Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

Haythorne, Elizabeth; Rohm, Maria; Bunt, Martijn van de; Brereton, Melissa F.; Tarasov, Andrei I.; Blacker, Thomas S.; Sachse, G.; Santos, Mariana Silva dos; Expósito, Raúl Terrón; Davis, Simon; Baba, Otto; Fischer, Román; Duchen, Michael R.; Rorsman, Patrik; MacRae, James I.; Ashcroft, Frances M.

doi:10.1038/s41467-019-10189-x

Cited by 229 publications

(248 citation statements)

References 58 publications

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“…Thus, our experimental approach better mimics the environment that b-cells from overfed, obese, or pre-diabetic patients may be subjected to, thereby avoiding more extreme mTORC1-mediated responses such as glucotoxicity-induced ER stress or glucose starvation-induced autophagy. In a recent study, INS-1 cells exposed to 25 mM glucose for 48 h had increased anaplerosis and flux through the pentose phosphate pathway (Haythorne et al, 2019), which are consistent with our findings. In contrast, oxidative metabolism was reduced and pyruvate metabolism was blocked in INS-1 cells exposed to 25 mM glucose for 48 h, which is the opposite result from what we obtained using 11 mM glucose and shorter exposure.…”

Section: Discussionsupporting

confidence: 93%

Exposure of Pancreatic β-Cells to Excess Glucose Results in Bimodal Activation of mTORC1 and mTOR-Dependent Metabolic Acceleration

et al. 2020

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Chronic exposure of pancreatic b-cells to excess glucose can lead to metabolic acceleration and loss of stimulus-secretion coupling. Here, we examined how exposure to excess glucose (defined here as concentrations above 5 mM) affects mTORC1 signaling and the metabolism of b-cells. Acute exposure to excess glucose stimulated glycolysis-dependent mTORC1 signaling, without changes in the PI3K or AMPK pathways. Prolonged exposure to excess glucose led to hyperactivation of mTORC1 and metabolic acceleration, characterized by higher basal respiration and maximal respiratory capacity, increased energy demand, and enhanced flux through mitochondrial pyruvate metabolism. Inhibition of pyruvate transport to the mitochondria decelerated the metabolism of b-cells chronically exposed to excess glucose and re-established glucose-dependent mTORC1 signaling, disrupting a positive feedback loop for mTORC1 hyperactivation. mTOR inhibition had positive and negative impacts on various metabolic pathways and insulin secretion, demonstrating a role for mTOR signaling in the long-term metabolic adaptation of b-cells to excess glucose.

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Section: Discussionsupporting

confidence: 93%

Exposure of Pancreatic β-Cells to Excess Glucose Results in Bimodal Activation of mTORC1 and mTOR-Dependent Metabolic Acceleration

et al. 2020

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“…However, triggering mechanisms of mitochondrial dysfunction and/ or inflammation in diabetes are still ill-understood. Chronic hyperglycaemia 46 was recently suggested to start a vicious cycle of progressive deterioration of β-cells by impairing insulin secretion and mitochondria. However, our study clearly demonstrated that non-diabetic subjects developed diabetes within 4 years when they showed high levels AhRL and/or MIS in serum (Fig.…”

Section: Discussionmentioning

confidence: 99%

Serum biomarkers from cell-based assays for AhRL and MIS strongly predicted the future development of diabetes in a large community-based prospective study in Korea

Lee

Park

Kang

et al. 2020

Sci Rep

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exposure to environment-polluting chemicals (epc) is associated with the development of diabetes. Many EPCs exert toxic effects via aryl hydrocarbon receptor (AhR) and/or mitochondrial inhibition. Here we investigated if the levels of human exposure to a mixture of EPC and/or mitochondrial inhibitors could predict the development of diabetes in a prospective study, the Korean Genome and epidemiological Study (KoGeS). We analysed AhR ligands (AhRL) and mitochondria-inhibiting substances (MiS) in serum samples (n = 1,537), collected during the 2008 Ansung KoGES survey with a 4-year-follow-up. Serum AhRL, determined by the AhR-dependent luciferase reporter assay, represents the contamination level of AhR ligand mixture in serum. Serum levels of MiS, analysed indirectly by MIS-ATP or MIS-ROS, are the serum MIS-induced mitochondria inhibiting effects on ATP content or reactive oxygen species (ROS) production in the cultured cells. Among 919 normal subjects at baseline, 7.1% developed impaired glucose tolerance (IGT) and 1.6% diabetes after 4 years. At the baseline, diabetic and iGt sera displayed higher AhRL and MiS than normal sera, which correlated with indices of insulin resistance. When the subjects were classified according to ROC cut-off values, fully adjusted relative risks of diabetes development within 4 years were 7.60 (95% CI, 4.23-13.64), 4.27 (95% CI, 2.38-7.64), and 21.11 (95% CI, 8.46-52.67) for AhRL ≥ 2.70 pM, MIS-ATP ≤ 88.1%, and both, respectively. Gender analysis revealed that male subjects with AhRL ≥ 2.70 pM or MIS-ATP ≤ 88.1% showed higher risk than female subjects. High serum levels of AhRL and/or MIS strongly predict the future development of diabetes, suggesting that the accumulation of AhR ligands and/or mitochondrial inhibitors in body may play an important role in the pathogenesis of diabetes.Exposure to multiple environment-polluting chemicals (EPC) is becoming increasingly important to understand the pathogenesis of metabolic disease and diabetes epidemics 1-3 . Many epidemiological studies have shown that high serum concentrations of EPCs are strongly associated with obesity 4 , diabetes 5 , and metabolic syndrome 6 . Many endocrine-disrupting chemicals (EDCs) 7,8 and metabolism-disrupting chemicals (MDCs) 2 are listed as causes of obesity and diabetes, and thus referred to as obesogens and diabetogens. However, establishing the cause-effect relationship between exposure to these chemicals and development of obesity or diabetes in humans have been inconsistent 9 . Among the many reasons behind this, the limitation of the methods estimating the exposure level to EPCs seems to be the most important 10,11 . Humans are exposed to an immense variety of

