Oxidative and ER stresses: breaking the cycle to preserve beta cells in diabetes

The prevalence of type 2 diabetes is increasing dramatically and poses a major health and socio-economic burden worldwide. High levels of saturated free fatty acids (FFAs), associated with Western diets and obesity, contribute to insulin resistance and beta cell failure and are predictive of the future development of type 2 diabetes. Mitochondrial dysfunction and endoplasmic reticulum (ER) stress play central roles in FFA-mediated beta cell dysfunction and death. The synthesis and secretion of insulin in response to glucose, poses a challenge to beta cell ER function. The unfolded protein response (UPR) is triggered to cope with perturbations to ER homeostasis but can ultimately lead to beta cell apoptosis if ER stress is not resolved. Withal, the excessive production of reactive oxygen species as byproducts of oxidative metabolism leads to oxidative stress, mitochondrial dysfunction and further aggravates ER stress. Here we have explored the molecular mechanisms underlying beta cell loss due to mitochondrial and ER dysfunction and demonstrated the potential of relieving oxidative and ER stresses as therapeutic approach for type 2 diabetes. Palmitate and oleate are the most common saturated and unsaturated FFAs in the circulation and thus widely used in lipotoxicity studies. Because FFAs have low aqueous solubility, they are often conjugated to albumin. We show that this binding critically determines the fraction of unbound FFA accessible for cellular uptake and consequently the biological effect of these fatty acids. By comparing different preparations of FFAs and bovine serum albumin, we have set up an in vitro model of lipotoxicity in pancreatic beta cells. Using this model, we have shown that the beta-carboline alkaloid compound harmine holds potential in preventing lipotoxic beta cell ER stress by regulating key factors in the UPR and the intrinsic pathway of apoptosis. Together with the previously reported mitogenic effects of harmine on human beta cells, these data support the anti-diabetic potential of this drug. The loss of function of the mitochondrial protein frataxin is responsible for the clinical and morphological manifestations of the neurodegenerative disease Friedreich ataxia, including the high prevalence of diabetes. Using this model of monogenic diabetes, we showed that frataxin deficiency leads to mitochondrial dysfunction and oxidative stress-mediated apoptosis in neuronal and beta cells. Glucagon-like peptide-1 analogs are known to improve beta cell function and survival and are currently used for the treatment of type 2 diabetes. These effects are in part attributed to the modulation of the UPR and apoptosis signaling. Here we have shown that these agents are able to protect frataxin-deficient sensory neurons and beta cells by normalizing mitochondrial oxidative state and improve mitochondrial function. Altogether, these finding suggests that prevention of beta cell mitochondrial and ER dysfunction through modulation of specific factors and pathways that signal oxidative and ER stress, has therapeutic potential in type 2 diabetes. A better understanding of such mechanisms should pave the way for the development of novel and targeted approaches to prevent type 2 diabetes.