In part 2 of this Exclusive Interview, Dr. Mark Huising talks with Diabetes in Control Publisher Steve Freed during the ADA meeting in San Diego, California about the impact of type 2 on delta cells and measuring the activity of these cells.
Dr. Mark O. Huising, PhD, is an assistant professor at UC Davis in California. His work has been focused on the evolution of immune and endocrine systems in early vertebrates.
Transcript of this video segment:
Steve Freed: A person who has type 2 diabetes where he is insulin resistant and has glucose toxicity, the beta cells don’t work very well in that environment, does that also…I presume it affects the delta cells in a similar way.
Mark Huising: So, the way the delta cell feedback breaks down in somebody with diabetes is beta cells, as I said before, they express urocortin 3 peptide and every time a beta cell secretes insulin, which talks to liver, skeletal muscle, adipose tissue, they secrete a little bit of urocortin 3. This urocortin 3, instead of talking to cells elsewhere, just talks to the neighboring delta cells. Delta cells respond to urocortin 3 by secreting somatostatin, and somatostatin talks back to beta cell and helps the beta cell shut down stop secreting, provided that the insulin it gave off was sufficient to bring glucose levels back down. Now that’s how it works in a healthy individual. What happens early on in somebody even with pre-diabetes and they’ve shown this not only in mice models but in human donor samples as well as in macaque models of pre-diabetes, that even in a pre-diabetic macaques, we see this urocortin 3 disappear really quite early on, signaling that this local feedback, the normal feedback that helps attenuate beta cell function really doesn’t work appropriately anymore. And what happens then, there’s two things that happen, the loss of urocortin 3 means that the break of beta cells goes away so you allow more insulin to come out which is a sort of adaptation but what it also does is it contributes to these wild, volatile swings of plasma glucose. Rather than timely and pre-emptively inhibiting insulin activity from beta cells to make sure that you arrive just back down at your normal target for glucose, insulin is not timely released. It stays high for too long, glucose overshoots its set point and now it’s going to have to activate some kind of counter regulatory mechanism to come back up and you can actually see that if you apply glucose monitoring to mice, which we’ve done. You can actually see that really volatile pattern associated with the loss of urocortin 3 feedback.
Steve Freed: Now we can measure activity of beta cells.
Mark Huising: um hm
Steve Freed: Can we do that with delta cells?
Mark Huising: We can do the exact same thing with delta cells. We could do it with elective physiology where you basically stick a thin glass capillary in a cell and measure the electrical currents. It’s really hard to do. It’s really specialized. And recently, people have made wonderful tools available where we don’t have to do it that way anymore. We can actually look at fluorescent proteins that light up as soon as the cell releases calcium and calcium is an important second messenger and is a wonderful proxy for hormone secretion. So, rather than looking at hormone secretion directly we can actually take islets, put them under a microscope, and watch them behave in real time and look at the activation of delta cells, or beta cells, or alpha cells as we apply different drugs and then study the effect on cell activity. So, it’s actually very cool to do, but also very instructive because we can start to really figure out which drugs or which peptide hormones or which pharmacological agents work directly on beta cells and which ones work because they activate or inhibit a neighboring cell like a delta cell.