beta-cell turnover: its assessment and implications.

Bonner-Weir, Susan

doi:10.2337/diabetes.50.2007.s20

Cited by 209 publications

(169 citation statements)

References 38 publications

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“…c Effect of tungstate treatment on islet insulin mRNA expression in diabetic treated and untreated rats. All figures are representative of three independent experiments replication and neogenesis [9,20]. As described before [22], an increase in intra-islet beta-cell replication in diabetic rats was observed, which was not changed by tungstate administration.…”

Section: Tungstate Effects Persist After Withdrawal Of Treatmentsupporting

confidence: 65%

“…Its impact on society is huge [1] and its chronic complications cause enormous human suffering [2]. The development of new therapies that are able to improve glybetween cell growth, proliferation, and destruction [9]. The formation of new beta cells arising from the ductal epithelium has been shown in the adult pancreas, although the precise progenitor cell population remains a matter of debate.…”

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confidence: 99%

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Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate

et al. 2004

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Aims/hypothesis. Sodium tungstate has recently emerged as an effective oral treatment for diabetes. We examined the effects of tungstate administration in the beta-cell mass of the pancreas as well as its therapeutic potential. Methods. Sodium tungstate was administered via drinking water to healthy and neonatal streptozotocin (nSTZ)-diabetic rats for one month. The pancreas from each rat was removed and morphometric and immunocytochemical studies were carried out. The molecular mechanism of tungstate's action was also studied. Results. In nSTZ rats administration of this compound normalised glycaemia, and increased insulinaemia and islet insulin content. Blood glucose concentrations were normalised as early as on day 4 of treatment, and tungstate treatment produced a partial recovery of beta-cell mass. The rats remained normoglycaemic after tungstate withdrawal. Morphometric studies showed that the increase in beta-cell mass was not due to beta-cell hypertrophy but to hyperplasia, with an increase in islet density in treated diabetic rats. Tungstate treatment increased extra-islet beta-cell replication without modifying intra-islet beta-cell replication rates. Moreover, the treatment induced increases in insulin-positive cells located close to ducts; and in PDX-1 positive cells scattered in the exocrine tissue, suggesting active neogenesis. In islets from treated diabetic rats, tungstate is able to increase the phosphorylation state of PDX-1 through the activation of p38. Conclusion/interpretation. These observations indicate that tungstate treatment is able to regenerate a stable, functional pancreatic beta-cell population which leads to and maintains normoglycaemia. [Diabetologia (2004)

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Section: Tungstate Effects Persist After Withdrawal Of Treatmentsupporting

confidence: 65%

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confidence: 99%

Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate

et al. 2004

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“…The pancreatic beta-cell compartment undergoes dynamic turnover with a certain fraction of cells being replaced over time [43]. The beta cells can respond to an increased demand for insulin by hyperplasia and hypertrophy and can also respond to diminished requirements by reducing beta-cell mass.…”

Section: Discussionmentioning

confidence: 99%

Differential beta cell responses to hyperglycaemia and insulin resistance in two novel congenic strains of diabetes (FVB-Lepr db ) and obese (DBA-Lep ob ) mice

Chua¹,

Liu

et al. 2002

Diabetologia

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Aims. Our goal was to identify genetic variants that determine the response to insulin resistance and hyperglycaemia. This report documents the diabetes syndrome of two new congenic strains of mice generated by the transfer of the Lepr db mutation to the FVB/NJ strain and the Lep ob mutation to the DBA/2J strain. Methods. Mice were characterised by measures of blood metabolites and hormones along with challenges with glucose and insulin injections. Histological examinations of the endocrine pancreas and the kidneys were also carried out. Results. Obese mice of the FVB-db congenic strain show long-term hyperglycaemia that is primarily due to severe insulin resistance. The hyperglycaemia in the fed state persists despite escalating secretion of insulin and massive increase of pancreatic beta cells. Obese FVB-db mice show evidence of mesangial matrix expansion, a hallmark of diabetic nephropathy.Leptin-deficient mice of the DBA-ob strain have variable obesity-diabetes. In mice with high insulin (>10 ng/ml), DBA-ob/ob mice maintain their increased adiposity and have a large increase in betacell number. In mice with low insulin (<1 ng/ml) DBA-ob/ob mice have greatly diminished adiposity. These mice have atrophied islets with evidence of increased beta-cell neogenesis from the ductal epithelium. Conclusions. The strain-specific responses suggest the existence of genetic variants that control insulin sensitivity and beta-cell responses in the strains described in this report. These new models of obesity-diabetes should prove useful in dissecting the genetic control of beta-cell responses to hyperglycaemia and insulin resistance. [Diabetologia (2002) [6,7], SHR [8], and LA [9]. In rats, it seems that only obese males are subject to developing severe hyperglycaemia and contraction of beta-cell numbers.The loss of beta cells in these obesity-diabetes models is not mediated by the immune system. Studies have shown that C57BLKS/J db/db (K-db) mice develop their characteristic diabetes phenotype independent of a functional immune system [10]. The response of the beta cell in these obese rodents is subject to dietary influences. When placed on a completely carbohydrate-free diet (CHO-free diet), obese C57BLKS/J db/db mice are able to maintain near-euglycaemia and preserve their pancreatic beta-cell mass [11].While these strain-specific phenotypes have been documented [4], some of the congenic strains have been lost. This report describes the generation and characterisation of several new congenic mouse strains carrying mutations of Lep or Lepr. The FVB congenic strains (FVB-db and FVB-ob) provide a new diabetes phenotype that has not been described previously. Obese FVB mice suffer a prolonged period of hyperglycaemia that produces massive expansion of beta-cell mass. We show data that the early onset of severe insulin resistance probably accounts for the hyperglycaemia of these strains. The islet hyperplasia of obese FVB mice suggests that prolonged hyperglycaemia does not eventually lead to complete betacell atro...

