Induction of Defective Insulin Secretion and Impaired Glucose Tolerance by Clonidine Selective Stimulation of Metabolic Alpha-adrenergic Pathways

Abstract

Clonidine is an antihypertensive drug that markedly suppresses plasma catecholamine levels. In an attempt to investigate the effects of suppression of endogenous catecholamine secretion on glucose homeostasis and glucoregulatory hormones, we administered oral clonidine to 20 normal male subjects, two patients with transsections of the cervical spinal cord, and one patient with an insulinoma. Unexpectedly, after a single dose of 0.5 ing. given to normal subjects, insulin concentrations fell and plasma glucose rose 12 ± 1 mg./dl. (p < 0.001; n = 6) without an increase in glucagon. After four days of clonidine treatment, plasma glucose again was elevated (Δ = +11 ± 3 mg./dl.; p < 0.01), while basal plasma insulin and glucagon levels remained unchanged. The acute insulin response to an intravenous glucose injection of 5 gm. decreased from 33 ± 7 to 11 ± 2 μU./ml. (n = 8; p < 0.01), and KG declined from 0.80 ± 0.13 to 0.53 ± 0.06 per cent per minute (p < 0.01). Similar responses were seen in the paraplegic patients. In contrast, expected responses to clonidine were not observed in the insulinoma patient preoperatively; these normal responses were restored after resection of the tumor. All metabolic alterations induced by clonidine were reversed by infusion of phentolamine, an alpha-adrenergic blocking agent. We conclude that clonidine causes hyperglycemia and inhibits insulin secretion through an alpha-adrenergic mechanism. Since plasma catecholamine concentrations and vascular tone were markedly reduced by clonidine, this drug appears to selectively stimulate metabolic adrenergic pathways different from those operative in vasomotor regulation.

Pharmacological effects and pharmacokinetics of atipamezole, a novel alpha 2‐adrenoceptor antagonist‐a randomized, double‐blind cross‐over study in healthy male volunteers.

“…a2-Adrenoceptors are thought to be involved in the regulation of insulin secretion, their activation by clonidine and other agonists leading to suppression of insulin release from pancreatic p-cells (Limone et al, 1983;Metz et al, 1978;Nakaki et al, 1980). The results obtained in humans with selective a2-adrenoceptor antagonists are to some extent confficting.…”

Low dose clonidine premedication accentuates the hyperglycemic response to surgery

“…This finding is in agreement with previous in vivo and in vitro observations showing a direct suppressory influence of clonidine on the pancreatic insulin secretion. 4,11 However, other mechanisms have also been proposed to be responsible for the hyperglycemic action of clonidine, such as increased gluconeogenesis or glycogenolysis, mediated via stimulation of α 2 adrenergic receptors located in the central nervous system. 12 The attenuation of the cortisol response by clonidine in our study is in contrast to the results of previous investigations reporting no modifying effect of clonidine administered at a higher dose (2 or 3 µg·kg -1 ) in unpremedicated patients undergoing abdominal hysterectomy.…”

Duration of analgesia, sensory and motor blockade and intra operative hemodynamic changes caused by intrathecal bupivacaine, bupivacaine plus clonidine and bupivacaine plus dexmedetomidine in spinal anesthesia: prospective, comparative study

“…12 Activation of the receptors in the brain and spinal cord inhibits neuronal firing causing hypotension, bradycardia, sedation, and analgesia. 13 In general, presynaptic activation of the α2-adrenoceptor inhibits the release of norepinephrine terminating the propagation of pain signals. Postsynaptic activation of α2-adrenoceptors in the central nervous system inhibits sympathetic activity and thus can decrease blood pressure and heart rate.…”