Sci. Aging Knowl. Environ., 27 February 2002
Vol. 2002, Issue 8, p. nw26
[DOI: 10.1126/sageke.2002.8.nw26]


No Take Backs: Mice that can't get rid of insulin develop signs of diabetes (Insulin resistance; Diabetes)

R. John Davenport;2002/8/nw26

Key Words: insulin resistance • diabetes • obesity • CEACAM1 • liver

Abstract: If the remnants of a meal aren't tidied, they can turn into a big mess, whether it's in your kitchen or your body. Insulin normally coordinates the cleanup of leftovers in the bloodstream. But cells can turn recalcitrant and ignore the hormone's directives. Researchers have blamed overproduction of insulin for this state, known as insulin resistance, which becomes increasingly common as people age and can lead to diabetes. But new work in mice suggests that ineptitude at getting rid of insulin after a sugar surge can also cause the trouble.

Eat a Krispy Kreme doughnut, and feel your blood sugar soar. In response, the pancreas produces insulin, which tells muscle, fat, and liver cells to soak up the sweets. Insulin sets off a chain reaction when it attaches to a cell surface receptor. The receptor adds a phosphate group to other proteins, which enables them to prod cells to absorb sugar and store it. As sugar concentration in the blood falls, liver cells take up insulin to shut off this response. Previous work hinted at a player involved in this insulin clearance pathway. Researchers had determined that a protein called CEACAM1 receives a phosphate group when cultured liver cells are treated with insulin and that cultured cells lacking CEACAM1 can't reabsorb the signaling molecule. But they didn't know whether CEACAM1 helps intact animals soak up insulin.

To answer that question, Poy and colleagues engineered a mutant mouse whose liver cells produce a version of CEACAM1 that lacks the site where phosphate attaches. The creatures are chubbier and carry more tummy fat than control animals do; in addition, two to five times the normal amount of insulin courses through the mutants' blood. To find out whether the mice produce extra insulin or can't get rid of what they make, the team injected radioactively labeled insulin into the animals' tails. After 1 hour, the mutant mice retained two to three times as much insulin in their blood as wild-type mice did. These and other experiments suggest that CEACAM1-defective mice can't efficiently remove insulin from the bloodstream.

The mutant mice also exhibit hallmarks of insulin resistance. They have abnormally large amounts of glucose in their blood and recover unusually slowly when the researchers inject them with the sugar. In addition, liver cells from mutant mice display fewer insulin receptors than do those from their wild-type siblings. Muscle and fat cells, however, retain their insulin sensitivity, indicating that the animals do not develop diabetes. Together, the results suggest that problems in insulin uptake can stimulate insulin resistance, although additional deficiencies are needed to trigger diabetes.

The results are provocative, says cell biologist Morris Birnbaum of the University of Pennsylvania in Philadelphia. But he cautions that the experiments on mice are "a far cry from showing that this ever really happens in people, much less is related to human disease." The work suggests, however, that telling the cleaning crew to go home once the job is done might be good for your health.

--R. John Davenport

M. N. Poy, Y. Yang, K. Rezaei, M. A. Fernstr´┐Żm, A. D. Lee, Y. Kido, S. K. Erickson, S. M. Najjar, CEACAM1 regulates insulin clearance in liver. Nature Genet., 19 February 2002 [e-pub ahead of print]. [Abstract] [Full Text]

Citation: R. J. Davenport, No Take Backs: Mice that can't get rid of insulin develop signs of diabetes (Insulin resistance; Diabetes). Science's SAGE KE (27 February 2002),;2002/8/nw26

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