B-cell size influences glucose-stimulated insulin secretion

Giordano, Emanuele; Cirulli, Vincenzo; Bosco, Domenico; Rouiller, D.; Halban, Philippe A.; Meda, Paolo

doi:10.1152/ajpcell.1993.265.2.c358

Cited by 60 publications

(54 citation statements)

References 24 publications

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“…We thus believe that cells with high levels of E-cadherin do so as a result of their high secretory capacity and not the contrary. In a previous work, using similar FACS and RHPA technologies used in this study, we demonstrated that insulin secretory activity of single b-cells correlated with their size (Giordano et al 1993). Here, a correlation between b-cell size and E-cadherin expression cannot be excluded.…”

Section: Discussionmentioning

confidence: 46%

Differential expression of E-cadherin at the surface of rat β-cells as a marker of functional heterogeneity

Bosco¹,

Rouiller²,

Halban³

2007

Journal of Endocrinology

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The aim of this study was to assess whether the expression of E-cadherin at the surface of rat b-cells is regulated by insulin secretagogues and correlates with insulin secretion. When cultured under standard conditions, virtually all b-cells expressed E-cadherin observed by immunofluorescence, but heterogeneous staining was observed. Using fluorescence-activated cell sorting (FACS), two b-cell sub-populations were sorted: one that was poorly labeled ('ECad-low') and another that was highly labeled ('ECad-high'). After 1-h stimulation with 16 . 7 mM glucose, insulin secretion (reverse hemolytic plaque assay) from individual ECad-high b-cells was higher than that from ECad-low b-cells. Ca 2C-dependent b-cell aggregation was increased at 16 . 7 mM glucose when compared with 2 . 8 mM glucose. E-cadherin at the surface of b-cells was increased after 18 h at 11 . 1 and 22 . 2 mM glucose when compared with 2 . 8 mM glucose, with the greatest increase at 22 . 2 mM glucoseC0 . 5 mM isobutylmethylxanthine (IBMX).While no labeling was detected on freshly trypsinized cells, the proportion of stained cells increased in a time-dependent manner during culture for 1, 3, and 24 h. This recovery was faster when cells were incubated at 16 . 7 vs 2 . 8 mM glucose. Cycloheximide inhibited expression of E-cadherin at 2 . 8 mM glucose, but not at 16 . 7 mM, while depolymerization of actin by either cytochasin B or latrunculin B increased surface Ecadherin at low glucose. In conclusion, these results show that expression of E-cadherin at the surface of islet b-cells is controlled by secretagogues including glucose, correlates with insulin secretion, and can serve as a surface marker of b-cell function.

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Section: Discussionmentioning

confidence: 46%

Differential expression of E-cadherin at the surface of rat β-cells as a marker of functional heterogeneity

Bosco¹,

Rouiller²,

Halban³

2007

Journal of Endocrinology

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“…As noted above, this stems from the fact that S6K1-deficient mice are hypoinsulinemic, a phenotype which we found was not associated with the transcription, synthesis, degradation, or intrinsic secretion of insulin, but with diminished β cell size (9,14). It is known that a decrease in β cell size has a proportionally larger negative effect on insulin secretion independent of secretory potential (15). Consistent with a role for S6K1 in this response, subsequent studType 2 diabetes mellitus (T2DM) is a worldwide heath problem that is characterized by insulin resistance and the eventual loss of β cell function.…”

Section: Introductionsupporting

confidence: 47%

S6K1 controls pancreatic β cell size independently of intrauterine growth restriction

Um¹,

Sticker-Jantscheff²,

Chau³

et al. 2015

J. Clin. Invest.

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“…One of the primary consequences of MyrAkt1 expression in pancreatic β cells is a striking hypertrophy (5,6) that may explain the increased capacity in insulin storage and release (23). In skeletal muscles, we have recently shown that S6K1 is required for the mTOR-dependent control of cell size by MyrAkt1 (24).…”

Section: Resultsmentioning

confidence: 99%

Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation

Alliouachene¹,

Tuttle²,

Boumard³

et al. 2008

J. Clin. Invest.

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Factors that promote pancreatic β cell growth and function are potential therapeutic targets for diabetes mellitus. In mice, genetic experiments suggest that signaling cascades initiated by insulin and IGFs positively regulate β cell mass and insulin secretion. Akt and S6 kinase (S6K) family members are activated as part of these signaling cascades, but how the interplay between these proteins controls β cell growth and function has not been determined. Here, we found that although transgenic mice overexpressing the constitutively active form of Akt1 under the rat insulin promoter (RIP-MyrAkt1 mice) had enlarged β cells and high plasma insulin levels, leading to improved glucose tolerance, a substantial proportion of the mice developed insulinomas later in life, which caused decreased viability. This oncogenic transformation tightly correlated with nuclear exclusion of the tumor suppressor PTEN. To address the role of the mammalian target of rapamycin (mTOR) substrate S6K1 in the MyrAkt1-mediated phenotype, we crossed RIP-MyrAkt1 and S6K1-deficient mice. The resulting mice displayed reduced insulinemia and glycemia compared with RIP-MyrAkt1 mice due to a combined effect of improved insulin secretion and insulin sensitivity. Importantly, although the increase in β cell size in RIP-MyrAkt1 mice was not affected by S6K1 deficiency, the hyperplastic transformation required S6K1. Our results therefore identify S6K1 as a critical element for MyrAkt1-induced tumor formation and suggest that it may represent a useful target for anticancer therapy downstream of mTOR.

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B-cell size influences glucose-stimulated insulin secretion

Cited by 60 publications

References 24 publications

Differential expression of E-cadherin at the surface of rat β-cells as a marker of functional heterogeneity

Differential expression of E-cadherin at the surface of rat β-cells as a marker of functional heterogeneity

S6K1 controls pancreatic β cell size independently of intrauterine growth restriction

Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation

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