Misfolded proteins clump together and inhibit insulin production, according to PNAS report.

Beta cells may shut down because of misfolding in proinsulin, the precursor of insulin, according to a team from the University of Michigan Medical School.

The scientists engineered the gene for human proinsulin to add a fluorescent tag. They then inserted the human gene into rat pancreas cells. Next, the team introduced a mutation into the tagged human insulin gene that causes the proinsulin molecule to fold incorrectly.

The Michigan team found that misfolded proinsulin stuck to other proinsulin in the endoplasmic reticulum. Simultaneously, this blocked the traffic of the normal proinsulin in the same cells. Also, this buildup in the endoplasmic reticulum directly inhibited insulin production in the beta cells, which ultimately died.

The research was done in collaboration with an investigator at the University of Chicago. It will be published early online in the Proceedings of the National Academy of Sciences.

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