Study shows that peptides causing migraines also affect insulin production, which could provide new preventative treatment for type 2 diabetes if harnessed effectively.
Migraine. Image Credit: fizkes/Shutterstock.com
Following the crumbs: exploring the link between migraines and diabetes in mice
Scientists have considered the association between migraines and diabetics extensively due to the unusual fact that people with migraines are less likely to develop type 2 diabetes, while people who develop diabetes become less prone to migraines.
New findings now shed light on the underlying link between these conditions as scientists have shown that peptides that cause migraine pain can affect insulin production, possibly by regulating the amount of secreted insulin or by increasing the number of pancreatic cells that produce it.
The study led by Thanh Do, Ph.D., is expected to be presented during the fall meeting of the American Chemical Society (ACS). The research group behind the project first became interested in the topic after studies first described an inverse relationship between the conditions.
Specifically, past research showed that two particular peptides— the calcitonin gene-related peptide (CGRP)and pituitary adenylate cyclase-activating polypeptide (PACAP) — play key roles in causing the pain of migraines.
Interestingly, these peptides as well as the related peptide amylin, are found in the pancreas, where their function is to release insulin from beta cells.
This is important as insulin controls blood sugar levels by helping to absorb glucose before storing or using it for energy, and this process is deregulated in type 2 diabetes as cells become resistant to insulin. This leads to a reduction in insulin absorption and higher blood sugar levels. In response, beta cells typically compensate by increasing insulin production but wear themselves out and die.
This is where the peptides are introduced as both CGRP and PACAP offer therapeutic targets to treat both migraine pain and type 2 diabetes. In particular, drugs to prevent migraine pain by interfering with CGRP and its cellular receptors recently went up for sale, and other treatments are being studied.
Yet, more research is needed to clarify the peptides’ mechanisms and the present study is trying to clarify contradictory findings of their effects on insulin.
Exploring potential mechanistic pathways to better understand the role of peptides
Researchers designed a new method to collect data from a few hundred beta cells, reporting successful trials with this technique, and also showing CGRP reduced insulin levels in mice.
This was of key interest as the insulin type that was reduced was insulin 2, the analog to human insulin, and may counter insulin resistance seen in type 2 diabetics. However, CGRP was not as effective in regulating mouse insulin 1, aligning with earlier findings that showed mice with only insulin 1 are prone to diabetic conditions.
Additionally, type 2 diabetes is associated with amylin aggregation, says Aleksandra Antevska, a graduate student in Do’s lab who is presenting the work at the meeting, and such aggregates may contribute to the beta cell damage causing type 2 diabetes, Do notes. Moreover, amylin and insulin are co-secreted by beta cells, and therefore using CGRP CGRP to limit insulin production could also limit amylin production, Do states.
Moreover, PACAP is also thought to play a protective role against type 2 diabetes, which is contradictory since PACAP also stimulates insulin release leading to insulin resistance in diabetics.
This conundrum is now a focal point of the researchers’ efforts, with initial findings showing PACAP actions may depend on glucose levels. Therefore, PACAP could be acting in a glucose-dependent fashion and promote beta-cell proliferation, which would avoid weakening existing cells and rather produce novel cells.
The emergence of a complex picture, but with promising implications
Despite these positive results, you can’t inject CGRP and PACAP into the body as therapeutic strategies for diabetes because these peptides cause migraine pain. But once we understand how they exert their effects on insulin secretion, we can design peptide analogs that would control insulin but would not bind to the pain receptor.”
Do
Since CGRP and PACAP can seemingly protect against diabetes, current anti-CGRP and anti-PACAP treatments could have unintentional consequences of increasing rather than reducing the risk of diabetes.
Furthermore, the peptides also have additional important functions throughout the boy, including the dilation of blood vessels, and disrupting such functions could have unpredictable consequences. In response, Do and other scientists are considering the potential risks of altering the peptides’ activity, whilst also maintaining research efforts on the action of these peptides.
This study is the first time the dual effects of CGRP on mouse insulin 1 and 2 release were observed and the functions of peptides were determined comprehensively, with findings associated with the same conditions in humans thanks to the findings focusing on related analogs.
Future research examining the implications of changes in peptide activity as well as the consideration of human trials using therapeutic drug treatments may further improve our understanding of CGRP and PACAP.
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