02-01-2020, Incretin (Endocrine Module)
What is appreciated about the Pharmacology Department at the esteemed Tulane University is that every day is another opportunity to stimulate the brain and learn something new. Incretins was a new topic to encounter. Initially encountered from the Gastrointestinal module, the blocking of incretin was the mechanism of Natalizumb with notable side effects. These proteins also play a role in the pathology of diabetes mellitus.
The negative feedback allows the human to slow down on consumption of food. The endocrine system signals that the body is full. Being full signals the internal anabolism of glycogen and the building of the alpha 1,6 bonds and alpha 1,4 glycosidic acetal linkages being built. Too much, then the acetyl-CoA will shift its direction to the synthesis of malonyl Coa. The biomarkers of Glucagon Like Peptide and Gastric Inhibitory Peptides signal the presence of food consumption.
The pancreas, derived from the endoderm, produces the hormone insulin and amylin. As reviewed from cellular biology, the ending “-in” hint that the receptors are located on the cellular exterior. The L cells from the gastrointestinal organs secrete GLP-1. The pancreatic response of insulin synthesis are part of the endocrine regulation that healthy patients take for granted. This critical pathway deviates from its intended prototypes for those with diabetes mellitus.
The gastrointestinal assist the hormonal response with the release of the GLP-1 and the body possesses versatility with its multiple pathways of metabolism shown with multiple arrows in biochemistry textbooks. The hepatic enzyme dipeptidyl peptidase-4 DPP-4 breaks down GLP-1. The body is not supposed to store protein, which the former instructor Dr. R. emphasized. Humans can analogize storage of carbohydrates and fats. It is not meant to store nonfunctional protein or enzymes that are not needed. The approach to protein is “We don’t make it til you order.”
Sitagliptin is a DPP-4 inhibitor, allowing the presence of GLP-1 to survive longer than its intended half life. Exenatide (Byetta ®) and Liraglutide (Victoza ®) are GLP-1 agonists. These drugs have been noted for efficiency aids for weight loss.
The altered incretin response has been noted for its correlation to diabetes. The normal response is show higher insulin response to oral versus intravenous applications of glucose. However, the responses do not show the same level of disparity among diabetic patients. Remember that incretin is the GI response to the postprandial state. The missing biomarker of low incretin response also confirms the pathology of Diabetes. The text PW notes that the reason for the insufficient incretin response is because of the pancreatic deficiency of properly response due to constant glycemic state.
Although the public simplifies diabetes mellitus simple as a high sugar disease, diabetes mellitus should also be considered as a protein misfolding disease, similar to what has been observed in the clinical indications of prions, Alzheimer’s, and Parkinson’s. Amyloid proteins have been observed in model organism in studies simulating the hyperglycemic state. The misfolded protein is completely useless due to the loss of tertiary and quaternary structures. The three-dimensional spatial structure is critical for any protein to perform its function. Correcting the misfolded protein will be considered a pharmacological target, thanks to the novel cost-efficient techniques with their potential to rapidly and efficiently manufacture antibodies not from the mainstay hamster ovary cells but from cheaper materials such as the E.Coli bacteria and yeast cells.
Extra Credit: Who were the researchers credited with this technology of protein refolding which has the potential for significantly decreasing the costs of cancer treatments?
Word Count: 700+ words
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