Role of insulin receptor substrate‐1 for diethylnitrosamine plus high‐fat diet‐induced hepatic tumorigenesis in mice

We investigated the role of insulin receptor substrate (Irs)‐1 for diethylnitrosamine (DEN) plus high‐fat (HF) diet‐induced hepatic tumorigenesis in mice. We gave DEN by intraperitoneal injection at the dose of 80 mg/kg to 18‐week‐old wild‐type (WT) and Irs1‐knockout (Irs1^−/−) mice, which were fed a HF diet from 8 weeks‐of‐age until they were killed (52 weeks). The Irs1^−/− mice showed significantly lower plasma alanine aminotransferase levels, triglyceride contents in the liver and also lower expression levels of the genes encoding inflammatory cytokines than the WT mice. The incidence of DEN plus HF diet‐induced hepatic tumors was 71.4% in the WT mice, whereas it was just 14.3% in the Irs1^−/− mice. The present study showed that Irs1 played an important role in DEN plus HF diet‐induced hepatic tumorigenesis.     

Protection from non-alcoholic steatohepatitis and liver tumourigenesis in high fat-fed insulin receptor substrate-1-knockout mice despite insulin resistance

Aims/hypothesis

Epidemiological studies have revealed that obesity and diabetes mellitus are independent risk factors for the development of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. However, the debate continues on whether insulin resistance as such is directly associated with NASH and liver tumourigenesis. Here, we investigated the incidence of NASH and liver tumourigenesis in Irs1 ^?/? mice subjected to a long-term high-fat (HF) diet. Our hypothesis was that hepatic steatosis, rather than insulin resistance may be related to the pathophysiology of these conditions.

Methods

Mice (8 weeks old, C57Bl/6J) were given free access to standard chow (SC) or an HF diet. The development of NASH and liver tumourigenesis was evaluated after mice had been on the above-mentioned diets for 60 weeks. Similarly, Irs1 ^?/? mice were also subjected to an HF diet for 60 weeks.

Results

Long-term HF diet loading, which causes obesity and insulin resistance, was sufficient to induce NASH and liver tumourigenesis in the C57Bl/6J mice. Obesity and insulin resistance were reduced by switching mice from the HF diet to SC, which also protected these mice against the development of NASH and liver tumourigenesis. However, compared with wild-type mice fed the HF diet, Irs1 ^?/? mice fed the HF diet were dramatically protected against NASH and liver tumourigenesis despite the presence of severe insulin resistance and marked postprandial hyperglycaemia.

Conclusions/interpretation

IRS-1 inhibition might protect against HF diet-induced NASH and liver tumourigenesis, despite the presence of insulin resistance.     

Glucose intolerance and associated factors in Mongolia: results of a national survey.

AIMS: Prevalence of glucose intolerance-diabetes and impaired glucose tolerance (IGT)-and of related conditions such as obesity and hypertension, was studied in six population samples in Mongolia in 1999. METHODS: Diagnosis of glucose intolerance was made on the basis of 2-h blood glucose concentration, according to criteria recommended by the latest report of a WHO Expert Group. RESULTS: Crude prevalence of diabetes was 2.9% (2.6% in men and 3.2% in women). Prevalence of IGT was 10.2% (9.3% in men and 10.8% in women). Age standardization to the standard world population of Segi resulted in a total sample prevalence of 3.1% for diabetes and 9.2% for IGT. Prevalence of abnormal glucose tolerance differed according to district of residence. Approximately one-third of the subjects with diabetes were diagnosed prior to the survey. Of those who were diagnosed previously, approximately one-half were not under any form of treatment. Subjects with abnormal glucose tolerance were older, more obese and had higher blood pressure and prevalence of hypertension than those with normoglycaemia. One-half of men and almost one-half of women were hypertensive. Three-quarters of the diabetic subjects were hypertensive. One-third of all subjects were centrally obese. Considering the conditions of principal interest-glucose intolerance, hypertension and obesity-one-half of all subjects demonstrated one or more of these conditions. Central obesity was the most common condition, followed by hypertension and then glucose intolerance. Central obesity and hypertension was the most common combination (17% of all subjects) and 4% exhibited all three conditions. CONCLUSIONS: Non-communicable diseases are already a threat to public health in Mongolia. Although the prevalence of diabetes is not high by international standards, the relatively high prevalence of IGT suggests that the situation may deteriorate in the future in the absence of concerted action to prevent and control diabetes and related conditions.