EXPERIMENTAL BENEFIT OF MOXONIDINE ON GLUCOSE-METABOLISM AND INSULIN-SECRETION IN THE FRUCTOSE-FED RAT

Objective Non-insulin-dependent diabetes mellitus (NIDDM) is often ass ociated with hypertension leading to a specifically high cardiovascula r risk in these patients. However, there is evidence that insulin resi stance and hyperinsulinaemia are not only characteristic for diabetic patients but also for some non-diabetic populations in which a cluster of cardiovascular risk factors is observed (hypertension, hypertrigly ceridaemia, obesity). Therefore, hyperinsulinaemia and insulin resista nce have been suggested to be of major pathophysiological importance f or the development of this syndrome (syndrome X). Since imidazoline re ceptors are currently considered to be a specific pharmacological targ et for blood pressure reduction, it is important to know whether and i n which way these compounds affect the glucose homoeostasis and insuli n release. Design The influence of moxonidine on glucose tolerance in vivo was determined in healthy control rats, in rats receiving a high fructose diet for 6 weeks to induce insulin resistance, hyperinsulinae mia and hypertension, and in rats receiving in addition to a high fruc tose diet moxonidine (1.5 mg/kg body weight daily), In vitro, using is olated pancreatic islets of mice, long-lasting effects (chronic) and i mmediate (acute) effects of moxonidine on beta-cell function were dete rmined by basal and glucose stimulated insulin release in two differen t experimental systems: (1) islets were exposed for 24 h (37 degrees C ) to various concentrations of moxonidine ranging from 1 nmol/l to 1 m mol/l, followed by a washing procedure to remove excess of moxonidine and then used for the beta-cell function test; (2) islet cultures were incubated again with moxonidine for 24 h (37 degrees C) with either 1 nmol/l or 1 mu mol/l. In contrast to the first experiments, however, after the washing procedure moxonidine was added at the same concentra tion as used for preincubation to test its direct effect on beta-cell function. Results In healthy control rats acute administration of moxo nidine in vivo impaired the glucose tolerance in high dosages, which e ffectively reduced the blood pressure (>1 mg/kg body weight). This eff ect was, however, smaller that that observed by clonidine, In fructose -fed rats, moxonidine completely prevented the development of insulin resistance, hyperinsulinaemia and hypertension. In vitro, pancreatic i slets preincubated with moxonidine exhibited dose-dependently both sti mulatory and inhibitory chronic effects on beta-cell function compared with that in controls. Preincubation of islet cultures with moxonidin e at concentrations between 1 nmol/l and I mmol/l resulted in a reduct ion of basal insulin release which was very pronounced at concentratio ns higher than 100 nmol/l. The results obtained for glucose-stimulated insulin release opposed in part those for basal insulin release, sinc e the preincubation with moxonidine up to 10 mu mol/l gave rise to an increased insulin release. An additional direct effect of moxonidine w ith a marked reduction of glucose-stimulated insulin release was obser ved, however, when moxonidine was present during the preincubation (24 h) and the functional test at a concentration of 1 nmol/l or 1 mu mol /l. Conclusions Our data suggest that a causal linkage exist between t he development of hypertension and insulin resistance/hyperinsulinaemi a in the high fructose diet rat model, Since central activation of imi dazoline receptors by moxonidine can prevent this syndrome, it follows that an overactivity of the sympathetic nervous system is of major im portance. Suppression of this sympathetic overactivity might be an eff ective approach to reduce hypertension and the concomitant metabolic d efect. Therefore, such an interventional strategy could contribute to reduce the cardiovascular risk of NIDDM patients and patients with oth er forms of insulin resistance/hyperinsulinaemia such as metabolic car diovascular syndrome.