Evidence for the homeostatic regulation of induced beta cell mass expansion

Lipsett, Mark; Austin, Emily; Castellarin, Mauro; Lemay, Jean-François; Rosenberg, Lawrence

doi:10.1007/s00125-006-0428-8

Cited by 19 publications

(15 citation statements)

References 53 publications

(73 reference statements)

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“…At least 40 islets/group (3,437 Ϯ 435 ␤-cell nuclei) were sampled. The ␤-cell proliferation was estimated by the percentage of PCNA-positive cells from the total of insulinpositive cells (20,39,42).…”

Section: Quantitative Approaches In Endocrine Pancreasmentioning

confidence: 99%

High doses of dexamethasone induce increased β-cell proliferation in pancreatic rat islets

Rafacho¹,

Cestari²,

Taboga³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

152

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Here, we report a model to study ␤-cell proliferation in living rats by administering three different doses of dexamethasone (0.1, 0.5, and 1.0 mg/kg ip, DEX 0.1, DEX 0.5, and DEX 1.0, respectively) for 5 days. Insulin sensitivity, insulin secretion, and histomorphometric data were investigated. Western blotting was used to analyze the levels of proteins related to the control of ␤-cell growth. DEX 1.0 rats, which present moderate hyperglycemia and marked hyperinsulinemia, exhibited a 5.1-fold increase in ␤-cell proliferation and an increase (17%) in ␤-cell size, with significant increase in ␤-cell mass, compared with control rats. The hyperinsulinemic but euglycemic DEX 0.5 rats also showed a significant 3.6-fold increase in ␤-cell proliferation. However, DEX 0.1 rats, which exhibited the lowest degree of insulin resistance, compensate for insulin demand by improving only islet function. Activation of the insulin receptor substrate 2/phosphatidylinositol 3-kinase/serine-threonine kinase/ribosomal protein S6 kinase pathway, as well as protein retinoblastoma in islets from DEX 1.0 and DEX 0.5, but not in DEX 0.1, rats was also observed. Therefore, increasing doses of dexamethasone induce three different degrees of insulin requirement in living rats, serving as a model to investigate compensatory ␤-cell alterations. Augmented ␤-cell mass involves ␤-cell hyperplasia and, to a lower extent, ␤-cell hypertrophy. We suggest that alterations in circulating insulin and, to a lesser extent, glucose levels could be the major stimuli for ␤-cell proliferation in the dexamethasone-induced insulin resistance.␤-cell growth; glucocorticoid; hyperglycemia; hyperinsulinemia; insulin resistance PANCREATIC ␤-CELLS ARE the only significant source of insulin, which is required for maintaining appropriate metabolic homeostasis and particularly to maintain glucose levels within a narrow range. However, failure of the ␤-cell capacity (␤-cell dysfunction and/or insufficient ␤-cell mass) contributes to the pathogenesis of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) (10, 18). Physiological or pathological states such as aging, pregnancy, insulin resistance, and obesity demand an increase in circulating insulin. Several ␤-cell adaptations are observed in these conditions, including increased insulin synthesis and secretion, hyperplasia, and hypertrophy (23,28,30). ␤-Cell mass plays an essential role in limiting the amount of insulin that is secreted in these systemic conditions of increased insulin demand. Patients with T2DM show reduced ␤-cell mass as a result of impaired ␤-cell proliferation and/or increased ␤-cell apoptosis, suggesting that adequate ␤-cell mass is required for prevention of diabetes (10, 18). Although remarkable improvements in the management of diabetic patients have occurred over recent years, new therapies are still needed to further improve metabolic control of this pathology (36).Amelioration of ␤-cell function and increase in ␤-cell number are important goals in diabetes research. Pancreatic ␤-cell mass r...

