Adaptation and failure of pancreatic β cells in murine models with different degrees of metabolic syndrome

Gema Medina-Gomez, Laxman Yetukuri, Vidya Velagapudi, Mark Campbell, Margaret Blount, Mercedes Jimenez-Linan, Manuel Ros, Matej Oresic, Antonio Vidal-Puig

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Abstract

The events that contribute to the expansion of β-cell mass and enhanced β-cell function in insulin-resistant states have not been elucidated fully. Recently, we showed that β-cell adaptation failed dramatically in adult, insulin-resistant POKO mice, which contrasts with the appropriate expansion of β cells in their ob/ob littermates. Thus, we hypothesised that characterisation of the islets in these mouse models at an early age should provide a unique opportunity to: (1) identify mechanisms involved in sensing insulin resistance at the level of the β cells, (2) identify molecular effectors that contribute to increasing β-cell mass and function, and (3) distinguish primary events from secondary events that are more likely to be present at more advanced stages of diabetes. Our results define the POKO mouse as a model of early lipotoxicity. At 4 weeks of age, it manifests with inappropriate β-cell function and defects in proliferation markers. Other well-recognised pathogenic effectors that were observed previously in 16-week-old mice, such as increased reactive oxygen species (ROS), macrophage infiltration and endoplasmic reticulum (ER) stress, are also present in both young POKO and young ob/ob mice, indicating the lack of predictive power with regards to the severity of β-cell failure. Of interest, the relatively preserved lipidomic profile in islets from young POKO mice contrasted with the large changes in lipid composition and the differences in the chain length of triacylglycerols in the serum, liver, muscle and adipose tissue in adult POKO mice. Later lipotoxic insults in adult β cells contribute to the failure of the POKO β cell. Our results indicate that the rapid development of insulin resistance and β-cell failure in POKO mice makes this model a useful tool to study early molecular events leading to insulin resistance and β-cell failure. Furthermore, comparisons with ob/ob mice might reveal important adaptive mechanisms in β cells with either therapeutic or diagnostic potential.
Original languageEnglish
Pages (from-to)582-592
Number of pages11
JournalDisease models & mechanisms
Volume2
Issue number11-12
DOIs
Publication statusPublished - 2009
MoE publication typeA1 Journal article-refereed

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Insulin
Macrophages
Medical problems
Insulin Resistance
Chain length
Infiltration
Liver
Muscle
Reactive Oxygen Species
Triglycerides
Tissue
Lipids
Defects
Chemical analysis
Endoplasmic Reticulum Stress
Adipose Tissue
Muscles
Serum

Cite this

Medina-Gomez, G., Yetukuri, L., Velagapudi, V., Campbell, M., Blount, M., Jimenez-Linan, M., ... Vidal-Puig, A. (2009). Adaptation and failure of pancreatic β cells in murine models with different degrees of metabolic syndrome. Disease models & mechanisms, 2(11-12), 582-592. https://doi.org/10.1242/dmm.003251
Medina-Gomez, Gema ; Yetukuri, Laxman ; Velagapudi, Vidya ; Campbell, Mark ; Blount, Margaret ; Jimenez-Linan, Mercedes ; Ros, Manuel ; Oresic, Matej ; Vidal-Puig, Antonio. / Adaptation and failure of pancreatic β cells in murine models with different degrees of metabolic syndrome. In: Disease models & mechanisms. 2009 ; Vol. 2, No. 11-12. pp. 582-592.
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abstract = "The events that contribute to the expansion of β-cell mass and enhanced β-cell function in insulin-resistant states have not been elucidated fully. Recently, we showed that β-cell adaptation failed dramatically in adult, insulin-resistant POKO mice, which contrasts with the appropriate expansion of β cells in their ob/ob littermates. Thus, we hypothesised that characterisation of the islets in these mouse models at an early age should provide a unique opportunity to: (1) identify mechanisms involved in sensing insulin resistance at the level of the β cells, (2) identify molecular effectors that contribute to increasing β-cell mass and function, and (3) distinguish primary events from secondary events that are more likely to be present at more advanced stages of diabetes. Our results define the POKO mouse as a model of early lipotoxicity. At 4 weeks of age, it manifests with inappropriate β-cell function and defects in proliferation markers. Other well-recognised pathogenic effectors that were observed previously in 16-week-old mice, such as increased reactive oxygen species (ROS), macrophage infiltration and endoplasmic reticulum (ER) stress, are also present in both young POKO and young ob/ob mice, indicating the lack of predictive power with regards to the severity of β-cell failure. Of interest, the relatively preserved lipidomic profile in islets from young POKO mice contrasted with the large changes in lipid composition and the differences in the chain length of triacylglycerols in the serum, liver, muscle and adipose tissue in adult POKO mice. Later lipotoxic insults in adult β cells contribute to the failure of the POKO β cell. Our results indicate that the rapid development of insulin resistance and β-cell failure in POKO mice makes this model a useful tool to study early molecular events leading to insulin resistance and β-cell failure. Furthermore, comparisons with ob/ob mice might reveal important adaptive mechanisms in β cells with either therapeutic or diagnostic potential.",
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Medina-Gomez, G, Yetukuri, L, Velagapudi, V, Campbell, M, Blount, M, Jimenez-Linan, M, Ros, M, Oresic, M & Vidal-Puig, A 2009, 'Adaptation and failure of pancreatic β cells in murine models with different degrees of metabolic syndrome', Disease models & mechanisms, vol. 2, no. 11-12, pp. 582-592. https://doi.org/10.1242/dmm.003251

