Mice homozygous for the diabetes spontaneous mutation (Leprdb) become identifiably obese around 3 to 4 weeks of age. Elevations of plasma insulin begin at 10 to 14 days and of blood sugar at 4 to 8 weeks. Affected mice are polyphagic, polydipsic, and polyuric. The course of the disease is markedly influenced by genetic background. On the C57BL/6 background there is compensatory hyperplasia of the islet B-cells, and continued hyperinsulinemia throughout an 18- to 20-month life span. Wound healing is delayed, and metabolic efficiency is increased. Although normal in body weight, blood glucose, and plasma insulin, heterozygotes (Leprdb/+) also have increased metabolic efficiency, and can survive a prolonged fast longer than controls. Experiments involving destruction of the ventromedial nucleus of the hypothalamus suggest that Leprdb may cause a defect in the hypothalamus. Steroid sulfotransferase enzymes, aberrantly expressed in diabetic mice, interact with the Leprdb mutation as modifiers of gender differences in obesity-induced diabetes susceptibility. Because Leprdb homozygotes are functionally sterile, the coat color marker misty (Dock7m) has been incorporated into stocks for maintenance of the diabetes mutation. The coupling double heterozygote, (Dock7m Leprdb/+ +, this strain) allows identification of homozygotes before the phenotype becomes severe.
The recessive misty mutation causes a mild dilution of coat color. On certain backgrounds, a white tail tip often accompanied by a belly spot is also present. Melanocytes from homozygous misty mice (Dock7m/Dock7m) have a highly dendritic shape, show deficient proliferation in culture and have much more melanin content. Fewer melanoblasts are found in primary cultures from Dock7m/Dock7m mice than from wildtype controls. Between two and five weeks of age, Dock7m/Dock7m mice are smaller than controls. At 35 days of age they are shorter, weigh 15% less on average, and have less inguinal adipose mass than controls. Misty homozygotes completely lack brown fat. Although platelet count, seratonin content and ATP content are normal, bleed time is increased and platelet AD levels are reduced in Dock7m/Dock7m homozygotes. (Woolley, 1941 and 1945; Truett et al. 1998; Sviderskaya et al. 1998.)
