Lipoprotein lipase activator NO-1886 improves fatty liver caused by high-fat feeding in streptozotocin-induced diabetic rats.

NO-1886 is a lipoprotein lipase (LPL) activator. Administration of NO-1886 results in an increase in plasma high-density lipoprotein cholesterol (HDL-C) and a decrease in plasma triglyceride (TG) levels. The aim of this study was to ascertain whether NO-1886 improves fatty liver caused by high-fat feeding in streptozotocin (STZ)-induced diabetic rats. Administration of NO-1886 resulted in increased plasma HDL-C levels and decreased TG levels without affecting total cholesterol and glucose levels in the diabetic rats. NO-1886 dose-dependently decreased liver TG contents and cholesterol contents, resulting in improvement of fatty liver. NO-1886 also reduced plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) that accompany fatty liver. The liver cholesterol contents were inversely correlated with plasma HDL-C levels (r = -0.5862, P <.001) and were positively correlated with plasma TG levels (r = 0.4083, P <.003). The liver TG contents were inversely correlated with plasma HDL-C levels (r = -0.6195, P <.001) and were positively correlated with plasma TG levels (r = 0.5837, P <.001). There was no correlation between plasma cholesterol levels, and cholesterol and TG contents in liver. These results indicate that reducing plasma TG levels and elevating in HDL-C levels may result in improving fatty liver.

Mechanisms of increased insulin resistance in non-cirrhotic patients with chronic hepatitis C virus infection.

BACKGROUND AND AIM: Evidence showing a higher prevalence of diabetes mellitus (DM) in patients with chronic hepatitis C virus (HCV) infection has been accumulating. However, the reason why chronic HCV infection promotes DM remains unknown. In the present study, the authors focused on non-cirrhotic and non-diabetic patients with chronic HCV infection and evaluated the factors responsible for increases in insulin resistance. METHODS: Fifty-six patients diagnosed with HCV-related chronic liver disease were included. Biochemical information including body mass index (BMI), aspartate aminotransferase (AST), alanine aminotransferase, cholinesterase, triglyceride, total cholesterol, hemoglobin, platelet count, glycosylated hemoglobin, immunoreactive insulin (IRI), and serum levels of tumor necrosis factor (TNF)-alpha and HCV-RNA were determined using venous blood samples obtained from each patient after overnight fasting. Homeostasis model assessment of insulin resistance (HOMA-IR), a simple and convenient measure of insulin resistance, was also calculated. The relationship between the stage of liver fibrosis and HOMA-IR, and the clinical factors responsible for the increase in HOMA-IR in non-diabetic patients was investigated. RESULTS: Homeostasis model assessment of insulin resistance and IRI levels increased parallel with the progression of fibrosis. Among the non-diabetic patients with mild to moderate liver fibrosis, BMI, serum levels of AST and TNF-alpha were related with HOMA-IR (BMI: r = 0.395, P = 0.041; AST: r = 0.465, P = 0.014; TNF-alpha: r = 0.396, P = 0.040). In contrast, HOMA-IR related to TNF-alpha (r = 0.526, P = 0.013) in non-diabetic patients with advanced liver fibrosis. CONCLUSION: Collectively, hepatic fibrosis and inflammation appear to play key roles in the increase in insulin resistance in patients with chronic HCV infection.

Ethyl icosapentate (omega-3 fatty acid) causes accumulation of lipids in skeletal muscle but suppresses insulin resistance in OLETF rats. Otsuka Long-Evans Tokushima Fatty.

Ethyl icosapentate (EPA) is known to improve insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM); however, its mechanism is unclear. In this study, we attempted to determine the mechanism of EPA's effects on insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Administration of EPA caused a reduction in plasma cholesterol and triglycerides, but increased cholesterol and triglyceride contents in skeletal muscle. EPA did not have an effect on glucose or insulin levels. EPA accelerated the glucose infusion rate (GIR) and improved the endothelium-dependent relaxation of OLETF rat the thoracic aorta caused by addition of acetylcholine. However, the improvement observed in endothelium-dependent relaxation disappeared after addition of N(w)-nitro-L-arginine (L-NA). Furthermore, when L-NA and indomethacine were added to the medium, relaxation of the aorta in EPA-treated rats was weaker than that in control rats. These actions may cause NO induction in the endothelium and an increase in prostaglandin I(2) (PGI(2)) and prostaglandin I(3) (PGI(3)) action, which in turn may result in improvement of insulin resistance.

Transition metals and polyol pathway in the development of diabetic neuropathy in rats.

