KK and KK/Upj-A^y /J

Inbr: F90 +. Albino. Genet: a, B, c, D, S. Origin: K. Kondo 1944 from Japanese dealer stock (Kasukabe group). Some substrains carry the yellow (A^y ) gene.

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Characteristics

Strain develops diabetes mellitus associated with insensitivity to insulin and intolerance to glucose without hyperglycaemia. When obesity is induced by nutrition, the yellow obese gene A^y or gold thioglucose treatment, the mice develop hyperglycaemia accompanying marked insensitivity of adipose tissue to insulin (Taketomi et al., 1973., 1973). Mice are inheritantly glucose intolerant with insulin resistance, and develop overt diabetes if they become obese due to dietary manipulation or aging (Ikeda, 1994). Mode of inheritance of glycosuria depends on both genetic and environmental factors with at least two major genes which are dominant in crosses with C57BL (Butler and Gerritsen, 1970; Butler, 1972). Moderate obesity (mature weight about 45 g) occurs by about 2 months and stabilises by 4-5 months. Carcase fat is about 33% of total. Bray and York (1971) state that the diabetes is characterised by hyperglycaemia, hyper-insulinaemia, glucose intolerance and hyperphagia, although the hyperglycaemia abates by about 1 year. Food restriction makes the animals more normal. There is an elevated pituitary growth hormone level, and significant glomerular lesions. Opperman et al. (1975) found that fasting results in impaired glucose tolerance. Glipizide, an oral hypoglycemic compound, improves glucose metabolism, decreases kidney size, prevents kidney glycoprotein and mesangial matrix accumulation, and reduces proteinuria in type II diabetic KK mice. This indicates that good glycemic control prevents further progression of established diabetic nephropathy in animals. (Reddi et al 1990). Senegrin-II from Polygala senegra significantly lowered blood glucose level in the KK-A^y mice (Kako et al,1995). Oral administration of low doses of argenine reduces kidney collagen accumulation, cross-linking, lipid peroxidation, glyoxidation, kidney weight and albuminuria. Reduction in proteinuria may be due to blocking of lipid peroxidation (Lubec et al, 1997). Weekly or every 2nd. week treatment of KK-A^y mice with Freund's complete adjuvent for 12 weeks reduced fatty changes in the liver and kidney glomerular lesions but pancreatic islet morphology was unchanged. No toxic effects were observed and it was concluded that this treatment could inhibit diabetic glomerular lesions (Muto et al, 1997).

Interstitial fibrotic heart lesions appear at 15 weeks in untreated KK mice, and progress with age. These were completely suppressed by treatment with diltiazem. These results suggest that hyperglycemia induces an anaerobic state in heart muscle leading to hypertrophy, degeneration and fibrosis which can be ameliorated by calcium antagonists (Shimada, 1993).

Corneal degeneration starts early in life, is progressive with age, tends to be bilateral, and is confined largely to the anterior part of the corneal centre (Huang and Sery, 1971). Using light and electron microscopy, the lenses of KK-A^y mice were normal at 2 months, showed some necrosis and intranuclear lesions of epithelial cells at 4 months with more marked changes at 6 and 12 months (Lu et al, 1993). The obese syndrome is also described by Stauffacher et al. (1971).

Resistant to development of anaphylactic shock from ovalbumin (cf. 6/13) (Tanioka and Esaki, 1971).

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Bray G. A. and York D. A. (1971) Genetically transmitted obesity in rodents. Physiol. Rev. 51, 598-646.

Butler L. and Gerritsen G. C. (1970) A comparison of the modes of inheritance of diabetes in the Chinese hamster and the KK mouse. Diabetologia 6, 163-167.

Butler L. (1972) The inheritance of glucosuria in the KK and AY mouse. Can. J. Genet. Cytol. 14, 265-269.

Huang L. H. and Sery T. W. (1971) Corneal degeneration in a congenitally diabetic inbred strain of mouse. Brit. J. Ophthalmol. 55, 266-271.

Ikeda H. (1994) KK mouse. Diabetes Research and Clinical Practice 24, S313-S316.

Kako M., Miura T., Usami M., Nishiyama Y., Ichimaru M., Moriyasu M., and Kato A. (1995) Effect of senegin-II on blood glucose in normal, and NIDDM mice. Biol. Pharmaceut. Bull. 18, 1159-1161.

Lu G., Uga S., Miyata M., and Ishikawa S. (1993) Histopathological study of congenitally diabetic yellow KK mouse lens. Japanese Journal of Ophthalmology 37, 369-378.

Lubec B., Aufricht C., Amann G., Kitzmuller E., and Hoger H. (1997) Arginine reduces kidney collagen accumulation, cross-linking, lipid peroxidation, glycoxidation, kidney weight and albuminuria in the diabetic KK mouse. Nephron 75, 213-218.

Muto Y., Satoh J., Muto G., Masuda T., Sagara M., Fukuzawa M., Miyaguchi S., Qiang X. L., Sakata Y., Nakazawa T., Ikehata F., and Toyota T. (1997) Effect of long-term treatment with complete Freund's adjuvant on KK-A^y mouse, a model of non-insulin-dependent diabetes mellitus. Clin. Immunol. Immunopathol. 83, 53-59.

Reddi A. S., Velasco C. A., Reddy P. R., and Khan M. Y. (1990) Diabetic microangiopathy in KK mice. VI. Effect of glycemic control on renal glycoprotein metabolism and established glomerulosclerosis. Exp. Mol. Path. 53, 140-151.

Shimada T. (1993) Correlation between metabolic and histopathological changes in the myocardium of the KK mouse. Effect of diltiazem on the diabetic heart. Jpn. Heart J. 34, 617-626.

Stauffacher W., Orci L., Cameron D. P., Burr I. M., and Renold A. E. (1971) Spontaneous hyperglycemia and/or obesity in laboratory rodents: an example of the possible usefulness of animal disease models with both genetic and environmental components. Recent Prog. Horm. Res. 27, 41-91.

Taketomi S., Tsuda M., Matsuo T., Iwatsuka H., and Suzuoki Z. (1973) Alterations of hepatic enzyme activities in KK and yellow KK mice with various diabetic states. Hormone Metab. Res. 5, 333-339.

Tanioka Y. and Esaki K. (1971) Strain differences in mortality of anaphylactic shock in mice-challenging by intravenous injection. Exp. Animals (Japan) 20, 127-130.

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INBRED STRAINS OF MICE
Updated 9 Apr. 1998
Michael FW Festing
MRC Toxicology Unit, Hodgkin Building,
University of Leicester, UK