GPHR-7060-02Sp20

05 - Incretins + Diabetes (Endocrine Module)

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    

05-2020 The fable of Helicobacter pylori + GI Module

Treating patients who have endured trauma will require expertise of the gastrointestinal system.  The GI has a mind of its mind that is prone to effects of stress and environmental hostility.  Therefore, the private sector with corporations like Dannon vest efforts to learn more about the microflora and identify specific targets to address the physiological effects of the enteric nervous system.  The discovery of H. Pylori proved to be a game changer.  Before the discovery, the physiological reactions were blamed on stress and spicy food.  Proper biomarkers have been identified to dismantle that long held mistaken belief.  

H Pylori

Since the curriculum makes room for science history, one can appreciate how far we’ve come and also resent for the regrettable mistaken beliefs and also a chance to marvel at the ridiculous beliefs  and general human idiocy, and its misconceptions that people have held as holy and above criticism, then maintained by those in power.  Mistaken beliefs have real consequences.

Memory:  The story of H. Pylori was told from a previous instructor of a cautionary tale for those who wanted to pursue science: you need more than book smarts and research prowess.  

The reading material for the GI Module included an article of its discovery, a game changer.  Before the discovery of the pathogen, it was considered a psychosomatic disorder of overly bossy mothers, implying that the proper role of the woman in the household as passive conformity. The renegade microbiologist “far from the medical mainstream” Robert Koch discovered the cause of tuberculosis. His nonviolent resistance to the mainstream paid off since we are all beneficiaries of his indefatigable pursuit.   The difficult isolation of the H Pylori thwarted Koch.    The featured excerpt from 1967 blames the “psychogenic symptoms” on role strain and role conflict in the family home and the particular failure of the woman to act as the docile nurturer.  

The isolation of the bacteria was difficult because it was present in individuals with no history of gastric inflammation.  Dr. Marshall volunteered as the model organism.  He infected himself and experienced gastritis.  But he had no ulcer.  Correlation of ulcer and the pathogen was concluded from epidemiology.

Patients were not recruited.  Samples from blood banks were analyzed.  The vector of transmission was through saliva.  The term “submerging” was used to correlate the prevalence of the diseases to socioeconomic determinants.

Poor hygiene, living in slums, and unsanitary conditions heighten the risk of infection.  The bacteria has two advantages of escaping detection: its special flagellate that allows it to swim and anchor itself to your bottom stomach lining.  Then, it establishes a comfortable residence in your acidic stomach by synthesizing the enzyme urease.  The products are carbon dioxide and ammonia, which is used to offset the hydrochloric acid in your stomach.  

What was unclear from the article was the presentation of the term “Lewis antigen” and the suggestion that individuals with certain blood types are more susceptible to the bacteria.  

“The Lewis antigen system is a human blood group system. It is based upon two genes on chromosome 19: FUT3, or Lewis gene; and FUT2, or Secretor gene. Both genes are expressed in glandular epithelia. FUT2 has a dominant allele which codes for an enzyme and a recessive allele which does not produce a functional enzyme. Wikipedia”

The article ends on an optimistic note for the aspiring scholar “to challenge accepted theories [...] with great benefit to society and science.”

True, if only one can survive being ridiculed as “weird” or “deviant” by the establishment that demands uniformity with the masses.  

“Discovery consists of seeing what everybody has seen and thinking what nobody has thought” Albert Szent-Györgyi was quoted.  

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 GPHR-7060  uses a “Self-Directed Learning (SDL)” mode.  The text also reiterated the social ostracism that Dr. Marshall endured in the discussion of stress effects on the gastrointestinal system.  He failed to conform.  All he had to do was to look at his peers and act like how they acted.   The world of Science needs to maintain a collegial environment.   His superiors just noticed a disruptive pattern of behavior.  So they laughed, mocked, and jeered at Dr. Warren and Dr. Marshall.

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The Washington Post also reported on another nonconformist, Dr. Li.  Thankfully, the government shut him down.  The Republic needs to maintain a collegial environment.  All Dr. Li had to do was to look around his peers and act like how they were acting.  Instead, he was too disruptive.  This was not to be tolerated.  

Word Count: 300+