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Cited by 225Pancreatic function and diabetesDiabetes Treatment and ManagementEndoplasmic Reticulum Stress and Disease

β-cell failure as a complication of diabetes

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Chang-Chen, K. J., Mullur, R., Bernal-Mizrachi, E.·2008·Reviews in Endocrine and Metabolic Disorders
DOI 10.1007/s11154-008-9101-5PMC PMC4456188
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Abstract

Type 2 diabetes mellitus is a complex disease characterized by beta-cell failure in the setting of insulin resistance. In early stages of the disease, pancreatic beta-cells adapt to insulin resistance by increasing mass and function. As nutrient excess persists, hyperglycemia and elevated free fatty acids negatively impact beta-cell function. This happens by numerous mechanisms, including the generation of reactive oxygen species, alterations in metabolic pathways, increases in intracellular calcium and the activation of endoplasmic reticulum stress. These processes adversely affect beta-cells by impairing insulin secretion, decreasing insulin gene expression and ultimately causing apoptosis. In this review, we will first discuss the regulation of beta-cell mass during normal conditions. Then, we will discuss the mechanisms of beta-cell failure, including glucotoxicity, lipotoxicity and endoplasmic reticulum stress. Further research into mechanisms will reveal the key modulators of beta-cell failure and thus identify possible novel therapeutic targets. Type 2 diabetes mellitus is a multifactorial disease that has greatly risen in prevalence in part due to the obesity and inactivity that characterize the modern Western lifestyle. Pancreatic beta-cells possess the potential to greatly expand their function and mass in both physiologic and pathologic states of nutrient excess and increased insulin demand. beta-cell response to nutrient excess occurs by several mechanisms, including hypertrophy and proliferation of existing beta-cells, increased insulin production and secretion, and formation of new beta-cells from progenitor cells [1, 2]. Failure of pancreatic beta-cells to adequately expand in settings of increased insulin demand results in hyperglycemia and diabetes. In this review, we will first discuss the factors involved in beta-cell growth and then discuss the mechanisms by which beta-cell expansion fails and leads to beta-cell failure and diabetes (Fig. 1).

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  • Over time, recurrent postprandial hyperglycemia and prolonged insulin secretion may promote β-cell stress and accelerate progression from impaired glucose tolerance to overt T2D.

    “Over time, both mechanisms, recurrent postprandial hyperglycemia and prolonged insulin secretion, may promote β-cell stress and accelerate progression from impaired glucose tolerance to overt T2D (34,35).”

    From Melatonin Impairs Glucose Tolerance, First-Phase Insulin Secretion, and Insulin Feedback Inhibition; Interaction With <i>MTNR1B</i> Diabetes Risk Variant (2026) · cites this paper as [35]

    The Glucotoxicity and ER Stress sections (page numbers unavailable) link chronic hyperglycemia and increased biosynthetic demand to β-cell dysfunction and stress. They do not specifically establish that recurrent postprandial hyperglycemia or prolonged insulin secretion accelerates progression from impaired glucose tolerance to overt type 2 diabetes. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Chang-Chen, K. J., Mullur, R., & Bernal-Mizrachi, E.
Affiliations
Washington University in St. Louis (US)
ORCID
Mullur, R.
Venue
Reviews in Endocrine and Metabolic Disorders
Publisher
Springer Science and Business Media LLC
Published
2008-09-06
Volume
9
Issue
4
Pages
329-343
ISSN
  • 1389-9155 (ISSN-L)
  • 1573-2606
DOI
10.1007/s11154-008-9101-5
PMC
PMC4456188
OpenAlex
W2013604729
Cited by
225
References
15
Citations by year
2026: 7 · 2025: 5 · 2024: 4 · 2023: 9 · 2022: 7 · 2021: 15 · 2020: 7 · 2019: 6 · 2018: 12 · 2017: 17 · 2016: 10 · 2015: 17 · 2014: 10 · 2013: 21 · 2012: 28
FWCI
2.83
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Reviews in Endocrine and Metabolic Disorders (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK073716)
Topics
  • Health Sciences › Medicine › Surgery › 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
pancreatic beta-cell failure, type 2 diabetes, beta-cell mass expansion, insulin resistance, glucotoxicity, lipotoxicity, endoplasmic reticulum stress, reactive oxygen species, JNK signaling, PDX1, ceramide, fatty acid oxidation, AMPK, apoptosis, insulin secretion, free fatty acids, obesity, therapeutic target
MeSH terms
Animals, Diabetes Mellitus, Type 2, Endoplasmic Reticulum, Fatty Acids, Nonesterified, Glucose, Humans, Insulin, Insulin Resistance, Placental Lactogen, Prolactin, Somatomedins, Growth Hormone, Apoptosis, Hepatocyte Growth Factor, Parathyroid Hormone-Related Protein, Cell Proliferation, Insulin-Secreting Cells, Incretins

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