The molecular mechanisms of pancreatic β-cell glucotoxicity: Recent findings and future research directions

Bensellam, Mohammed; Laybutt, D. Ross; Jonas, Jean‐Christophe

doi:10.1016/j.mce.2012.08.003

Cited by 252 publications

(253 citation statements)

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“…1,18,27). In this study, acute pharmacological GK activation increased the glucose sensitivity of control islets but failed at restoring ␤-cell glucose responsiveness in rat islets cultured for 1 wk at nonstimulating or very high vs. intermediate glucose concentration.…”

Section: Discussionmentioning

confidence: 59%

“…This possible caveat of GKAs has been previously considered nonrelevant on the ground that ␤-cell stimulation is reduced following the GKA-mediated reduction in glycemia (12). However, given the metabolic heterogeneity of ␤-cells in rodent islets (37), the present study suggests that GKAs may be beneficial in poorly responsive ␤-cells while being simultaneously toxic to middle-and highly-responsive ␤-cells through a variety of mechanisms proposed to contribute to glucotoxicity (1). If such "glucotoxic-like" effects of long-term GKA treatment at intermediate glucose concentration were confirmed in human islets, it could contribute to the secondary failure of GKAs in T2D (22,31,47).…”

Section: E636mentioning

confidence: 65%

“…It also sheds light on the mechanism of ROS production during culture at high glucose, suggesting this event is independent of glucose metabolism and acceleration of mitochondrial electron transport chain and might therefore involve other pathways, e.g., AGE's formation and activation of RAGE (1).…”

Section: E636mentioning

confidence: 92%

“…The beneficial effect of culture at G10 vs. G5 is usually attributed to the stimulation of energetic metabolism. In contrast, the deleterious effects of culture at G30 vs. G10, which we later refer to as glucotoxicity, could result from the further increase in metabolism with increased production of reactive oxygen species (ROS) and endoplasmic reticulum stress or from various mechanisms that do not exclusively depend on glucose metabolism, e.g., through increased glycation of extracellular proteins, activation of the receptor for advanced glycation end products (RAGE), or a hypothetical osmotic effect of high glucose concentrations (1).…”

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confidence: 99%

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Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration

Roma

Duprez

Jonas³

2015

American Journal of Physiology-Endocrinology and Metabolism

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Roma LP, Duprez J, Jonas JC. Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration. Am J Physiol Endocrinol Metab 309: E632-E639, 2015. First published August 11, 2015; doi:10.1152/ajpendo.00154.2015.-In rat pancreatic islets, ␤-cell gene expression, survival, and subsequent acute glucose stimulation of insulin secretion (GSIS) are optimally preserved by prolonged culture at 10 mM glucose (G10) and markedly altered by culture at G5 or G30. Here, we tested whether pharmacological glucokinase (GK) activation prevents these alterations during culture or improves GSIS after culture. Rat pancreatic islets were cultured 1-7 days at G5, G10, or G30 with or without 3 M of the GK activator Ro 28-0450 (Ro). After culture, ␤-cell apoptosis and islet gene mRNA levels were measured, and the acute glucose-induced increase in NAD(P)H autofluorescence, intracellular calcium concentration, and insulin secretion were tested in the absence or presence of Ro. Prolonged culture of rat islets at G5 or G30 instead of G10 triggered ␤-cell apoptosis and reduced their glucose responsiveness. Addition of Ro during culture differently affected ␤-cell survival and glucose responsiveness depending on the glucose concentration during culture: it was beneficial to ␤-cell survival and function at G5, detrimental at G10, and ineffective at G30. In contrast, acute GK activation with Ro increased the glucose sensitivity of islets cultured at G10 but failed at restoring ␤-cell glucose responsiveness after culture at G5 or G30. We conclude that pharmacological GK activation prevents the alteration of ␤-cell survival and function by long-term culture at G5 but mimics glucotoxicity when added to G10. The complex effects of glucose on the ␤-cell phenotype result from changes in glucose metabolism and not from an effect of glucose per se. apoptosis; glucotoxicity; insulin secretion; pancreatic ␤-cell GLUCOSE STIMULATION OF INSULIN SECRETION (GSIS) by endocrine pancreatic ␤-cells depends on the acceleration of glucose metabolism through glycolysis and the TCA cycle, with enhanced production of metabolic coupling factors (25,39,41). Besides these rapid effects, glucose exerts complex long-term effects on the ␤-cell phenotype (2,10,16,18,27,45). During long-term culture of rodent islets, ␤-cell gene expression, survival, and glucose responsiveness are optimally preserved in the presence of 10 mM glucose (G10), whereas they are markedly altered by culture at either nonstimulating (G5) or very high (G30) glucose concentrations. In other words, culture at G10 vs. G5 is beneficial, whereas culture at G30 vs. G10 is detrimental to ␤-cell gene expression, survival, and glucose responsiveness. The beneficial effect of culture at G10 vs. G5 is usually attributed to the stimulation of energetic metabolism. In contrast, the deleterious effects of culture at G30 vs. G10, which we later refer to as glucotoxicity, could result from the further increase in metabolism with increased production o...

