How migraines protect against diabetes

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ATLANTA, Aug. 26, 2021 — People who get migraines are less likely to develop type 2 diabetes, while some people who develop diabetes become less prone to migraines. Today, scientists studying the link between these conditions report how the peptides that cause migraine pain can influence production of insulin in mice, possibly by regulating the amount of secreted insulin or by increasing the number of pancreatic cells that produce it. These findings could improve methods to prevent or treat diabetes.

The researchers will present their results at the fall meeting of the American Chemical Society (ACS). ACS Fall 2021 is a hybrid meeting being held virtually and in-person Aug. 22-26, and on-demand content will be available Aug. 30-Sept. 30. The meeting features more than 7,000 presentations on a wide range of science topics.

The link between the two diseases isn’t obvious: “Migraines happen in the brain, while diabetes is associated with the pancreas, and these organs are far from each other,” says Thanh Do, Ph.D., the project’s principal investigator. His group became interested in the subject after a number of papers described an inverse relationship between the conditions.

Researchers already knew that two peptides in the nervous system — calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) — play a major role in causing the pain of migraines. These same peptides, along with the related peptide amylin, are also found in the pancreas. There, they influence release of insulin from beta cells.

Insulin regulates blood sugar levels by helping other cells in the body absorb glucose and either store it or use it for energy. In type 2 diabetes, those other cells become resistant to insulin and less capable of absorbing glucose, leading to high blood sugar levels. The beta cells initially compensate by ramping up insulin production but eventually wear themselves out and die, exacerbating the issue.

Because of their role in migraine and diabetes, CGRP and PACAP offer targets for therapies that could treat either of these conditions. Migraine drugs that interfere with CGRP and its cellular receptors recently went on the market, and other treatments are being studied. Yet, more research is needed to clarify the peptides’ effects. Do is trying to clear up contradictory findings about their impact on insulin.

To probe the peptides’ activity in mice, Do’s University of Tennessee group devised a method to glean data from just a few hundred beta cells. They recently reported that this technique showed that CGRP lowered levels of mouse insulin 2, the analog of human insulin. This may counter the insulin resistance that develops in type 2 diabetes, Do says. But CGRP was less effective at regulating mouse insulin 1, which agrees with early studies showing that mice with only insulin 1 are prone to developing diabetes.

The disease is also associated with aggregation of amylin, says Aleksandra Antevska, a graduate student in Do’s lab who is presenting the work at the meeting. These aggregates may contribute to the beta cell damage that helps cause type 2 diabetes, Do notes. Because amylin and insulin are co-secreted by beta cells, using CGRP to limit insulin production could also limit amylin production, he says. That could protect the cells and help normalize their function.

PACAP, too, is thought to play a protective role against type 2 diabetes. That’s confusing since PACAP has been shown to stimulate insulin release, which leads to insulin resistance, Do says. His team is now trying to resolve this conundrum. The group’s initial findings show that PACAP’s actions could depend on glucose levels. The team has found preliminary evidence that PACAP regulates insulin in a glucose-dependent manner and promotes beta cell proliferation, rather than prodding existing beta cells to work harder — thus avoiding the risk of wearing out the existing cells. They are developing analytical methods to test this.

“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,” Do says. “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.”

Because CGRP and PACAP can seemingly protect against diabetes, Do and others worry that the anti-CGRP and anti-PACAP treatments under development or already on the market for migraine could have the unintended consequence of increasing the risk of diabetes. In addition, these peptides are involved in numerous other beneficial functions in the body, such as blood vessel dilation. So Do and other scientists are also exploring the potential risks of altering the peptides’ activity.

A recorded media briefing on this topic will be posted Thursday, Aug. 26 at 9 a.m. Eastern time at www.acs.org/acsfall2021briefings.

The researchers acknowledge support and funding from the University of Tennessee.

The American Chemical Society (ACS) is a nonprofit organization chartered by the U.S. Congress. ACS’ mission is to advance the broader chemistry enterprise and its practitioners for the benefit of Earth and all its people. The Society is a global leader in promoting excellence in science education and providing access to chemistry-related information and research through its multiple research solutions, peer-reviewed journals, scientific conferences, eBooks and weekly news periodical Chemical & Engineering News. ACS journals are among the most cited, most trusted and most read within the scientific literature; however, ACS itself does not conduct chemical research. As a leader in scientific information solutions, its CAS division partners with global innovators to accelerate breakthroughs by curating, connecting and analyzing the world’s scientific knowledge. ACS’ main offices are in Washington, D.C., and Columbus, Ohio.

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Title
Elucidating molecular connections between migraine and diabetes via neuropeptides

Abstract
Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance leading to pancreatic β-cell dysfunction. For several decades, the accumulation and aggregation of amylin has been implicated in the loss of β-cells. However, anti-aggregation treatments have not been effective. Alternatively, lowering the production of amylin could be a better approach. Since amylin is co-secreted with insulin from β-cells, peptides that regulate insulin secretion but do not harm the β-cells will likely keep the level of amylin under control. Genetically reducing insulin secretion has been shown to increase insulin sensitivity and extend the life span in old mice. Recently, an inverse relation between T2DM and migraine has been observed. We hypothesize that the protective effect of migraine against diabetes is attributed to the elevated concentration of signaling peptides including calcitonin gene-related peptides (CGRPs) or pituitary adenylate cyclase-activating peptide (PACAP). Using a liquid chromatography ion mobility spectrometry-mass spectrometry (LC-IMS-MS) optimized for volume-limited samples (<150 cells per analysis), we showed that human α-CGRP remodeled amylin aggregation and suppressed mouse Ins2 secretion. Interestingly, α-CGRP oligomers stimulated mouse Ins1, indicating the dual effect of this peptide on regulating insulin. This is the first time the dual effects of CGRP on mouse Ins1 and Ins2 release were observed from isolated single mouse islets. Finally, while rodents are the most widely used preclinical animal model in diabetes research, they have a two-gene insulin system while humans only have one. The mouse Ins1 gene is considered to be a duplicate and defective of Ins2. Ins2 is the ancestral gene and the human orthologue. Our LC-IMS-MS study also showed that mature mouse Ins1 and Ins2 adopt drastically different structures which may account for their diverged functions.

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