A new mutation (db 3J) at the diabetes locus in strain 129/J mice

Abstract

A spontaneous recessive mutation appearing in strain 129/J mice at the diabetes (db) locus on Chromosome 4 has been characterized. The new allele, designated db3J, produced hyperphagia and severe obesity. Mutants weighed in excess of 70 g by 6 months of age, compared to 22-28 g for lean littermates. Although the disease was similar to the mild hyperglycaemia-severe obesity syndrome exhibited by db gene presentation on the C57BL/6J inbred background, the syndrome in 129/J mice reduced lifespan, with mutants exhibiting sudden weight loss, hypoglycaemia, and a 67% mortality between 6 and 14 months of age. Mutant males, but not females, were transiently hyperglycaemic between 2 to 4 months of age, attaining a maximum mean blood sugar of 196 +/- 27 (SEM) mg/dl. Thereafter glucose levels declined to normoglycaemic values (80-100 mg/dl), and with increasing age, mutants of both sexes became hypoglycaemic (60 mg/dl at 9 months). Mutants of both sexes were extremely hyperinsulinaemic at the earlier ages, with mean plasma insulin at months 5 reflecting 30-fold elevations above normal for males and 18-fold for females. These levels diminished with age, the decline being more marked in males. Plasma glucagon levels were 3-fold elevated in the younger mutants of both sexes (86 pg/ml versus 28 pg/ml in normal mice), mean levels increasing to almost 5-fold above mean control vaues in the older age group (198 pg/ml versus 41 pg/ml in normal mice). Histopathological findings were limited to pancreas. Increasing necrosis of the exocrine, but not endocrine, pancreas was noted in aging mutants. Aldehyde fushsin staining of the mutant pancreas revealed hyperplastic islets filled with heavily granulated B-cells. B-cell hyperplasia was accompanied by a 30-fold increase over controls in pancreatic insulin content in the 8 month old mutants, whereas pancreatic glucagon content was only doubled. Morphometric analysis showed less than a 2-fold increase in the mean number of A-cells per islet. Thus, an interesting feature of expression of the diabetes gene in the 129/J strain is the persisting hyperglucagonaemia in the face of moderating hyperinsulinaemia.

Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity

“…It has also been shown that the specific strain on which the mutation is maintained determines the response of the endocrine pancreas to hyperglycemia and insulin resistance (5). For example, some strains, such as C57BL/6J and 129/J, have the ability to undergo compensatory hyperplasia of the pancreatic insulin-producing cells, with the resultant phenotype of near-euglycemia due to hyperinsulinemia (19). It is possible that ␤-cell hyperplasia and the resultant hyperinsulinemia are dependent on IL-6, since our IL-6 Ϫ/Ϫ mice became hyperglycemic on a high-fat diet.…”

Transgenic Complementation of Leptin-Receptor Deficiency

“…Consistent with this inference, db/db mice, which lack only functional LEPR-B, develop an obesity/diabetes syndrome apparently identical to ob/ob mice and are unresponsive to peripheral or central leptin administration (9). Furthermore, mice and rats possessing allelic mutations in the Lepr gene that affect all LEPR isoforms (db 3J [21], db Pas [22], db NCSU [23], fa [24], and fa-f [25]) exhibit the db/db obesity/diabetes phenotype. Studies in vitro have revealed LEPR-A signaling activities (e.g., immediate-early genes [26]) but the physiological relevance of this pathway to in vivo energy and glucose homeostasis is not clear.…”

Class I MHC-Binding Characteristics of the 129/J Ly49 Repertoire

“…For example, 129/J mice are more susceptible to intracellular pathogens, such as the WA1 piroplasm and Sendai virus, than B6 mice (28,29). Also, 129/J mice are more prone to the induction of autoimmune diseases such as experimental autoimmune encephalomyelitis and show greater disease severity in diabetes models than B6 mice (30,31). In contrast, 129/J mice are relatively resistant to tumor induction by various carcinogenic agents and display a lower spontaneous overall tumor incidence (32)(33)(34).…”