Researchers from Tufts University devised a novel experiment wherein they engineered beta cells of the pancreas and transplanted these cells onto the pancreas of diabetic mice. This resulted in two to three times insulin production by the diabetic mice that helped them control their blood sugar. These transplanted cells could be controlled using light exposure explained scientists, making this a path breaking study for diabetics.
The results of the study were published in the latest issue of the journal ACS Synthetic Biology and the study was titled, “Amelioration of diabetes in a murine model upon transplantation of pancreatic β-cells with optogenetic control of cyclic AMP.”
Researchers induced engineered pancreatic beta cells to secrete insulin when exposed to blue light. Insulin is shown here as a space filling atomic model. Image Credit: Tufts University
Diabetes mellitus, especially type II variety, affects millions of people around the world with at least 30 million Americans being diabetics according to the Centers for Disease Control and Prevention (CDC). Insulin production from the pancreatic beta cells helps control the blood sugar and if there is low insulin production or the body does not respond adequately to the insulin production (insulin resistance), there is inadequate blood sugar control that leads to hyperglycemia or high blood sugar. Hyperglycemia is associated with several health problems including recurrent infections, heart disease, eye damage, diabetic foot etc. Type I diabetes is also associated with low insulin in the body due to the body’s immune system destroying the beta cells of the pancreas. While type II diabetes can be treated using oral medications and insulin injections, type I diabetes can be treated using insulin injections alone. Some medications used in type II diabetes may stimulate insulin production from the pancreas.
The team of researchers created these cells that could be switched on or off using light and they could help patients with low insulin production explain the researchers. These cells could also help diabetics who produced normal insulin but were less sensitive to the insulin produced. In the test mice, they noted that no external medication or insulin injections were necessary for the mice to have a good blood sugar control.
For this study the team used “optogenetics” technology. They explained that using this method they could manipulate proteins that could alter their actions on their exposure to light. They engineered the pancreatic beta cells with a gene that would code specifically for an enzyme called the photoactivatable adenylate cyclase (PAC). PAC in turn is capable of producing a cyclic adenosine monophosphate (cAMP) molecule when it is exposed to a blue light. This causes the beta cells to become sensitive to glucose triggers that allow for the release of insulin from those cells.
The researchers explained that not only the light stimulus, the cells would also secrete two to three times of insulin only when blood glucose amount is high. When glucose levels in the blood are low, there is minimal insulin secretion. Among diabetics insulin and medication use leads to dangerously low levels of blood sugar in the body called hypoglycaemia which, if not treated or managed adequately could even be fatal. With the use of these engineered beta cells the secretion of insulin is triggered only by high blood sugar and the risk of hypoglycaemia thus remains low.
In their procedure, the researchers transplanted the engineered pancreatic beta cells under the skin of mice models of diabetes. These mice were treated initially with a drug called streptozotocin to induce diabetes like features in them complete with high blood sugar and low levels of insulin secretion. Thereafter the engineered cells were transplanted under their skin. The researchers noted that there was reduced blood sugar and good control of diabetes. Insulin levels in blood were raised when the skin was exposed to blue light, they wrote.
Emmanuel Tzanakakis, professor of chemical and biological engineering at the School of Engineering at Tufts University and corresponding author of the study, said in explanation, “It's a backwards analogy, but we are actually using light to turn on and off a biological switch. In this way, we can help in a diabetic context to better control and maintain appropriate levels of glucose without pharmacological intervention. The cells do the work of insulin production naturally and the regulatory circuits within them work the same; we just boost the amount of cAMP transiently in beta cells to get them to make more insulin only when it's needed.”
Fan Zhang, first author of the study and a student in Tzanakakis' lab at Tufts said, “There are several advantages to using light to control treatment. Obviously, the response is immediate; and despite the increased secretion of insulin, the amount of oxygen consumed by the cells does not change significantly as our study shows. Oxygen starvation is a common problem in studies involving transplanted pancreatic cells.”
Authors wrote in conclusion, “Transplantation of these cells into streptozotocin-treated mice resulted in improved glucose tolerance, lower hyperglycemia, and higher plasma insulin when subjected to illumination. Embedding optogenetic networks in β-cells for physiologically relevant control of GSIS (glucose-stimulated insulin secretion) will enable novel solutions potentially overcoming the shortcomings of current treatments for diabetes.”
They used the blue light as an on and off switch to increase the insulin production and the team explains that this optogenetic mechanism is being studied in a variety of diseases.
This study was funded partially by a National Science Foundation NSF grant.
Amelioration of Diabetes in a Murine Model upon Transplantation of Pancreatic β-Cells with Optogenetic Control of Cyclic Adenosine Monophosphate Fan Zhang and Emmanuel S. Tzanakakis ACS Synthetic Biology 2019 8 (10), 2248-2255 DOI: 10.1021/acssynbio.9b00262, https://pubs.acs.org/doi/pdf/10.1021/acssynbio.9b00262