Cited by 743Pancreatic function and diabetesDiabetes Treatment and ManagementEndoplasmic Reticulum Stress and Disease

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Minireview: Secondary β-Cell Failure in Type 2 Diabetes—A Convergence of Glucotoxicity and Lipotoxicity

Poitout, Vincent, Robertson, R. Paul·2002·Endocrinology

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Abstract

Chronic hyperglycemia and hyperlipidemia can exert deleterious effects on beta-cell function, respectively referred to as glucotoxicity and lipotoxicity. Over time, both contribute to the progressive deterioration of glucose homeostasis characteristic of type 2 diabetes. The mechanisms of glucotoxicity involve several transcription factors and are, at least in part, mediated by generation of chronic oxidative stress. Lipotoxicity is probably mediated by accumulation of a cytosolic signal derived from the fatty acid esterification pathway. Our view that hyperglycemia is a prerequisite for lipotoxicity is supported by several recent studies performed in our laboratories. First, prolonged in vitro exposure of isolated islets to fatty acids decreases insulin gene expression in the presence of high glucose concentrations only, and glucose is rate-limiting for the incorporation of fatty acids into neutral lipids. Second, normalization of blood glucose in Zucker diabetic fatty rats prevents accumulation of triglycerides and impairment of insulin gene expression in islets, whereas normalization of plasma lipid levels is without effect. Third, high-fat feeding in Goto-Kakizaki rats significantly impairs glucose-induced insulin secretion in vitro, whereas a similar diet has no effect in normoglycemic animals. We propose that chronic hyperglycemia, independent of hyperlipidemia, is toxic for beta-cell function, whereas chronic hyperlipidemia is deleterious only in the context of concomitant hyperglycemia.

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“The resulting high glucose causes fatigue in β-cells and oxidative stress (Brownlee 2003, Poitout and Robertson, 2002).”
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Recent Updates in Pharmacological Properties of Chitooligosaccharides
Marmouzi, I., Ezzat, S. M., Salama, M. M., Merghany, R. M., Attar, A. M., Eldesoky, A. M., & Mohamed, S. O. (2019) · BioMed Research International · doi:10.1155/2019/4568039 · Cited by 28
“COS also can defend INS-1 cell against apoptosis [83] which occurs as a result of increasing the circulating glucose, saturated FA [84, 85], inflammatory markers [86], and oxidative stress [87–89].”
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“The hypothesis proposed in this review is that glucotoxicity and lipotoxicity are in fact synergistic, and that lipotoxicity only exists in the context of chronic hyperglycemia (Poitout and Robertson 2002).”
BackgroundSelf-citation
Evidence that protein kinase Cdelta is not required for palmitate-induced cytotoxicity in BRIN-BD11 beta-cells.
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“Previous studies have shown that the combination of HG þ PA are potent inducers of ER stress and b-cell dysfunction in pancreatic b-cells (Poitout and Robertson, 2002; Poitout et al., 2010).”
Background
Palmitic acid acutely inhibits acetylcholine- but not GLP-1-stimulated insulin secretion in mouse pancreatic islets
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Background
Lack of GPR40 / FFAR 1 does not induce diabetes even under insulin resistance condition
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Mutated ATP synthase induces oxidative stress and impaired insulin secretion in β‐cells of female BHE/cdb rats
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“Therefore, we hypothesized that impaired GSIS and disrupted islet morphology might be associated with markers of oxidative stress in addition to lower ATP production in BHE/cdb rats exhibiting impaired glucose tolerance.”
BackgroundInfluential
High-throughput screening for fatty acid uptake inhibitors in humanized yeast identifies atypical antipsychotic drugs that cause dyslipidemias
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Fasiglifam/TAK-875, a Selective GPR40 Agonist, Improves Hyperglycemia in Rats Unresponsive to Sulfonylureas and Acts Additively with Sulfonylureas
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“This is thought to be broadly associated with b -cell exhaustion by long-term overstimulation and glucose toxicity caused by poor glycemic control (Poitout and Robertson, 2002; Rustenbeck, 2002).”
Background
Treatment of hyperglycaemia in newly diagnosed diabetic patients is associated with a reduction in oxidative stress and improvement in β‐cell function
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“Progressive decline of β-cell function in pre-diabetes is partially attributed to increasing ‘hyperglycaemia’ (glucotoxicity) [14,49].”
Background
Control of Voltage-gated Potassium Channel Kv2.2 Expression by Pyruvate-Isocitrate Cycling Regulates Glucose-stimulated Insulin Secretion
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Blood Glucose Control for Individuals with Type-2 Diabetes
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Authors: Poitout, V., & Robertson, R. P.
Affiliations: University of Washington (US)
Corresponding author: Poitout, Vincent
ORCID: Poitout, Vincent
Robertson, R. Paul
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2002-02
Volume: 143
Issue: 2
Pages: 339-342
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/endo.143.2.8623
OpenAlex: W1971701221
Cited by: 743
References: 0
Citations by year: 2026: 6 · 2025: 9 · 2024: 9 · 2023: 11 · 2022: 13 · 2021: 24 · 2020: 23 · 2019: 16 · 2018: 22 · 2017: 24 · 2016: 20 · 2015: 49 · 2014: 41 · 2013: 41 · 2012: 45
FWCI: 37.55
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (R-01-DK-38325, R01 DK 58096)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords: type 2 diabetes, beta-cell dysfunction, glucotoxicity, lipotoxicity, hyperglycemia, hyperlipidemia, oxidative stress, transcription factors, fatty acid esterification, insulin gene expression, glucose-stimulated insulin secretion, triglyceride accumulation, high-fat diet, islets
MeSH terms: Animals, Chronic Disease, Diabetes Mellitus, Type 2, Humans, Hyperglycemia, Hyperlipidemias, Islets of Langerhans

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Minireview: Secondary β-Cell Failure in Type 2 Diabetes—A Convergence of Glucotoxicity and Lipotoxicity

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