Weighing up β-cell mass in mice and humans: Self-renewal, progenitors or stem cells?

Hanley, Neil A.; Hanley, Karen Piper; Miettinen, Päivi J.; Otonkoski, Timo

doi:10.1016/j.mce.2008.03.001

Cited by 36 publications

(34 citation statements)

References 107 publications

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“…1a, e), were significantly lower (both p <0.01) in type 2 diabetic samples. Altogether, although obtained from a relatively small number of samples, these results largely confirm previous work reporting a decreased amount of beta cells in type 2 diabetes [2][3][4][5][6]. However, the main aim of the present study was to evaluate if this apparent loss of beta cells may be overestimated.…”

Section: Resultssupporting

confidence: 90%

“…Studies with pancreatic samples obtained at autopsy, from organ donors or after pancreatectomy have shown that beta cell mass is significantly reduced in type 2 diabetic individuals [2][3][4][5][6]. However, beta cell functional defects also play a major role in the pathophysiology of the disease [7], and improvements at this level may better explain, for instance, why 30-100% of patients who have undergone bariatric surgery may show diabetes remission within a few days after surgery and only a 1-2% weight loss [8].…”

Section: Introductionmentioning

confidence: 99%

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Are we overestimating the loss of beta cells in type 2 diabetes?

et al. 2013

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Aims/hypothesis Previous work has demonstrated that beta cell amount (whether measured as beta cell mass, beta cell volume or insulin-positive area) is decreased in type 2 diabetes; however, recent findings suggest that mechanisms other than death may contribute to beta cell failure in this disease. To better characterise beta cell mass and function in type 2 diabetes, we performed morphological, ultra-structural and functional studies using histological samples and isolated islets. Methods Pancreases from ten non-diabetic (ND) and ten matched type 2 diabetic organ donors were studied by insulin, glucagon and chromogranin A immunocytochemistry and electron microscopy (EM). Glucose-stimulated insulin secretion was assessed using isolated islets and studies were performed using independent ND islet preparations after 24 h exposure to 22.2 mmol/l glucose. Results Immunocytochemistry showed that the fractional islet insulin-positive area was lower in type 2 diabetic islets (54.9± 6.3% vs 72.1±8.7%, p <0.01), whereas glucagon (23.3 ± 5.4% vs 20.2 ± 5.3%) and chromogranin A (86.4±6.1% vs 89.0±5.5%) staining was similar between the two groups. EM showed that the proportion of beta cells in type 2 diabetic islets was only marginally decreased; marked beta cell degranulation was found in diabetic beta cells; these findings were all reproduced after exposing isolated ND islets to high glucose. Glucose-stimulated insulin secretion was 40-50% lower from type 2 diabetic islets ( p <0.01), which again was mimicked by culturing non-diabetic islets in high glucose. Conclusions/interpretation These results suggest that, at least in subgroups of type 2 diabetic patients, the loss of beta cells as assessed so far might be overestimated, possibly due to changes in beta cell phenotype other than death, also contributing to beta cell failure in type 2 diabetes.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Are we overestimating the loss of beta cells in type 2 diabetes?

et al. 2013

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“…NGN3, an unambiguous marker for islet progenitors, was absent in normal islets and markedly increased in STZ-IMT504 rats, suggesting that IMT504 may be triggering NGN3 synthesis in pancreas-resident progenitor cells [9], similar to what was observed when administrating bone marrow-derived cells [10]. Our results are consistent with the view that the adult pancreas retains the potential to reactivate its embryonic mode of beta cell formation under the proper stimuli [11], and this capacity is greatly enhanced by IMT504. Nevertheless, progenitor recruitment from other compartments may also occur.…”

Section: Discussionsupporting

confidence: 88%

Oligodeoxynucleotide IMT504 induces a marked recovery in a streptozotocin-induced model of diabetes in rats: correlation with an early increase in the expression of nestin and neurogenin 3 progenitor cell markers

Bianchi

Hernando-Insúa²,

Chasseing

et al. 2010

Diabetologia

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Aims/hypothesis IMT504 is an oligonucleotide that promotes tissue repair in bone injury and neuropathic pain models by stimulating progenitor cells. Here we evaluated the effect of IMT504 on the recovery of islet function in a streptozotocin (STZ)-induced model of diabetes in the rat. Methods Male Sprague-Dawley rats were injected with STZ (60 mg/kg, i.p., day1) or citrate buffer (Control). Animals with glycaemia between 11 and 20 mmol/l on day 4 were injected with IMT504 (4 mg/animal in saline, s.c., STZ-IMT504) or with saline (STZ-Saline) for 10 days. Glycaemia and water and food intake were recorded for 33 days. Intraperitoneal glucose tolerance tests (IPGTTs) were performed on day30. On day35, overnight-fasted animals were killed and blood samples and pancreases collected for hormonal and histological studies. A second group of STZ-IMT504 rats was killed, together with Control and STZ-Saline rats, after two consecutive days of blood glucose decreases after the beginning of IMT504 treatment. Pancreases were collected and proliferating cell nuclear antigen (PCNA), nestin and neurogenin 3 (NGN3) detected by immunohistochemistry. Results IMT504 greatly improved blood glucose and food and water intakes in STZ-IMT504 rats by day8, as well as IPGTTs on day30. Significant increases in islet number and beta cell content were observed in STZ-IMT504 rats (day 33). Furthermore, after two to five IMT504 injections, blood glucose decreased, and an increase in pancreatic nestin (mainly in endothelial cells), PCNA and NGN3 production (in islets) was observed in STZ-IMT504 rats. Conclusions/interpretation IMT504 induced a marked recovery of STZ-induced diabetes that correlated with early production of progenitor cell markers, such as nestin and NGN3.

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“…Moreover, most evidence for the presence of stem/progenitor cell-like populations in nondissociated adult human pancreatic tissue has been limited to detecting equivocal stem cell marker expression in various pancreatic cell types (53,(55)(56)(57). Here for the first time, we report that b-cell stress/hyperglycemia stimulates an adult tissue progenitor cell population within human islets to proliferate and produce more insulin + progeny.…”

Section: Discussionmentioning

confidence: 81%

Diabetes Enhances the Proliferation of Adult Pancreatic Multipotent Progenitor Cells and Biases Their Differentiation to More β-Cell Production

et al. 2014

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Endogenous pancreatic multipotent progenitors (PMPs) are ideal candidates for regenerative approaches to compensate for b-cell loss since their b-cell-producing capacities as well as strategic location would eliminate unnecessary invasive manipulations. However, little is known about the status and potentials of PMPs under diabetic conditions. Here we show that b-cell metabolic stress and hyperglycemia enhance the proliferation capacities of adult PMP cells and bias their production of progeny toward b-cells in mouse and human. These effects are dynamic and correlate with functional b-cell regeneration when conditions allow.

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Weighing up β-cell mass in mice and humans: Self-renewal, progenitors or stem cells?

Cited by 36 publications

References 107 publications

Are we overestimating the loss of beta cells in type 2 diabetes?

Are we overestimating the loss of beta cells in type 2 diabetes?

Oligodeoxynucleotide IMT504 induces a marked recovery in a streptozotocin-induced model of diabetes in rats: correlation with an early increase in the expression of nestin and neurogenin 3 progenitor cell markers

Diabetes Enhances the Proliferation of Adult Pancreatic Multipotent Progenitor Cells and Biases Their Differentiation to More β-Cell Production

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