ArticleDiabetologia2011
Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure.
Article in Diabetologia, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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51 citing papers in PubMed, 91 citations in OpenAlex.
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- Identification of additional body weight QTLs in the Berlin Fat Mouse BFMI861 lines using time series data.Scientific reports · 2024Article
- PyCreas: a tool for quantification of localization and distribution of endocrine cell types in the islets of Langerhans.Frontiers in endocrinology · 2023Article
- Targeting pancreatic β cells for diabetes treatment.Nature metabolism · 2022Review
- Heterogeneous Development of β-Cell Populations in Diabetes-Resistant and -Susceptible Mice.Diabetes · 2022Article
- Resistance Exercise Training Improves Metabolic and Inflammatory Control in Adipose and Muscle Tissues in Mice Fed a High-Fat Diet.Nutrients · 2022Article
- Targeting β-cell dedifferentiation and transdifferentiation: opportunities and challenges.Endocrine connections · 2021Review
- Reduced Liver Autophagy in High-Fat Diet Induced Liver Steatosis in New Zealand Obese Mice.Antioxidants (Basel, Switzerland) · 2021Article
- β cell aging and age-related diabetes.Aging · 2021Review
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- Islet Health, Hormone Secretion, and Insulin Responsivity with Low-Carbohydrate Feeding in Diabetes.Metabolites · 2020Review
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- MicroRNA-24 promotes pancreatic beta cells toward dedifferentiation to avoid endoplasmic reticulum stress-induced apoptosis.Journal of molecular cell biology · 2019Article
- Alterations in Beta Cell Identity in Type 1 and Type 2 Diabetes.Current diabetes reports · 2019Review
- In Vivo Rodent Models of Type 2 Diabetes and Their Usefulness for Evaluating Flavonoid Bioactivity.Nutrients · 2019Review
- Diet-induced β-cell insulin resistance results in reversible loss of functional β-cell mass.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisCarbohydrate-free diet prevents hyperglycaemia and beta cell destruction in the New Zealand Obese (NZO) mouse model. Here we have used a sequential dietary regimen to dissociate the effects of obesity and hyperglycaemia on beta cell function and integrity, and to study glucose-induced alterations of key transcription factors over 16 days.
methodsMice were rendered obese by feeding a carbohydrate-free diet for 18 weeks. Thereafter, a carbohydrate-containing diet was given. Plasma glucose, plasma insulin and total pancreatic insulin were determined, and forkhead box O1 protein (FOXO1) phosphorylation and the transcription factors pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 protein (NKX6.1) and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (MAFA) were monitored by immunohistochemistry for 16 days.
resultsDietary carbohydrates produced a rapid and continuous increase in plasma glucose in NZO mice between day 2 and 16 after the dietary challenge. Hyperglycaemia caused a dramatic dephosphorylation of FOXO1 at day 2, followed by a progressive depletion of insulin stores. The loss of beta cells was triggered by apoptosis (detectable at day 8), associated with reduction of crucial transcription factors (PDX1, NKX6.1 and MAFA). Incubation of isolated islets from carbohydrate-restricted NZO mice or MIN6 cells with palmitate and glucose for 48 h resulted in a dephosphorylation of FOXO1 and thymoma viral proto-oncogene 1 (AKT) without changing the protein levels of both proteins. CONCLUSIONS/
interpretationThe dietary regimen dissociates the effects of obesity (lipotoxicity) from those of hyperglycaemia (glucotoxicity) in NZO mice. Obese NZO mice are unable to compensate for the carbohydrate challenge by increasing insulin secretion or synthesising adequate amounts of insulin. In response to the hyperglycaemia, FOXO1 is dephosphorylated, leading to reduced levels of beta cell-specific transcription factors and to apoptosis of the cells.
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