Abstract
BackgroundThe combination of elevated glucose and free-fatty acids (FFA), prevalent in diabetes, has been suggested to be a major contributor to pancreatic β-cell death. This study examines the synergistic effects of glucose and FFA on β-cell apoptosis and the molecular mechanisms involved. Mouse insulinoma cells and primary islets were treated with palmitate at increasing glucose and effects on apoptosis, endoplasmic reticulum (ER) stress and insulin receptor substrate (IRS) signaling were examined.Principal FindingsIncreasing glucose (5–25 mM) with palmitate (400 µM) had synergistic effects on apoptosis. Jun NH2-terminal kinase (JNK) activation peaked at the lowest glucose concentration, in contrast to a progressive reduction in IRS2 protein and impairment of insulin receptor substrate signaling. A synergistic effect was observed on activation of ER stress markers, along with recruitment of SREBP1 to the nucleus. These findings were confirmed in primary islets. The above effects associated with an increase in glycogen synthase kinase 3β (Gsk3β) activity and were reversed along with apoptosis by an adenovirus expressing a kinase dead Gsk3β.Conclusions/SignificanceGlucose in the presence of FFA results in synergistic effects on ER stress, impaired insulin receptor substrate signaling and Gsk3β activation. The data support the importance of controlling both hyperglycemia and hyperlipidemia in the management of Type 2 diabetes, and identify pancreatic islet β-cell Gsk3β as a potential therapeutic target.
Highlights
The natural history of Type 2 diabetes mellitus (T2D) includes a progressive decline in b-cell function associated with peripheral insulin resistance
This study examined the sequence of molecular events that may be involved in this process, and resulted in several novel observations: 1) While early induction of Jun NH2terminal kinase (JNK) plays a role in free-fatty acids (FFA)-induced apoptosis [13,16], it does not appear involved in the high glucose potentiation of FFA effects; 2) the potentiating effects of glucose and FFA on endoplasmic reticulum (ER) stress result in activation of ER-associated Sterol regulatory element-binding protein-1 (SREBP1) and ATF3 leading to reduced IRS2 expression further impairing insulin-receptor substrate-Propidium Iodide (PI)-3K-Akt signaling, and 3) treatment with an adenovirus expressing a kinase dead glycogen synthase kinase 3b (Gsk3b) significantly restored Pdx1 levels, and reduced the apoptosis induced by high glucose and FFA
Together these findings provide a molecular model for the synergistic effects of glucose and FFA on islet cell death and identify potentially useful therapeutic targets
Summary
The natural history of Type 2 diabetes mellitus (T2D) includes a progressive decline in b-cell function associated with peripheral insulin resistance. The search for molecular mechanisms for glucose potentiation of FFA- induced b-cell dysfunction has been the subject of several recent studies (see [7] for review). The first study showing that the FFA oleate impaired insulin signaling in insulinoma cells demonstrated that the cells were protected from FFA-induced apoptosis by expressing a constitutively active Akt [8]. ER stress in insulinoma cells was shown to impair insulin signaling through activation of ATF3, an ER stress response protein that was implicated in suppression of IRS2 expression [14]. The combination of elevated glucose and free-fatty acids (FFA), prevalent in diabetes, has been suggested to be a major contributor to pancreatic b-cell death. Mouse insulinoma cells and primary islets were treated with palmitate at increasing glucose and effects on apoptosis, endoplasmic reticulum (ER) stress and insulin receptor substrate (IRS) signaling were examined
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
