Obesity and non-insulin-dependent diabetes mellitus in Swiss-Webster mice associated with late-onset hepatocellular carcinoma

Abstract

Genetic mutations resulting in obesity and type 2 diabetes mellitus (T2D) are described for both inbred and outbred mice. However, no known mouse model completely recapitulates human T2D and its comorbidities. We identified a cohort of obese, male, outbred Swiss-Webster (SW) mice as polyuric, polydipsic, glucosuric, and hyperglycemic. Prevalence of glucosuria in the SW colony reached 60% (nZ70) in males 8 weeks to 6 months of age. Despite severe obesity in some females, no females were diabetic. Pathologic findings in affected males included cachexia, dilated gastrointestinal tracts with poor muscular tone, pancreatic islet degeneration and atrophy with compensatory metaplasia and/or neogenesis, bacterial pyelonephritis, membranous glomerulopathy, and late-onset hepatic tumors with macrosteatosis, microsteatosis, and hydropic change in aged males. Serum insulin correlated with blood glucose in a nonlinear pattern, suggestive of islet exhaustion. Circulating leptin levels showed a weak inverse correlation with glucose. Diabetic males were bred with obese colony females to produce 20 male and 20 female offspring. Prevalence of diabetes in male offspring was 80% (16/20) with a median age of onset of 18 weeks. By contrast, no diabetic females were identified, despite being significantly more obese than males. Male predominance is likewise a feature of T2D in humans. To our knowledge, this is the first documentation of hepatocellular carcinoma and islet metaplasia and/or neogenesis in a spontaneous outbred mouse model of T2D. The SW availability and histopathologic features represent a promising new model for the study of T2D.

Genetic Factors, Viral Infection, Other Factors and Liver Cancer: An Update on Current Progress

“…The OR of HCC among subjects with both HCV infection and DM was 11.601 when being compared with the DM-free subjects (Hung et al,2010), subsequently, prospective study with 1,470 subjects was conducted and found that the risk effect of DM was selective and only can be observed among those with chronic hepatitis C without cirrhosis after eradication of HCV . Animal testing in Swiss-Webster mice also confirmed the positive association and biological evidence was obtained (Lemke et al, 2008). As seen in the study conducted in the United States (Hassan MM et al, 2010), the adjusted OR of DM related to HCC risk was 4.2, furthermore, they also found that the risk would increase with the diabetes duration.…”

Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice

“…Moreover, no animals developed polyuria, polydipsia, hyperphagia, and/or body wasting characteristic of diabetes. 17 Thus, despite high circulating insulin levels, AB6F1 mice did not exhibit obesity or T2D. These results demonstrate that AB6F1 but not B6AF1 male mice develop spontaneous hyperinsulinemia on a standard chow diet and that this insulin resistance is not associated with morbid obesity, metabolic syndrome, or T2D.…”

Metformin and lung cancer risk of patients with type 2 diabetes mellitus: A meta-analysis

“…Increasing evidence has strengthened that hyperglycemia, obesity-related insulin resistance and secondary hyperinsulinemia are important regulators of the development of cancer (27)(28)(29)(30). Recent data have suggested that insulin and insulin secretagogues (sulfonylureas and glinides) may increase the overall cancer incidence (21,31,32), but insulin sensitizers (metformin and thiazolidinedione) are associated with the reduction of the cancer incidence (33,34).…”