A team of bioengineers at the University of California, Los Angeles (UCLA) has developed a form of “smart” insulin that can respond to changing blood glucose levels and so prevent potentially fatal episodes of hypoglycemia in patients with diabetes. Described in a paper in the Proceedings of the National Academy of Sciences (PNAS), the modified insulin, dubbed i-insulin, comprises an insulin analog attached to a glucose transporter (Glut) inhibitor, which acts to prevent over-uptake of glucose into cells if blood glucose levels drop. When tested in diabetic mice the modified insulin kept blood glucose levels within the normal range for longer, and protected the animals from becoming hypoglycemic even when an extra dose of the i-insulin was administered.

“Our new i-insulin works like a ‘smart’ key,” explained research lead Zhen Gu, PhD, a professor of bioengineering at the UCLA Samueli School of Engineering. “The insulin lets glucose get into the cell, but the added inhibitor molecule prevents too much from going in when blood glucose is normal. This keeps blood sugar at normal levels and reduces the risk of hypoglycaemia.” Gu and colleagues reported on the i-insulin in a paper titled, “Glucose transporter inhibitor-conjugated insulin mitigates hypoglycemia.

Diabetes mellitus results when the body cannot produce enough insulin, or doesn’t effectively use the insulin that is produced, and cannot control blood levels of glucose. The disease affects more than 400 million people worldwide, and for those with type 1 diabetes and advanced type 2 disease treatment involves daily injections or even continuous infusions of insulin.

Patients must monitor their blood glucose daily, adjust their carbohydrate intake, and calculate how much insulin they need. Administering too much insulin can result in hypoglycemia, which results when blood sugar levels become too low, and can lead to seizures, coma, and potentially even death.

Insulin works by attaching to a receptor on the cell surface, which triggers glucose transporter (Glut) molecules within the cell to mobilize to the cell surface, and shuttle glucose from the blood into the cell. The UCLA team and collaborators have now developed an insulin conjugate that comprises an insulin analog attached to an insulin-facilitated, glucose transporter inhibitor. The presence of the Glut inhibitor means that the insulin analog can reversibly bind to Glut on cell membranes, but how strongly it binds depends on the concentration of glucose in the blood, so the system essentially becomes glucose-responsive. “Upon subcutaneous injection, this insulin analog can bind to insulin receptors (IR) as well as endogenous Glut, establishing an in situ-generated reservoir of insulin analog,” the authors explained.

When blood glucose concentrations rise after a meal, the insulin analog-Glut complex dissociates, liberating the Glut on the plasma membrane, as well as the free insulin analog. “The free insulin analog can subsequently bind to IR to trigger the translocation of Glut4 to cell membranes and enhance glucose clearance into muscle and fat,” they continued. “Meanwhile, the Glut, which is previously inaccessible to glucose as part of the insulin analog-Glut complex, can enhance the blood glucose clearance.”

While an excess dose of a regular insulin would induce overexpression of Glut on the plasma membrane, which could result in hypoglycemia, the formation of reversible glucose-responsive insulin analog-Glut complexes temporarily blocks the glucose transporter molecules, reducing the risk of hypoglycemia.

The researchers first evaluated the i-insulin in an in vitro system using erythrocyte ghosts, and then carried out a series of tests in a drug-induced mouse model of type 1 diabetes. Animals given a single subcutaneous injection of the i-insulin maintained normal blood glucose levels for more than 10 hours, whereas mice given native insulin maintained normoglycemia for just 4 hours. “Of note is that mice treated with i-insulin showed negligible hypoglycemia,” the authors wrote. “This i-insulin can also rapidly respond to high glucose levels,” noted Jinqiang Wang, PhD, the study’s co-lead author and a postdoctoral researcher in Gu’s research group. “For example, after a meal, when glucose levels climb, the insulin level in the bloodstream also quickly increases, which helps normalize the glucose level.”

Blood cells with i-insulin that have been tagged with a red fluorescent dye. [Zhen Gu Lab/UCLA]
When mice were given a second injection of either i-insulin or native insulin three hours after the first treatment, the i-insulin-treated mice were still able to maintain normal blood glucose levels, whereas the animals given native insulin showed marked hypoglycemia. And while normal, healthy mice became severely hypoglycemic when treated using native insulin, healthy animals given the i-insulin were protected from a severe drop in blood sugar. “i-insulin only slightly lowered blood glucose of healthy mice,” the investigators stated.

They claim that bioresponsive insulin-mediated treatment could “revolutionize” diabetes therapy. “An insulin molecule with the properties of glucose responsiveness and hypoglycemia mitigation would offer a novel approach to regulate blood glucose levels with low risk for hypoglycemia,” the investigators concluded. The system could be further fine-tuned by modifying components including the glucose transporter inhibitor, insulin, and spacer. “The new insulin has the potential to be optimized for response times and how long it could last in the body before another dose would be required,” Gu said.

For the reported studies animals were given subcutaneous injections, but the scientists suggest that i-insulin could also be formulated for delivery via transdermal microneedle patch, or as orally delivered pills. “… this glucose-responsive insulin can be further integrated with painless transdermal microneedle array patch to generate a new version of ‘smart insulin patch’ or oral delivery systems to form ‘smart insulin pills,’” the scientists stated.

“The next step is to further evaluate the long-term biocompatibility of the modified insulin system in an animal model before determining whether to move to clinical trials,” said co-author John Buse, PhD, director of the Diabetes Care Center at the University of North Carolina at Chapel Hill School of Medicine. “The vision, if realized, would be one of the most exciting advances in diabetes care.”

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