Mmm… post-lunch blood glucose spike! Sitting down at my quiet computer, I can nearly hear my pancreatic islet cells working away, pumping out insulin to keep my blood glucose levels in check. Unfortunately, millions of people are not so well-protected from the glycemic havoc so mercilessly wreaked by chocolate cake. For people with type 1 diabetes (T1D), an autoimmune reaction kills insulin-producing β cells, leaving them unable to secrete insulin. In type 2 diabetes, the body loses its ability to respond to insulin. In both cases, the main treatments still require diet and lifestyle changes, but even if followed meticulously, such measures don’t always work.
In a sweet new pair of papers, Martin Fussenegger’s lab at ETH Zurich has used two different synthetic biology approaches to dynamically correct both type 1 and type 2 diabetes in mice . In both papers, researchers engineered synthetic gene circuits into human kidney cells (HEK293), embedded them in alginate micro-beads, and implanted the combination into diabetic mice.
Anti-Diabetes Circuit One: Glucose + Calcium → Insulin or GLP1
In the first paper, a team led by Mingqi Xie coupled calcium signaling induced by high glucose to secretion of insulin or GLP1. To do this in kidney cells, they first had to insert the gene for a voltage-gated calcium channel, Cav1.3. When blood glucose is high, this channel opens, causing an influx of calcium. Next, they found an engineered, calcium-sensitive promoter to drive gene expression when intracellular calcium was high.
For type 1 diabetic mice, they made the cells produce insulin, and for type 2 diabetic mice, they produced the therapeutic protein GLP1. In both cases, the implanted, engineered cells lowered the mice’s persistent high blood sugar and improved glucose homeostasis in response to a meal. Importantly, modeling and experiments showed that the treatment was safe, with minimal danger of an insulin overdose.
Anti-Diabetes Circuit 2: Insulin → Adponectin
For dessert, Haifeng Ye took over the kitchen, serving up another synthetic gene circuit to correct the insulin resistance in type 2 diabetes. This strategy took advantage of the MAPK pathway that naturally responds to insulin. The key innovation for this dish was a fusion between ELK1 (a component of the insulin response pathway) and TetR, a non-native transcription factor.
When insulin is high, the hybrid transcription factor activates expression of adiponectin, a natural hormone that increases the body’s insulin sensitivity. Again, following transplantation of engineered cells into type 2 diabetic mice, they kept blood sugar in check. As a final aperitif, diabetic mice with these engineered implants even ate less and lost weight!