Susceptibility to Fatty Acid-Induced β-Cell Dysfunction Is Enhanced in Prediabetic Diabetes-Prone BioBreeding Rats: A Potential Link Between β-Cell Lipotoxicity and Islet Inflammation

Tang, Christine; Naassan, Anthony E.; Chamson-Reig, Astrid; Koulajian, Khajag; Goh, Tracy; Yoon, F.; Oprescu, Andrei I.; Ghanim, Husam; Lewis, Gary F.; Dandona, Paresh; Donath, Marc Y.; Ehses, Jan A.; Arany, Edith; Giacca, Adria

doi:10.1210/en.2012-1720

Cited by 36 publications

(36 citation statements)

References 60 publications

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“…7 In the diabetes-prone BioBreeding rat, an animal model of T1D, increasing the plasma-free fatty acid levels by two-fold significantly impaired beta cell function and augmented islet cytokine levels. 33 …”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress sensitizes pancreatic beta cells to interleukin-1β-induced apoptosis via Bim/A1 imbalance

et al. 2013

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We have recently shown that the crosstalk between mild endoplasmic reticulum (ER) stress and low concentrations of the pro-inflammatory cytokine interleukin (IL)-1β exacerbates beta cell inflammatory responses via the IRE1α/XBP1 pathway. We presently investigated whether mild ER stress also sensitizes beta cells to cytokine-induced apoptosis. Cyclopiazonic acid (CPA)-induced ER stress enhanced the IL-1β apoptosis in INS-1E and primary rat beta cells. This was not prevented by XBP1 knockdown (KD), indicating the dissociation between the pathways leading to inflammation and cell death. Analysis of the role of pro- and anti-apoptotic proteins in cytokine-induced apoptosis indicated a central role for the pro-apoptotic BH3 (Bcl-2 homology 3)-only protein Bim (Bcl-2-interacting mediator of cell death), which was counteracted by four anti-apoptotic Bcl-2 (B-cell lymphoma-2) proteins, namely Bcl-2, Bcl-XL, Mcl-1 and A1. CPA+IL-1β-induced beta cell apoptosis was accompanied by increased expression of Bim, particularly the most pro-apoptotic variant, small isoform of Bim (BimS), and decreased expression of A1. Bim silencing protected against CPA+IL-1β-induced apoptosis, whereas A1 KD aggravated cell death. Bim inhibition protected against cell death caused by A1 silencing under all conditions studied. In conclusion, mild ER stress predisposes beta cells to the pro-apoptotic effects of IL-1β by disrupting the balance between pro- and anti-apoptotic Bcl-2 proteins. These findings link ER stress to exacerbated apoptosis during islet inflammation and provide potential mechanistic targets for beta cell protection, namely downregulation of Bim and upregulation of A1.

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Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress sensitizes pancreatic beta cells to interleukin-1β-induced apoptosis via Bim/A1 imbalance

et al. 2013

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“…Stomach content did not differ between animals in the different diet groups, but there was a clear lipid layer in plasma of many of the animals on the fcHF diet and even more for animals on the fcHFHS diet. As lipids infused directly in the blood stream can reduce insulin sensitivity (Lam et al 2003, Tang et al 2013, Pereira et al 2014, we therefore choose to provide animals with chow only the evening before the clamp and remove the saturated fat and/or sucrose from the cage. All rats received 20 g of chow.…”

Section: Hyperinsulinemic Euglycemic Clamp and Stable Isotope Infusionmentioning

confidence: 99%

Differential effects of hypercaloric choice diets on insulin sensitivity in rats

Diepenbroek

Eggels

Ackermans

et al. 2017

Journal of Endocrinology

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We showed previously that rats on a free-choice high-fat, high-sugar (fcHFHS) diet become rapidly obese and develop glucose intolerance within a week. Interestingly, neither rats on a free-choice high-fat diet (fcHF), although equally obese and hyperphagic, nor rats on a free-choice high-sugar (fcHS) diet consuming more sugar water, develop glucose intolerance. Here, we investigate whether changes in insulin sensitivity contribute to the observed glucose intolerance and whether this is related to consumption of saturated fat and/or sugar water. Rats received either a fcHFHS, fcHF, fcHS or chow diet for one week. We performed a hyperinsulinemic-euglycemic clamp with stable isotope dilution to measure endogenous glucose production (EGP; hepatic insulin sensitivity) and glucose disappearance (Rd; peripheral insulin sensitivity). Rats on all free-choice diets were hyperphagic, but only fcHFHS-fed rats showed significantly increased adiposity. EGP suppression by hyperinsulinemia in fcHF-fed and fcHFHS-fed rats was significantly decreased compared with chow-fed rats. One week fcHFHS diet also significantly decreased Rd. Neither EGP suppression nor Rd was affected in fcHS-fed rats. Our results imply that, short-term fat feeding impaired hepatic insulin sensitivity, whereas short-term consumption of both saturated fat and sugar water impaired hepatic and peripheral insulin sensitivity. The latter likely contributed to glucose intolerance observed previously. In contrast, overconsumption of only sugar water affected insulin sensitivity slightly, but not significantly, in spite of similar adiposity as fcHF-fed rats and higher sugar intake compared with fcHFHS-fed rats. These data imply that the palatable component consumed plays a role in the development of site-specific insulin sensitivity.

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“…In some cases inflammatory signals are propagated via intracellular lipid species as described below. Lipid exposure in vivo increases islet inflammation, and inflammatory cytokines and immune cells are present in the pancreas in T2D (recent examples: [17, 18]). Treating beta cells with palmitate increased chemokine production and recruitment of pro-inflammatory macrophages, via TLR4-Myd88 [19].…”

Section: Extracellular Signals Influencing Lipotoxicitymentioning

confidence: 99%

Lipotoxicity in the Pancreatic Beta Cell: Not Just Survival and Function, but Proliferation as Well?

2014

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Free fatty acids (FFAs) exert both positive and negative effects on beta cell survival and insulin secretory function, depending on concentration, duration, and glucose abundance. Lipid signals are mediated not only through metabolic pathways, but also through cell surface and nuclear receptors. Toxicity is modulated by positive signals arising from circulating factors such as hormones, growth factors and incretins, as well as negative signals such as inflammatory mediators and cytokines. Intracellular mechanisms of lipotoxicity include metabolic interference and cellular stress responses such as oxidative stress, endoplasmic reticulum (ER) stress, and possibly autophagy. New findings strengthen an old hypothesis that lipids may also impair compensatory beta cell proliferation. Clinical observations continue to support a role for lipid biology in the risk and progression of both type 1 (T1D) and type 2 diabetes (T2D). This review summarizes recent work in this important, rapidly evolving field.

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Susceptibility to Fatty Acid-Induced β-Cell Dysfunction Is Enhanced in Prediabetic Diabetes-Prone BioBreeding Rats: A Potential Link Between β-Cell Lipotoxicity and Islet Inflammation

Cited by 36 publications

References 60 publications

Endoplasmic reticulum stress sensitizes pancreatic beta cells to interleukin-1β-induced apoptosis via Bim/A1 imbalance

Endoplasmic reticulum stress sensitizes pancreatic beta cells to interleukin-1β-induced apoptosis via Bim/A1 imbalance

Differential effects of hypercaloric choice diets on insulin sensitivity in rats

Lipotoxicity in the Pancreatic Beta Cell: Not Just Survival and Function, but Proliferation as Well?

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