ER stress in rodent islets of Langerhans is concomitant with obesity and β-cell compensation but not with β-cell dysfunction and diabetes

Abstract

Objective:The objective of this study was to determine whether ER stress correlates with β-cell dysfunction in obesity-associated diabetes.Methods:Quantitative RT-PCR and western blot analysis were used to investigate changes in the expression of markers of ER stress, the unfolded protein response (UPR) and β-cell function in islets isolated from (1) non-diabetic Zucker obese (ZO) and obese female Zucker diabetic fatty (fZDF) rats compared with their lean littermates and from (2) high-fat-diet-fed fZDF rats (HF-fZDF), to induce diabetes, compared with age-matched non-diabetic obese fZDF rats.Results:Markers of an adaptive ER stress/UPR and β-cell function are elevated in islets isolated from ZO and fZDF rats compared with their lean littermates. In islets isolated from HF-fZDF rats, there was no significant change in the expression of markers of ER stress compared with age matched, obese, non-diabetic fZDF rats.Conclusions:These results provide evidence that obesity-induced activation of the UPR is an adaptive response for increasing the ER folding capacity to meet the increased demand for insulin. As ER stress is not exacerbated in high-fat-diet-induced diabetes, we suggest that failure of the islet to mount an effective adaptive UPR in response to an additional increase in insulin demand, rather than chronic ER stress, may ultimately lead to β-cell failure and hence diabetes.

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells

“…We further show that downregulation of the adaptive UPR is associated with impaired ER-to-Golgi protein trafficking and increased beta cell death during hypoxic stress. These findings indicate for the first time that hypoxia may contribute to the decline of the adaptive UPR in type 2 diabetes islets [14][15][16] and in islet graft failure [17]. Furthermore, our results provide JNK and DDIT3 activation as molecular mechanisms for downregulation of the adaptive UPR during hypoxic stress.…”

“…However, irresolvable ER stress triggers apoptosis via several effectors including c-Jun N-terminal kinase (JNK), DNAdamage inducible transcript 3 (DDIT3; also known as CHOP/GADD153), ATF3 and Tribbles homolog 3 (TRB3) [11][12][13]. Interestingly, recent studies suggest that a progressive decline in the adaptive UPR characterises beta cell failure in type 2 diabetes [14][15][16] as well as in islet transplantation [17]. Therefore, knowledge of the regulatory mechanisms controlling the adaptive UPR is crucial.…”

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

“…Thus, adaptive UPR genes were upregulated in the islets of obese, prediabetic fZDF rats fed a chow diet (model of β-cell compensation) in comparison to agematched lean controls. However, UPR gene expression was downregulated in diabetic fZDF rats fed a high-fat diet (model of β-cell decompensation) in comparison to age-matched obese, prediabetic fZDF rats fed a chow diet, in parallel with altered β-cell differentiation (Omikorede et al 2013). Noteworthy, in vitro, proteomic analysis of glucose-responsive (low passage; more differentiated) vs glucose non-responsive (high passage; less differentiated) MIN6 cells also revealed downregulation of HSPA5, HSP90B1, PDI and ERP29 (Dowling et al 2006).…”

A Reevaluation of the Role of the Unfolded Protein Response in Islet Dysfunction: Maladaptation or a Failure to Adapt?

“…Similarly, in islets isolated from diabetic HFD-fed obese female ZDF (HFD-fZDF) rats, another well-characterized rodent model of type 2 diabetes, there is no detectable increase in the phosphorylation status of eIF2a and IRE1 compared with age-matched obese prediabetic fZDF rats (37). In addition, the expression of markers of an adaptive UPR are also either significantly decreased or show a tendency toward a decrease in animal models of diabetes, and surprisingly this is invariably associated with no change or a decrease in CHOP expression (an indicator of the activation of a proapoptotic UPR) (36,37) (Table 1).…”

“…In islets isolated from these mice, the expression of markers of an adaptive UPR increases between 6 and 16 weeks of age (36), which is concomitant with an increase in b-cell mass and function. Likewise, the islets isolated from Zucker and female Zucker diabetic fatty (ZDF) rats or prediabetic db/db mice, genetic models of obesity and b-cell compensation, have increased expression of markers of the adaptive UPR compared with their lean controls (36,37). The story is similar with HFD-fed mice, which are considered a more physiologically relevant model of insulin resistance-associated b-cell compensation (38), as their islets also have increased expression of markers of an adaptive UPR compared with their lean controls (29,39).…”