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September 17th, 2012
As regular readers of this blog know, after a long preparation we have started crucial large-mammal studies, using the pig model, at Prof. Jonathan Lakey’s laboratory at the University of California, Irvine. The studies are ongoing and we are learning much.
In science you build on the work of those before you. (Isaac Newton: “If I have seen further it is by standing on ye sholders of Giants.” [sic] ) So we looked for the best pig diabetes papers to help guide us. The one we found most useful is this paper from the University of Wuerzburg (Germany), and I’ll share some details on how their report compares to our efforts to control diabetes in a pig.
We were pleased to find in the German study a precedent for the use of Continuous Glucose Monitoring (CGM). Not only would this produce more data on how the Islet Sheets function, but it would also help produce the best possible management of the pig’s blood sugar during the diabetic period before sheets are implanted. We had already arranged to work with Dexcom to use its CGM product. The Wuetzburg group used a similar product from Medtronic. Their purpose was to investigate the use of a minipig model for type 1 diabetes research. Our purpose is to evaluate the function of the Islet Sheet in the pig model.
We have found the management of diabetes in pigs to be a challenge, as did they. Here is Figure 7 from their paper (2 days of data):
And here is some data from the first diabetic pig at UCI (also 2 days of data):
Both groups monitored blood sugar continuously (dark blue triangles in Fig. 7; light blue in the UCI graph) and measured blood glucose with sticks and skin punctures (magenta squares above; purple diamonds below). In other ways the protocols are significantly different. Wuerzburg fed the pigs once a day (red dots); Irvine feeds them twice a day (green squares). A single daily feeding simplifies management of the pig’s diabetes by having one mealtime insulin dose. Twice daily feedings are probably better for the pig because the animal’s natural adaptation is omnivorous: it eats often when awake.
Wuerzburg administers insulin in the form of Lantus (green triangles) and Novomix (red triangles) to the pigs ad lib; Irvine administers Lantus (yellow circles) and Novolog (orange) twice a day at mealtime, using a sliding scale developed at the Gonda Diabetes Center at UCLA by Dr. Andrew Drexler and Certified Diabetes Educator Carolyn Robertson.
Both groups found that diabetes in these pigs is hard to control! For one thing, the pigs don’t know that the glucose meter is good for their health, so they try to remove the irritating sensor. And even in a normal laboratory pig, blood sugar can vary from under 40 to over 100; their control is not as tight as healthy human beings have naturally.
Our goal at UCI is to get the pig’s average blood glucose as low as possible with minimal hypoglycemia before implantation of the Islet Sheets. Not only is this good control good for the pig, it will make good Islet Sheet function more likely because (perhaps surprisingly) islets have a lower insulin secretion when blood sugars are high. In human beings maximal insulin secretion is found in the blood sugar range of 140-200. Higher blood sugars actually inhibit islet function.
On a personal note, it is exciting to be part of the crucial Islet Sheet studies. The research group at UC Irvine is doing very good work, and we are getting support from Dexcom. And I am helping to manage a brother diabetic, albeit a porcine one.