Maintenance of β-Cell Maturity and Plasticity in the Adult Pancreas

Szabat, Marta; Lynn, Francis C.; Hoffman, Brad G.; Kieffer, Timothy J.; Allan, Douglas W.; Johnson, James D.

doi:10.2337/db11-1361

Cited by 64 publications

(59 citation statements)

References 90 publications

(130 reference statements)

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“…β Cells are highly differentiated cells with more than 30% of mRNA that encodes insulin (28). Developing and maintaining such a differentiated status is an active process that requires energy (29). Energy is also necessary for cell proliferation.…”

Section: Figurementioning

confidence: 99%

Development of a conditionally immortalized human pancreatic β cell line

Scharfmann¹,

Pechberty²,

Hazhouz³

et al. 2014

J. Clin. Invest.

170

193

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Diabetic patients exhibit a reduction in β cells, which secrete insulin to help regulate glucose homeostasis; however, little is known about the factors that regulate proliferation of these cells in human pancreas. Access to primary human β cells is limited and a challenge for both functional studies and drug discovery progress. We previously reported the generation of a human β cell line (EndoC-βH1) that was generated from human fetal pancreas by targeted oncogenesis followed by in vivo cell differentiation in mice. EndoC-βH1 cells display many functional properties of adult β cells, including expression of β cell markers and insulin secretion following glucose stimulation; however, unlike primary β cells, EndoC-βH1 cells continuously proliferate. Here, we devised a strategy to generate conditionally immortalized human β cell lines based on Cre-mediated excision of the immortalizing transgenes. The resulting cell line (EndoC-βH2) could be massively amplified in vitro. After expansion, transgenes were efficiently excised upon Cre expression, leading to an arrest of cell proliferation and pronounced enhancement of β cell-specific features such as insulin expression, content, and secretion. Our data indicate that excised EndoC-βH2 cells are highly representative of human β cells and should be a valuable tool for further analysis of human β cells.

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Section: Figurementioning

confidence: 99%

Development of a conditionally immortalized human pancreatic β cell line

Scharfmann¹,

Pechberty²,

Hazhouz³

et al. 2014

J. Clin. Invest.

170

193

View full text Add to dashboard Cite

show abstract

“…Insulin levels can be tempered through stimulation or repression of its secretion, and insulin production is also subject to modulation, at the level of transcription, mRNA stability, translation and processing (Melloul et al 2002, Fu et al 2013. Basal insulin levels are also modulated chronically through changes in the number of beta-cells and their differentiation status (Szabat et al 2012). One of the unexpected insights from our studies on insulinmutant mice is that although differences in gene dosage (and therefore insulin synthesis) usually translate into measurable changes in insulin secretion in the long-term (Mehran et al 2012, Templeman et al 2015, this is not always the case .…”

Section: Nutritional Regulation Of Insulin Secretionmentioning

confidence: 99%

A causal role for hyperinsulinemia in obesity

Templeman

Skovsø

Page

et al. 2017

Journal of Endocrinology

134

116

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Insulin modulates the biochemical pathways controlling lipid uptake, lipolysis and lipogenesis at multiple levels. Elevated insulin levels are associated with obesity, and conversely, dietary and pharmacological manipulations that reduce insulin have occasionally been reported to cause weight loss. However, the causal role of insulin hypersecretion in the development of mammalian obesity remained controversial in the absence of direct loss-of-function experiments. Here, we discuss theoretical considerations around the causal role of excess insulin for obesity, as well as recent studies employing mice that are genetically incapable of the rapid and sustained hyperinsulinemia that normally accompanies a high-fat diet. We also discuss new evidence demonstrating that modest reductions in circulating insulin prevent weight gain, with sustained effects that can persist after insulin levels normalize. Importantly, evidence from long-term studies reveals that a modest reduction in circulating insulin is not associated with impaired glucose homeostasis, meaning that body weight and lipid homeostasis are actually more sensitive to small changes in circulating insulin than glucose homeostasis in these models. Collectively, the evidence from new studies on genetic loss-of-function models forces a re-evaluation of current paradigms related to obesity, insulin resistance and diabetes. The potential for translation of these findings to humans is briefly discussed.

