Pancreatic β Cell Dedifferentiation as a Mechanism of Diabetic β Cell Failure
Open accessAbstract
Diabetes is associated with β cell failure. But it remains unclear whether the latter results from reduced β cell number or function. FoxO1 integrates β cell proliferation with adaptive β cell function. We interrogated the contribution of these two processes to β cell dysfunction, using mice lacking FoxO1 in β cells. FoxO1 ablation caused hyperglycemia with reduced β cell mass following physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrated that loss of β cell mass was due to β cell dedifferentiation, not death. Dedifferentiated β cells reverted to progenitor-like cells expressing Neurogenin3, Oct4, Nanog, and L-Myc. A subset of FoxO1-deficient β cells adopted the α cell fate, resulting in hyperglucagonemia. Strikingly, we identify the same sequence of events as a feature of different models of murine diabetes. We propose that dedifferentiation trumps endocrine cell death in the natural history of β cell failure and suggest that treatment of β cell dysfunction should restore differentiation, rather than promoting β cell replication.
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β-cell mass in T2DM may have been underestimated due to equating a reduction in insulin staining/content with a reduction in β-cell number.
“Furthermore, there is evidence that β-cell mass in T2DM may have been underestimated due to equating a reduction in insulin staining/content with a reduction in β-cell number (97, 429, 667).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [667]
The Results sections on cell-autonomous dedifferentiation and relevance to type 2 diabetes (pages unavailable) show that cells descended from β-cells can lose insulin staining while endocrine mass persists in diabetic mice. This supports the proposed reason an insulin-based estimate could be too low, but the paper does not establish that β-cell mass estimates in people with T2DM have been underestimated. (LLM, conf=0.82)
Experimental — accuracy not yet measuredβ-Cell dysfunction due to FoxO1 deficiency during pregnancy and aging is primarily associated with β-cell dedifferentiation rather than death in mice.
“Mouse studies led by Accili and colleagues ( 34 ) have shown that β-cell dysfunction due to FoxO1 deficiency during pregnancy and aging is primarily associated with β-cell dedifferentiation rather than death.”
From β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment (2014) · cites this paper as [34]
Reduced prohormone processing enzyme expression has been described in models of islet dedifferentiation.
“Additionally, reduced prohormone processing enzyme expression has also been described in models of islet dedifferentiation, a phenotype observed in our models, with an increase in proinsulin relative to insulin staining, and decreased expression of processing enzymes [44].”
The essential mechanisms behind bariatric surgery are weight loss and decrease in body fat content, rather than any direct surgical effect.
“The essential mechanisms behind bariatric surgery are weight loss and decrease in body fat content, rather than any direct surgical effect.27,28,29,30,31”
From Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial (2018) · cites this paper as [27]
The Results section discusses mouse models of β-cell dysfunction, and the Discussion addresses β-cell dedifferentiation under metabolic stress; neither addresses the mechanisms of bariatric surgery. Searches for bariatric surgery, weight loss, body-fat reduction, and direct surgical effects found no relevant passage in our copy. (LLM, conf=0.74)
Experimental — accuracy not yet measuredA subset of islet beta-cells may undergo conversion into other endocrine islet cell types in T2D, which may account for increased alpha-cell population and distorted insulin-to-glucagon ratios.
“Evidence is emerging that a subset of islet beta-cells may undergo conversion into other endocrine islet cell types in T2D, which may account for the increased alpha-cell population observed in some T2D patients and their distorted insulin-to-glucagon ratios.156”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [156]
In ADVANCE, microvascular benefit was shown, with magnitude related to degree of glucose control and affecting largely renal outcomes (reduction in microalbuminuria).
“Such a microvascular benefit was also shown in ADVANCE, the magnitude being related to the degree of glucose control and affecting largely renal outcomes (essentially a reduction in microalbuminuria)124.”
From Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future (2014) · cites this paper as [124]
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References 60 · Cited by 1,415
- Authors
- Talchai, C., Xuan, S., Lin, H. V., Sussel, L., & Accili, D.
- Affiliations
- Columbia University (US)
- Lilly (China) (CN)
- Corresponding author
- Accili, Domenico
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 150
- Issue
- 6
- Pages
- 1223-1234
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3445031
- OpenAlex
- W2061574308
- Cited by
- 1,415
- References
- 60
- Citations by year
- 2026: 75 · 2025: 85 · 2024: 89 · 2023: 114 · 2022: 123 · 2021: 137 · 2020: 125 · 2019: 101 · 2018: 86 · 2017: 107 · 2016: 102 · 2015: 104 · 2014: 79 · 2013: 77 · 2012: 11
- FWCI
- 88.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 380 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL087123)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK057539, DK63608, R01DK058282, R37DK058282, DK-64819, DK58282, P30DK063608, R01DK082590, R01DK064819)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- beta-cell failure, FOXO1, diabetes mellitus, beta-cell mass, beta-cell proliferation, beta cell differentiation, progenitor-like cells, neurogenin 3, Oct4, Nanog, L-myc, hyperglucagonemia, hyperglycemia, multiparity, aging, lineage tracing
- MeSH terms
- Forkhead Box Protein O1, Animals, Diabetes Mellitus, Type 2, Insulin, Male, Pancreas, Insulin-Secreting Cells, Mice, Forkhead Transcription Factors, Cell Dedifferentiation
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