The Roles of Stressed Endoplasmic Reticulum on Type II Diabetes

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The rough endoplasmic reticulum (ER) is the site of synthesis for many proteins in the cell. It also assists in the subsequent protein folding via numerous proteins housed in its lumen. However, the rough ER can be subjected to stress and protein folding may not always be completed or properly executed. ER stress leading to an accumulation of both unfolded and misfolded proteins triggers the unfolded protein response, or UPR. The UPR is a mechanism by which the ER increases its protein folding capacity and decreases its client load, thus enabling it to cope with the stress. However, extended periods of UPR activation due to extreme and prolonged ER stress harms the cell. Correlational and mechanistic research studies have shown that sustained UPR contributes to the pathogenesis of Type II Diabetes—a disorder characterized by raised blood sugar levels due to insulin resistance. Obesity, the most common cause of type II Diabetes, causes ER stress that triggers two UPR signal transduction pathways—the Inositol requiring protein–1 (IRE1) and protein kinase RNA-like ER kinase (PERK) pathways. IRE1 leads to insulin resistance by inactivating an adaptor protein needed for insulin’s interaction with its receptor. PERK amplifies elevated blood sugar levels by activating an apoptotic agent that targets the insulin-producing beta cells of the pancreas. Currently, various medical treatments for Type II Diabetes are being pursued. This includes non-peptide insulin action enhancers, incretins and glucokinase activators.
Type II Diabetes
Insulin is a hormone produced by the pancreas in response to high blood sugar levels (Vijan, 2010). It stimulates cells to uptake glucose, where it can either be metabolized for energy or stored as glycogen (e...

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...cokinase activation also lowers blood glucose by promoting glycogen synthesis in the liver (Pal, 2009).
In conclusion, Type II Diabetes is mediated by prolonging the endoplasmic reticulum’s unfolded protein response, or UPR (Ozcan and Tabas, 2012). Obesity subjects the ER to extreme stress which triggers excessive activation of both the IRE1 and PERK signalling pathways of the UPR (Wu and Kaufman, 2006). These lead to insulin resistance, as well as death of pancreatic cells that produce insulin, respectively (Ozcan and Tabas, 2012). Various treatments are now being used to address Type II Diabetes. This includes TLK16998-based drugs that enhance insulin action, intestinal GLP-1 incretins that increase insulin and supress glucagon, and glucokinase activators that upregulate insulin secretion and promote glucose storage in the form of glycogen (Tahrani et al., 2011).

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