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. 2014 Feb 11:4:4054.
doi: 10.1038/srep04054.

Aberrant islet unfolded protein response in type 2 diabetes

Feyza Engin  1 , Truc Nguyen  1 , Alena Yermalovich  1 , Gökhan S Hotamisligil  2
Affiliations

Aberrant islet unfolded protein response in type 2 diabetes

Feyza Engin et al. Sci Rep. .

Abstract

The endoplasmic reticulum adapts to fluctuations in demand and copes with stress through an adaptive signaling cascade called the unfolded protein response (UPR). Accumulating evidence indicates that the canonical UPR is critical to the survival and function of insulin-producing pancreatic β-cells, and alterations in the UPR may contribute to the pathogenesis of type 2 diabetes. However, the dynamic regulation of UPR molecules in the islets of animal models and humans with type 2 diabetes remains to be elucidated. Here, we analyzed the expression of activating factor 6 (ATF6α) and spliced X-box binding protein 1 (sXBP1), and phosphorylation of eukaryotic initiation factor 2 (eIF2α), to evaluate the three distinct branches of the UPR in the pancreatic islets of mice with diet- or genetic-induced obesity and insulin resistance. ATF6 and sXBP1 expression was predominantly found in the β-cells, where hyperglycemia coincided with a decline in expression in both experimental models and in humans with type 2 diabetes. These data suggest alterations in the expression of UPR mediators may contribute to the decline in islet function in type 2 diabetes in mice and humans.

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Figures

Figure 1
Figure 1. Expression of UPR mediators in the islets of ob/ob mice at different stages of the disease.
(a). Fasting blood glucose of 4-week-old C57/BL6 and ob/ob mice (b). Fasting serum insulin level of 4-week-old C57/BL6 and ob/ob mice. Immunofluorescence analysis was performed in pancreas sections of 4-week-old C57/BL6 and ob/ob mice (n = 4) by co-staining with (c). anti-ATF6α, (d). anti-sXBP1, or (e). anti-P-eIF2α (red) and anti-insulin (green) antibodies. Quantification of relative fluorescence intensity (RFI) was performed on 10–20 islets per mouse and calculated using MATLAB® (lower panels). (f–j). Analysis of fasting insulin and glucose levels, and UPR mediator expression in 8-week-old C57/BL6 and ob/ob mice. (k–o). Analysis of 18 week-old mice as described above. All data are presented as mean ± SEM, with statistical analysis performed by Student's t test (***p < 0.001, **p < 0.005, *p < 0.05).
Figure 2
Figure 2. Expression of UPR markers in the islets of a diet induced animal model of obesity and insulin resistance.
Wild type male mice (n = 4 for each group) were placed either on regular (chow) or high fat diet (HFD). (a–c). Analysis of body weight, fasting glucose, and serum insulin after one week on diet. Immunofluorescence analysis was performed using (d). anti-ATF6 (red), (e). anti-sXBP1 (red), or (f). anti-P-eIF2α (red), and anti-insulin antibodies (green). Quantification was performed on 10–20 islets per mouse. (g–l). Mice and pancreas sections were analyzed as above after 13 weeks on diet. Data are presented as mean ± SEM, with statistical analysis performed by Student's t test (***p < 0.001, *p < 0.05).
Figure 3
Figure 3. Expression of UPR mediators in the islets of type 2 diabetic humans.
(a). Pancreas sections from non-diabetic and diabetic patients were obtained from nPOD and co-stained with anti-ATF6α (red), and anti-insulin (green) antibodies (upper panel) and 10–20 islets per sample were quantified by MATLAB® (lower panel). (b). Pancreas sections from non-diabetic and diabetic subjects co-stained with anti-sXBP1 (red) and anti-insulin (green) antibodies (upper panel) and 10–20 islets per sample were quantified by MATLAB® (lower panel). (c). Pancreas sections from non-diabetic and diabetic subjects co-stained with anti-P-eIF2α (red) and anti-insulin (green) antibodies (upper panel) and 10–20 islets per sample per time point were quantified by MATLAB® (lower panel). All data are presented as mean ± SEM, with statistical analysis performed by one-way ANOVA (***p < 0.001, **p < 0.005, *p < 0.05).
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References

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