Pyruvate kinase modulates the link between β‐cell fructose metabolism and insulin secretion

The FASEB Journal, Год журнала: 2025, Номер 39(7)

Опубликована: Март 28, 2025

Abstract The intricate link between glucose metabolism, ATP production, and glucose‐stimulated insulin secretion (GIIS) in pancreatic β‐cells has been well established. However, the effects of other digestible monosaccharides on this mechanism remain unclear. This study examined interaction intracellular fructose metabolism GIIS using MIN6‐K8 β‐cell lines mouse islets. Fructose at millimolar concentrations potentiated presence stimulatory levels (8.8 mM) glucose. potentiation was dependent sweet taste receptor‐activated phospholipase Cβ2 (PLCβ2) signaling. Concurrently, metabolic tracing 13 C‐labeled conjunction with biochemical analyses demonstrated that blunted glucose‐induced increase ATP/ADP ratio. Mechanistically, is substantially converted to 1‐phosphate (F1P) expense ATP. F1P directly inhibited PKM2 (pyruvate kinase M2), thereby reducing later glycolytic flux used for production. Remarkably, F1P‐mediated inhibition counteracted by TEPP‐46, a small‐molecule activator. TEPP‐46 restored ratio, leading enhancement fructose‐potentiated cells, normal islets, fructose‐unresponsive diabetic These findings reveal an antagonistic interplay β‐cells, highlighting as crucial regulator broadening our understanding relationship fuel secretion.

Язык: Английский

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Do We Need a New Hypothesis for KATP Closure in β-Cells? Distinguishing the Baby From the Bathwater

Diabetes, Год журнала: 2024, Номер 73(6), С. 844 - 848

Опубликована: Апрель 19, 2024

Язык: Английский

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Role of hypoxia-inducible factor 1 in type 1 diabetes

Trends in Pharmacological Sciences, Год журнала: 2024, Номер 45(9), С. 798 - 810

Опубликована: Авг. 9, 2024

Язык: Английский

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The Synergistic Impact of Glycolysis, Mitochondrial OxPhos, and PEP Cycling on ATP Production in Beta Cells

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(4), С. 1454 - 1454

Опубликована: Фев. 10, 2025

Pancreatic beta cells regulate insulin secretion in response to glucose by generating ATP, which modulates ATP-sensitive potassium channels (KATP) channel activity and Ca2+ dynamics. We present a model of ATP production pancreatic cells, focusing on dynamics within the bulk cytosol, submembrane region, microdomains near KATP channels. is generated through glycolysis, mitochondrial oxidative phosphorylation (OxPhos), glycolytic pyruvate kinase-mediated phosphoenolpyruvate (PEP) production, supported PEP cycling between mitochondria cytosol. The examines relation oscillations, elucidating their interdependent Our findings demonstrate that both OxPhos PEP-mediated contribute substantially cellular levels. Specifically, glycolysis are crucial for initial (first-phase) increase subplasmalemmal effectively “filling up” pool cells. In second phase, coordinated pathways enables cost-effective fine-tuning levels, with localized effects microdomains. This addresses clarifies recent debate regarding mechanisms sufficient concentrations achieved close glucose-stimulated offering novel insights into regulation energy activity.

Язык: Английский

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The effects of free fatty acid-free bovine serum albumin and palmitate on pancreatic β-cell function

Islets, Год журнала: 2025, Номер 17(1)

Опубликована: Март 16, 2025

Pancreatic β-cells release insulin in response to fluctuations plasma glucose, amino acids, and free fatty acids (FFA). Clonal cell lines isolated islets serve as essential early models for studying the impact of nutrients evaluating potential therapies address β-cell dysfunction. Acute chronic changes FFA levels have been shown positive negative effects on function both vivo vitro. A key problem comparing islet lipid studies from different laboratories is that a wide variety methods are used isolate, culture, assess function. The current study compares bovine serum albumin (BSA) types preparation clonal 832/13 cells human islets. Changing percentage culture conditions when using FFA-free BSA can negatively affect compared regular BSA. Preparing palmitate with rescue secretion treating alone Different preparing unique secretion. Overall, interpreting lipids complicated by number variables need be controlled experiments.

Язык: Английский

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Diuretics: a review of the pharmacology and effects on glucose homeostasis

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Март 28, 2025

Thiazides, thiazide-like and loop diuretics are commonly prescribed to manage hypertension heart failure. The main mechanism of action these involve inhibition Na+ reabsorption in the kidneys, leading increased urine production. While effective, diuretics, particularly hydrochlorothiazide, have been linked altered glucose metabolism other metabolic issues. These disruptions fuel homeostasis not clearly related their primary fluid management, raising concerns for patients with syndrome, which high blood pressure coexists obesity, insulin resistance, intolerance dyslipidemia. In this review, we conducted an extensive examination existing literature on classes covering publications from late 1950s present. Our objective was investigate origins, development current understanding widely recognized association between use general potential negative impact homeostasis. We focused clinical experimental evidence most diuretics: chlorthalidone, bumetanide furosemide. On one hand, supports hypothesis that effects primarily little, if any observed diuretics. addition, do appear be diuretic or intended pharmacological targets, about long-term specific vulnerable populations, including those syndrome. using animal models suggest variable secretion metabolism. Although mechanisms involved understood, further research is needed uncover molecular by certain disrupt contribute disturbances.

