Targeting Mitochondrial Calcium Uptake with the Natural Flavonol Kaempferol, to Promote Metabolism/Secretion Coupling in Pancreatic β-cells.

Flavien Bermont,Christian Chabert,Marine R-C Kraus,Jerome N Feige,Guillaume Jacot,Aurelie Hermant,Romy Benninga,Jaime Santo-Domingo,Umberto De Marchi

doi:10.3390/nu12020538

Flavien Bermont, Christian Chabert + Show 7 more

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https://doi.org/10.3390/nu12020538

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Abstract

Pancreatic β-cells secrete insulin to lower blood glucose, following a meal. Maintenance of β-cell function is essential to preventing type 2 diabetes. In pancreatic β-cells, mitochondrial matrix calcium is an activating signal for insulin secretion. Recently, the molecular identity of the mitochondrial calcium uniporter (MCU), the transporter that mediates mitochondrial calcium uptake, was revealed. Its role in pancreatic β-cell signal transduction modulation was clarified, opening new perspectives for intervention. Here, we investigated the effects of a mitochondrial Ca2+-targeted nutritional intervention strategy on metabolism/secretion coupling, in a model of pancreatic insulin-secreting cells (INS-1E). Acute treatment of INS-1E cells with the natural plant flavonoid and MCU activator kaempferol, at a low micromolar range, increased mitochondrial calcium rise during glucose stimulation, without affecting the expression level of the MCU and with no cytotoxicity. Enhanced mitochondrial calcium rises potentiated glucose-induced insulin secretion. Conversely, the MCU inhibitor mitoxantrone inhibited mitochondrial Ca2+ uptake and prevented both glucose-induced insulin secretion and kaempferol-potentiated effects. The kaempferol-dependent potentiation of insulin secretion was finally validated in a model of a standardized pancreatic human islet. We conclude that the plant product kaempferol activates metabolism/secretion coupling in insulin-secreting cells by modulating mitochondrial calcium uptake.

Highlights

Targeting pancreatic β-cells is a promising strategy to treat diabetes, due to the crucial role of the pancreatic β-cells in the pathogenesis of both type 1 and type 2 diabetes
To assess the possibility of targeting the mitochondrial Ca2+ in pancreatic β-cell metabolism/secretion coupling, the expression level of mitochondrial calcium uniporter (MCU) protein was investigated in a model of glucose-sensitive pancreatic β-cells, named INS-1E β-cells [17]
We checked the effect of the acute treatment with kaempferol on HeLa cells, a system in which mitochondrial calcium uptake is activated by that polyphenol [10]

Summary

Introduction

Targeting pancreatic β-cells is a promising strategy to treat diabetes, due to the crucial role of the pancreatic β-cells in the pathogenesis of both type 1 and type 2 diabetes. Preservation, expansion, or improved function of β-cells are current approaches for targeting this cell type in the management of diabetes. Within this framework, targeting mitochondrial Ca2+ in pancreatic β-cells is emerging as an innovative and promising strategy for diabetic patients. Mitochondrial matrix Ca2+ has been demonstrated to be an activating signal for insulin secretion [2]. Mitochondrial Ca2+ rise has been suggested to contribute to the improvement of glucose-stimulated insulin secretion by sulfonylurea compounds in type 2 diabetic patients [4]. Genetic evidences have recently demonstrated the high impact of mitochondrial Ca2+ uptake for pancreatic β-cell signal transduction and insulin secretion [5,6,7]

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