Role of vesicular monoamine transporter type 2 in rodent insulin secretion and glucose metabolism revealed by its specific antagonist tetrabenazine

Abstract

Despite different embryological origins, islet b-cells and neurons share the expression of many genes and display multiple functional similarities. One shared gene product, vesicular monoamine transporter type 2 (VMAT2, also known as SLC18A2), is highly expressed in human b-cells relative to other cells in the endocrine and exocrine pancreas. Recent reports suggest that the monoamine dopamine is an important paracrine and/or autocrine regulator of insulin release by b-cells. Given the important role of VMAT2 in the economy of monoamines such as dopamine, we investigated the possible role of VMAT2 in insulin secretion and glucose metabolism. Using a VMAT2-specific antagonist, tetrabenazine (TBZ), we studied glucose homeostasis, insulin secretion both in vivo and ex vivo in cultures of purified rodent islets. During intraperitoneal glucose tolerance tests, control rats showed increased serum insulin concentrations and smaller glucose excursions relative to controls after a single intravenous dose of TBZ. One hour following TBZ administration we observed a significant depletion of total pancreas dopamine. Correspondingly, exogenous L-3,4-dihydroxyphenylalanine reversed the effects of TBZ on glucose clearance in vivo. In in vitro studies of rat islets, a significantly enhanced glucose-dependent insulin secretion was observed in the presence of dihydrotetrabenazine, the active metabolite of TBZ. Together, these data suggest that VMAT2 regulates in vivo glucose homeostasis and insulin production, most likely via its role in vesicular transport and storage of monoamines in b-cells.

Altered serotonin (5-HT) 1D and 2A receptor expression may contribute to defective insulin and glucagon secretion in human type 2 diabetes

“…*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. [31] and either metabolized by monoamine oxidases [32] or again loaded into insulin granules through vesicular monoamine transporters [3]. Therefore, the local concentration of 5-HT in the intra islet milieu most likely varies, but could potentially be high immediately after acute insulin release.…”

“…Monoaminergic neurotransmitters stored within the islets have been proposed to regulate glucose stimulated insulin secretion (GSIS) in a paracrine and/or autocrine fashion in rodents [2,3]. This circuitry of monoamines most likely receives input from sympathetic and parasympathetic innervation of islets, which at least in rodents play an important role in regulation of hormone secretion as rodent islets are richly supplied with both cholinergic and adrenergic axons [4].…”

In vivo imaging of vesicular monoamine transporter 2 in pancreas using an 18F epoxide derivative of tetrabenazine

“…The new VMAT2 ligands are likely bound to the beta cells. Although, the possible correlation between VMAT2 ligand binding of beta cells in the pancreas and total beta cell mass has been reported, but their quantitative relationship has not been fully established [21, 23]. We, and other researchers in this exciting field, are generating additional data on the relationship between VMAT2 binding and beta cell mass.…”

“…1) has been successfully applied in the diagnosis of Parkinson’s disease for the past decade [18–20]. Recently, high level of VMAT2 gene expression in the pancreas was detected [21–23]. The feasibility of using [ 11 C](+)-DTBZ, a VMAT2 ligand, for PET imaging of the pancreas in monkeys and humans has also been reported [3, 21, 24, 25].…”

Localization and Expression of VMAT2 Aross Mammalian Species

“…The discovery of VMAT2 expression in endocrine pancreas occasioned considerable efforts to localize VMAT2 in the pancreas and to employ VMAT2 as a marker for beta cell mass in human patients (Bormans, 2010; Ichise & Harris, 2010; Kung et al, 2008; Normandin et al, 2012; Saisho et al, 2008). Unfortunately, some confusion arose as to the appropriateness of TBZ for beta cell imaging when attempts to optimize this procedure in rodent models led to conflicting results (Freeby et al, 2008; Ichise & Harris, 2010; Raffo et al, 2008; Souza et al, 2006). We have since clarified these, to some extent, by reporting a survey of those mammalian species that as adults do or do not express VMAT2 and/or VMAT2 mRNA in beta cells of the pancreas (Fig.…”