Cannabinoid Receptors are Coupled to Stimulation of Insulin Secretion from Mouse MIN6 β-cells

Abstract

Endocannabinoid lipids are known to exert orexigenic effects via central cannabinoid CB1 and CB2 receptors, which have also been identified in islet endocrine cells. However, there is no consensus on whether the receptors are expressed by β-cells, nor what effect CB1 and CB2 receptor agonists have on insulin secretion. In the current study we have therefore used the mouse MIN6 β-cell line rather than primary islets, which are heterogeneous clusters of endocrine cells. Cannabinoid receptor and diacylglycerol lipase isoform mRNAs were detected in MIN6 cells by RT-PCR and immunocytochemistry was used to identify cannabinoid receptor expression by MIN6 cells. Changes in cyclic AMP and intracellular calcium were measured by immunoassay and microfluorimetry, respectively, and insulin secretion from perifused MIN6 pseudoislets was determined by radioimmunoassay. MIN6 β-cells express the cannabinoid synthesising enzyme diacylglycerol lipase and CB1 and CB2 receptors, which are coupled to inhibition of β-cell cyclic AMP generation and stimulation of intracellular calcium levels. Cannabinoid receptor activation with pharmacological agonists resulted in reversible elevations in insulin secretion at both 2 mM and 20 mM glucose. Synthesis of endocannabinoids by β-cells may provide an additional mechanism for stimulation of insulin secretion through activation of β-cell CB1 and/or CB2 cannabinoid receptors.

Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice

“…While several in vitro studies have found increased insulin secretion following CB1 activation (Bermúdez-Silva et al, 2008; Duvivier et al, 2009; Getty-Kaushik et al, 2009; Juan-Pico et al, 2006; Li et al, 2010; Malenczyk et al, 2013; Matias et al, 2006), others found decreases in insulin release (Anderson et al, 2013; Li et al, 2011; Nakata and Yada, 2008). One potential explanation for these discrepancies is that ECs, which are elevated under obese conditions, act on CB1 and it in turn regulates factors, such as incretins, found only in the whole organism that are absent in isolated islet and β cell cultures.…”

Mitochondria: a possible nexus for the regulation of energy homeostasis by the endocannabinoid system?

“…For example, stimulation of CB1R and/or CB2R activity using selective agonists applied by static incubation has reported to reduce glucose-stimulated insulin secretion from isolated mouse and human islets (66,93). Contrary to these findings, however, there is also evidence that supports the view that cannabinoid receptor activation may act to potentiate insulin secretion when agonists are applied using a dynamic perifusion flow culture system (73). Therefore, further work will be required to establish which of these models better represents modulation by the ECS in vivo.…”

Discovery and characterization of novel smallmolecule agonists of G protein-coupled receptor 119

“…A number of nutrients, hormones, and neurotransmitters have been found to influence glucose-stimulated insulin secretion (GSIS) via G protein-coupled receptors (GPCRs), including GLP-1R, GPR40, GPR120, and CB1/2 [6][7][8][9][10] . Recently, the oleoylethanolamide (OEA)-and lysophosphatidylcholine (LPC)-activated GPR119 was shown to facilitate GSIS.…”