Inbred Strains
of Mice: KK
Inbr: F90 +. Albino. Genet:
a, B, c, D, S. Origin: K. Kondo 1944
from Japanese dealer stock (Kasukabe group). Some substrains carry the
yellow (
Ay ) gene.
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
Ay
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-
Ay
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-
Ay 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-Ay
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).
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-Ay
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.
INBRED STRAINS OF MICE
Updated 9 Apr. 1998
Michael FW
Festing
MRC Toxicology Unit, Hodgkin Building,
University of Leicester,
UK
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