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A yin-yang balancing act on blood vessels

The incretin hormones GLP-1 and GIP act like the yin and yang on the body´s blood vessels. While GLP-1 has been associated with protective effects according to new research GIP can contribute to an increased risk of stroke. The findings are published in the scientific journal Diabetes.

The incretin hormones GIP and GLP-1 are released from the intestine after eating to stimulate insulin secretion from the pancreas, helping the blood sugar to return to normal levels after a meal.

Researchers consider incretin hormones to be of interest for several reasons, including:
* The latest developed drugs for type 2 diabetes, so-called DPP-4 inhibitors, specifically target the incretin system and increase the levels of these hormones in the blood, which has a positive effect by maintaining normal blood sugar levels.
* Recently it has become clearer that the incretin hormones also affect tissues and organs other than the pancreas, including the heart and blood vessels.

In the current study, presented in the scientific journal Diabetes, researchers question whether the effects from the DPP-4 inhibitors are all positive, as so far believed.

“The main focus when it comes to DPP-4 inhibitors has been on GLP-1, which has been shown to have protective effects on the cardiovascular system, while little attention has been paid to potential effects of GIP, which is also affected by DPP-4 inhibitors”, says Professor Maria Gomez at Lund University, who led the study.

In this new study, the researchers show that a common variant (occurring in approximately 30% of the population) in the gen that encodes for the GIP receptor, is linked to a higher risk of stroke in patients with type 2 diabetes. They also show how GIP unexpectedly leads to an increased production of the protein osteopontin in the vascular wall, and that this occurs via local release of endothelin-1.

Maria Gomez’s research group is behind previous findings linking osteopontin to diabetes and cardiovascular disease.

“Osteopontin is not only an inflammatory marker but an active player that contributes to accelerated atherosclerosis in the vascular wall”, says researcher Lisa Berglund who is first author of the study.

The researchers also show that healthy vessels have low to insignificant levels of GIP receptors and osteopontin, while the amount of these proteins dramatically increases in arteries from patients with cardiovascular disease or from diabetic mice.

“We also found that patients with cardiovascular disease and type 2 diabetes have higher levels of circulating GIP hormone in their blood”, says Professor Maria Gomez.

“Unlike GLP-1, which has been shown to contribute to an increased production of protective and vasodilating nitric oxide (NO), we see that GIP may contribute to an increased production of endothelin-1, which promotes vasoconstriction and stimulates inflammation and cell growth in the blood vessel walls. GIP and GLP-1 appear to act like yin and yang on blood vessels, therefore, more studies on the long-term effects of DPP-4 inhibitors are needed”, says Lisa Berglund.


Title: Glucose-Dependent Insulinotropic Polypeptide (GIP) Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

Authors: Lisa M. Berglund, Valeriya Lyssenko, Claes Ladenvall, Olga Kotova, Andreas Edsfeldt, Kasper Pilgaard, Sami Alkayyali, Charlotte Brøns, Carol Forsblom, Anna Jonsson, Anna V. Zetterqvist, Mihaela Nitulescu, Christian Ruiz McDavitt, Pontus Dunér, Alena Stancáková, Johanna Kuusisto, Emma Ahlqvist, Maria Lajer, Lise Tarnow, Sten Madsbad, Peter Rossing, Timothy J. Kieffer, Olle Melander, Marju Orho-Melander, Peter Nilsson, Per-Henrik Groop, Allan Vaag, Bengt Lindblad, Anders Gottsäter, Markku Laakso, Isabel Goncalves, Leif Groop & Maria F. Gomez

Scientific journal and link when published in Diabetes

For more information about the study:
Professor Maria F. Gomez, +46 40 248842, +46 70 2226216, maria [dot] gomez [at] med [dot] lu [dot] se

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