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Section: Discussionmentioning

confidence: 59%

Section: E636mentioning

confidence: 65%

Section: E636mentioning

confidence: 92%

mentioning

confidence: 99%

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Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration

Roma

Duprez

Jonas³

2015

American Journal of Physiology-Endocrinology and Metabolism

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“…A hiperglicemia e hiperlipidemia por períodos prolongados (glicolipotoxicidade), comuns na obesidade, conduzem à deficiência orgânica das células β pancreáticas, refletida na resistência à insulina autócrina, na expressão diminuída dos genes envolvidos na produção da insulina, na diminuição de células β causada por apoptose e finalmente na secreção inadequada de insulina. Consequentemente, a deficiência de insulina produzida no pâncreas relativa à obesidade é consequência do dano celular e da ineficiência na síntese de insulina, acarretando o desenvolvimento do diabetes tipo 2 (ALEJANDRO et al, 2015;BENSELLAM; LAYBUTT; JONAS, 2012). …”

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Efeito dos compostos fenólicos do camu-camu e do cupuaçu no desenvolvimento da obesidade e diabetes mellitus tipo 2

Barros¹

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Efeito dos compostos fenólicos do camu-camu e do cupuaçu no desenvolvimento da obesidade e diabetes mellitus tipo 2Ao meu marido Edgard, por seu amor, sua compressão e seu apoio em todas as fases deste trabalho. Você foi a pessoa que mais acreditou desde o começo, e seu incentivo foi fundamental! Obrigada por mudar sua vida para poder realizar um sonho meu! Aos meus pais Marina e Luiz Carlos e à minha irmã e amiga Marta pelo carinho, apoio incondicional e por sempre demonstrarem orgulho desta jornada.À minha querida prima e amiga Camila e ao meu irmão Roberto, mesmo que distantes fisicamente, por me tranquilizarem nos momentos difíceis e por me inspiraram como pesquisadores.Aos meus colegas de laboratório e amigos queridos: Alice, Carlos, Ciça, Daniel, Diully, Flavinha, Gabi Cunha, Gabi Pedrosa, Helô, Luana, Marcela, Marcio, Renata e Taty pela companhia, amizade e troca de conhecimentos, obrigada a todos vocês! À Fernanda Santana, por sua amizade e ajuda com as análises de lipídeos.À Beatriz Mendonça, "minha filhinha" querida, pela participação na parte experimental, sempre com comprometimento e alegria.À Joana, por nos ajudar a manter o "antigo" laboratório em ordem. The incidence of obesity and type 2 diabetes reached epidemic proportions in recent years, arriving to billions of people around the world. The discovery of innovative ways that can reduce the metabolic abnormalities associated with these diseases is essential to minimize its impact on the population's quality of life and the economy of the countries. Many studies have demonstrated that food bioactive compounds have beneficial health effects. Camu-camu and cupuassu are native fruits of the Amazon region with unexplored agroeconomic potential, which contain a large number of phytochemical compounds that can act on body metabolism.Thus, the objective of this study was verify the effects of phenolic compounds of camu-camu and cupuassu extracts on the development of obesity and type 2 diabetes in vivo and in vitro, and identfy the possible metabolites involved in these effects. The phenolic compound-rich extracts were obtained from commercial frozen fruit pulps by solid phase extraction, characterized by high-performance liquid chromatography (HPLC/DAD) and evaluated for inhibition of digestive enzymes activities in vitro. Then, the extracts were tested at two different doses (2.25 and 4.5 mg catechin equivalents/kg body weight for cupuassu; 7 and 14 mg of gallic acid equivalents/kg body weight for camu camu) in an animal model (C57BL/6J mice) of obesity and insulin resistance induced by high fat high sucrose diet. The effects of extract supplementation on glucose and lipid homeostasis were assessed by serum analysis, insulin and glucose tolerance tests in mice, and contents of fat in liver and fecal samples.Camu camu extract presented flavonols, ellagic acid and ellagitannins in its composition.Supplementation with camu camu phenolic extract reduced weight gain and decreased glucose and insulin intolerance independent of the dose administered. However...

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Carbohydrate response element‐binding protein (ChREBP) mediates decreased SNAP25 expression in islets from diabetic Goto‐Kakizaki (GK) rats

Hu,

Lan,

Yao

et al. 2024

FEBS Open Bio

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SNAP25 plays an essential role in the glucose‐stimulated insulin secretion (GSIS) of pancreatic β‐cells. Carbohydrate response element‐binding protein (ChREBP) is an important transcription factor in β‐cells and, in this study, we aimed to explore whether ChREBP regulates SNAP25 expression in β‐cells. We show that diabetic Goto‐Kakizaki (GK) rats exhibited impaired insulin secretion and hyperglycemia, along with decreased SNAP25 expression and ChREBP phosphorylation in islets. SNAP25 knockdown decreased GSIS in β‐cells, while SNAP25 overexpression increased GSIS in β‐cells. Activation or overexpression of ChREBP led to reduced SNAP25 expression and subsequent suppression of GSIS. Conversely, ChREBP knockdown mitigated the reduction in SNAP25 expression caused by high glucose. Mechanistically, the activation of ChREBP by high glucose increased its occupancy and decreased the level of H3K4me3 at the Snap25 promoter. Our findings reveal the novel regulatory mechanisms of SNAP25 expression in β‐cells and suggest that SNAP25 may be involved in the regulation of β‐cell secretory function controlled by ChREBP.

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The molecular mechanisms of pancreatic β-cell glucotoxicity: Recent findings and future research directions

Cited by 252 publications

References 476 publications

Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration

Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration

Efeito dos compostos fenólicos do camu-camu e do cupuaçu no desenvolvimento da obesidade e diabetes mellitus tipo 2

Carbohydrate response element‐binding protein (ChREBP) mediates decreased SNAP25 expression in islets from diabetic Goto‐Kakizaki (GK) rats

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