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“…A number of studies have demonstrated that mitochondrial dysfunction contributes to the deterioration of beta cell function and plays a role in the development of T2D [3,14,[51][52][53]. Deletion of Drp1 from primary mouse beta cells resulted in glucose intolerant mice, with impaired GSIS and abnormal mitochondrial morphology associated with lower expression of MFN1, MFN2 and OPA1 [54,55].…”

Section: Discussionmentioning

confidence: 99%

Mitofusins Mfn1 and Mfn2 are required to preserve glucose-but not incretin- stimulated beta cell connectivity and insulin secretion

Georgiadou

Muralidharan

Martínez

et al. 2020

Preprint

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Background and aims: Mitochondria are highly dynamic organelles, fundamental to cellular energy homeostasis. Mitochondrial metabolism of glucose is essential for the initiation of insulin release from pancreatic beta cells. Whether mitochondrial ultrastructure, and the proteins controlling fission and fusion, are important for glucose recognition are unclear. Mitochondrial fusion is supported by proteins including mitofusin 1 (MFN1), mitofusin 2 (MFN2) and optic atrophy (OPA1), and fission by dynamin-related protein 1 (DRP1). Here, we generated mice with beta cell-selective, adult-restricted deletion of Mfn1 and Mfn2 (bMfn1/2-KO), and explored the impact on insulin secretion and glucose homeostasis in vivo and in vitro. Materials and methods: C57BL/6J mice bearing Mfn1 and Mfn2 alleles with loxP sites, were crossed to animals carrying an inducible Cre recombinase at the Pdx1 locus (Pdx CreERT ). Isolated islets were used for live beta cell fluorescence imaging of cytosolic (Cal-520) or mitochondrial (Pericam) free Ca 2+ concentration and membrane potential (TMRE). Mitochondrial network characteristics were quantified using super resolution fluorescence and transmission electron microscopy. Beta cellbeta cell connectivity was assessed using the Pearson (R) analysis and Monte Carlo simulation in intact mouse islets. Intravital imaging was performed in mice injected with an adeno-associated virus to express the cytosolic Ca 2+ sensor GCaMP6s selectively in beta cells and TMRM to visualise mitochondria using multiphoton microscopy. Results: bMfn1/2-KO mice displayed higher fasting glycaemia than control littermates at 14 weeks (8.6 vs 6.4 mmol/L, p>0.05) and a >five-fold decrease in plasma insulin post-intraperitoneal glucose injection (5-15 min, p<0.0001). Mitochondrial length, and glucose-induced Ca 2+ accumulation, mitochondrial hyperpolarisation and beta cell connectivity were all significantly reduced in bMfn1/2-KO mouse islets. Examined by intravital imaging of the exteriorised pancreas, antiparallel changes in cytosolic Ca 2+ and mitochondrial membrane potential, observed in control animals in vivo, were suppressed after Mfn1/2 deletion. 3 Conclusion: Mitochondrial fusion and fission cycles are essential in the beta cell to maintain normal mitochondrial bioenergetics and glucose sensing both in vitro and in the living mouse. Such cycles may be disrupted in some forms of diabetes to impair mitochondrial function and, consequently, insulin secretion. R Pearson correlation coefficient TMRE Tetramethylrhodamine ethyl ester TMRM Tetramethylrhodamine methyl ester WT Wild-type

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Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

Cited by 229 publications

References 58 publications

Exposure of Pancreatic β-Cells to Excess Glucose Results in Bimodal Activation of mTORC1 and mTOR-Dependent Metabolic Acceleration

Exposure of Pancreatic β-Cells to Excess Glucose Results in Bimodal Activation of mTORC1 and mTOR-Dependent Metabolic Acceleration

Serum biomarkers from cell-based assays for AhRL and MIS strongly predicted the future development of diabetes in a large community-based prospective study in Korea

Mitofusins Mfn1 and Mfn2 are required to preserve glucose-but not incretin- stimulated beta cell connectivity and insulin secretion

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