Amantadine reduces glucagon and enhances insulin secretion throughout the oral glucose tolerance test: central plus peripheral nervous system mechanisms

Abstract

Objective: The purpose of the trial was to examine the effects of amantadine, a N-methyl-D-aspartate (NMDA) antagonist, on the oral glucose tolerance test (OGTT) plus insulin, glucagon and neurotransmitters circulating levels. Previous findings showed that hyperinsulinism and type 2 diabetes are positively associated with neural sympathetic and adrenal sympathetic activities, respectively. These peripheral sympathetic branches depend on the pontine (A 5 -noradrenergic) and the rostral ventrolateral (C 1 -adrenergic) medullary nuclei. They are excited by glutamate axons which act at NMDA postsynaptic receptors. Research design and methods: One OGTT plus placebo and one OGTT plus oral amantadine test were carried out two weeks apart in 15 caucasic normal voluntary humans. Noradrenaline, adrenaline, dopamine, plasma-free serotonin, platelet serotonin, glucose, glucagon, and insulin were measured throughout the 180-minute testing period. Results: Maximal reductions of plasma glucose and glucagon plus exacerbated insulin rises were significantly greater throughout the oral glucose plus amantadine test than those registered throughout the oral glucose plus placebo challenge. The above findings were paralleled by greater than normal noradrenaline/adrenaline plasma ratio increases. In addition, maximal reductions of the platelet serotonin and plasma serotonin circulating values contrasted with the normal rises of these parameters, always registered during the glucose load plus placebo challenge. Conclusion: This study supports the theory that amantadine might be a powerful antidiabetic tool and could be added to the therapeutic arsenal against type 2 diabetes.

Effects of amantadine on circulating neurotransmitters in healthy subjects

“…Furthermore, plasma serotonin excites the medullary area postrema (it is located outside of the blood brain barrier) (Reynolds et al 1989; Wilson and Bonham 1994). This nucleus sends excitatory axons to the C1(Ad) nuclei (Gauthier and Reader 1982; Urbanski and Sapru 1988), thus minimization of this mechanism is responsible for the inhibition of the adrenal sympathetic activity, normally registered during postprandial periods (Lechin 2000; Lechin et al 1993; 2009). Hence, amantadine would also be able to annul adrenal sympathetic activity throughout the minimization of the area postrema—C1(Ad) axis which depends on the serotonin release by enterochromaffin cells during postprandial parasympathetic period.…”

“…The above parameters have been investigated also in a great deal of psychiatric and somatic diseases during both relapses and remission periods (Lechin et al 1996; Lechin and van der Dijs 2006a, b). Finally, although we have investigated the effects of amantadine on circulating neurotransmitters throughout the oral glucose challenge (Lechin et al 2009), we decided to assess the above parameters without the sugar administration.…”

Anorexia nervosa depends on adrenal sympathetic hyperactivity: opposite neuroautonomic profile of hyperinsulinism syndrome

“…Whereas patients affected by hyperinsulinism and hypoglycemia can be successfully treated with drugs that minimize neural sympathetic activity,7 abrogation of the adrenal sympathetic branch by drugs which minimize the C1 adrenal medullary and dorsal raphe (5-HT) axis, eg, buspirone,41 amantadine,43,44 and/or tianeptine,36,37,45 would be able to reverse clinical and radiologic symptoms in AN patients 26…”

Anorexia nervosa versus hyperinsulinism: therapeutic effects of neuropharmacological manipulation

“…We have also shown that amantadine, a N-methyl-D-aspartate (glutamate) antagonist, is able to enhance insulin secretion and lower plasma glucagon levels 2–8. Considering that both the metabolic and hormonal effects are paralleled by the attenuation of neural sympathetic and adrenal sympathetic activity, respectively, we inferred that neuropharmacological drugs able to attenuate the hyperactivity of the C1(Ad) medullary nuclei3–8 might be powerful tools for treating adrenal sympathetic predominance, including the anorexia nervosa syndrome.…”