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Br J Pharmacol. 2015 Sep;172(18):4519-4534. doi: 10.1111/bph.13236. Epub 2015 Aug 3.

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

Author information

1
Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), University of the Ryukyus, Okinawa, Japan.
2
The Diabetes and Life-Style Related Disease Center, Tomishiro Central Hospital, Okinawa, Japan.
3
Okinawa Daiichi Hospital, Okinawa, Japan.
4
Tanaka Clinic, Okinawa, Japan.
5
Department of Molecular Anatomy, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
6
Department of Molecular and Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
7
Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
8
Department of Neurosurgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
9
Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Tochigi, Japan.
10
Division of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Osaka, Japan.
11
Institute for Genome Research, University of Tokushima, Tokushima, Japan.
12
Department of Cardio-Diabetes Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.

Abstract

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.

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