Enhanced glucose-induced intracellular signaling promotes insulin hypersecretion: Pancreatic beta-cell functional adaptations in a model of genetic obesity and prediabetes

Irles, Esperanza; Ñeco, Patricia; Lluesma, Mónica; Villar-Pazos, Sabrina; Santos-Silva, Junia Carolina; Vettorazzi, Jean Franciesco; Alonso-Magdalena, Paloma; Carneiro, Everardo M.; Boschero, Antônio Carlos; Nadal, Ángel; Quesada, Iván

doi:10.1016/j.mce.2015.01.033

Cited by 54 publications

(58 citation statements)

References 61 publications

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“…3 B ). 52 Mn 2+ was readily taken up by islets, even in the presence of low (1 mmol/L) glucose, as expected for the high basal Ca 2+ and insulin secretion reported for ob / ob β-cells (22). 52 Mn 2+ uptake was significantly enhanced ( P < 0.05) when the islets were stimulated with 10 mmol/L glucose.…”

Section: Resultssupporting

confidence: 70%

Radiomanganese PET Detects Changes in Functional β-Cell Mass in Mouse Models of Diabetes

et al. 2017

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The noninvasive measurement of functional β-cell mass would be clinically valuable for monitoring the progression of type 1 and type 2 diabetes as well as the viability of transplanted insulin-producing cells. Although previous work using MRI has shown promise for functional β-cell mass determination through voltage-dependent Ca2+ channel (VDCC)–mediated internalization of Mn2+, the clinical utility of this technique is limited by the cytotoxic levels of the Mn2+ contrast agent. Here, we show that positron emission tomography (PET) is advantageous for determining functional β-cell mass using 52Mn2+ (t1/2: 5.6 days). We investigated the whole-body distribution of 52Mn2+ in healthy adult mice by dynamic and static PET imaging. Pancreatic VDCC uptake of 52Mn2+ was successfully manipulated pharmacologically in vitro and in vivo using glucose, nifedipine (VDCC blocker), the sulfonylureas tolbutamide and glibenclamide (KATP channel blockers), and diazoxide (KATP channel opener). In a mouse model of streptozotocin-induced type 1 diabetes, 52Mn2+ uptake in the pancreas was distinguished from healthy controls in parallel with classic histological quantification of β-cell mass from pancreatic sections. 52Mn2+-PET also reported the expected increase in functional β-cell mass in the ob/ob model of pretype 2 diabetes, a result corroborated by histological β-cell mass measurements and live-cell imaging of β-cell Ca2+ oscillations. These results indicate that 52Mn2+-PET is a sensitive new tool for the noninvasive assessment of functional β-cell mass.

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Section: Resultssupporting

confidence: 70%

Radiomanganese PET Detects Changes in Functional β-Cell Mass in Mouse Models of Diabetes

et al. 2017

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“…The results highlight the plasticity of the secretory capacity of individual pancreatic beta-cells in response to increased insulin demand. These data are also consistent with evidence from obesity and pregnancy models (Sorenson and Brelje 1997;Irles, Neco et al 2015). However, the mechanism of beta-cell hyperfunction in the context of normal glycemia of stage 1 db/db is not yet clear.…”

Section: Resultssupporting

confidence: 85%

“…Experiments on spontaneously hypertensive rats or partially pancreatectomised rats suggested a lower glucose set-point for insulin secretion which results in more insulin secreted at a given level of glucose (Chen, Hosokawa et al 1994;Hosokawa, Hosokawa et al 1995). Moreover, study in the genetic obesity ob/ob mice indicated a significant plasticity in individual beta-cell function to maintain normal FBG in face of insulin resistance (Irles, Neco et al 2015). Contrarily, evidence exists for lower beta-cell function in women with former gestational diabetes mellitus or NGT people who are first degree relatives of T2D patients, which implied earlier disturbances in the beta-cell function of predisposed people than often appreciated (Pimenta, Korytkowski et al 1995;van Haeften 2002).…”

Section: Stage 1-compensationmentioning

confidence: 99%

“…Further support for an increase in beta-cell number, comes from animal models where, increased beta-cell mass, or islet size, have been shown in pre-diabetic Zucker Diabetic Fatty rats (Pick, Clark et al 1998), Tallyho diabetic mice (Mao, Dillon et al 2014), ob/ob mice (Irles, Neco et al 2015) and animals fed a high fat diet (Hull, Kodama et al 2005;Terauchi, Takamoto et al 2007;Gonzalez, Merino et al 2013). …”

Section: Introductionmentioning

confidence: 96%

“…Most recently, it has been shown in the ob/ob model of obesity that, in addition to increased numbers of beta-cells, there is an increase in secretion per cell (Irles, Neco et al 2015).…”

