Endoplasmic Reticulum Stress and Type 2 DiabetesEdit
The Endoplasmic Reticulum (ER) is an important organelle in the cell that performs a wide variety of tasks including and not limited to protein folding, modification, and transfer of membrane proteins to and from Golgi apparatus. Also, the maintenance of ER homeostasis in insulin-secreting beta-cells is extremely important, because when the ER’s homeostasis is disrupted, the ER generates an unfolded protein response (UPR), to maintain homeostasis of this organelle. However, if homeostasis is not restored, the ER promotes death signal pathways. Observations have shown that type 2 diabetes is an important causal factor in the disruption of ER homeostasis and subsequent death of insulin secreting beta cells.
The frequency of Type 2 diabetes in society has dramatically increased due to unhealthy living and eating lifestyles with the consumption of foods rich in fat. Type 2 diabetes consists of a mixture of metabolic conditions characterized by increased levels of blood glucose. The disease develops in areas of the body that are resistant to insulin. Also it is important to note that the disease develops only when beta-cell dysfunction appears. Blood glucose and fatty acids that cannot be properly stored or excreted can overload the cell and disrupt ER and mitochondrial functions. High glucose and saturated fatty acids cause beta cell failure and subsequent oxidative stress through its metabolism.
ER Stress by LipotoxicityEdit
Elevated levels of plasma free fatty acids (FFA) are associated with high fat diets and obesity in humans. Free fatty acids are considered to be vital mediators of apoptosis and dysfunction of pro insulin beta cells in type 2 diabetes. It is known that both unsaturated and saturated FFas inhibit proinsulin synthesis. The precise mechanism of Beta cell dysfunction and apoptosis is not yet fully understood. There is great evidence of long saturated fatty acid chains being responsible for the induction of ER stress and subsequent beta cell failure.
ER Stress by GlucotoxicityEdit
Insulin deficiency associated with insulin resistance is known to cause blood glucose levels to remain high (hyperglycemia). Over stimulated beta cells show a gradual decrease of glucose-induced insulin secretion and insulin gene expression and eventually impaired beta-cell function and survival. This phenomenon is known as gucotoxicity. As blood glucose levels continue to remain high, the glucose that originally served as fuel is now used to generate detrimental metabolites for beta cells.
1. Endoplasmic reticulum stress and type 2 diabetes. Back SH, Kaufman RJ.