Inhibition of endoplasmic reticulum stress ameliorates alterations in WFS1 expression and reduces high-fat diet-induced pancreatic islet insulin secretion in rats.

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Consuming a high fat diet causes various metabolic diseases including metabolic syndrome and type 2 diabetes by developing insulin resistance and even decreasing insulin production.

For example a good way to induce Parkinson's syndrome in rats is to feed them a very high fat diet. Alzheimer's disease has sometimes been referred to as type 3 diabetes.

A mystery is that of ALS (Charcot's disease) where we often have insulin resistance, but very rarely comorbid diabetes. It also seems that the existence of misfolded proteins in the cytoplasm of patients is linked to stress in the endoplasmic reticulum, a cell organ whose function is precisely to fold the proteins newly produced by the ribosomes, before they are sent to their destination in the Golgi apparatus.

Long-term exposure to saturated fatty acids (SAFAs) in pancreatic β cells causes desensitization and impaired insulin secretion.

For example, consumption for three months of a very high fat diet containing pork fat and sunflower oil (80% fat) reduced the insulin content of pancreatic islets in mice (50%), proinsulin mRNA (35%), insulin biosynthesis and secretion in response to glucose (50%), and glucose oxidation.

According to previous research, WFS1 (Wolfram syndrome 1) is involved in insulin synthesis and release, as well as mass preservation of pancreatic β cells. This Wfs1 gene was first identified by Wolfram and Wagener (1983) in patients with Wolfram syndrome (i.e. diabetes mellitus and optic nerve atrophy).

The WFS1 gene expresses a glycoprotein in the endoplasmic reticulum (endoplasmic reticulum) of pancreatic β cells, heart, placenta, lungs and brain.

Saturated fatty acids like palmitate induce endoplasmic reticulum stress. Studies have shown that there is a mutual relationship between oxidative stress and endoplasmic reticulum stress. It is found in palm oil, but also in all animal (butter, cheese, milk and meat) or vegetable fats and oils.

During endoplasmic reticulum stress, WFS1 expression increases to inhibit stress signaling and thus prevent apoptosis (one of the processes leading to cell death).

Given the role of the WFS1 protein in maintaining endoplasmic reticulum homeostasis, it is expected that the expression of this protein is increased in the endoplasmic reticulum of β-cells, and its translocation to the cytoplasm is reduced. and leads to a decrease in pancreatic islet GSIS and insulin content.

Although many studies have investigated the effects of each very high fat diet and the involvement of WFS1 in insulin synthesis and secretion, no study has examined the interaction of very high fat diet and WFS1 in relation to insulin synthesis and secretion and therefore glucose homeostasis.

After weaning, the rats were divided into six groups and fed a normal diet and a very high fat (30%) diet for 20 weeks, followed by 4-phenyl butyric acid (4-PBA, an inhibitor endoplasmic reticulum stress) was administered. Note that this is one of the two components of the AMX0035.

After performing a glucose tolerance test, the animals were dissected and their pancreases removed for endoplasmic reticulum extraction, islet isolation, and GSIS evaluation. Additionally, pancreatic endoplasmic reticulum stress biomarkers.

This very high-fat diet decreased pancreatic protein WFS1 and GSH levels, and increased pancreatic catalase activity. As a result, it increased the levels of BIP, CHOP and WFS1 proteins in the ER extracted from the pancreas. In addition, the very high-fat diet caused glucose intolerance and decreased GSIS and insulin content of islets.

However, administration of 4-PBA restored previous levels. It therefore appears that consumption of very high fat diet by inducing pancreatic endoplasmic reticulum stress altered WFS1 expression levels, reduced GSIS and islet insulin content and ultimately impaired glucose homeostasis.

The administration of 4-PBA does not seem to me to be a solution to the problem of the stress of the endoplasmic reticulum, on the other hand it is certainly a means of mitigating a dramatic consequence of this stress: Cell death, which

Yet, administration of 4-PBA does not seem to me to be a solution to the problem of the stress of the endoplasmic reticulum, on the other hand it is certainly a means of mitigating a dramatic consequence of this stress: Cell death, which in the case of ALS most certainly affects the cells that consume the most energy, such as skeletal muscles and motor neurons.

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