Stabilization of epoxyeicosatrienoic
acids (EETs) levels via soluble
epoxide hydrolase (sEH) deletion or its pharmacological inhibition have been shown to have beneficial effects on
inflammation,
ischemia,
hypertension and diabetes. Owing to the diverse role of EETs, current study was designed to evaluate the therapeutic potential of 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)
urea (TPPU), a novel sEHI against
fructose-induced diabetes and related complications in rats. Sprague-Dawley rats (200 - 230 g) were divided into four different groups, each containing 10 animals. One group served as a normal control and received standard diet and
drinking water. The second group served as a diseased control and received standard diet, 25%
fructose in
drinking water and was treated with vehicle only. The third and fourth groups received standard diet, 25%
fructose in
drinking water and TPPU (2 mg/kg) or
metformin (150 mg/kg), respectively. All treatments were given orally for 12 weeks. At the end of the study, blood samples were collected to measure serum
insulin levels and other biochemical parameters. Animals were dissected to collect tissue specimens for histological and immunohistochemistry analysis. Animals fed on
fructose and treated with vehicle demonstrated elevated blood
insulin and
glucose levels as well as high levels (P < 0.001) of
triglycerides (TGs),
cholesterol,
low-density lipoprotein (
LDL) and homeostatic model assessment of
insulin resistance (HOMA-IR) compared to naive rats. Similarly, the levels of
alkaline phosphatase (ALP),
alanine aminotransferase (ALT),
urea and
uric acid were significantly (P < 0.001) increased in vehicle treated
fructose fed animals. TPPU (2 mg/kg p.o.) and simultaneously fed on
fructose for 12 weeks substantially decreased HOMA-IR levels, lowered
blood glucose, serum
cholesterol, LDLs and TGs) while
high-density lipoproteins (HDL) levels were increased compared to untreated animals.
Metformin, a standard reference drug showed similar results. Microscopic studies of liver and pancreatic sections of TPPU treated animals showed marked improvement in cellular architecture compared to untreated animals. Current study demonstrated profound therapeutic potential of TPPU against
fructose induced-diabetes and related metabolic complications which was evident by its attenuating effect
fructose-induced
hyperglycemia,
hyperlipidemia and impaired renal and hepatic
serum markers.