β Cell–specific deletion of Zfp148 improves nutrient-stimulated β cell Ca2+ responses

Emfinger, Christopher H.; Klerk, Eleonora de; Schueler, Kathryn L.; Rabaglia, Mary E.; Stapleton, Donnie S.; Simonett, Shane P.; Mitok, Kelly A.; Wang, Ziyue; Paulo, João A.; Yu, Qinq; Cardone, Rebecca L.; Foster, Harris E.; Lewandowski, Sophie L.; Perales, José C.; Kendziorski, Christina; Gygi, Steven P.; Kibbey, Richard G.; Keller, Mark P.; Hebrok, Matthias; Merrins, Matthew J.; Attie, Alan D.

doi:10.1172/jci.insight.154198

Cited by 5 publications

(10 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TRRUST transcription factor motif database and ARCHS4 Tissue signature database (C) as well as pathway enrichments for the Elsevier Pathway database and KEGG 2021 Human pathway database (D) (-log 10 (p-values)), for the highly correlated (red) and anticorrelated (blue) proteins to 8 A D metric. Databases were queried using Enrichr (39, 40).…”

Section: Resultsmentioning

confidence: 99%

“…Our previous genetic screen for drivers of islet function observed that many of the quantitative trait loci (QTL) appearing for ex vivo islet traits had effects driven by the SNPs from the wild-derived strains as opposed to the traditional inbred groups (13). The QTL mediated by Zfp148 , which drives Ca 2+ and insulin secretion phenotypes in beta cells (38), also had strong strain effects from wild-derived strains (13).…”

Section: Discussionmentioning

confidence: 99%

“…8 mM glucose was first used to survey glycolytic responses, because we have observed that several strains reliably oscillate at this glucose concentration. Furthermore, this glucose concentration remains close to the stimulatory threshold, thus reducing the possibility of oscillations plateauing if islet Ca 2+ responses were left-shifted in any strains (23, 39, 40). We then added QLA as fuel to engage mitochondrial metabolism and paracrine signaling from α-cells, providing a survey of α-to-β cell communication in the islet (6, 7, 41, 42).…”

Section: Discussionmentioning

confidence: 99%

“…Of note, the studies were done in acute slice culture, in only one sex, and the frequencies detected did not resemble the (at least for the C57 lines) the slow oscillations observed in isolated islets from these inbred strains (e.g. Figure 1, (18,38)).…”

Section: Strains Segregate By Their Phylogenetic Originsmentioning

confidence: 93%

“…Isolated islets were kept in RPMI-based medium (see above) overnight prior to perifusion, which was performed as previously described, with minor modifications (38, 73). Islets were equilibrated in 2 mM glucose for 55 minutes, after which 100 μL fractions were collected every minute with the perifusion solutions set at a flow rate of 100 μL/min.…”

Section: Methodsmentioning

confidence: 99%

See 4 more Smart Citations

Novel regulators of islet function identified from genetic variation in mouse islet Ca²⁺oscillations

Emfinger

Clark

Schueler

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca2+ into β-cells triggers insulin release. Since genetics strongly influences variation in islet secretory responses, we surveyed islet Ca2+ dynamics in eight genetically diverse mouse strains. We found high strain variation in response to four conditions: 1) 8 mM glucose; 2) 8 mM glucose plus amino acids; 3) 8 mM glucose, amino acids, plus 10nM GIP; and 4) 2 mM glucose. These stimuli interrogate β-cell function, α-cell to β-cell signaling, and incretin responses. We then correlated components of the Ca2+ waveforms to islet protein abundances in the same strains used for the Ca2+ measurements. To focus on proteins relevant to human islet function, we identified human orthologues of correlated mouse proteins that are proximal to glycemic-associated SNPs in human GWAS. Several orthologues have previously been shown to regulate insulin secretion (e.g. ABCC8, PCSK1, and GCK), supporting our mouse-to-human integration as a discovery platform. By integrating these data, we nominated novel regulators of islet Ca2+ oscillations and insulin secretion with potential relevance for human islet function. We also provide data for identifying appropriate mouse strains in which to study these regulators.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Strains Segregate By Their Phylogenetic Originsmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Novel regulators of islet function identified from genetic variation in mouse islet Ca²⁺oscillations

Emfinger

Clark

Schueler

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Recent drug development of dorzagliatin, a new glucokinase activator, with the potential to treat Type 2 diabetes: A review study

Jiang,

Wang,

Dong

et al. 2024

Journal of Diabetes

View full text Add to dashboard Cite

Type 2 diabetes mellitus (T2DM) is a complicated disease related to metabolism that results from resistance to insulin and sustained hyperglycemia. Traditional antidiabetic drugs cannot meet the demand of different diabetes patients for reaching the glycemic targets; thus, the identification of new antidiabetic drugs is urgently needed for the treatment of T2DM to enhance glycemic control and the prognosis of patients suffering from T2DM. Recently, glucokinase (GK) has attracted much attention and is considered to be an effective antidiabetic agent. Glucokinase activators (GKA) represented by dorzagliatin could activate GK and mimic its function that triggers a counter‐regulatory response to blood glucose changes. Dorzagliatin has shown great potential for glycemic control in diabetic patients in a randomized, double‐blind, placebo‐controlled Phase 3 trial (SEED study) and had a favorable safety profile and was well tolerated (DAWN study). In the SEED study, dorzagliatin significantly reduced glycosylated hemoglobin (HbA1c) by 1.07% and postprandial blood glucose by 2.83 mol/L, showing the great potential of this drug to control blood glucose in diabetic patients, with good safety and good tolerance. An extension of the SEED study, the DREAM study, confirmed that dorzagliatin monotherapy significantly improved 24‐h glucose variability and increased time in range (TIR) to 83.7% over 46 weeks. Finally, the clinical study of dorzagliatin combined with metformin (DAWN study) confirmed that dorzagliatin could significantly reduce HbA1c by 1.02% and postprandial blood glucose by 5.45 mol/L. The current review summarizes the development of GK and GKA, as well as the prospects, trends, applications, and shortcomings of these treatments, especially future directions of clinical studies of dorzagliatin.image

show abstract