Abstract
Islet dysfunction mediated by oxidative and mitochondrial stress contributes to the development of type 1 and 2 diabetes. Acetate and butyrate, produced by gut microbiota via fermentation, have been shown to protect against oxidative and mitochondrial stress in many cell types, but their effect on pancreatic β-cell metabolism has not been studied. Here, human islets and the mouse insulinoma cell line MIN6 were pre-incubated with 1, 2, and 4 mM of acetate or butyrate with and without exposure to the apoptosis inducer and metabolic stressor streptozotocin (STZ). Both short-chain fatty acids (SCFAs) enhanced the viability of islets and β-cells, but the beneficial effects were more pronounced in the presence of STZ. Both SCFAs prevented STZ-induced cell apoptosis, viability reduction, mitochondrial dysfunction, and the overproduction of reactive oxygen species (ROS) and nitric oxide (NO) at a concentration of 1 mM but not at higher concentrations. These rescue effects of SCFAs were accompanied by preventing reduction of the mitochondrial fusion genes MFN, MFN2, and OPA1. In addition, elevation of the fission genes DRP1 and FIS1 during STZ exposure was prevented. Acetate showed more efficiency in enhancing metabolism and inhibiting ROS, while butyrate had less effect but was stronger in inhibiting the SCFA receptor GPR41 and NO generation. Our data suggest that SCFAs play an essential role in supporting β-cell metabolism and promoting survival under stressful conditions. It therewith provides a novel mechanism by which enhanced dietary fiber intake contributes to the reduction of Western diseases such as diabetes.
Highlights
Acetate and butyrate are short-chain fatty acids (SCFAs) and the main large intestinal microbiota fermentation products of soluble fibers
Butyrate had a dose-dependent effect on islet viability; 1 mM butyrate showed a significant increase of 25.7 ± 3.2% (p < 0.001) compared to untreated controls, whereas the higher dosage of 4 mM led to a significant decrease in cell viability by 13.2 ± 4.1% (p < 0.05)
Since acetate and butyrate at a concentration of 1 mM positively influenced islet viability, we performed immunofluorescent staining on human islets to confirm the expression of the two major receptors for SCFAs GPR41 and 43
Summary
Acetate and butyrate are short-chain fatty acids (SCFAs) and the main large intestinal microbiota fermentation products of soluble fibers. SCFAs have been reported to attenuate various inflammatory responses and metabolism disorders [1,2]. SCFAs are reported to promote insulin sensitivity and metabolism in obese individuals by increasing fat oxidation, energy expenditure, and decreasing lipolysis [5,6,7,8]. The effects of SCFA are not restricted to the intestine, as they have been reported to enter the peripheral circulation and to participate in peripheral tissue metabolism. Glucose metabolism has shown to be impacted by acetate and butyrate, there are no studies yet that address the effects of SCFAs on pancreatic islets [14,15]
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