Adaptation and failure of pancreatic β cells in murine models with different degrees of metabolic syndrome. / Medina-Gomez, Gema; Yetukuri, Laxman; Velagapudi, Vidya; Campbell, Mark; Blount, Margaret; Jimenez-Linan, Mercedes; Ros, Manuel; Oresic, Matej; Vidal-Puig, Antonio.

In: Disease models & mechanisms, Vol. 2, No. 11-12, 2009, p. 582-592.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Adaptation and failure of pancreatic β cells in murine models with different degrees of metabolic syndrome

AU - Medina-Gomez, Gema

AU - Yetukuri, Laxman

AU - Velagapudi, Vidya

AU - Campbell, Mark

AU - Blount, Margaret

AU - Jimenez-Linan, Mercedes

AU - Ros, Manuel

AU - Oresic, Matej

AU - Vidal-Puig, Antonio

PY - 2009

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N2 - The events that contribute to the expansion of β-cell mass and enhanced β-cell function in insulin-resistant states have not been elucidated fully. Recently, we showed that β-cell adaptation failed dramatically in adult, insulin-resistant POKO mice, which contrasts with the appropriate expansion of β cells in their ob/ob littermates. Thus, we hypothesised that characterisation of the islets in these mouse models at an early age should provide a unique opportunity to: (1) identify mechanisms involved in sensing insulin resistance at the level of the β cells, (2) identify molecular effectors that contribute to increasing β-cell mass and function, and (3) distinguish primary events from secondary events that are more likely to be present at more advanced stages of diabetes. Our results define the POKO mouse as a model of early lipotoxicity. At 4 weeks of age, it manifests with inappropriate β-cell function and defects in proliferation markers. Other well-recognised pathogenic effectors that were observed previously in 16-week-old mice, such as increased reactive oxygen species (ROS), macrophage infiltration and endoplasmic reticulum (ER) stress, are also present in both young POKO and young ob/ob mice, indicating the lack of predictive power with regards to the severity of β-cell failure. Of interest, the relatively preserved lipidomic profile in islets from young POKO mice contrasted with the large changes in lipid composition and the differences in the chain length of triacylglycerols in the serum, liver, muscle and adipose tissue in adult POKO mice. Later lipotoxic insults in adult β cells contribute to the failure of the POKO β cell. Our results indicate that the rapid development of insulin resistance and β-cell failure in POKO mice makes this model a useful tool to study early molecular events leading to insulin resistance and β-cell failure. Furthermore, comparisons with ob/ob mice might reveal important adaptive mechanisms in β cells with either therapeutic or diagnostic potential.

AB - The events that contribute to the expansion of β-cell mass and enhanced β-cell function in insulin-resistant states have not been elucidated fully. Recently, we showed that β-cell adaptation failed dramatically in adult, insulin-resistant POKO mice, which contrasts with the appropriate expansion of β cells in their ob/ob littermates. Thus, we hypothesised that characterisation of the islets in these mouse models at an early age should provide a unique opportunity to: (1) identify mechanisms involved in sensing insulin resistance at the level of the β cells, (2) identify molecular effectors that contribute to increasing β-cell mass and function, and (3) distinguish primary events from secondary events that are more likely to be present at more advanced stages of diabetes. Our results define the POKO mouse as a model of early lipotoxicity. At 4 weeks of age, it manifests with inappropriate β-cell function and defects in proliferation markers. Other well-recognised pathogenic effectors that were observed previously in 16-week-old mice, such as increased reactive oxygen species (ROS), macrophage infiltration and endoplasmic reticulum (ER) stress, are also present in both young POKO and young ob/ob mice, indicating the lack of predictive power with regards to the severity of β-cell failure. Of interest, the relatively preserved lipidomic profile in islets from young POKO mice contrasted with the large changes in lipid composition and the differences in the chain length of triacylglycerols in the serum, liver, muscle and adipose tissue in adult POKO mice. Later lipotoxic insults in adult β cells contribute to the failure of the POKO β cell. Our results indicate that the rapid development of insulin resistance and β-cell failure in POKO mice makes this model a useful tool to study early molecular events leading to insulin resistance and β-cell failure. Furthermore, comparisons with ob/ob mice might reveal important adaptive mechanisms in β cells with either therapeutic or diagnostic potential.

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DO - 10.1242/dmm.003251

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Medina-Gomez G, Yetukuri L, Velagapudi V, Campbell M, Blount M, Jimenez-Linan M et al. Adaptation and failure of pancreatic β cells in murine models with different degrees of metabolic syndrome. Disease models & mechanisms. 2009;2(11-12):582-592. https://doi.org/10.1242/dmm.003251