An insulin-mimicking peptide not only lowers blood sugars, but also slows the progression of atherosclerosis in mice
Recent findings suggest a novel approach for protecting people with diabetes from their higher risk of advanced blood vessel disease, which sets the stage for early heart attacks and strokes.
A cross section of an advanced atherosclerotic lesion from a mouse with metabolic syndrome. This lesion has expanded so that it is blocking almost the entire blood vessel, and has many features seen in lesions from patients with metabolic syndrome. The insulin-mimetic peptide S597 prevents the formation of this type of advanced atherosclerotic lesions.
Credit: Jenny Kanter and Karin Bornfeldt/University of Washington School of Medicine
Cardiovascular problems from atherosclerosis - plaque-like lesions forming in artery walls - are the major cause of death in people with type 2 diabetes and metabolic syndrome.
People with metabolic syndrome exceed the normal range for several clinical measurements: blood pressure, blood sugar levels, harmful lipids, body mass index, and belly fat.
The researchers studied mice with metabolic syndrome. The mice were obese and had impaired glucose tolerance, a sign of pre-diabetes. In the study, an insulin-mimicking synthetic peptide called S597 was shown to both reduce blood sugar levels and slow the progression of atherosclerotic lesions.
Insulin, even when it controls diabetes, does not prevent atherosclerosis.
The findings are published in the Feb. 26 issue of Diabetes, a peer-reviewed scientific journal of the American Diabetes Association.
The senior author is Karin E. Bornfeldt, University of Washington School of Medicine professor of medicine, Division of Metabolism, Endocrinology and Nutrition. Jenny Kanter, UW research assistant professor of medicine, was the lead author. They are scientists at the UW Medicine Diabetes Institute.
The study was conducted as a research collaboration with Novo Nordisk A/S.
Although S597 is composed of a single chain of amino acids and looks nothing like insulin, S597 can still activate insulin receptors. But, unlike insulin, it's more selective in what it turns on inside the cells.
This study showed that, when S597 binds to insulin receptors, it preferentially activated a signaling arm known as the Akt arm, which is associated with lowering blood sugar levels and with other beneficial effects. It only weakly activated, or may have even prevented the activation of, another signaling arm, called the Erk arm, that is suspected of causing undesirable side effects.
The researchers were impressed by the mechanisms behind the S597 slow-down of atherosclerotic lesions.
Atherosclerosis starts with fatty streaks appearing in blood vessel walls. As the atherosclerotic lesion grows, inflammation provoked by obesity and recruitment of immune cells can speed the growth of the plaque.
Certain white blood cells, particularly monocytes that participate in inflammation, and macrophages, or "big eaters" that are supposedly the bloodstream's cleanup crew, are among the culprits. They can become overladen by engulfing lipids, and can turn into foam cells. These cells gather, and then perish. The core of the lesion fills with dead cells and other debris. If it ruptures, a clot can rapidly form in the vessels of the heart or brain.
In mice given S597, the problem with excessive white cells in the lesion seems to be nipped at its source: the early stages of production of inflammatory monocytes and macrophages. The S597 treated mice did not seem prone to the high white cell count characteristic of the inflammation induced by metabolic syndrome and obesity.
In fact, the amount of blood-forming stem cells in the bone marrow was lowered to levels observed in lean, healthy mice. These stem cells exhibited less activity from the undesirable signaling pathway originating in the insulin receptors.
The numbers of macrophages dying in the lesion were also fewer. While the number of intact cleanup cells rose, the relative content of macrophages in the lesion cores did not go up. The S597 may have either kept more macrophages alive longer or impeded their pile up.
Probably because of all this influence on white cells, the lesions did not grow with the rapidity expected in diabetes and metabolic syndrome. The researchers also saw that lesions with debris-filled cores were less common in these mice.
The researchers noted that the S597 did not alter cholesterol levels in the plasma or systemic inflammation overall.
"Cholesterol lowering drugs like statins are making a big impact in our ability to prevent cardiovascular disease associated with metabolic syndrome and diabetes," Bornfeldt said. "We think that the results of this new study provide a conceptually novel treatment strategy to explore as an additional possibility for protecting against advanced atherosclerosis associated with metabolic syndrome and type 2 diabetes."
There is only one previous study of the effects of S597 in living organisms. This new study is believed to be the first reported to evaluate the effects of S597 on the blood vessel system.
Funding for this work came in part from National Institutes of Health grants and from a STAR postdoctoral fellowship from Novo Nordisk.
Three researchers on the study are employed by Novo Nordisk A/S, which also supplied the S597 peptide for testing.
Leila Gray | EurekAlert!
Scientists learn more about how gene linked to autism affects brain
19.06.2018 | Cincinnati Children's Hospital Medical Center
Overdosing on Calcium
19.06.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau
In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.
Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...
Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...
Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.
Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...
The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.
Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.
An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.
Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...
13.06.2018 | Event News
08.06.2018 | Event News
05.06.2018 | Event News
20.06.2018 | Materials Sciences
20.06.2018 | Materials Sciences
20.06.2018 | Materials Sciences