Язык: Английский

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Bayliss–Starling Prize Lecture: K_ATP channel pathophysiology – a whole‐body odyssey

The Journal of Physiology, Год журнала: 2025, Номер unknown

Опубликована: Май 31, 2025

Abstract First identified 40 years ago in cardiac myocytes, ATP‐sensitive potassium (K ATP ) channels have been found almost all excitable tissues, with paradigmatic inhibition by and activation ADP underlying their physiological role coupling cellular metabolism to electrical activity. Cloning of the genes, 30 ago, revealed unique assembly as four Kir6.x pore‐forming subunit proteins sulfonylurea receptor (SURx) has since led discovery a spectrum monogenic diseases resulting from gain‐ (GOF) or loss‐of‐function (LOF) mutations, turn leading recognition novel roles pathophysiological consequences throughout body. With this perspective, lecture represents personal view these discoveries potential for future insights. image

Язык: Английский

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Advances in small-molecule insulin secretagogues for diabetes treatment

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 178, С. 117179 - 117179

Опубликована: Июль 26, 2024

Diabetes, a metabolic disease caused by abnormally high levels of blood glucose, has prevalence rate worldwide and causes series complications, including coronary heart disease, stroke, peripheral vascular end-stage renal retinopathy. Small-molecule compounds have been developed as drugs for the treatment diabetes because their oral advantages. Insulin secretagogues are class small-molecule used to treat diabetes, include sulfonylureas, non-sulfonylureas, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase 4 inhibitors, other novel insulin secretagogues. However, many cause different side effects, posing huge challenges drug monotherapy selection. Therefore, use must be improved. This article reviews mechanism, advantages, limitations, potential risks provide future research directions on diabetes.

Язык: Английский

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What do stimulated beta cells have in common with cancer cells?

Biosystems, Год журнала: 2024, Номер 242, С. 105257 - 105257

Опубликована: Июнь 12, 2024

This study investigates the metabolic parallels between stimulated pancreatic beta cells and cancer cells, focusing on glucose glutamine metabolism. Addressing significant public health challenges of Type 2 Diabetes (T2D) cancer, we aim to deepen our understanding mechanisms driving insulin secretion cellular proliferation. Our analysis anaplerotic cycles role NADPH in biosynthesis elucidates their vital functions both processes. Additionally, point out that cell types share an antioxidative response mediated by Nrf2 signaling pathway, glutathione synthesis, UCP2 upregulation. Notably, facilitates transfer C4 metabolites, enhancing reductive TCA cycle Furthermore, observe hypoxic responses are transient post-stimulation but persistent cells. By synthesizing these insights, research may suggest novel therapeutic targets for T2D, highlighting shared strategies comparative not only illuminates complexity conditions also emphasizes crucial pathways function survival, offering fresh perspectives tackling T2D challenges.

Язык: Английский

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Pyruvate kinase modulates the link between β-cell fructose metabolism and insulin secretion

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 15, 2024

2 ABSTRACT Glucose triggers insulin secretion from pancreatic β-cells through intracellular glucose metabolism, ATP production, and closure of ATP-sensitive K + channels (K channels). Fructose also stimulates secretion, but the underlying mechanisms remain unclear. This study investigated contribution phospholipase C (PLC) signaling fructose metabolism to fructose-stimulated (FSIS) using MIN6-K8 clonal mouse islets. Fructose-induced PLC activation, assessed by inositol 1-phosphate accumulation, was reduced in fructose-unresponsive β-cell models, such as diabetic islets channel-deficient β-cells, suggesting that responsiveness is primarily determined signaling. Although FSIS dependent on Ca 2+ influx, ATP/ADP ratio unexpectedly lowered fructose, suppression hardly affected FSIS. Metabolic flux analysis revealed accumulation (F1P) suppressed pyruvate kinase (PK) activity, contributing depletion. Strikingly, a small-molecule PK activator, TEPP-46, antagonized F1P-mediated suppression, prevented drop ratio, restored cells, normal islets, These findings metabolic effects identified key regulator linking FSIS, thereby providing new insights into potential therapeutic targets for fructose-associated diseases. 1 GRAPHICAL Left: Fructose-stimulated driven sweet taste receptor (STR)-mediated β-cells. Meanwhile, does not promote because causes (F1P), which suppresses M2 (PKM2), lowering ratio. Right: A activator counteracted PKM2 inhibition, decrease, substantially enhanced Thus, has been

Язык: Английский

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