Pancreatic development and maturation of the islet B cell

Madsen, Ole; Jensen, Jan; Blume, Niels; Petersen, Helle V.; Lund, Kaare; Karlsen, Christina; Andersen, Frank G.; Jensen, Per Bo; Larsson, Lars‐Inge; Serup, Palle

doi:10.1007/978-3-642-60659-5_16

Cited by 5 publications

(7 citation statements)

References 106 publications

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“…At this stage most of the cells express PDX-1, the master regulator of pancreas development [14], and glucagonpositive cells can be detected, although these first glucagonpositive cells are post-mitotic and do not contribute to the final alpha cell pool [18]. One day later, insulin-positive cells appear, and over the next 2-3 days, cells are frequently found to express both hormones together [19]. However, alpha and beta cells appear to be derived independently in the mouse pancreas [20].…”

Section: Discussionmentioning

confidence: 98%

Streptozotocin-induced partial beta cell depletion in nude mice without hyperglycaemia induces pancreatic morphogenesis in transplanted embryonic stem cells

Takeshita¹,

Kodama²,

Yamamoto³

et al. 2006

Diabetologia

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Aims/hypothesis It appears that the adult pancreas has limited regenerative ability following beta cell destruction by streptozotocin (STZ). However, it is not clear if this limitation is due to an inability to respond to, rather than an absence of, regenerative stimuli. In this study we aimed to uncouple the regenerative signal from the regenerative response by using an exogenous stem cell source to detect regenerative stimuli produced by the STZ-injured pancreas at physiological blood glucose levels. Method Adult nude mice received 150 mg/kg STZ and 1Â10 6 J1 mouse embryonic stem (ES) cells by i.p. injection. Permanent beta cell depletion of 50% was estimated from the ratio of beta:alpha cells in pancreata from STZ-treated mice compared with control animals after 24 days. Results Transplanted ES cells homed to the STZ-injured pancreas and formed tumours. Immunocytochemical analysis of pancreas-associated ES tumours revealed foci containing insulin/PDX-1 double-positive and glucagonpositive/PDX-1-negative cell clusters associated with PDX-1-positive columnar lumenal epithelium and extensive α-amylase-positive pancreatic acini comprising approximately 0.1% of ES tumour volume. Conclusions/interpretation These data indicate that (1) the adult pancreas produces a milieu of regenerative stimuli following beta cell destruction, and (2) this is not dependent on hyperglycaemic conditions; (3) these regenerative stimuli appear to recapitulate the signalling pathways of embryonic development, since both exocrine and endocrine lineages are produced from PDX-1-positive precursor epithelium. This model will be useful for characterising the regenerative mechanisms in the adult pancreas.

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Section: Discussionmentioning

confidence: 98%

Streptozotocin-induced partial beta cell depletion in nude mice without hyperglycaemia induces pancreatic morphogenesis in transplanted embryonic stem cells

Takeshita¹,

Kodama²,

Yamamoto³

et al. 2006

Diabetologia

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“…Recently, intracerebroventricular administration of GLP-1 was shown to elicit a potent suppression of food intake (54)(55)(56), and moreover, GLP-1 has been shown to inhibit NPY-induced feeding (55). In contrast, peripheral administration of single high doses of GLP-1 to rats failed to elicit significant changes in food intake (3,55,56), in spite of the finding that peripheral GLP-1 can access the subfornical organ and the area postrema of the brain (57). However, GLP-1 is degraded extensively and very rapidly in the circulation after peripheral administration (58) which may be the main reason for the lack of effect of single injections.…”

Section: Discussionmentioning

confidence: 99%

“…New England Deaconess hospital (NEDH) rats (Møllegaard, Lille Skensved, Denmark) were transplanted with the glucagonoma line MSL-G-AN as described previously (2,3). Study 1.…”

Section: Animal Studiesmentioning

confidence: 99%

Transplantable rat glucagonomas cause acute onset of severe anorexia and adipsia despite highly elevated NPY mRNA levels in the hypothalamic arcuate nucleus.

