Endogenous α2A-Adrenoceptor–Operated Sympathoadrenergic Tones Attenuate Insulin Secretion via cAMP/TRPM2 Signaling

Abstract

In pancreatic β-cells, pharmacological concentrations of catecholamines, including adrenaline, have been used to inhibit insulin release and explore the multiple mechanisms involved. However, the significance of these signaling pathways for physiological adrenergic functions in β-cells is largely unknown. In the process of glucose-induced insulin secretion, opening of background current through nonselective cation channels (NSCCs) might facilitate membrane depolarization by closure of the ATP-sensitive K channels. Here, we examined whether physiological insulinostatic adrenaline action is mediated via the transient receptor potential melastatin 2 (TRPM2) channel, a type of NSCC, in β-cells. Results showed that physiological concentrations of adrenaline strongly suppressed glucose-induced and incretin-potentiated cAMP production and insulin secretion and inhibited NSCCs current and membrane excitability via the α2A-adrenoceptor in wild-type mice; however, insulin secretion was not attenuated in TRPM2-knockout (KO) mice. Administration of yohimbine, an α2-adrenoceptor antagonist, failed to affect glucose tolerance in TRPM2-KO mice, in contrast to an improved glucose tolerance in wild-type mice receiving the antagonist. The current study demonstrated that a physiological concentration of adrenaline attenuates insulin release via coupling of α2A-adrenoceptor to cAMP/TRPM2 signaling, thereby providing a potential therapeutic tool to treat patients with type 2 diabetes.

Molecular Regulations and Functions of the Transient Receptor Potential Channels of the Islets of Langerhans and Insulinoma Cells

“…The role of TRPM2 in stimulating insulin secretion by picomolar concentrations of GLP-1 has not been reported. Low concentration of adrenaline inhibits glucose-and GLP-1-induced insulin secretion by activating the α2A adrenoceptor, inhibiting cAMP signaling and thereby inhibiting the TRPM2 channel [54]. Nanomolar concentrations of ghrelin inhibit glucose-induced insulin secretion by inhibiting cAMP formation and thereby reducing the TRPM2 current [55].…”

α2-adrenergic signaling disrupts β cell BDNF-TrkB receptor tyrosine kinase signaling

“…(70, 73,74). α 2 -adrenergic signaling is well-known to antagonize insulin secretion in β cells, largely through heterotrimeric G i/o proteins (49,54,75,76). In tandem with this effect, α 2 -adrenergic signaling blocks glucose stimulated ERK phosphorylation (49), presumably due to membrane hyperpolarization, inhibition of adenylyl cyclase and blockade of calcium influx.…”

“…Endogenous plasma epinephrine concentrations in humans are usually 10-100 pg/ml (77,78), but can increase to 1000 pg/ml (79) during infusions of drugs or epinephrine itself (10 pg/ml = 54.5 pM, 1000 pg/ml = 5.4 nM). Both high (µM) and low (nM) doses of epinephrine have been proposed to inhibit insulin secretion through different mechanisms (54). In the case of nanomolar concentrations of epinephrine, cAMP-TRPM2 channel activity is suppressed, blunting glucose-induced insulin secretion, although sulfonylurea-induced secretion was unaffected.…”

“…We found EGF signaling to ERK1/2 was partially inhibited with epinephrine pre-treatment (Fig 4D), however BDNF-TrkB signaling appeared more sensitive. Recent findings suggest supraphysiologic (µM) doses of epinephrine inhibit insulin secretion by hyperpolarizing the plasma membrane, while more physiologic (nM) doses block cAMP/TRPM2 activation without substantial hyperpolarization (54). We treated MIN6 cells with 5 nM or 5 µM epinephrine and tested the response to BDNF and EGF.…”

Hypoglycemic Emergency in Patients With Diabetic Kidney Disease

“…This single-center observational study indicated that hypoglycemia caused by SU agents likely occurred in elderly patients, in addition to those with CKD. In a SU agent-induced hypoglycemic state, the endogenous physiological concentration of catecholamine could not suppress insulin secretion completely (3). Urinary excretion of secreted insulin decreased according to the CKD progression and the incidence of hypoglycemia increased as CKD stage increased (2).…”