 1 and 2 mo of restored metabolic control, obtained by human insulin (DNA-recombinant) therapy. Improved metabolic control was characterized by an increase of AT III activity (P < 0.05), a decrease of mean daily blood glucose, and stable HbA1 and glycosylated proteins (P < 0.05), while AT III concentration did not vary. On the other hand, a significant inverse correlation between AT III activity and glycosylated proteins was found during both the first and second months (r = −0.54 and r = −0.53, respectively; P < 0.01). Moreover, no correlation between AT III activity and AT III concentration was found. These data suggest that impaired metabolic control may alter the biologic activity of AT III in diabetes, but not its plasma concentration.

Plasma glucose lowering effect of spartein sulphate infusion in non-insulin dependent (Type 2) diabetic subjects

SummarySparteine sulphate, given i.v. as a bolus of 15 mg/ml plus 90 mg in 0.9% NaCl 100 ml over 60 min, increases plasma insulin and decreases plasma glucose and adrenaline in non-insulin dependent (Type II) diabetic subjects. The hypoglycaemic effect was also evident in the presence of a high plasma glucose level produced by Biostator changing glucose infusion from 20.2±2.8 to 26.4±4.2 mg · kg−1 · min−1 (p<0.01), and it was potentiated by simultaneous infusion of arginine.No additional effect of sparteine on the peripheral sensitivity to insulin were detected by the euglycaemic, hyperinsulinaemic glucose clamp technique, as the glucose infusion rate (3.1±0.8 vs 2.6±1.2 mg · kg−1 · min−1) was not statistically significant different in the last 60 min of the experiment.It is concluded that sparteine sulphate enhances β-cell secretion, causing a fall in the plasma glucose concentration.

Low-Dose Iloprost Infusion Improves Insulin Action in Aged Healthy Subjects and NIDDM Patients

OBJECTIVE To investigate the effect of iloprost infusion on insulin action. RESEARCH DESIGN AND METHODS Thirteen healthy subjects and 13 non-insulin-dependent diabetes mellitus (NIDDM) patients matched for age (68.2 ± 0.5 vs. 67.9 ± 0.5 years, NS), gender ratio (7 men:6 women vs. 6 men:7 women), body weight, body fat distribution, arterial blood pressure, and plasma triglycéride levels (1.89 ± 0.09 vs. 1.87 ± 0.08 mmol/l, NS) were studied. In eight healthy subjects and eight NIDDM patients, we studied insulin action by euglycemic glucose clamp (insulin infusion rate 2 mU · kg−1 · min−1) along with saline and iloprost delivery (0.7 ng · kg−1 · min−1). In the other five subjects of each group, forearm blood flow and insulin-mediated glucose uptake during saline and iloprost infusion (0.7 ng · kg−1 · min1) were investigated. RESULTS Iloprost infusion improved insulin-stimulated whole-body glucose uptake and oxidative and nonoxidative glucose metabolism in both study groups. Forearm blood flow under basal conditions and with insulin infusion (2 mU · kg−1 · min−1) did not show any significant difference from that during saline and iloprost infusion (0.7 ng · kg−1 · min−1) in healthy subjects and diabetic patients. CONCLUSIONS Iloprost infusion improves insulin action in healthy subjects and NIDDM patients.

Modulation by verapamil of insulin and glucagon secretion in man.

SummaryThe present investigation was designed to evaluate the effect of acute and protracted verapamil administration on insulin and glucagon secretion in man. For this purpose, 14 normal subjects received two consecutive glucose pulses (5 g i.v. in less than 20 sec or 20 g i.v. in less than 1 min, 7 subjects for each group), 70 or 90 min apart, before and during an infusion of verapamil (160 μg/min). Seven additional normal subjects received two consecutive arginine pulses (5 g i.v.), 70 min apart. In 14 inpatients with coronary heart disease, we investigated the effect of protracted verapamil administration. Seven of these subjects underwent two oral glucose tolerance tests (100 g) and the other 7 two arginine tests (30 g) before and after a 10-day treatment with verapamil, 240 mg/die p.o. divided into three doses; the last dose, 80 mg, was given orally 1 h before the performance of the post-treatment test. Verapamil significantly inhibited the acute insulin response (AIR, mean change from 3–10 min) to glucose (5 g), as well as the AIR and AGR (acute glucagon response) to arginine (5 g). By contrast, verapamil failed to alter significantly the AIR to the higher glucose pulse. There was no significant change of oral glucose tolerance after verapamil, nor was there a change in insulin response to oral glucose. By contrast, insulin and glucagon responses to arginine infusion were significantly reduced by the drug.

Effect of sparteine sulphate upon basal and nutrient-induced insulin and glucagon secretion in normal man

SummaryInfusion of a therapeutic dose of sparteine sulphate, increased the basal plasma insulin level and lowered plasma glucose. When an intravenous glucose tolerance test was performed with the infusion, the total insulin AUC was significantly larger than in absence of sparteine (2025 vs 1464 µU/ml×min), plasma glucose levels were lower and improved glucose utilization was observed (kg:1.55 vs 1.39%). In the presence of arginine, sparteine sulphate stimulated both β and α cells, increasing both the total insulin (1907 vs 1516 µU/ml×minp<0.02) and total glucagon AUCs (7616±654 vs 6789±707 pg/ml×minp<0.01). Thus, sparteine sulphate increased both basal and nutrient-induced insulin and glucagon secretion in normal man.

Relationship between autonomic cardiac activity, b-cell function, anthropometrics and metabolic indices in type II diabetics

objective Recent studies have demonstrated that C‐peptide exerts beneficial effects on the diabetic state, including improvements in kidney and nerve function. Thus, we investigated the effect of residual pancreatic C‐peptide secretion on the cardiac autonomic nervous system in well‐ and poorly controlled type II diabetic patients.