Jensen¹,

Blume²,

Mikkelsen³

et al. 1998

J. Clin. Invest.

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We have isolated a stable, transplantable, and small glucagonoma (MSL-G-AN) associated with abrupt onset of severe anorexia occurring 2-3 wk after subcutaneous transplantation. Before onset of anorexia, food consumption is comparable to untreated controls. Anorexia is followed by adipsia and weight loss, and progresses rapidly in severity, eventually resulting in reduction of food and water intake of 100 and 80%, respectively. During the anorectic phase, the rats eventually become hypoglycemic and hypothermic. The tumor-associated anorexia shows no sex difference, and is not affected by bilateral abdominal vagotomy, indicating a direct central effect. The adipose satiety factor leptin, known to suppress food intake by reducing hypothalamic neuropeptide Y (NPY) levels, was not found to be expressed by the tumor, and circulating leptin levels were reduced twofold in the anorectic phase. A highly significant increase in hypothalamic (arcuate nucleus) NPY mRNA levels was found in anorectic rats compared with control animals. Since elevated hypothalamic NPY is among the most potent stimulators of feeding and a characteristic of most animal models of hyperphagia, we conclude that the MSL-G-AN glucagonoma releases circulating factor(s) that overrides the hypothalamic NPY-ergic system, thereby eliminating the orexigenic effect of NPY. We hypothesize a possible central role of proglucagon-derived peptides in the observed anorexia.

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“…Thus, glucagon and glucagon-like peptide-1 7-36 amide [GLP-1 amide)] are the main secretory products; however, glicentinrelated polypeptide, oxyntomodulin, GLP-2, as well as other processing variants of GLP-1 are secreted also (8). The MSL-G-AN tumor line causes an abrupt onset of severe anorexia and adipsia 4-5 wk after transplantation (9), the nature of which remains unsolved. Despite hyperglucagonemia, other murine glucagonomas are not associated with severe anorexia (1,2), although a prominent weight loss may be seen in the glucagonoma syndrome in humans (10).…”

Section: Introductionmentioning

confidence: 99%

Potent inhibitory effects of transplantable rat glucagonomas and insulinomas on the respective endogenous islet cells are associated with pancreatic apoptosis.

Blume¹,

Skouv²,

Larsson³

et al. 1995

J. Clin. Invest.

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Effects of transplantable rat insulinomas (IN) and glucagonomas (GLU) on the endogenous pancreas were analyzed using morphometry, immunocytochemistry, in situ hybridization, and staining for apoptotic cells. Hyperinsulinemia (IN-rats) and hyper-GLP-1/glucagonemia (GLU-rats) were both associated with marked islet atrophy (67 and 76% of control average planimetrical islet area, respectively). Selective islet B cell inhibition of proinsulin (I and II) genes as well as of expression of the insulin gene transcription factor, IPF1/STF1, was found in IN-rats. Moreover, these islets were characterized by significant B cells apoptosis in the absence of infiltrating lymphocytes. In GLU-rats selective islet A cell inhibition was observed at the level of glucagon mRNA. These islets contained small, highly condensed but clearly active B cells with prominent IPF1/STF1-positive nuclei, surrounded by densely packed glucagon-negative cells with reduced cytoplasm. Furthermore, an active apoptotic process was found exclusively in the exocrine pancreas of GLU-rats. Thus, in IN-rats, islet B cell mass reduction is distinguished by non-immune-mediated programmed cell death, while GLU-rats exhibit A cell mass reduction by cytoplasmic retraction and selective exocrine apoptosis. (J. Clin. Invest. 1995. 96:2227-2235

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Pancreatic development and maturation of the islet B cell

Cited by 5 publications

References 106 publications

Streptozotocin-induced partial beta cell depletion in nude mice without hyperglycaemia induces pancreatic morphogenesis in transplanted embryonic stem cells

Streptozotocin-induced partial beta cell depletion in nude mice without hyperglycaemia induces pancreatic morphogenesis in transplanted embryonic stem cells

Transplantable rat glucagonomas cause acute onset of severe anorexia and adipsia despite highly elevated NPY mRNA levels in the hypothalamic arcuate nucleus.

Potent inhibitory effects of transplantable rat glucagonomas and insulinomas on the respective endogenous islet cells are associated with pancreatic apoptosis.

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