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“…Quantification of ␤-cell mass was done by the planimetry method (27), and analysis of ␤-cell proliferation was performed as described (28) …”

Section: Methodsmentioning

confidence: 99%

Activin B receptor ALK7 is a negative regulator of pancreatic β-cell function

Bertolino

Holmberg

Reissmann

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

113

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All major cell types in pancreatic islets express the transforming growth factor (TGF)-␤ superfamily receptor ALK7, but the physiological function of this receptor has been unknown. Mutant mice lacking ALK7 showed normal pancreas organogenesis but developed an age-dependent syndrome involving progressive hyperinsulinemia, reduced insulin sensitivity, liver steatosis, impaired glucose tolerance, and islet enlargement. Hyperinsulinemia preceded the development of any other defect, indicating that this may be one primary consequence of the lack of ALK7. In agreement with this, mutant islets showed enhanced insulin secretion under sustained glucose stimulation, indicating that ALK7 negatively regulates glucose-stimulated insulin release in ␤-cells. Glucose increased expression of ALK7 and its ligand activin B in islets, but decreased that of activin A, which does not signal through ALK7. The two activins had opposite effects on Ca 2؉ signaling in islet cells, with activin A increasing, but activin B decreasing, glucosestimulated Ca 2؉ influx. On its own, activin B had no effect on WT cells, but stimulated Ca 2؉ influx in cells lacking ALK7. In accordance with this, mutant mice lacking activin B showed hyperinsulinemia comparable with that of Alk7 ؊/؊ mice, but double mutants showed no additive effects, suggesting that ALK7 and activin B function in a common pathway to regulate insulin secretion. These findings uncover an unexpected antagonism between activins A and B in the control of Ca 2؉ signaling in ␤-cells. We propose that ALK7 plays an important role in regulating the functional plasticity of pancreatic islets, negatively affecting ␤-cell function by mediating the effects of activin B on Ca 2؉ signaling.T he signaling networks controlling metabolic processes are highly regulated and integrate the actions of both positively and negatively acting components from many different signaling pathways. Members of the transforming growth factor (TGF)-␤ superfamily, including TGF-␤s, growth and differentiation factors (GDFs), bone morphogenetic proteins (BMPs) and activins, have been implicated in the regulation of several metabolic processes. These ligands signal via distinct complexes of type I and type II receptor serine-threonine kinases, each binding to different classes of TGF-␤ ligands (1, 2). The main and most widely studied signaling pathway downstream of these receptors involves activation and nuclear translocation of Smad proteins, which in turn regulate gene transcription through multiple interactions with distinct sets of transcription factors in a cell type-specific manner (1, 2). Although less well understood, Smad-independent pathways have also been described in a variety of cell systems and involve the activation of MAP kinases, small GTPases, and Ca 2ϩ mobilization (3).Identification of cell-intrinsic factors controlling the specification and function of pancreatic endocrine cells is of major importance for understanding the regulation of blood-glucose homeostasis. The characterization of signals regul...

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beta-cell turnover: its assessment and implications.

Cited by 209 publications

References 38 publications

Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate

Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate

Differential beta cell responses to hyperglycaemia and insulin resistance in two novel congenic strains of diabetes (FVB-Lepr db ) and obese (DBA-Lep ob ) mice

Activin B receptor ALK7 is a negative regulator of pancreatic β-cell function

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