Lin28/let-7 pathway plays an unexpected key role in type 2 diabetes

New study connects the cancer gene Lin28 to glucose metabolism; may shed light on unifying principles in type 2 diabetes

A pathway activated in cancer plays an unexpected key role in metabolic diseases like type 2 diabetes, according to a study by researchers at Children's Hospital Boston. Evidence that the Lin28/let-7 pathway influences the cellular response to glucose provides a unifying theme to perplexing data that associates human genetic variation with diabetes risk.

The multi-institutional research team led by George Q. Daley, MD, PhD, director of Stem Cell Transplantation and a leader in the Stem Cell Research Program at Children's Hospital Boston – reported their findings in the September 30 issue of the journal Cell.

Let-7 is a microRNA, a small RNA that dampens the expression of a large set of genes related to cell growth and development. Previously, the Daley lab reported that Lin28, an RNA-binding protein found at high levels in the embryo, blocks let-7 production and is aberrantly expressed in about 15% of all cancers.

"The relationship between Lin28 and let-7 is ancient, found in organisms as diverse as worms, mice, and humans," said Daley, a professor of biological chemistry and molecular pharmacology at Harvard Medical School and a Howard Hughes Medical Institute investigator. "This suggested to us that the Lin28/let-7 pathway was profoundly important, but we didn't expect such exciting results."

In the current study, Daley and his team, led by Hao Zhu and Ng Shyh-Chang, set out to study cancer by developing a trio of mouse models with altered expression of Lin28 and let-7. What they discovered, instead, were profound effects on glucose metabolism. When fed a high-fat diet, normal mice develop obesity and diabetes, but mice engineered to express surplus Lin28 remained lean and processed glucose efficiently while mice engineered to express surplus let-7 became diabetic even on a normal diet.

"The results were startling," said Daley. "Previously we had considered these molecules only as regulators of cell growth and cancer. But in these mice we discovered remarkable effects on sugar processing and diabetes."

Molecular studies showed that Lin28 and let-7 exert their influence on glucose control at multiple points along the evolutionarily ancient insulin signaling pathway. Components of this pathway, which manages growth and glucose metabolism at the cellular level, are also tied to the survival of multiple kinds of cancer.

"Cancer cells have a metabolism that is very embryo-like," Daley noted, "so we speculate that tumors take advantage of the Lin28/let-7 pathway to turn back the clock, in metabolic terms. It's a avenue we'll to study further."

To link their findings in mice to human metabolism, the researchers examined data on genetic variation found in patients with type 2 diabetes together with co-author David Altshuler of Harvard Medical School, a world authority on the genetics of diabetes. They found that many diabetes-associated genes were known or predicted let-7 targets.

"It can be difficult to link genetic association data to actual biochemical pathways in the cell," Daley explained. "Let-7 has hundreds, maybe even thousands, of gene targets. The genetic data, coupled to the striking similarities between the way our mice and patients with diabetes handle glucose argues that regulation by Lin28/let-7 is a unifying feature of many genes associated with diabetes."