The DOI matches its Crossref record; 110 of the 110 references it cites were found in a registry or an index.
Stress-impaired transcription factor expression and insulin secretion in transplanted human islets
Open accessAbstract
Type 2 diabetes is characterized by insulin resistance, hyperglycemia, and progressive β cell dysfunction. Excess glucose and lipid impair β cell function in islet cell lines, cultured rodent and human islets, and in vivo rodent models. Here, we examined the mechanistic consequences of glucotoxic and lipotoxic conditions on human islets in vivo and developed and/or used 3 complementary models that allowed comparison of the effects of hyperglycemic and/or insulin-resistant metabolic stress conditions on human and mouse islets, which responded quite differently to these challenges. Hyperglycemia and/or insulin resistance impaired insulin secretion only from human islets in vivo. In human grafts, chronic insulin resistance decreased antioxidant enzyme expression and increased superoxide and amyloid formation. In human islet grafts, expression of transcription factors NKX6.1 and MAFB was decreased by chronic insulin resistance, but only MAFB decreased under chronic hyperglycemia. Knockdown of NKX6.1 or MAFB expression in a human β cell line recapitulated the insulin secretion defect seen in vivo. Contrary to rodent islet studies, neither insulin resistance nor hyperglycemia led to human β cell proliferation or apoptosis. These results demonstrate profound differences in how excess glucose or lipid influence mouse and human insulin secretion and β cell activity and show that reduced expression of key islet-enriched transcription factors is an important mediator of glucotoxicity and lipotoxicity.
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“Stress from a high glucose environment can cause downregulation of key islet genes and decreased function in human islets135 and animal models123, implicating that adequate glucose control is important for β cell health in the immediate aftermath of transplantation.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [135]
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1 retracted
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Metadata
- Authors
- Dai, C., Kayton, N. S., Shostak, A., Poffenberger, G., Cyphert, H. A., Aramandla, R., Thompson, C., Papagiannis, I. G., Emfinger, C., Shiota, M., Stafford, J. M., Greiner, D. L., Herrera, P. L., Shultz, L. D., Stein, R., & Powers, A. C.
- Affiliations
- Vanderbilt University Medical Center (US)
- VA Tennessee Valley Healthcare System (US)
- University of Massachusetts Chan Medical School (US)
- University of Geneva (CH)
- Jackson Laboratory (US)
- Corresponding author
- Powers, Alvin C.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2016-04-11
- Volume
- 126
- Issue
- 5
- Pages
- 1857-1870
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC4855919
- OpenAlex
- W2329987517
- Cited by
- 109
- References
- 109
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 14 · 2023: 14 · 2022: 7 · 2021: 18 · 2020: 11 · 2019: 9 · 2018: 7 · 2017: 12 · 2016: 1
- FWCI
- 10.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- U.S. Department of Veterans Affairs (I01 BX002223, BX002223, BX000666, I01 BX000666)
- Vanderbilt University (DK20593)
- Leona M. and Harry B. Helmsley Charitable Trust (2012PG-T1D018, 2015PG-T1D057)
- National Institutes of Health (1s10od021630-01, 1uc4dk104218-01, 5p60dk020593-31)
- Vanderbilt Diabetes Research and Training Center, Vanderbilt University Medical Center (DK-20593)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK68854, DK68764, UC4-DK-104218, DK-97829, DK-63439, R01DK068764, P60-DK020593, DK-108120, U01DK089572, DK89538, DK69603, DK-89572, DK66636, DK-72473, DK-94199, R21DK066636, R21DK068854, DK 07563, DK104211, DK92758, DK 20593, U01DK089538, DK104218, R21DK063439, R01DK097829, DK62641, DK-106755, R24DK092758, UC4DK104211, R01DK069603, R21DK062641, R24DK106755, R33DK066636, UC4DK108120, R01DK050203, U01DK072473, R56DK050203, R01DK094199, T32DK007563, P30DK020593, R01DK090570)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- type 2 diabetes, islet transplantation, insulin secretion, glucotoxicity, lipotoxicity, hyperglycemia, insulin resistance, beta-cell dysfunction, NKX6.1, MAFB, transcription factors, antioxidant enzymes, superoxide, amyloid fibril formation, beta-cell proliferation, beta-cell apoptosis, species differences
- MeSH terms
- Animals, Gene Expression Regulation, Humans, Islets of Langerhans Transplantation, Mice, Knockout, Homeodomain Proteins, Insulin-Secreting Cells, MafB Transcription Factor, Mice, Heterografts
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