Section: Introductionmentioning

confidence: 99%

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Structural and functional changes of pancreatic beta-cells during the progression of disease in the Leprdb model of type 2 diabetes

Hoang¹

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It is well established that changes in insulin secretion play an important role in the pathogenesis of type 2 diabetes. However, the underlying mechanisms of secretory changes occurring at the pancreatic beta-cell level are not fully elucidated. Therefore, this thesis focuses on the modulation of beta-cell function, particularly insulin granule exocytosis, during the progression of type 2 diabetes using the BKS.Cg-Dock7m+/+Lepr db /J (Lepr db mice) as a model of disease.I applied a variety of in vivo and in vitro methods to this project and further refined a livecell two-photon assay which I used to measure the numbers and kinetics of granule fusion events within intact islets.Using this latter technique, in the first part of the project I aimed to test a prevalent hypothesis that granule fusion behaviour changes in disease. Three indices of the post-fusion granule behaviour were compared between islets from animals with overt diabetes (db/db) and wild type. There was no difference in two indices of the fusion-granule behaviour; lifetime of granule fusion and post-fusion fluorescence intensity. The only change was a small increase in the percentage of recaptured granules (or "kiss-and-run" exocytosis) in db/db islets. In contrast to this minor change in granule fusion kinetics, further work showed that the main secretory deficit of frank diabetes, in db/db islets, is due to the loss of responding beta-cells and a reduction in the numbers of exocytic fusing granules in the remaining responsive cells.In the second part of the project I studied disease progression in the Lepr db model. Based on the area under the curve of the glucose tolerance tests, each db/db mouse was classified into one of four stages of disease, ranging from pre-diabetes (stage 1) to severe diabetes (stage 4). The results indicated that changes in islet size and insulin content occurred across all stages of disease severity.At stage 1, there was an increase in islet insulin content due to both an increased number of betacells and increased insulin content in each cell, whereas at stages 2-4, there was a progressive loss of islet insulin content that is a reflection of loss of content from individual beta-cells.Finally, in terms of beta-cell function, the data revealed that modulation of function characterised all stages of disease severity in db/db mice. In stage 1 there was an upregulation in the number of fusion of insulin-containing granules as well as the prevalence of compound exocytosis.At later disease stages there was a loss of glucose-induced insulin-granule fusion which my data indicated was due to impairment in glucose sensing. This work demonstrates that beta-cell function is intimately associated with pre-diabetes and progression to diabetes and adds weight to clinical strategies for therapeutic intervention as early as possible. Page | iiIn summary, the results show that the major factors in the disease phenotype are changes in the numbers of responding beta-cells and the numbers of fusing granules rather than the kinetic...

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Unfolded protein response is involved in geniposide‐regulating glucose‐stimulated insulin secretion in INS‐1 cells

Hao

Shen

Yin

et al. 2019

Cell Biochemistry & Function

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The growing evidence shows that in the early stage of type 2 diabetes mellitus (T2DM) development, when challenged by hyperglycemia and/or insulin resistance, pancreatic islets would produce more insulin to maintain the balance of blood sugar, but at the same time, endoplasmic reticulum (ER) stress will be initiated for the reason of over‐compensation, which might be a crucial caused factor of dysfunction and death of pancreatic beta cell. In this study, we showed that high glucose induced a remarkably unfolded protein response (UPR) with the phosphorylation of PERK/eIF2α and IRE1α in INS‐1 cells, but geniposide prevented the role of high glucose on the phosphorylation of PERK/eIF2α and IRE1α, respectively. Although inhibition of Txnip expression by siRNA had no significant effect on geniposide‐regulating UPR, PERK and IRE1α were associated with geniposide‐regulating Txnip degradation and glucose‐stimulated insulin secretion (GSIS) in high glucose‐cultured INS‐1 cells. All these data suggest that geniposide might be an important regulator of ER stress and GSIS, and a promising compound for the treatment of T2DM. Significance of the study Mounting evidence indicates that endoplasmic reticulum (ER) stress plays an essential role to maintain the normal cellular functions and dysfunction. In this study, we revealed that geniposide might be an important regulator of ER stress and glucose‐stimulated insulin secretion in pancreatic beta cells.

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Enhanced glucose-induced intracellular signaling promotes insulin hypersecretion: Pancreatic beta-cell functional adaptations in a model of genetic obesity and prediabetes

Cited by 54 publications

References 61 publications

Radiomanganese PET Detects Changes in Functional β-Cell Mass in Mouse Models of Diabetes

Radiomanganese PET Detects Changes in Functional β-Cell Mass in Mouse Models of Diabetes

Structural and functional changes of pancreatic beta-cells during the progression of disease in the Leprdb model of type 2 diabetes

Unfolded protein response is involved in geniposide‐regulating glucose‐stimulated insulin secretion in INS‐1 cells

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