Effects of metformin on peripheral insulin sensitivity and intracellular lipid contents in muscle and liver of overweight Japanese subjects.

AIM: Recent studies suggest that insulin resistance is associated with increased intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) contents. While metformin improves insulin resistance mainly in liver, its effects on IHL and IMCL have not been clarified yet. The aim of this study was to investigate the effects of low-dose metformin (750 mg/day) on peripheral insulin sensitivity, IHL and IMCL. METHODS: Before and 3 months after low-dose metformin therapy, eight overweight/obese Japanese subjects [body mass index (BMI) >25 kg/m2] were studied with blood sampling, measurement of IHL and IMCL by 1H magnetic resonance spectroscopy and glucose infusion rate (GIR) during euglycaemic-hyperinsulinaemic clamp as an index of peripheral insulin sensitivity. RESULTS: A 3-month low-dose metformin therapy did not alter body weight, total body fat, fat distribution or physical activity level but increased GIR by 31% (from 6.24 +/- 0.86 to 7.82 +/- 0.82 mg/kg/min, p < 0.01). Although metformin treatment did not alter IMCL (from 4.1 +/- 1.0 to 4.2 +/- 0.9, not significant), it decreased IHL by 21% (from 15.9 +/- 2.8 to 11.8 +/- 2.2%, p < 0.05). CONCLUSIONS: A 3-month low-dose metformin treatment improved peripheral insulin sensitivity and reduced IHL, without significantly changing BMI, adiposity or IMCL.

Amelioration of glucose tolerance by hepatic inhibition of nuclear factor kappaB in db/db mice.

AIMS/HYPOTHESIS: Recent studies have identified the involvement of inhibitor IkappaB kinase (IKK) in the pathogenesis of insulin resistance. To investigate the mechanism involved, we examined the role of nuclear factor kappaB (NF-kappaB), the distal target of IKK, in hepatic glucose metabolism. METHODS: To inhibit NF-kappaB activity, db/db mice were infected with adenovirus expressing the IkappaBalpha super-repressor. RESULTS: The IkappaBalpha super-repressor adenovirus infection caused a moderate reduction of NF-kappaB activity in liver. The treatment was associated with improved glucose tolerance, reduction in the serum insulin level, and increased hepatic triacylglycerol and glycogen contents, but had no effect on insulin-stimulated phosphorylation of Akt. On the other hand, quantification of mRNA in the liver revealed marked reduction of expression of gluconeogenic genes, such as those encoding phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, concurrent with reduced expression of gene encoding peroxisome proliferator-activated receptor gamma coactivator-1alpha (PPARGC1A, also known as PGC-1alpha). Furthermore, the production of super-repressor IkappaBalpha suppressed the increase in blood glucose level after pyruvate injection. CONCLUSIONS/INTERPRETATION: Our results indicate that moderate inhibition of NF-kappaB improved glucose tolerance through decreased gluconeogenesis associated with reduced PGC-1alpha gene expression in db/db mice, and suggest that inhibition of NF-kappaB activity in liver is a potentially suitable strategy for the normalisation of blood glucose concentration in type 2 diabetes.