Short chain fatty acids stimulate insulin secretion and reduce apoptosis in mouse and human islets in vitro: Role of free fatty acid receptor 2

Pingitore, Attilio; González-Abuín, Noemi; Ruz‐Maldonado, Inmaculada; Huang, Guo Cai; Frost, Gary; Persaud, Shanta J.

doi:10.1111/dom.13529

Cited by 73 publications

(62 citation statements)

References 37 publications

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“…Butyrate is an important SCFA and was not studied by Pingitore et al, but it was shown in our study to contribute together with acetate to rescue β-cell mitochondrial processes such as respiration, ATP generation, and dynamics when exposed to STZ. This underlines and corroborates previous studies [16,29], demonstrating that SCFAs, which are microbial fermentation products of dietary fibers, can play a role in the prevention, delaying, or treatment of diabetes by making β-cells more resistant to oxidative stress. This is, to the best of our knowledge, a new mechanism by which dietary fiber intake can contribute to lowering of the long list of Western diseases.…”

Section: Discussionsupporting

confidence: 91%

“…Pingitore et al demonstrate that acetate and propionate stimulate insulin secretion via the phospholipase C/protein kinase C pathways and that effects are dependent on GPR43. The anti-apoptotic impact of acetate and propionate are also reported to be GPR43-dependent [16]. Here, we investigate the effect of acetate but also of another important SCFA butyrate in rescuing β-cells compromised by an insulin-producing β-cell specific toxin, STZ, that disturbs mitochondrial metabolism [24].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, acetate and propionate have been reported to improve insulin secretion and to protect against apoptosis in β-cells damaged by the cytokines interferon gamma, tumor necrosis factor alpha, and interleukin 1 beta and the fatty acid sodium palmitate [16,29]. Pingitore et al demonstrate that acetate and propionate stimulate insulin secretion via the phospholipase C/protein kinase C pathways and that effects are dependent on GPR43.…”

Section: Discussionmentioning

confidence: 99%

“…Islets are known to express the SCFA receptors GPR 41 and 43, indicating that SCFAs might be involved in islet-cell metabolism and mitochondrial function [16,17]. Mitochondrial dysfunction of the insulin-producing β-cells might lead to β-cell apoptosis through the generation of free radicals and eventually to metabolic disorder and diabetes [18,19].…”

Section: Introductionmentioning

confidence: 99%

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Acetate and Butyrate Improve β-cell Metabolism and Mitochondrial Respiration under Oxidative Stress

Kuwabara

Haan

et al. 2020

IJMS

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acetate and Butyrate Improve β-cell Metabolism and Mitochondrial Respiration under Oxidative Stress

Kuwabara

Haan

et al. 2020

IJMS

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“…Pretreatment with a high 1 mM sodium acetate largely rescued cell death. Similarly, in mouse islets, 20-h cytokine and palmitate treatment caused apoptosis, which was rescued by either 1 mM sodium acetate or propionate, both of which were very high doses [56]. This direct and indirect evidence clearly demonstrated that SCFAs protect β-cells from the damages caused by free fatty acids (FFAs) and cytokines, and suggested a role of FFA2 in signaling.…”

Section: Acetate and Propionate Protect β-Cells From Cytokine-inducedmentioning

confidence: 75%

Controversial Roles of Gut Microbiota-Derived Short-Chain Fatty Acids (SCFAs) on Pancreatic β-Cell Growth and Insulin Secretion

Liu

Segovia

Yuan

et al. 2020

IJMS

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In the past 15 years, gut microbiota emerged as a crucial player in health and disease. Enormous progress was made in the analysis of its composition, even in the discovery of novel species. It is time to go beyond mere microbiota-disease associations and, instead, provide more causal analyses. A key mechanism of metabolic regulation by the gut microbiota is through the production of short-chain fatty acids (SCFAs). Acting as supplemental nutrients and specific ligands of two G-protein-coupled receptors (GPCRs), they target the intestines, brain, liver, and adipose tissue, and they regulate appetite, energy expenditure, adiposity, and glucose production. With accumulating but sometimes conflicting research results, key questions emerged. Do SCFAs regulate pancreatic islets directly? What is the effect of β-cell-specific receptor deletions? What are the mechanisms used by SCFAs to regulate β-cell proliferation, survival, and secretion? The receptors FFA2/3 are normally expressed on pancreatic β-cells. Deficiency in FFA2 may have caused glucose intolerance and β-cell deficiency in mice. However, this was contrasted by a double-receptor knockout. Even more controversial are the effects of SCFAs on insulin secretion; there might be no direct effect at all. Unable to draw clear conclusions, this review reveals some of the recent controversies.

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Interorgan crosstalk in pancreatic islet function and pathology

Evans

Wei

2022

FEBS Letters

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Pancreatic b cells secrete insulin in response to glucose, a process that is regulated at multiple levels, including a network of input signals from other organ systems. Impaired islet function contributes to the pathogenesis of type 2 diabetes mellitus (T2DM), and targeting inter-organ communications, such as GLP-1 signalling, to enhance b-cell function has been proven to be a successful therapeutic strategy in the last decade. In this review, we will discuss recent advances in inter-organ communication from the metabolic, immune and neural system to pancreatic islets, their biological implication in normal pancreas endocrine function and their role in the (mal)adaptive responses of islet to nutrition-induced stress.

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Short chain fatty acids stimulate insulin secretion and reduce apoptosis in mouse and human islets in vitro: Role of free fatty acid receptor 2

Abstract: Our results indicate that FFAR2 directly mediates both the stimulatory effects of SA and SP on insulin secretion and their protection against islet apoptosis. We have also shown that SCFA coupling in islets occurs via Gq-coupled intracellular signalling.

Cited by 73 publications

References 37 publications

Acetate and Butyrate Improve β-cell Metabolism and Mitochondrial Respiration under Oxidative Stress

Acetate and Butyrate Improve β-cell Metabolism and Mitochondrial Respiration under Oxidative Stress

Controversial Roles of Gut Microbiota-Derived Short-Chain Fatty Acids (SCFAs) on Pancreatic β-Cell Growth and Insulin Secretion

Interorgan crosstalk in pancreatic islet function and pathology

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