The Expression of Aldolase B in Islets Is Negatively Associated With Insulin Secretion in Humans

Gerst, Felicia; Jaghutriz, Benjamin Assad; Staiger, Harald; Schulte, Anke M.; Lorza‐Gil, Estela; Kaiser, G; Panse, Madhura; Haug, Sieglinde; Heni, Martin; Schütz, M; Stadion, Mandy; Schürmann, Annette; Marzetta, Flavia; Ibberson, Mark; Sipos, Bence; Fend, Falko; Fleming, Thomas; Nawroth, Peter P.; Königsrainer, Alfred; Nadalin, Silvio; Wagner, Silvia; Fritsche, Andreas; Richter, Daniela; Solimena, Michele; Häring, Hans‐Ulrich; Ullrich, Susanne; Wagner, Róbert

doi:10.1210/jc.2018-00791

Cited by 48 publications

(33 citation statements)

References 41 publications

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“…In our study, aldolase B was the most upregulated protein in diabetic βV59M islets, increasing >65-fold. Transcriptomics indicates that aldolase B mRNA is also highly upregulated in rat islets cultured at high glucose 40 and in β-cells of T2D subjects 42,43 , where it correlates positively with HbA1c and negatively with insulin release 43 . In hepatocytes, aldolase A mainly participates in glycolysis, whereas aldolase B is principally involved in gluconeogenesis 44 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…5f ). Increased expression of Aldob and Slc5a10 is associated with decreased insulin secretion 37 , 56 , suggesting their contribution to impaired GSIS. Importantly, upregulation of Aldob, Slc5a10, and Wnt5b mRNAs is correlated with diabetes 37 , 56 – 58 .…”

Section: Discussionmentioning

confidence: 99%

“…Increased expression of Aldob and Slc5a10 is associated with decreased insulin secretion 37 , 56 , suggesting their contribution to impaired GSIS. Importantly, upregulation of Aldob, Slc5a10, and Wnt5b mRNAs is correlated with diabetes 37 , 56 – 58 . These results agree with our previous findings that the CCR4–NOT complex is involved in regulation of energy metabolism genes 15 – 18 .…”

Section: Discussionmentioning

confidence: 99%

Loss of β-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA deadenylation

et al. 2020

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Pancreatic β-cells are responsible for production and secretion of insulin in response to increasing blood glucose levels. Defects in β-cell function lead to hyperglycemia and diabetes mellitus. Here, we show that CNOT3, a CCR4-NOT deadenylase complex subunit, is dysregulated in islets in diabetic db/db mice, and that it is essential for murine β cell maturation and identity. Mice with β cell-specific Cnot3 deletion (Cnot3βKO) exhibit impaired glucose tolerance, decreased β cell mass, and they gradually develop diabetes. Cnot3βKO islets display decreased expression of key regulators of β cell maturation and function. Moreover, they show an increase of progenitor cell markers, β cell-disallowed genes, and genes relevant to altered β cell function. Cnot3βKO islets exhibit altered deadenylation and increased mRNA stability, partly accounting for the increased expression of those genes. Together, these data reveal that CNOT3-mediated mRNA deadenylation and decay constitute previously unsuspected post-transcriptional mechanisms essential for β cell identity.

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“…Thus, the observation in our data that EGA surgery increased Gck expression ( p < 0.05) and decreased Fbp2 (Table S4) may explain the reduction in beta cell sensitivity at low glucose observed in EGA-ob mice. Additionally, it has been demonstrated that expression of AldoB was negatively correlated with insulin secretion in pancreatic islets [87] and that increased expression of AldoB in murine islets induced impaired GSIS and ATP production [88] . AldoB was the most down-regulated gene in islets from EGA-ob mice suggesting a possible role for this enzyme in the regulation of beta cell function in the context of surgery.…”

Section: Discussionmentioning

confidence: 99%

A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice

et al. 2020

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Background Bariatric surgery is an effective treatment for type 2 diabetes. Early post-surgical enhancement of insulin secretion is key for diabetes remission. The full complement of mechanisms responsible for improved pancreatic beta cell functionality after bariatric surgery is still unclear. Our aim was to identify pathways, evident in the islet transcriptome, that characterize the adaptive response to bariatric surgery independently of body weight changes. Methods We performed entero-gastro-anastomosis (EGA) with pyloric ligature in leptin-deficient ob/ob mice as a surrogate of Roux-en-Y gastric bypass (RYGB) in humans. Multiple approaches such as determination of glucose tolerance, GLP-1 and insulin secretion, whole body insulin sensitivity, ex vivo glucose-stimulated insulin secretion (GSIS) and functional multicellular Ca 2+ -imaging, profiling of mRNA and of miRNA expression were utilized to identify significant biological processes involved in pancreatic islet recovery. Findings EGA resolved diabetes, increased pancreatic insulin content and GSIS despite a persistent increase in fat mass, systemic and intra-islet inflammation, and lipotoxicity. Surgery differentially regulated 193 genes in the islet, most of which were involved in the regulation of glucose metabolism, insulin secretion, calcium signaling or beta cell viability, and these were normalized alongside changes in glucose metabolism, intracellular Ca 2+ dynamics and the threshold for GSIS. Furthermore, 27 islet miRNAs were differentially regulated, four of them hubs in a miRNA-gene interaction network and four others part of a blood signature of diabetes resolution in ob/ob mice and in humans. Interpretation Taken together, our data highlight novel miRNA-gene interactions in the pancreatic islet during the resolution of diabetes after bariatric surgery that form part of a blood signature of diabetes reversal. Funding European Union's Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking (RHAPSODY), INSERM, Société Francophone du Diabète, Institut Benjamin Delessert, Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1), Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA 16/0005485) project grants, National Science Foundation (310030–188447), Fondation de l'Avenir.

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The Expression of Aldolase B in Islets Is Negatively Associated With Insulin Secretion in Humans

Abstract: Our analyses suggest that increased ALDOB expression in human islets is associated with lower insulin secretion.

Cited by 48 publications

References 41 publications

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

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

Loss of β-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA deadenylation

A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice

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