BACKGROUND: The transition metal-catalyzed reaction is a major source of oxygen free radicals, which play an important role in vascular dysfunction leading to ischemia in diabetic tissues. The inhibition of polyol pathway hyperactivity has been reported to ameliorate neurovascular abnormalities in diabetic rats and has been proposed to improve the oxygen free radical scavenging capacity. The present study was conducted to compare the effect of a transition metal chelating agent, trientine (TRI), on diabetic neuropathy with that of an aldose reductase inhibitor, NZ-314 (NZ). METHODS: Diabetic rats were divided into three groups: (1). untreated, (2). TRI-treated, and (3). NZ-treated. TRI (20 mg/kg) or NZ (100 mg/kg) was administered by gavage or chow containing NZ, respectively, for 8 weeks. Motor nerve conduction velocity (MNCV), coefficient of variation of the R - R interval on electrocardiogram (CVr-r), sciatic nerve blood flow (SNBF), platelet aggregation activities, and serum concentrations of malondialdehyde were measured. RESULTS: Untreated diabetic rats showed delayed MNCV, decreased CV(R-R), and reduced SNBF compared to normal rats. TRI or NZ completely prevented these deficits. Platelet hyperaggregation activities in diabetic rats were prevented by NZ, but not by TRI. Increased concentrations of malondialdehyde in diabetic rats were partially but significantly ameliorated by either TRI or NZ. CONCLUSIONS: These observations suggest that increased free radical formation through the transition metal-catalyzed reaction plays an important role in the development of diabetic neuropathy and that the preventive effect of an aldose reductase inhibitor on diabetic neuropathy may also be mediated by decreasing oxygen free radicals.

A lipoprotein lipase activator, NO-1886 prevents impaired endothelium-dependent relaxation of aorta caused by exercise in aged rats.

Exercise decreases plasma total cholesterol and triglycerides, and simultaneously, increases high density lipoprotein (HDL) cholesterol. As a result, exercise is believed to aid in preventing atherosclerosis. However, we do not know whether exercise protects against the development of atherosclerosis in the elderly. The aim of this study was to ascertain whether the lipoprotein lipase activator NO-1886 had an effect on the prevention of atherosclerosis in aged rats which undergo exercise. Exercise for 3 months did not affect plasma lipids but decreased the accumulation of visceral fat in 2-year-old rats (aged rat). Exercise also resulted in an elevation of plasma lipid peroxide (LPO) levels and impaired the endothelium-dependent relaxation of the thoracic aorta caused by acetylcholine in aged rats. On the other hand, NO-1886 decreased plasma triglycerides and increased HDL cholesterol and suppressed the elevation of plasma LPO levels caused by exercise. Furthermore, NO-1886 prevented impaired endothelium-dependent relaxation caused by exercise. In summary, the results of our study indicate that exercise may cause impaired endothelium-dependent relaxation by elevation of LPO in aged rats, and that NO-1886 prevents this impaired endothelium-dependent relaxation of aorta by reducing plasma triglycerides, elevating HDL cholesterol, and suppressing the elevation of plasma LPO caused by exercise.

Correlation between lipid and glycogen contents in liver and insulin resistance in high-fat-fed rats treated with the lipoprotein lipase activator NO-1886.

Insulin resistance results in accumulation of triglyceride content and reduction of glycogen content in skeletal muscle. However, very few studies have measured lipid content and glycogen content in liver associated with insulin resistance. We studied the relationship between liver lipid content, liver glycogen, and insulin resistance in high-fat-fed rats, which are animal models of insulin resistance. High-fat-fed rats were hyperlipidemic, hyperglycemic, and hyperinsulinemic. Furthermore, the glucose infusion rates (GIR) were lower (normal rats, 10.35 +/- 1.66; high-fat-fed rats, 4.86 +/- 0.93 mg/kg/min; P <.01) and the triglyceride and cholesterol contents in liver were higher in the high-fat-fed rats than in normal rats. On the other hand, the glycogen content in liver was lower than in normal rats. There was an inverse relationship between liver triglyceride content and liver glycogen content. When the lipoprotein lipase (LPL) activator NO-1886 was administered to the high-fat-fed rats at a daily dose of 50 mg/kg body weight for 10 weeks, GIR (9.87 +/- 3.76 mg/kg/min, P <.05 v high-fat-fed control group) improved, causing an improvement of the hyperlipidemia, hyperglycemia, and hyperinsulinemia. Furthermore, NO-1886 decreased triglyceride and cholesterol concentrations and increased glycogen content in liver of the high-fat-fed rats. In this study, we found that insulin resistance caused fatty liver and reduced glycogen content in liver. Administration of the LPL activator NO-1886 improved the insulin resistance, resulting in an improvement in the relationship between triglyceride and glycogen content in liver of high-fat-fed rats.