The Poy lab shows that a complex microRNA pathway governs the body’s response to insulin resistance
Our daily lives are marked by cycles – wakefulness and sleep, activity and rest, eating and fasting – through which most biological activity must continue in a balanced way. We don’t have to eat all the time because our cells can store nutrients for later use. Eating causes a quick rise in glucose, one of the body’s main sources of energy, but too much sugar in the bloodstream is toxic. When levels surpass a certain point, cells should absorb glucose. They are told to do so by the hormone insulin, which is produced by specialized beta cells in the pancreas. But in the disease diabetes type 2, cells become resistant to insulin stimulation and don’t respond properly. The body tries to compensate by creating more beta cells, which then secrete more insulin. It’s as if cells have become deaf, and the body raises the volume of the signal in hopes that the message will get through.
How the body senses insulin resistance and stimulates the production of more beta cells has been unclear. Matthew Poy’s lab at the MDC has now solved a crucial part of the puzzle. In a recent article in Cell Metabolism, the scientists unravel several layers of regulation by which cells control the production of specific proteins and respond to insulin resistance.
The study demonstrates that beta cells require a protein called Ago2 to begin this type of proliferation. Normally the production of Ago2 is braked by a small RNA molecule (miR-184). During insulin resistance, however, beta cells stop creating miR-184. As a result they release the brake on Ago2, which stimulates their proliferation and the secretion of more insulin.
Understanding this process required that the lab unravel the details of an intricate, switch-back route by which the information in genes leads to the production of proteins (or not). Proteins such as Ago2 are encoded in genes, which can be transcribed into messenger RNA molecules and then translated into proteins. But our genome also encodes at least 2,000 short microRNA molecules (miRNAs) which can block this process. MiRNAs have sequences that cause them to dock onto messenger RNAs and trigger their destruction before they can be translated into proteins.
In recent years scientists have discovered that miRNAs target many – if not most – human messengers and thus play a crucial role in fine-tuning the amounts of proteins produced by cells. MiR-184 apparently docks onto Ago2 messenger RNA and limits its production in this way.
Matthew and his lab have been studying the influence of miRNAs on beta cells for several years. “Many technologies are available now including small RNA sequencing techniques that can be implemented to detect changes in miRNAs in b-cells and study the amounts of these molecules that were being produced in disease models,” Matthew says. “A few years ago we discovered that healthy beta cells turned out large amounts of one such molecule, miR-375.”
This is where the story becomes a complicated affair of regulators regulating the regulators of regulators. (If you don’t like brain teasers, skip this paragraph and the next.) miR-375 normally docks onto the messenger of a protein called Cadm1. Cadm1 suppresses beta-cell proliferation. In other words, the production of more beta cells depends on eliminating Cadm1. Achieving that requires more miR-375.
Sudhir Tattikota, Thomas Rathjen, and other members of Matthew’s lab established this connection and figured out how Ago2 contributes to the process. When it’s around, Ago2 helps miR-375 establish contact with the Cadm1 messenger. So put together, the whole tortuous chain looks like this: miR-184 blocks the production of Ago2. As a result, Ago2 doesn’t help miR-375 find and block its target. That means the beta cells produce more Cadm1, don’t reproduce, and don’t produce more insulin.
Put more simply: LESS miR-184 means MORE Ago2 and MORE miR-375 activity, which means LESS Cadm1 and MORE beta cells. To simplify further, consider just the input and output: less miR-184 leads to more beta cells and more insulin. (And vice-versa.) Matthew and his colleagues have clarified the links in this pathway by revealing the roles of Ago2 and Cadm1.
The take-home message? “Insulin resistance is a symptom of the growing epidemic of diabetes type 2,” Matthew says. “The body compensates by stimulating the growth of new beta cells and increasing production of the insulin signal. We’ve shown for the first time how several layers of the miRNA pathway work together to stimulate the growth of the insulin-producing cells.”
The scientists used a mouse model in which insulin resistance could be tuned up and down. When they restored the animals’ sensitivity to the hormone, beta cells produced more miR-184 and didn’t proliferate. This demonstrates that the microRNA acts as a crucial part of the mechanism that detects insulin resistance.
The study revealed another aspect of insulin sensitivity which may open new possibilities for treating diabetes type 2. When people reduce their intake of carbohydrates, which are the main source of glucose, the liver begins converting fat into substances called ketone bodies, an alternative source of energy. This type of diet has been found effective in treating some forms of epilepsy, likely because it alters the biochemistry of nerve cells.
“The literature reports that this ketogenic diet also improves insulin sensitivity and affects glucose levels,” Matthew says. “If our mouse model is put on a ketogenic diet, we also see a rise in miR-184 levels. This may indicate that our dietary intake may influence pancreatic beta cells in ways that are still unclear. That offers new opportunities to investigate both the mechanisms of insulin resistance and potential therapies.”
– Russ Hodge
Reference:
Tattikota SG, Rathjen T, McAnulty SJ, Wessels HH, Akerman I, van de Bunt M, Hausser J, Esguerra JL, Musahl A, Pandey AK, You X, Chen W, Herrera PL, Johnson PR, O’Carroll D, Eliasson L, Zavolan M, Gloyn AL, Ferrer J, Shalom-Feuerstein R, Aberdam D, Poy MN. Argonaute2 Mediates Compensatory Expansion of the Pancreatic β Cell. Cell Metab. 2014 Jan 7;19(1):122-34. doi: 10.1016/j.cmet.2013.11.015. Epub 2013 Dec 19.
Link to the original paper:
http://www.ncbi.nlm.nih.gov/pubmed/24361012
Home page of the Poy lab:
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