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Allelic Variation on Chromosome 5 Controls ß-Cell Mass Expansion during Hyperglycemia in Leptin Receptor-Deficient Diabetes Mice

Institute of Human Nutrition (N.L.) and Division of Molecular Genetics (H.L., Q.L., Q.X., X.S., B.D., J.L.), Department of Pediatrics, Columbia University, New York, New York 10032; and Division of Endocrinology (S.M.L., S.C.), Department of Medicine, Albert Einstein College of Medicine, New York, New York 10461

Address all correspondence and requests for reprints to: Streamson Chua, Jr., M.D., Ph.D., Belfer 701, Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, New York, New York 10461. E-mail: schua{at}aecom.yu.edu.

Leptin signaling is a critical component of normal insulin sensitivity. Overt hyperglycemia and type 2 diabetes mellitus can be manifested in states of leptin signaling deficiencies by the additional effects of other genetic factors. We have previously described the contrasting insulin sensitivities and glycemic states of two congenic diabetes (db/db) mouse strains. C57BL/6J db/db mice have mild insulin resistance and achieve euglycemia with mild hyperinsulinemia. FVB db/db mice have severe insulin resistance and are hyperglycemic despite escalating hyperinsulinemia with expanded pancreatic ß-cell mass. Analysis of obese progeny from the two reciprocal backcrosses suggests that genetic modifiers for insulin sensitivity are separable from loci that modulate ß-cell mass. A genome scan of the backcross to FVB suggests that one or more modifier genes are present on chromosome 5. This evidence is supported by the phenotypes of multiple incipient congenic strains wherein the hyperglycemia observed in obese FVB mice is reproduced. With similar degrees of hyperglycemia in obese mice of these strains, the haplotype at chromosome 5 is associated with ß-cell mass and circulating insulin concentrations. Finally, we offer arguments that production of multiple incipient congenic lines is an economical alternative to the production of speed congenic strains.

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