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.
Highlights
Type-2 diabetes mellitus (T2DM) is a disorder that is characterised by high blood glucose concentration in the context of insulin resistance and/or relative insulin deficiency
Insulin resistance contributes to the pathogenesis of T2DM, it is the failure of pancreatic b-cells to secrete sufficient insulin to maintain normoglycemia, due to a decrease in b-cell function and mass, that results in the development of T2DM
The chronic incubation of isolated islets of Langerhans or clonal b-cell lines with FFAs leads to cell dysfunction and death, which is associated with the induction of ER stress and chronic activation of the unfolded protein response (UPR).[4,5,6,7,8]
Summary
The objective of this study was to determine whether ER stress correlates with b-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 b-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 b-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.
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