Tufts University researchers have shown that glucose levels can be controlled in a mouse model of diabetes through optogenetics. When exposed to light, engineered pancreatic beta cells transplanted into diabetic mice produced more than two to three times the typical level of insulin. The light-switchable cells are designed to compensate for the lower insulin production or reduced insulin response found in diabetic individuals. The researchers sought to develop a new way to amplify insulin production while maintaining the important real-time link between the release of insulin and concentration of glucose in the bloodstream. Using optogenetics, they engineered pancreatic beta cells with a gene that encodes a photoactivatable adenylate cyclase (PAC) enzyme. The PAC produces the molecule cyclic adenosine monophosphate (cAMP) when exposed to blue light, which in turn cranks up the glucose-stimulated production of insulin in the beta cell. With this approach, insulin production can increase two- to threefold, but only when the blood glucose amount is high. At low levels of glucose, insulin production remains low. This avoids a common drawback of diabetes treatments, which can overcompensate on insulin exposure and leave the patient with harmful or dangerously low blood sugar (hypoglycemia). The researchers found that transplanting the engineered pancreatic beta cells under the skin of diabetic mice led to improved tolerance and regulation of glucose, fewer cases of hyperglycemia, and higher levels of plasma insulin when subjected to illumination with blue light. Exposure to blue light flipped the cells’ switch from normal to boost mode. “It’s a backwards analogy, but we are actually using light to turn on and off a biological switch,” said professor Emmanuel Tzanakakis. “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.” Researchers induced engineered pancreatic beta cells to secrete insulin when exposed to blue light. Insulin is shown here as a space-filling atomic model. Courtesy of Tufts University. Embedding optogenetic networks in beta cells for physiologically relevant control of glucose-stimulated insulin secretion could enable novel solutions, potentially overcoming the shortcomings of current treatments for diabetes. “There are several advantages to using light to control treatment,” researcher Fan Zhang said. “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.” Further development of this approach could include embedding sources of light — for example, tiny, remotely triggered LEDs — for improved illumination and coupling to a glucose sensor for the creation of a bioartificial pancreas device. Such optogenetic approaches using light-activatable proteins for modulating the function of cells are being explored in many biological systems and have fueled efforts toward the development of a new genre of treatments. The research was published in ACS Synthetic Biology (https://doi.org/10.1021/acssynbio.9b00262).