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“…We recently showed (10) that loss of b-cell identity with the conversion of b-cells into glucagon-containing a-cells can occur in human pancreatic islets ex vivo. A number of transcription factors have been identified to be essential for the development and maintenance of functional b-cells (11,12). Recent reports (13,14) indicate that a selective loss of transcription factors MafA, Nkx6.1, and Pdx1 is associated with b-cell dysfunction and T2DM.…”

mentioning

confidence: 99%

Loss of β-Cell Identity Occurs in Type 2 Diabetes and Is Associated With Islet Amyloid Deposits

et al. 2015

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Loss of pancreatic islet b-cell mass and b-cell dysfunction are central in the development of type 2 diabetes (T2DM). We recently showed that mature human insulincontaining b-cells can convert into glucagon-containing a-cells ex vivo. This loss of b-cell identity was characterized by the presence of b-cell transcription factors (Nkx6.1, Pdx1) in glucagon + cells. Here, we investigated whether the loss of b-cell identity also occurs in vivo, and whether it is related to the presence of (pre)diabetes in humans and nonhuman primates. We observed an eight times increased frequency of insulin + cells coexpressing glucagon in donors with diabetes. Up to 5% of the cells that were Nkx6.1 + but insulin 2 coexpressed glucagon, which represents a five times increased frequency compared with the control group. This increase in bihormonal and Nkx6.1 + glucagon + insulin 2 cells was also found in islets of diabetic macaques. The higher proportion of bihormonal cells and Nkx6.1 + glucagon + insulin 2 cells in macaques and humans with diabetes was correlated with the presence and extent of islet amyloidosis. These data indicate that the loss of b-cell identity occurs in T2DM and could contribute to the decrease of functional b-cell mass. Maintenance of b-cell identity is a potential novel strategy to preserve b-cell function in diabetes.Loss of pancreatic b-cell mass and b-cell dysfunction are central in the development of type 2 diabetes (T2DM) and, in combination with peripheral insulin resistance, lead to hyperglycemia (1). Whereas b-cells, on the one hand, fail to properly secrete insulin at a given glucose level, there is also a progressive decline in the number of b-cells (2,3). Loss of b-cell mass has been ascribed to increased apoptosis in T2DM (4). In patients with T2DM, b-cell mass can be up to 40-60% lower than in healthy control subjects (4-6). In addition, abnormal function of glucagon-producing a-cells leading to hyperglucagonemia is associated with T2DM (7). b-cell dedifferentiation and subsequent transition to other islet cell types were suggested as an alternative explanation for the loss of functional b-cell mass in mice (8,9). In this concept, b-cells lose insulin content and insulin secretory capacity followed by the production of other endocrine hormones such as glucagon (8). We recently showed (10) that loss of b-cell identity with the conversion of b-cells into glucagon-containing a-cells can occur in human pancreatic islets ex vivo.A number of transcription factors have been identified to be essential for the development and maintenance of functional b-cells (11,12). Recent reports (13,14) indicate that a selective loss of transcription factors MafA, Nkx6.1, and Pdx1 is associated with b-cell dysfunction and T2DM. Chronic hyperglycemia in rats is accompanied by the loss of b-cell transcription factors (15). Moreover, mouse b-cells that genetically lack FOXO1 can dedifferentiate in vivo under conditions of metabolic stress and subsequently can convert (or transdifferentiate) into glucagonproducing a-cells...

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Maintenance of β-Cell Maturity and Plasticity in the Adult Pancreas

Cited by 64 publications

References 90 publications

Development of a conditionally immortalized human pancreatic β cell line

Development of a conditionally immortalized human pancreatic β cell line

A causal role for hyperinsulinemia in obesity

Loss of β-Cell Identity Occurs in Type 2 Diabetes and Is Associated With Islet Amyloid Deposits

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