A Novel GLP1 Receptor Interacting Protein ATP6ap2 Regulates Insulin Secretion in Pancreatic Beta Cells

Dai, Feihan F.; Bhattacharjee, Ananya; Liu, Ying; Batchuluun, Battsetseg; Zhang, Ming; Wang, Xinye Serena; Huang, Xinyi; Luu, Lemieux; Zhu, Dan; Gaisano, Herbert Y.; Wheeler, Michael B.

doi:10.1074/jbc.m115.648592

Cited by 27 publications

(28 citation statements)

References 69 publications

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“…The fasting plasma samples were collected from these 140 women at the baseline examination (at 6-9 weeks postpartum), all confirmed not to have type 2 diabetes at the baseline exam via the 2 h 75 g OGTT. Details of the SWIFT prospective cohort design and follow-up are published elsewhere [30,[37][38][39][40]. For women who progressed to type 2 diabetes during the 2 years follow-up period (n = 55), termed here as the 'follow-up' time point, the newly diagnosed incident type 2 diabetes was referred to as 'case'.…”

Section: Methodsmentioning

confidence: 99%

“…Plasma samples (n = 3) were subjected to sphingolipid profiling through LC-MS/MS at the Analytical Facility for Bioactive Molecules, SickKids, Toronto. The pancreases (n = 7) were fixed for insulin staining by using the standard protocol [37] of the Centre for Phenogenomics (TCP), Sinai Health System Institute, Toronto. The 40× images of pancreatic slices were produced at TCP and analysed by Aperio ImageScope software package (Wetzlar, Germany).…”

Section: Predictive Analyticsmentioning

confidence: 99%

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The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes

et al. 2019

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Aims/hypothesis Gestational diabetes mellitus (GDM) affects up to 20% of pregnancies, and almost half of the women affected progress to type 2 diabetes later in life, making GDM the most significant risk factor for the development of future type 2 diabetes. An accurate prediction of future type 2 diabetes risk in the early postpartum period after GDM would allow for timely interventions to prevent or delay type 2 diabetes. In addition, new targets for interventions may be revealed by understanding the underlying pathophysiology of the transition from GDM to type 2 diabetes. The aim of this study is to identify both a predictive signature and early-stage pathophysiology of the transition from GDM to type 2 diabetes. Methods We used a well-characterised prospective cohort of women with a history of GDM pregnancy, all of whom were enrolled at 6-9 weeks postpartum (baseline), were confirmed not to have diabetes via 2 h 75 g OGTT and tested anually for type 2 diabetes on an ongoing basis (2 years of follow-up). A large-scale targeted lipidomic study was implemented to analyse~1100 lipid metabolites in baseline plasma samples using a nested pair-matched case-control design, with 55 incident cases matched to 85 non-case control participants. The relationships between the concentrations of baseline plasma lipids and respective follow-up status (either type 2 diabetes or no type 2 diabetes) were employed to discover both a predictive signature and the underlying pathophysiology of the transition from GDM to type 2 diabetes. In addition, the underlying pathophysiology was examined in vivo and in vitro. Results Machine learning optimisation in a decision tree format revealed a seven-lipid metabolite type 2 diabetes predictive signature with a discriminating power (AUC) of 0.92 (87% sensitivity, 93% specificity and 91% accuracy). The signature was highly robust as it includes 45-fold cross-validation under a high confidence threshold (1.0) and binary output, which together minimise the chance of data overfitting and bias selection. Concurrent analysis of differentially expressed lipid metabolite pathways uncovered the upregulation of α-linolenic/linoleic acid metabolism (false discovery rate [FDR] 0.002) and fatty acid biosynthesis (FDR 0.005) and the downregulation of sphingolipid metabolism (FDR 0.009) as being strongly associated with the risk of developing future type 2 diabetes. Focusing specifically on sphingolipids, the downregulation of sphingolipid metabolism

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Section: Methodsmentioning

confidence: 99%

Section: Predictive Analyticsmentioning

confidence: 99%

The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes

et al. 2019

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“…The protocols for quantitative and digital droplet PCR (ddPCR) have been previously described (28,29). The comparative cycle threshold (2 2DDCt ) method was applied to calculate the relative expression of target gene in each sample, relative to control in the quantitative PCR.…”