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Section: Quantitative Approaches In Endocrine Pancreasmentioning

confidence: 99%

High doses of dexamethasone induce increased β-cell proliferation in pancreatic rat islets

Rafacho¹,

Cestari²,

Taboga³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

152

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“…In this sense, endogenous b-cell mass expansion and, consequently, the reversal of hyperglycemic states in animal models are being actively investigated (Rosenberg et al 2004, Lipsett et al 2006. Among the protocols used for this purpose INGAP-PP seems to be a suitable tool, but its mechanism of action is not yet completely elucidated.…”

Section: Introductionmentioning

confidence: 99%

Islet neogenesis-associated protein signaling in neonatal pancreatic rat islets: involvement of the cholinergic pathway

Barbosa¹,

Bordin²,

Anhê³

et al. 2008

Journal of Endocrinology

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Islet neogenesis associated protein (INGAP) increases islet mass and insulin secretion in neonatal and adult rat islets. In the present study, we measured the short-and long-term effects of INGAP-PP (a pentadecapeptide having the 104-118 amino acid sequence of INGAP) upon islet protein expression and phosphorylation of components of the PI3K, MAPK and cholinergic pathways, and on insulin secretion. Short-term exposure of neonatal islets to INGAP-PP (90 s, 5, 15, and 30 min) significantly increased Akt1 -Ser473 and MAPK3/1 -Thr202/Tyr204 phosphorylation and INGAP-PP also acutely increased insulin secretion from islets perifused with 2 and 20 mM glucose. Islets cultured for 4 days in the presence of INGAP-PP showed an increased expression of Akt1, Frap1, and Mapk1 mRNAs as well as of the muscarinic M3 receptor subtype, and phospholipase C (PLC)-b2 proteins. These islets also showed increased Akt1 and MAPK3/1 protein phosphorylation. Brief exposure of INGAP-PP-treated islets to carbachol (Cch) significantly increased P70S6K -Thr389 and MAPK3/1 phosphorylation and these islets released more insulin when challenged with Cch that was prevented by the M3 receptor antagonist 4-DAMP, in a concentration-dependent manner. In conclusion, these data indicate that short-and long-term exposure to INGAP-PP significantly affects the expression and the phosphorylation of proteins involved in islet PI3K and MAPK signaling pathways. The observations of INGAPP-PP-stimulated up-regulation of cholinergic M3 receptors and PLC-b2 proteins, enhanced P70S6K and MAPK3/1 phosphorylation and Cch-induced insulin secretion suggest a participation of the cholinergic pathway in INGAP-PP-mediated effects.

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“…Pancreatic b-cell mass is tightly regulated, [1][2][3] reflecting the net effect of homeostatic mechanisms that include proliferation, neogenesis and apoptosis. 4 With respect to neogenesis, small clusters of b-cells in close proximity to pancreatic ducts are taken as a surrogate measure, 5,6 given that this is the mechanism by which islets form during pancreatic organogenesis.…”

mentioning

confidence: 99%

Cellular origins of adult human islet in vitro dedifferentiation

Hanley

Pilotte

Massie

et al. 2008

Laboratory Investigation

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Cultured human islets can be dedifferentiated to duct-like structures composed mainly of cytokeratin þ and nestin þ cells. Given that these structures possess the potential to redifferentiate into islet-like structures, we sought to elucidate their specific cellular origins. Adenoviral vectors were engineered for b-, a-, d-or PP-cell-specific GFP expression. A doublestranded system was designed whereby cultures were infected with two vectors: one expressed GFP behind the cumateinducible promoter sequence, and the other expressed the requisite transactivator behind the human insulin, glucagon, somatostatin or pancreatic polypeptide promoter. This system labels hormone þ cells in the islet in a cell-specific manner, allowing these cells to be tracked during the course of transformation from islet to duct-like structure. Post-infection, islets were cultured to induce dedifferentiation. Fluorescence microscopy demonstrated that a-, d-and PP-cells contributed equally to the cytokeratin þ population, with minimal b-cell contribution, whereas the converse was true for nestin þ cells. Complementary targeted cell ablation studies, using streptozotocin or similar adenoviral expression of the Bax (Bcl2-associated X protein) toxigene, validated these findings and suggested a redundancy between a-, d-and PP-cells with respect to cytokeratin þ cell derivation. These results call into question the traditional understanding of islet cells as being terminally differentiated and provide support for the concept of adult islet morphogenetic plasticity.

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Evidence for the homeostatic regulation of induced beta cell mass expansion

Cited by 19 publications

References 53 publications

High doses of dexamethasone induce increased β-cell proliferation in pancreatic rat islets

High doses of dexamethasone induce increased β-cell proliferation in pancreatic rat islets

Islet neogenesis-associated protein signaling in neonatal pancreatic rat islets: involvement of the cholinergic pathway

Cellular origins of adult human islet in vitro dedifferentiation

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