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Aims/hypothesis: This study aimed to examine if beta-aminoisobutyric acid (BAIBA) is (i) secreted by skeletal muscle in humans during exercise, (ii) associated with insulin secretory function in vivo, and (iii) directly linked with acute glucose-mediated insulin release by pancreatic beta cells in vitro. Methods: Following 2-weeks of single-leg immobilization, plasma BAIBA concentrations were measured in the brachial artery and the femoral veins of each leg in healthy male subjects, at rest and during two-legged dynamic knee-extensor exercise. During a 2-h hyperglycamic clamp, insulin secretory function and levels of plasma BAIBA were assessed in non-diabetic individuals, non-diabetic individuals following 24-h hyperglycemia and patients with type 2 diabetes. Direct effects of BAIBA on acute glucose-mediated insulin release were probed in INS-1832/3 cells under normal and ‘diabetes-like’ conditions. Finally, the effect of BAIBA on mitochondrial function was assessed in INS-1832/3 cells using extracellular flux analysis. Results: (i) BAIBA is released from skeletal muscle at rest and during exercise under healthy conditions but is suppressed during exercise following leg immobilization, (ii) plasma BAIBA concentrations inversely associate with insulin secretory function in humans, (iii) BAIBA lowers mitochondrial energy metabolism in INS-1 832/3 cells in parallel with decreased insulin secretionConclusion/interpretation: BAIBA is a myokine released by skeletal muscle during exercise and indepedantly alters the triggering pathway of insulin secretion in cultured INS-1832/3 cells.

Antiretroviral therapy (ART), a life-saving treatment strategy in HIV/AIDS, has been implicated in increasing the risk of type 2 diabetes mellitus (T2DM). Direct damaging effects on beta-cell function and survival by either non-nucleoside reverse transcriptase inhibitors (NNRTIs) or nucleoside/tide reverse transcriptase inhibitors (NRTIs) may predispose individuals to developing T2DM or if already type 2 diabetic, to insulin dependency. The aim of this study was to investigate the effects of the NNRTIs efavirenz, rilpivirine and doravirine, and the NRTIs tenofovir disoproxil fumarate and emtricitabine, on beta-cell function and survival while suggesting potential cellular and molecular mechanism(s). Our results show contrasting effects within the NNRTI class as doravirine did not cause damaging effects in the rat insulinoma INS-1E cells while efavirenz and rilpivirine reduced insulin release and cell viability, and induced apoptosis in INS-1E cells. Additionally, efavirenz and rilpivirine increased ROS generation, disrupted Δψm and upregulated the mRNA and protein expression of CHOP and GRP78, key markers of endoplasmic reticulum stress. In silico docking studies predict a possible inhibition of the mitochondrial ATP synthase by rilpivirine. On the contrary, both the NRTIs tenofovir disoproxil fumarate and emtricitabine did not affect GSIS, cell viability and apoptosis/necrosis levels in INS-1E cells. The deleterious effects observed in beta-cells exposed to efavirenz or rilpivirine may be, at least partially, mediated by oxidative stress and mitochondrial toxicity. These findings provide potential mechanism(s) by which efavirenz and rilpivirine may contribute to the pathogenesis of T2DM and the progression of T2DM to insulin dependency in HIV-infected type 2 diabetics., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The islets of Langerhans harbor multiple endocrine cell types that continuously respond to circulating nutrient levels in order to adjust their secretion of catabolic and anabolic hormones. Stimulus-secretion coupling in these cells is largely of metabolic nature; that is, metabolism of nutrient fuels yields signals that trigger and amplify secretion of hormones. Hence, metabolism in this micro-organ is in a major way in control of whole-body metabolism. Therefore, insights into islet metabolism are critical to understand how secretion of insulin is regulated and why it is perturbed in type 2 diabetes. Metabolomics aims at characterizing a wide spectrum of metabolites in cells, tissues and body fluids. For this reason, this technique is well suited to supply information on stimulus-secretion coupling. Here, we summarize metabolomics studies in islets and β-cells, highlight important discoveries that would have been difficult to make without this technology but also raise awareness of challenges and bottlenecks that curtail its use in metabolic research., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Pancreatic β-cells apoptosis and dysfunction induced by glucose toxicity were attributed to the formation of excess oxidative damage. Some studies have found that hydroxysafflor yellow A has strong effects to scavenge oxidative stress and inhibit apoptosis. In order to explore the influence of HSYA on oxidative stress induced by high glucose and the potential mechanisms, we set up a high glucose damage model and induced oxidative stress in INS-1 rat insulinoma cells. N-acetylcysteine was added as a group of oxidative stress scavenger. After 72 h of cultivation, the related indexes of oxidative stress (reactive oxygen species, catalase, glutathione peroxidase, lipid peroxidation, and superoxide dismutase), apoptosis (caspase3, parp) and the function of glucose stimulated insulin secretion were determined. In addition, the signaling pathway proteins of C-Jun NH2 -terminal kinases (JNK), phosphorylated JNK, C-jun, phosphorylated C-jun were evaluated. Fluorescence microscopy, qRT-PCR, western blotting were the main methods used in the experiment. Our results showed that hydroxysafflor yellow A reduced pancreatic β-cells apoptosis by attenuating oxidative damage, and JNK/c-Jun signaling pathway was involved. It indicated a significant mechanism for the positive impacts of HSYA on oxidative stress induced by high glucose, and provide important basis for using HSYA in diabetic prevention and therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Glucose can acutely reduce mitochondrial glutathione redox state in rat islets. However, whether glucose-stimulated mitochondrial glutathione redox state relates to glucose-stimulated insulin secretion (GSIS) remains unknown. We used genetically encoded redox-sensitive GFPs to target the mitochondria to monitor glutathione redox changes during GSIS in rat pancreatic β-cells. The results showed that mitochondrial glutathione was more reduced during GSIS, whereas inhibition of this glutathione reduction impaired insulin secretion. In isolated rat pancreatic islets glutathione reduction in mitochondria and the first phase of GSIS were concurrence at the early stage of glucose-stimulation. Our results suggest that the glucose-induced glutathione reduction in mitochondria is primarily required for the first phase of GSIS., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Live cell imaging has revealed that calcium ions (Ca(2+)) pass in and out of many cellular organelles. However, technical hurdles have limited measurements of Ca(2+) in acidic organelles, such as endosomes. Although evidence hints that endosomes play a role in Ca(2+) signaling, direct measurements within endosomal lumina represent one of the final frontiers in organelle imaging. To measure Ca(2+) in a TiVAMP-positive endosome sub-population, the pH-resistant ratiometric Ca(2+) biosensor GEM-GECO1 and the ratiometric pH biosensor mKeima were used. A positive correlation between acidic endosomal pH and higher Ca(2+) was observed within these Rab5a- and Rab7-positive compartments. Ca(2+) concentration in most endosomes was estimated to be below 2μM, lower than Ca(2+) levels in several other intracellular stores, indicating that endosomes may take up Ca(2+) during physiological stimulation. Indeed, endosomes accumulated Ca(2+) during glucose-stimulation, a condition where endosomal pH did not change. Our biosensors permitted the first measurements revealing a role for endosomes in cellular Ca(2+) homeostasis during physiological stimulation., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)