Reversing the chain The mitochondrial electron transport chain is a major part of cellular metabolism and plays key roles in both cellular respiration and the synthesis of critical metabolites. Typically, electrons flow through the electron transport chain in a specific direction, ending up with oxygen as the terminal electron acceptor. Spinelli et al . characterized an alternative path of electron flow through the transport chain, ending with fumarate as the electron acceptor (see the Perspective by Baksh and Finley). This pathway operates under conditions of limited oxygen availability, and the authors have confirmed its activity in vivo in a mouse model, observing that the propensity to use this pathway varied between organs. —YN

Peer review information Nature Metabolism thanks Ping-Chih Ho, Luke O'Neill and the other, anonymous, reviewer for their contribution to the peer review of this work. Primary Handling Editor: Isabella Samuelson, in collaboration with the Nature Metabolism team.

Glucagon-like peptide-1 (GLP-1) shows robust protective effects on β-cell survival and function and GLP-1 based therapies are successfully applied for type-2 diabetes (T2D) and obesity. Another cleavage product of pro-glucagon, Glucagon-like peptide-2 (GLP-2; both GLP-1 and GLP-2 are inactivated by DPP-4) has received little attention in its action inside pancreatic islets. In this study, we investigated GLP-2 production, GLP-2 receptor (GLP-2R) expression and the effect of GLP-2R activation in human islets. Isolated human islets from non-diabetic donors were exposed to diabetogenic conditions: high glucose, palmitate, cytokine mix (IL-1β/IFN-γ) or Lipopolysaccharide (LPS) in the presence or absence of the DPP4-inhibitor linagliptin, the TLR4 inhibitor TAK-242, the GLP-2R agonist teduglutide and/or its antagonist GLP-2(3-33). Human islets under control conditions secreted active GLP-2 (full-length, non-cleaved by DPP4) into the culture media, which was increased by combined high glucose/palmitate, the cytokine mix and LPS and highly potentiated by linagliptin. Low but reproducible GLP-2R mRNA expression was found in all analyzed human islet isolations from 10 donors, which was reduced by pro-inflammatory stimuli: the cytokine mix and LPS. GLP-2R activation by teduglutide neither affected acute or glucose stimulated insulin secretion nor insulin content. Also, teduglutide had no effect on high glucose/palmitate- or LPS-induced dysfunction in cultured human islets but dampened LPS-induced macrophage-dependent IL1B and IL10 expression, while its antagonist GLP-2(3-33) abolished such reduction. In contrast, the expression of islet macrophage-independent cytokines IL6, IL8 and TNF was not affected by teduglutide. Medium conditioned by teduglutide-exposed human islets attenuated M1-like polarization of human monocyte-derived macrophages, evidenced by a lower mRNA expression of pro-inflammatory cytokines, compared to vehicle treated islets, and a reduced production of itaconate and succinate, marker metabolites of pro-inflammatory macrophages. Our results reveal intra-islet production of GLP-2 and GLP-2R expression in human islets. Despite no impact on β-cell function, local GLP-2R activation reduced islet inflammation which might be mediated by a crosstalk between endocrine cells and macrophages.

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