A novel insulinotropic mechanism of whole grain‐derived γ‐oryzanol via the suppression of local dopamine D₂ receptor signalling in mouse islet

Background and Purpose

γ‐Oryzanol, derived from unrefined rice, attenuated the preference for dietary fat in mice, by decreasing hypothalamic endoplasmic reticulum stress. However, no peripheral mechanisms, whereby γ‐oryzanol could ameliorate glucose dyshomeostasis were explored. Dopamine D₂ receptor signalling locally attenuates insulin secretion in pancreatic islets, presumably via decreased levels of intracellular cAMP. We therefore hypothesized that γ‐oryzanol would improve high‐fat diet (HFD)‐induced dysfunction of islets through the suppression of local D₂ receptor signalling.

Experimental Approach

Glucose metabolism and regulation of molecules involved in D₂ receptor signalling in pancreatic islets were investigated in male C57BL/6J mice, fed HFD and treated with γ‐oryzanol . In isolated murine islets and the beta cell line, MIN6 , the effects of γ‐oryzanol on glucose‐stimulated insulin secretion (GSIS) was analysed using siRNA for D₂ receptors and a variety of compounds which alter D₂ receptor signalling.

Key Results

In islets, γ‐oryzanol enhanced GSIS via the activation of the cAMP/PKA pathway. Expression of molecules involved in D₂ receptor signalling was increased in islets from HFD‐fed mice, which were reciprocally decreased by γ‐oryzanol. Experiments with siRNA for D₂ receptors and D₂ receptor ligands in vitro suggest that γ‐oryzanol suppressed D₂ receptor signalling and augmented GSIS.

Conclusions and Implications

γ‐Oryzanol exhibited unique anti‐diabetic properties. The unexpected effects of γ‐oryzanol on D₂ receptor signalling in islets may provide a novel; natural food‐based, approach to anti‐diabetic therapy.

DOI: 10.1111/bph.13236

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