Can insulin produced in lettuce cure type 1 diabetes some day? Possibly. In mice, it seems to modulate the immune attack on the beta cells that is the hallmark of type 1 diabetes. But the pathway is complex.
Therapeutic insulin is usually injected. This is for two reasons. First, most proteins are partically digested in the stomach. The very acid stomach first denatures the proteins. This means that the very specific folding of a protein that gives it specificity is destroyed, and the protein goes from a compact structure to a long chain of amino acids (the building blocks of proteins).
Then the digestive enzyme pepsin, which works best in an acid environment like the stomach, begins to chop the long chain into smaller bits. Hence, no more insulin.
The second reason is that in a healthy person, the gut easily absorbs small molecules like glucose or individual amino acids. It doesn’t usually absorb a lot of proteins in their intact form. So even if insulin were able to make it through the stomach, it wouldn’t be absorbed very well.
Inhaled insulin was developed as one way to get around these two problems. There’s no acid in the lungs, and they are able to absorb some of the inhaled insulin intact. Insulin sprays in which the insulin is absorbed through the skin of the mouth are another approach.
Now researchers at the University of Central Florida, led by Henry Daniell, are working at an ingenious method to allow insulin – as well as various vaccines – to be delivered orally to the gut, where the insulin can act as an immunomodulator, a substance that modulates your immune system response.
First, they’re producing the proteins in genetically modified plants. They’ve used tobacco and, more recently, lettuce to produce human proinsulin (the compound that is broken down in the beta cells into insulin and C-peptide).
Other researchers have produced insulin in other plants, for example, safflower. But by inserting the insulin gene in the plant chloroplasts – the tiny organs in plant cells that take energy from the sun and use it to make carbohydrates – Daniell’s group has gotten high yields of proinsulin without the danger that the altered genes will spread through pollen. This is because chloroplasts are inherited only through maternal cells, not through pollen (male cells).
Next, by grinding up the plant tissue and feeding the ground up tissue to mice, they’ve managed to bypass the protein destruction that usually occurs in the stomach. In essence, the plant cells with their cellulose walls are encapsulating the proinsulin and protecting it. Once in the intestine, the plant cells are slowly digested and the proinsulin complex is released.
That leaves the last problem: the fact that intestinal cells don’t take up intact proteins very well. To solve this problem, they’ve complexed the proinsulin with something called cholera toxin B. This is a nontoxic part (the B subunit) of cholera toxin that stimulates intestinal cells to take up proteins.
For the cholera bacterium, it’s a trick to get the intestinal cells to take up the intact cholera toxin. For the researchers, it’s a trick to get the intestinal cells to take up intact proinsulin.
This system stimulates uptake by cells of the intestinal immune system as well. In NOD (nonobese diabetic – a standard rodent model of type 1 diabetes) mice, the uptake by the immune cells resulted in a significant increase in compounds that suppress immune responses. The result was a reduction in the immune system attack on the beta cells. It is immunological attack on the beta cells that causes their destruction and is the cause of type 1 diabetes.
In the mice, eventually the beta cells recovered, and their blood glucose levels returned to normal.
Daniell said that after the proinsulin complex is taken up into the interstitial fluid, it does not get transformed into insulin and C-peptide, so there’s no danger that eating a lot of the complex would have an effect on blood glucose levels.
The researchers are hoping that this technique, using insulin from modified lettuce plants, can be used to stop beta cell destruction in people who are in the very early stages of type 1 diabetes, when they still have many beta cells left. It might even work in those who have already been diagnosed with type 1 diabetes.
Like much research in mice, however, this treatment is not something that is going to be available tomorrow. Cures in mice don’t always translate into human cures. But, like the Toronto work last fall that showed that type 1 diabetes could be cured in mice by manipulating the nerves to the beta cells, this research is a fascinating new approach to the complex problem of diabetes.
“This is a totally new approach. It has great promise,” said Daniell. He said that human clinical trials of the lettuce system are in the works.
Read the Reuters news article on insulin produced in genetically modified plants by clicking here.