Exenetide drama ends in failure - Cure Parkinson's
Exenetide drama ends in failure
darn, that's a disappointment all these years of hype what a let-down.
Thanks for sharing. I was just wondering about this.
”The full results of the Exenatide-PD3 study, a phase 3 clinical trial of Type 2 diabetes drug exenatide (Bydureon), have now been published. They report that the study unfortunately did not meet its primary or secondary endpoints.
The full results of the Exenatide-PD3 study have now been published in the scientific journal, The Lancet, and is publicly available.”
so considering how exenatide works I am wondering what was the theory as to why it would help slow Parkinson's progression. It seems like it must have been a hypothesis that involved blood sugar. One thing I find particularly puzzling is it says that this drug slows gastric emptying so why would that be good considering that this can be a troubling symptom in Parkinson's even before using this medication. Here is a description of how it works:
"Mechanism of action
Exenatide binds to the intact human Glucagon-like peptide-1 receptor (GLP-1R) in a similar way to the human peptide glucagon-like peptide-1 (GLP-1); exenatide bears a 50% amino acid homology to GLP-1 and it has a longer half-life in vivo.[22]
Exenatide is believed to facilitate glucose control in at least five ways:
Exenatide augments pancreas response[23] (i.e. increases insulin secretion) in response to eating meals; the result is the release of a higher, more appropriate amount of insulin that helps lower the rise in blood sugar from eating. Once blood sugar levels decrease closer to normal values, the pancreas response to produce insulin is reduced; other drugs (like injectable insulin) are effective at lowering blood sugar, but can "overshoot" their target and cause blood sugar to become too low, resulting in the dangerous condition of hypoglycemia.
Exenatide also suppresses pancreatic release of glucagon in response to eating, which helps stop the liver from overproducing sugar when it is unneeded, which prevents hyperglycemia (high blood sugar levels).
Exenatide helps slow down gastric emptying and thus decreases the rate at which meal-derived glucose appears in the bloodstream.
Exenatide has a subtle yet prolonged effect to reduce appetite, promote satiety via hypothalamic receptors (different receptors than for amylin). Most people using exenatide slowly lose weight, and generally the greatest weight loss is achieved by people who are the most overweight at the beginning of exenatide therapy. Clinical trials have demonstrated the weight reducing effect continues at the same rate through 2.25 years of continued use. When separated into weight loss quartiles, the highest 25% experience substantial weight loss, and the lowest 25% experience no loss or small weight gain.
Exenatide reduces liver fat content. Fat accumulation in the liver or nonalcoholic fatty liver disease (NAFLD) is strongly related with several metabolic disorders, in particular low HDL cholesterol and high triglycerides, present in patients with type 2 diabetes. It became apparent that exenatide reduced liver fat in mice,[24] rat[25] and more recently in man.[26]"
Whenever I see proposed research I like to try to find out what the researchers are thinking and why they are inclined to think that what they want to try could have potential benefits.
Well the PD idea had nothing to do with blood sugar or diabetes
maybe it was related to insulin resistance:
"While the exact cause-and-effect relationship is still being researched, growing evidence suggests that Parkinson's disease is associated with insulin resistance, meaning that people with Parkinson's often show signs of their bodies not responding effectively to insulin, potentially contributing to the severity of their symptoms and disease progression; however, it's not definitively established whether Parkinson's directly causes insulin resistance or if they are both influenced by shared underlying mechanisms.
Key points about the connection:
Brain insulin resistance:
Research indicates that insulin resistance can occur in the brain of Parkinson's patients, which may directly impact the function of dopamine-producing neurons affected in the disease.
Clinical implications:
Studies have shown that people with Parkinson's who are insulin resistant may experience more severe motor symptoms like tremors, rigidity, and slow movements.
Potential mechanisms:
Alpha-synuclein aggregation: Insulin resistance may contribute to the accumulation of alpha-synuclein, a protein associated with Parkinson's pathology.
Mitochondrial dysfunction: Impaired insulin signaling can disrupt mitochondrial function, which is also implicated in Parkinson's disease.
Neuroinflammation: Insulin resistance may promote neuroinflammatory processes in the brain. "
" exenatide (a type of GLP-1 receptor agonist) is considered to have a positive effect on insulin resistance, meaning it can help improve the body's sensitivity to insulin by impacting both hepatic (liver) and adipose tissue insulin resistance; research shows it can potentially reduce insulin resistance in individuals with type 2 diabetes.
Key points about exenatide and insulin resistance:
Mechanism of action:
Exenatide works by stimulating the release of insulin from the pancreas when blood sugar levels are high, and it also slows gastric emptying, which can contribute to better blood sugar control and improved insulin sensitivity.
Impact on liver and fat tissue:
Studies have shown that exenatide can improve insulin resistance in both the liver and adipose tissue, which are key areas where insulin resistance often occurs.
Potential benefits:
Using exenatide can lead to reduced blood sugar levels, weight loss, and improved overall metabolic health in individuals with type 2 diabetes"
GLP-1 receptor activation in neurons. Stimulation of the GLP-1R leads to an increase in intracellular cAMP, activating protein kinase A (PKA), and phosphoinositide 3-kinase (PI3K), which phosphorylate and activates a variety of downstream signalling pathways that can be simplified into 2 branches: the Raf-1/MEK-MAP-K (mitogen associated protein kinase)/ERK (extracellular signal regulated kinase) and (PI3K)/protein kinase B(AKT) pathways which can modulate intracellular events such as activation of calcium channels, enhancing protein synthesis, cellular proliferation and mitochondrial biogenesis while inducing inhibition of apoptosis, inflammation and protein aggregation – promoting cell survival and neuroprotection.
I was in that trial and if I remember correctly, meta data indicated that users of Exenatide who used it for treatment of diabetes and also had Parkinson’s possibly showed either slower progression and/or symptomatic relief.
I believe that most trials for repurposed drugs are the result of data analysis showing a positive trend regarding other diseases. Viagra was originally developed for heart related chest pain.
So the insulin resistance angle might be part of it
This looked obvious for a while. If the results were good, there would have been leaks from participants and clinicians who couldn’t contain their excitement. But everything sounded flat
liraglutide continues in studies and so does lixenatide. Both small molecule glp1s. Exenatide showed positive benefit with younger onset under 60yoa in the larger cohort study and annovis was adding a glp 1 component in there buntanetap product so it still seems somewhat confusing . I think this isnt the last we will hear on the GLP 1 saga. I hope the ongoing glp studies still in play will continue in a positive light so not letting this 1 out of 5 outcomes kill my hope . Time will tell🤞
HIV Anti-viral Drug Lopinavir–Ritonavir was a failure in Chinese COVID-19 Clinical trial
How do you manage to clean round the ends of your teeth and keep your mouth clean?
Difficulty in Rolling in Bed 
In denial 
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