Evolving insights regarding mechanisms for the inhibition of insulin release by norepinephrine and heterotrimeric G proteins

Abstract

Straub SG, Sharp GW. Evolving insights regarding mechanisms for the inhibition of insulin release by norepinephrine and heterotrimeric G proteins. Am J Physiol Cell Physiol 302: C1687-C1698, 2012. First published April 4, 2012 doi:10.1152/ajpcell.00282.2011.-Norepinephrine has for many years been known to have three major effects on the pancreatic ␤-cell which lead to the inhibition of insulin release. These are activation of K ϩ channels to hyperpolarize the cell and prevent the gating of voltage-dependent Ca 2ϩ channels that increase intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) and trigger release; inhibition of adenylyl cyclases, thus preventing the augmentation of stimulated insulin release by cyclic AMP; and a "distal" effect that occurs downstream of increased [Ca 2ϩ ]i to inhibit exocytosis. All three are mediated by the pertussis toxin (PTX)-sensitive heterotrimeric Gi and Go proteins. The distal inhibitory effect on exocytosis is now known to be due to the binding of G protein ␤␥ subunits to the synaptosomal-associated protein of 25 kDa (SNAP-25) on the soluble NSF attachment protein receptor (SNARE) complex. Recent studies have uncovered two more actions of norepinephrine on the ␤-cell: 1) retardation of the refilling of the readily releasable granule pool after it has been discharged, an action that is mediated by G␣i 1 and/or G␣i2; and 2) inhibition of endocytosis that is mediated by Gz. Of importance also are new findings that G␣o regulates the number of docked granules in the ␤-cell, and that G␣o 2 maintains a tonic inhibitory influence on secretion. The latter provides another explanation as to why PTX, which blocks the effect of G␣o2, was initially called "islet activating protein." Finally, there is clear evidence that overexpression of ␣ 2A-adrenergic receptors in ␤-cells can cause type 2 diabetes. pancreatic ␤-cell; K ϩ channels; adenylyl cyclases; exocytosis; granule pools; endocytosis NOREPINEPHRINE IS RESPONSIBLE for multiple effects in the body as it acts as a hormone after its release from the adrenal medulla along with epinephrine, and as a neurotransmitter when released by the central and sympathetic nervous systems. It has important functions on the cardiovascular system, on muscle, liver, and adipose tissue, and in the control of whole body metabolism. This review, however, focuses on the effects of norepinephrine on the pancreatic ␤-cell and recent advances in our knowledge. Norepinephrine has three major effects on the ␤-cell that lead to the inhibition of insulin release (65,74,102,104). It activates K ϩ channels to hyperpolarize the cell. This prevents or reverses depolarization and the consequent gating of voltage-dependent Ca 2ϩ channels that increase intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and trigger insulin release. It inhibits adenylyl cyclases, thus preventing the augmentation of stimulated insulin release, and it has a "distal" effect that occurs downstream of increased [Ca 2ϩ

Differing Effects when Using Phenylephrine and Norepinephrine To Augment Cerebral Blood Flow after Traumatic Brain Injury in the Immature Brain

“…We did not observe any changes in PaO 2 or FiO 2 requirements during PE or NE infusions. Norepinephrine is a known an inhibitor of insulin release from pancreatic -cells, while phenylephrine has been reported to have little or no influence on blood glucose levels 27,28 . Not surprisingly, we did observe higher blood glucose levels in animals receiving NE infusions compared with animals receiving PE infusions.…”

Catechol-O-methyltransferase association with hemoglobin A1c

“…This process can lead to hyperglycemia, particularly in individuals with diabetes [6]. Dopamine and norepinephrine also participate in glucose metabolism by controlling insulin secretion during glucose stimulation [7], effects that may be reduced in patients with diabetes [8] and obesity [9]. …”

The rs10885122 polymorphism of the adrenoceptor alpha 2A (ADRA2A) gene in Euro-Brazilians with type 2 diabetes mellitus

“…The effects of norepinephrine on pancreatic b-cells are primarily mediated by adrenoceptor alpha 2A, which is encoded by the ADRA2A gene (HGNC: 281; OMIM: 104210) (6). Since norepinephrine inhibits both of the major pathways by which glucose induces biphasic insulin secretion and adrenoceptor alpha 2A is the responsible for these effects, genetic variations of the ADRA2A gene may be candidates for T2D susceptibility (7)(8)(9)(10)(11)(12).…”