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Blockage of insulin absorption – the role of the blood vessels in insulin resistance

No. 19 | 27/03/2020 | by Koh

For insulin to take effect and glucose to be transported from the blood to the muscle cells, the hormone first has to cross the endothelium, the cell layer that lines the inside of the blood vessels. Scientists from the German Cancer Research Center and from University Hospital Heidelberg and University medicine Mannheim have now established that a signaling pathway that prevents this step is stimulated in obese mice, hence promoting insulin resistance. The researchers have thus made a crucial contribution to enhancing our understanding of metabolic syndrome and the development of diabetes.

Caveolae (cyan) in blood vessels (magenta) of the cardiac muscle.
© Iris Moll/DKFZ

One of the main causes of type 2 diabetes mellitus is insulin resistance. The functions of the pancreatic hormone insulin include enabling glucose to be transported from the blood to the muscle cells. Thus the cells are supplied with glucose, an important source of energy, and at the same time the blood sugar level drops. Insulin resistance, a pre-stage of diabetes, is a condition in which the tissue is not able to respond to insulin appropriately and to absorb sugar. If this condition persists, the pancreas begins to produce an increasing amount of insulin, but the blood sugar level continues to rise. If the pancreas is unable to cope, this leads to a relative lack of insulin. Obese individuals are particularly at risk here.

The exact mechanisms behind insulin resistance have not yet been fully explained. Scientists from the German Cancer Research Center (DKFZ) and from Heidelberg University Hospital and University Medicine Mannheim have now established that the endothelium – the cell layer that lines the inside of the blood vessels – may play an important role. "That would seem likely, because insulin needs to cross this layer when it is transported from the blood to the muscle cells," explained Andreas Fischer, a DKFZ scientist and a physician at Heidelberg University Hospital.

Fischer and his team are investigating the signaling pathways that regulate the transport of nutrients, hormones, immune cells, and cancer cells through the vessel walls. They are focusing particularly on what is known as the Notch signaling pathway. Endothelial cells stimulate this molecular communication channel so that fatty acids can pass through the cell layer. Fischer examined what happens in mice if there is a surplus of fatty acids, as there is for example in chronic obesity.

The researchers found that the Notch signaling pathway is more active in obese rodents than in normal-weight mice. Moreover, the obese mice were less sensitive to insulin and had a higher blood sugar level.

To determine whether Notch really plays a key role here, Fischer and his team examined specially bred mice in which the Notch signaling pathway is permanently active. The scientists did in fact find insulin resistance and an increased blood sugar level even in young, slim, and apparently healthy animals. However, when they blocked Notch, even animals that were fed an extremely fatty diet did not develop insulin resistance.

In addition, the researchers established that Notch activation prevents 'caveolae' from forming in the endothelium. Caveolae are tiny, sack-like invaginations of the plasma membrane that are responsible for transporting insulin molecules through the cell membrane, among other things.

"The Notch signaling pathway thus directly controls insulin transport through the vessel wall, and permanent activation leads to insulin resistance," Fischer explained, summarizing the results. This finding makes a key contribution to gaining a better understanding of metabolic syndrome – and to finding out how obesity and a high-calorie diet lead to type 2 diabetes.

Notch cannot simply be deactivated in patients to stimulate insulin uptake again, however. As Fischer already established previously, the Notch signaling pathway is responsible for fatty acids reaching the cardiac muscle cells. Fatty acids are the heart's main source of energy. Notch blockage can therefore cause cardiac insufficiency.

"We assume that Notch is a kind of switch and that there is a balance between the active and inactive states of the signaling pathway under normal physiological conditions in a healthy organism," Fischer remarked. The goal now is to find out what disrupts this balance in obese individuals.

Hasan, SS, Jabs M, Taylor J, Wiedmann L, Leibing, T, Nordström V, Federico G, Roma LP, Carlein C, Wolff G, Ekim-Üstünel B, Brune M, Moll I, Tetzlaff F, Gröne HJ, Fleming T, Cyrill Géraud C, Herzig S, PP, Fischer, A: Endothelial Notch signaling controls insulin transport in muscle. EMBO Molecular Medicine 2020, DOI: 10.15252/emmm.201809271

A photo for the press release is available at:
Photo caption: Caveolae (cyan) in blood vessels (magenta) of the cardiac muscle.

Note on use of images related to press releases
Use is free of charge. The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) permits one-time use in the context of reporting about the topic covered in the press release. Images have to be cited as follows: "Source: Iris Moll/DKFZ.
Distribution of images to third parties is not permitted unless prior consent has been obtained from DKFZ's Press Office (phone: ++49-(0)6221 42 2854, E-mail: Any commercial use is prohibited.

With more than 3,000 employees, the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is Germany’s largest biomedical research institute. DKFZ scientists identify cancer risk factors, investigate how cancer progresses and develop new cancer prevention strategies. They are also developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to questions relating to cancer.

To transfer promising approaches from cancer research to the clinic and thus improve the prognosis of cancer patients, the DKFZ cooperates with excellent research institutions and university hospitals throughout Germany:

  • National Center for Tumor Diseases (NCT, 6 sites)
  • German Cancer Consortium (DKTK, 8 sites)
  • Hopp Children's Cancer Center (KiTZ) Heidelberg
  • Helmholtz Institute for Translational Oncology (HI-TRON Mainz) - A Helmholtz Institute of the DKFZ
  • DKFZ-Hector Cancer Institute at the University Medical Center Mannheim
  • National Cancer Prevention Center (jointly with German Cancer Aid)
The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.


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