Glucolipotoxicity of the pancreatic beta cell
Open accessAbstract
The concept of glucolipotoxicity refers to the combined, deleterious effects of elevated glucose and fatty acid levels on pancreatic beta-cell function and survival. Significant progress has been made in recent years towards a better understanding of the cellular and molecular basis of glucolipotoxicity in the beta cell. The permissive effect of elevated glucose on the detrimental actions of fatty acids stems from the influence of glucose on intracellular fatty acid metabolism, promoting the synthesis of cellular lipids. The combination of excessive levels of fatty acids and glucose therefore leads to decreased insulin secretion, impaired insulin gene expression, and beta-cell death by apoptosis, all of which probably have distinct underlying mechanisms. Recent studies from our laboratory have identified several pathways implicated in fatty acid inhibition of insulin gene expression, including the extracellular-regulated kinase (ERK1/2) pathway, the metabolic sensor Per-Arnt-Sim kinase (PASK), and the ATF6 branch of the unfolded protein response. We have also confirmed in vivo in rats that the decrease in insulin gene expression is an early defect which precedes any detectable abnormality in insulin secretion. While the role of glucolipotoxicity in humans is still debated, the inhibitory effects of chronically elevated fatty acid levels has been clearly demonstrated in several studies, at least in individuals genetically predisposed to developing type 2 diabetes. It is therefore likely that glucolipotoxicity contributes to beta-cell failure in type 2 diabetes as well as to the decline in beta-cell function observed after the onset of the disease.
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Metabolic and oxidative stress, primarily from obesity's excessive nutritional state, leads to β-cell damage associated with glucotoxicity, lipotoxicity, and glucolipotoxicity.
“Metabolic and oxidative stress, primarily from obesity’s excessive nutritional state, leads to β-cell damage associated with glucotoxicity, lipotoxicity, and glucolipotoxicity ( 42 ).”
From β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment (2014) · cites this paper as [42]
The Introduction (page not provided) links obesity with β-cell failure and identifies glucotoxicity, lipotoxicity, and glucolipotoxicity as proposed contributors to declining β-cell function. The Conclusions (page not provided) also discuss nutrient excess and oxidative stress, but describe some early responses as adaptive. The claim overstates the paper by presenting obesity-driven metabolic and oxidative stress as an established cause of β-cell damage; the paper says the contribution of glucolipotoxicity to human β-cell failure remains debated. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn vitro studies have found that exposure of islet beta-cells to glucolipotoxicity conditions results in impaired GSIS, impaired insulin expression, and cell death by apoptosis.
“A number of in vitro studies, using insulin-secreting cells and isolated islets, have found that exposure of islet beta-cells to glucolipotoxicity conditions results in impaired GSIS, impaired insulin expression, and cell death by apoptosis.167,168”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [167]
Application of in vitro glucolipotoxicity experiments to in vivo situations is questionable.
“The application of these experiments to in vivo situations is questionable as it has been demonstrated that non-diabetic obese subjects exhibit increased insulin secretion and an increase in beta-cell number and mass, and islet amyloid deposits are rare in these individuals as aforementioned in this review.”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [167]
Findings that glucolipotoxicity impairs beta-cell function likely do not apply to non-obese/overweight diabetic individuals.
“Despite the evidence generated by both in vitro and in vivo studies supporting that glucolipotoxicity impairs beta-cell function, these findings likely do not apply to non-obese/overweight diabetic individuals.”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [167]
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References 149 · Cited by 382
- Authors
- Poitout, V., Amyot, J., Semache, M., Zarrouki, B., Hagman, D., & Fontés, G.
- Affiliations
- Université de Montréal (CA)
- Corresponding author
- Poitout, Vincent
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
- Publisher
- Elsevier BV
- Published
- 2010-03
- Volume
- 1801
- Issue
- 3
- Pages
- 289-298
- ISSN
- 1388-1981 (ISSN-L)
- PMC
- PMC2824006
- OpenAlex
- W2101369715
- Cited by
- 382
- References
- 149
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 19 · 2023: 23 · 2022: 22 · 2021: 27 · 2020: 28 · 2019: 36 · 2018: 25 · 2017: 27 · 2016: 22 · 2015: 29 · 2014: 30 · 2013: 26 · 2012: 28
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Canadian Institutes of Health Research (MOP77686, 77686)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK058096, R01 DK 58096, R01DK058096)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- glucolipotoxicity, pancreatic beta cells, beta-cell death, insulin gene expression, insulin secretion, fatty acid metabolism, ERK signaling, PASK, unfolded protein response, ATF6, type 2 diabetes, beta-cell failure
- MeSH terms
- Animals, Fatty Acids, Female, Glucose, Humans, Insulin Resistance, Male, Obesity, Insulin-Secreting Cells, Lipid Metabolism Disorders
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