I've written before about glucagon (here and here) and have suggested that we need more research on alpha cells and glucagon, which sometimes seem to be ignored. Robert Unger has been writing about this for decades, but most researchers continue to focus on insulin.
In general, glucagon does the opposite of insulin. Insulin is produced by the beta cells in the pancreas and makes blood glucose (BG) levels go down. Glucagon is produced in the alpha cells in the pancreas and makes them go up. It's the ratio of the two that is important.
And now comes research showing that certain versions of the TCF7L2 gene, which are known to increase the risk of type 2 diabetes and were thought to work by inhibiting the secretion of insulin by the beta cells, may also work by making the alpha cells resistant to the action of insulin, which normally shuts them off. The senior author of the paper, Adrian Vella, kindly sent me the full text of the article.
When everything is working correctly, you eat carbohydrate and your beta cells produce and secrete insulin, which helps muscle and fat cells take up glucose. The insulin also turns down the secretion of glucagon by the alpha cells, which makes sense. Glucagon makes the liver produce and release a lot of glucose, and that's not something you want when your BG levels are already high.
The problem is that when you have type 2 diabetes, not only are your insulin levels too low to overcome your insulin resistance, but your glucagon levels are too high. And for those with the high-risk version (TT) of the TCF7L2 gene (and I have the protective version, CC, according to 23&Me), one reason for this high glucagon level seems to be that the insulin doesn't turn down its production in the alpha cells. So even when you eat carbohydrate and have enough insulin, the liver keeps pouring out glucose.
The study also showed a slight decrease in insulin production in those with the high-risk version of the gene, but no difference in the effectiveness of the insulin that was produced.
The differences in glucagon levels in those with the high-risk version of the TCF7L2 gene were not enormous. Clearly, the high-risk version of the gene is not the only contributor to type 2 diabetes. But that is consistent with the idea that type 2 diabetes is caused by small effects from many genes and not just one gene, as occurs in MODY, or maturity onset diabetes of the young. That's one reason why there's so much variation in the way we respond to various factors. I may have a defect in a different gene or genes than you do.
But this research is a reminder that alpha cells and glucagon are important contributors to the type 2 diabetes puzzle, and genetic and environmental effects on alpha cells may turn out to be as important as the effects on beta cells. "It demonstrates a completely novel mechanism of predisposition to diabetes that could lead to novel therapies," said Vella.