Highlights
- S597, an Insulin-mimicking (insulin-like) peptide can reduce both blood sugar levels and slow the progression of atherosclerosis.
- Insulin therapy, even when it controls diabetes, cannot prevent atherosclerosis.
- People with diabetes have higher risk of developing advanced blood vessel diseases such as atherosclerosis.
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.
The senior author is Karin E. Bornfeldt, University of Washington School of Medicine professor of medicine, Division of Metabolism, Endocrinology, and Nutrition. Jenny Kanter, a UW research assistant professor of medicine, was the lead author. They are scientists at the UW Medicine Diabetes Institute.
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.
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 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 evaluating the effects of S597 on the blood vessel system.
Reference
- Jenny E. Kanter, Farah Kramer, Shelley Barnhart, et.al . A Novel Strategy to Prevent Advanced Atherosclerosis and Lower Blood Glucose in a Mouse Model of Metabolic Syndrome, Diabetes (2018). https://doi.org/10.2337/db17-0744
Source-Eurekalert