Insulin-independent promotion of chemically induced hepatocellular tumor development in genetically diabetic mice.
Diabetes mellitus has been proposed as an epidemiological risk factor for human liver cancer development. One reasonable possibility is that this is attributable to hyperinsulinemia compensatory for obesity-related insulin resistance. However, diabetes mellitus is a complex disease with multiple abnormal conditions essentially caused by hyperglycemia. Therefore, it is not evident whether hyperinsulinemia is prerequisite for the elevated cancer risk. To gain a clue to answer this question, we characterized chemically induced hepatocarcinogenesis in diabetic model mice genetically deficient for insulin. Akita inbred mice originating from the C57BL/6 strain carry a heterozygous germline mutation of the insulin II gene and suffer from inherited insulin deficiency and diabetes in an autosomal dominant manner. They were mated with normal C3H/HeJ mice with high sensitivity to liver carcinogenesis and the resultant F(1) littermates, which were either normal or insulin deficient, were exposed to diethylnitrosamine and induced hepatocellular tumors were evaluated for number, size, proliferative activity, and apoptosis. Unexpectedly, both mean and total volumes of hepatocellular tumors in the insulin-deficient animals were more than twofold larger than those in the normal controls, with no significant difference in tumor number. The tumors in insulin-deficient mice showed a significantly lower frequency of apoptosis but no alteration in cell proliferation. In conclusion, our results indicate that insulin-independent liver tumor promotion occurred in diabetic mice. Clearly, insulin-independent mechanisms for the human case also deserve consideration.
Department of Pathology, Kochi University School of Medicine, Nankoku, Kochi, Japan.
Kohtaro
K
Yamasaki
Yoshihiro
Y
Hayashi
Sumika
S
Okamoto
Makoto
M
Osanai
Gang-Hong
GH
Lee
D000818:Animals; D048909:Diabetes Complications / Q000209:etiology*; D004052:Diethylnitrosamine; D018095:Germ-Line Mutation; D007328:Insulin / Q000172:deficiency* / Q000235:genetics / Q000627:therapeutic use; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D025481:Phosphofructokinase-2 / Q000032:analysis / Q000235:genetics
D007328:Insulin; D004052:Diethylnitrosamine; D025481:Phosphofructokinase-2