Now, this expansion of beta cell mass in response to insulin resistance is not unheard of; other researchers have shown that beta cells increase their replication rates in certain types of insulin resistance, in response to glucose, and even in pregnancy. However, the growth seen with S961 was much more dramatic, and so the researchers decided to figure out what might be causing the beta cell growth.
The researchers first checked whether the drug was causing beta cells to grow directly, but the drug alone had no effect on beta cells. The researchers next looked at the levels of genes in the liver, fat tissue, and skeletal muscle of the mice. They compared the mice treated with the drug to untreated mice, and were able to find one particular gene that was present at a very high rate in the treated livers and fat, but not in the untreated. This gene had previously been predicted and identified as Gm6484, but the authors of the study have decided to name it betatrophin.
This gene betatrophin is abundant in liver tissue for many mammals, including humans, and gets turned into a protein that the researchers showed can be excreted from the liver into the bloodstream. The researchers next had to check whether betatrophin was actually the gene that mattered with the mice that were treated with S961. To do this, they injected mouse livers with the gene such that the livers would begin to make the betatrophin protein. Even in the absence of insulin resistance, this production of betatrophin by the liver resulted in rapid expansion of the beta cells in the mice, with a replication rate 17 times higher than normal. Further, the betatrophin-expressing mice had lower fasting blood glucose values and improved glucose tolerance compared to normal mice.
To summarize, then: researchers identified a protein, betatrophin, produced by the liver that leads to increased rates of beta cell replication, and thus more beta cells and more insulin capacity. If you’re still with me, you’re probably asking, “Well, wait, but what is betatrophin actually doing?” The answer to that important question is that the researchers don’t know yet. Based on the fact that they had to make the liver produce betatrophin, and they couldn’t just inject betatrophin into circulation in the mice or put betatrophin directly on beta cells, it seems that the effect of betatrophin is indirect, and likely there are other proteins or hormones between betatrophin and beta cell replication.
Even so, the researchers here have taken a very interesting first step in identifying betatrophin, and it is exciting to think what might come of this over the next few years as the scientists try to figure out how exactly betatrophin is working, and how we might be able to leverage its activity (and the activity of the other proteins it effects) to increase beta cell replication in humans who have a shrinking supply of beta cells. Clearly, there is quite a bit to do before this betatrophin pathway is useful in human treatment, but this first step certainly introduces new and intriguing possibilities.
Karmel Allison is science editor of ASweetLife. She writes the blog Where is My Robot Pancreas?.
Follow Karmel on Twitter (@karmel_a)