Type 2 diabetes mellitus is frequently accompanied by
fatty liver/nonalcoholic fatty liver disease. Hence, accumulation of
lipids in the liver is considered to be one of the risk factors for
insulin resistance and
metabolic syndrome.
Ursodeoxycholic acid (UDCA) is widely used for the treatment of
liver dysfunction. We investigated the
therapeutic effects of UDCA on
type 2 diabetes mellitus exacerbating hepatic steatosis and the underlying mechanisms of its action using KK-A(y) mice fed a high-fat diet. KK-A(y) mice were prefed a high-fat diet; and 50, 150, and 450 mg/kg of UDCA was orally administered for 2 or 3 weeks. Administration of UDCA decreased fasting
hyperglycemia and
hyperinsulinemia. Hyperinsulinemic-euglycemic clamp analyses showed that UDCA improved hepatic (but not peripheral)
insulin resistance. Hepatic
triglyceride and
cholesterol contents were significantly reduced by treatment with UDCA, although the genes involved in the synthesis of
fatty acids and
cholesterol, including
fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-coenzyme A
reductase, were upregulated. Fecal levels of
bile acids, neutral
sterols,
fatty acids, and
phospholipids were significantly increased by UDCA treatment. The gene expression levels and
protein phosphorylation levels of endoplasmic reticulum stress markers were not changed by UDCA treatment. These results indicate that UDCA ameliorates
hyperglycemia and
hyperinsulinemia by improving hepatic
insulin resistance and steatosis in high-fat diet-fed KK-A(y) mice. Reduction of hepatic
lipids might be due to their excretion in feces, followed by enhanced utilization of
glucose for the synthesis of
fatty acids and
cholesterol.
Ursodeoxycholic acid should be effective for the treatment of
type 2 diabetes mellitus accompanying hepatic steatosis.