Section: Quantitative and Digital Droplet Pcrmentioning

confidence: 99%

“…The whole pancreas was stretched in the paraffin block to maximize the pancreatic area acquired on the sections. Sections close to the middle of the pancreata (representing the largest pancreatic area of the pancreas) were stained for insulin and glucagon as previously described (28). Section images were acquired using an Aperio Imagescope (v.12.3.2.8013; Leica Biosystems, Wetzlar, Germany) with the insulin and whole-section area calculated.…”

Section: Immunohistochemistry Immunofluorescence and Confocal Micromentioning

confidence: 99%

GABA promotes β‐cell proliferation, but does not overcome impaired glucose homeostasis associated with diet‐induced obesity

et al. 2018

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γ‐Aminobutyric acid (GABA) administration has been shown to increase β‐cell mass, leading to a reversal of type 1 diabetes in mice. Whether GABA has any effect on β cells of healthy and prediabetic/glucose‐intolerant obese mice remains unknown. In the present study, we show that oral GABA administration (ad libitum) to mice indeed increased pancreatic β‐cell mass, which led to a modest enhancement in insulin secretion and glucose tolerance. However, GABA treatment did not further increase insulin‐positive islet area in high fat diet‐fed mice and was unable to prevent or reverse glucose intolerance and insulin resistance. Mechanistically, whether in vivo or in vitro, GABA treatment increased β‐cell proliferation. In vitro, the effect was shown to be mediated via the GABAA receptor. Single‐cell RNA sequencing analysis revealed that GABA preferentially up‐regulated pathways linked to β‐cell proliferation and simultaneously down‐regulated those networks required for other processes, including insulin biosynthesis and metabolism. Interestingly, single‐cell differential expression analysis revealed GABA treatment gave rise to a distinct subpopulation of β cells with a unique transcriptional signature, including urocortin 3 (ucn3), wnt4, and hepacam2. Taken together, this study provides new mechanistic insight into the proliferative nature of GABA but suggests that β‐cell compensation associated with prediabetes overlaps with, and negates, its proliferative effects.—Untereiner, A., Abdo, S., Bhattacharjee, A., Gohil, H., Pourasgari, F., Ibeh, N., Lai, M., Batchuluun, B., Wong, A., Khuu, N., Liu, Y., Al Rijjal, D., Winegarden, N., Virtanen, C., Orser, B. A., Cabrera, O., Varga, G., Rocheleau, J., Dai, F. F., Wheeler, M. B. GABA promotes β‐cell proliferation, but does not overcome impaired glucose homeostasis associated with diet‐induced obesity. FASEB J. 33, 3968–3984 (2019). http://www.fasebj.org

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“…Finally, PRR expression is described in both human and mouse pancreatic islet cells and can modulate GLP1R signaling and insulin processing to affect insulin secretion. 98 Additionally, PRR expression was reduced in islet cells from humans with diabetes compared with healthy control subjects, raising the possibility of a role for the PRR in insulin processing and/or secretion.…”

Section: Role Of the (Pro)renin Receptor In Glucose And Lipid Metabolismmentioning

confidence: 99%

The (pro)renin receptor: an emerging player in hypertension and metabolic syndrome

Ramkumar

Kohan

2019

Kidney International

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The (pro)renin receptor (PRR) is a multifunctional protein that is expressed in multiple organs. Binding of prorenin/ renin to the PRR activates angiotensin II-dependent and angiotensin II-independent pathways. The PRR is also involved in autophagy and Wnt/ß catenin signaling, functions that are not contingent on prorenin binding. Emerging evidence suggests that the PRR plays an important role in blood pressure regulation and glucose and lipid metabolism. Herein, we review PRR function in health and disease, with particular emphasis on hypertension and the metabolic syndrome.

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A Novel GLP1 Receptor Interacting Protein ATP6ap2 Regulates Insulin Secretion in Pancreatic Beta Cells

Cited by 27 publications

References 69 publications

The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes

The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes

GABA promotes β‐cell proliferation, but does not overcome impaired glucose homeostasis associated with diet‐induced obesity

The (pro)renin receptor: an emerging player in hypertension and metabolic syndrome

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