Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic β-cells
Open accessAbstract
Insulin secretion from pancreatic β-cells is impaired in all forms of diabetes. The resultant hyperglycaemia has deleterious effects on many tissues, including β-cells. Here we show that chronic hyperglycaemia impairs glucose metabolism and alters expression of metabolic genes in pancreatic islets. In a mouse model of human neonatal diabetes, hyperglycaemia results in marked glycogen accumulation, and increased apoptosis in β-cells. Sulphonylurea therapy rapidly normalizes blood glucose levels, dissipates glycogen stores, increases autophagy and restores β-cell metabolism. Insulin therapy has the same effect but with slower kinetics. Similar changes are observed in mice expressing an activating glucokinase mutation, in in vitro models of hyperglycaemia, and in islets from type-2 diabetic patients. Altered β-cell metabolism may underlie both the progressive impairment of insulin secretion and reduced β-cell mass in diabetes.
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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 [97]
The Results (‘Diabetes duration impacts β-cell function’; page unavailable) define β-cell mass in diabetic mice by the extent of insulin staining, while the Discussion reports similar changes in insulin content or staining in T2DM. This supports the concern that staining need not directly measure cell number, but the paper does not establish that β-cell number or mass in people with T2DM has been underestimated. (LLM, conf=0.82)
Experimental — accuracy not yet measuredT2DM human islets accumulate large amounts of glycogen, like diabetic mouse β-cells.
“This idea is supported by the fact that like diabetic mouse β-cells (97), T2DM human islets accumulate large amounts of glycogen (97, 685).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [97]
Chronic hyperglycemia is associated with marked changes in expression of metabolic genes in mouse β-cells, and similar changes are observed in islets from individuals with T2DM.
“Chronic hyperglycemia is also associated with marked changes in expression of metabolic genes in mouse β-cells (97) and similar changes are observed in islets from individuals with T2DM (409, 430, 606).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [97]
Impaired β-cell metabolism in type 2 diabetes donor islets and in hyperglycaemic mouse neonatal diabetes β-cells supports the idea that inhibition of mitochondrial metabolism is central to β-cell dysfunction.
“Impairment in β-cell metabolism observed in islets from donors with T2DM and in β-cells from a mouse model of human neonatal diabetes upon exposure to hyperglycaemia support the notion that inhibition of mitochondrial metabolism is central to β-cell dysfunction143,144.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [144]
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- Authors
- Brereton, M. F., Rohm, M., Shimomura, K., Holland, C., Tornovsky-Babeay, S., Dadon, D., Iberl, M., Chibalina, M. V., Lee, S., Glaser, B., Dor, Y., Rorsman, P., Clark, A., & Ashcroft, F. M.
- Affiliations
- University of Oxford (GB)
- Hadassah Medical Center (IL)
- Hebrew University of Jerusalem (IL)
- Churchill Hospital (GB)
- Corresponding author
- Ashcroft, Frances M.
- ORCID
- Venue
- Nature Communications
- Published
- 2016-11-24
- Volume
- 7
- Issue
- 1
- Pages
- 13496-13496
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5123088
- OpenAlex
- W2553890212
- Cited by
- 124
- References
- 60
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 12 · 2023: 10 · 2022: 19 · 2021: 12 · 2020: 12 · 2019: 10 · 2018: 15 · 2017: 11
- FWCI
- 13.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Ulster University Research Portal (Ulster University) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (884655, 095531/Z/11/Z, 095531, 089795)
- University of Oxford
- European Commission (322620)
- Israel Science Foundation
- Novo Nordisk
- Japan Society for the Promotion of Science (26461366)
- 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
- hyperglycemia, pancreatic beta cells, glycogen accumulation, beta-cell apoptosis, insulin secretion, neonatal diabetes, sulphonylurea therapy, insulin therapy, autophagy, glucokinase mutations, glucose metabolism, type 2 diabetes, beta-cell mass, islets
- MeSH terms
- Animals, Autophagy, Blood Glucose, Cell Line, Diabetes Mellitus, Type 2, Disease Models, Animal, Glucokinase, Glycogen, Humans, Hyperglycemia, Hypoglycemic Agents, Infant, Newborn, Infant, Newborn, Diseases, Insulin, Mutation, Sulfonylurea Compounds, Apoptosis, Insulin-Secreting Cells, Mice, Rats, In Vitro Techniques
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