Article

Hypoglycemic agent YM440 suppresses hepatic glucose output via gluconeogenesis by reducing glucose-6-phosphatase activity in obese Zucker rats.

Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co, Ltd, Ibaraki, Tsukuba, Japan
European journal of pharmacology (Impact Factor: 2.59). 06/2003; 468(2):151-8. DOI: 10.1016/S0014-2999(03)01670-4
Source: PubMed

ABSTRACT Using a glucose clamp, we had shown that YM440, (Z)-1,4-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]but-2-ene, reduced the increased hepatic glucose output in obese Zucker rats. We further examined effects of YM440 on 14C-incorporation from [14C]bicarbonate into blood glucose via gluconeogenesis, and on gluconeogenic enzymatic activities. Fed obese Zucker rats showed a 4-fold increase of 14C-incorporation into blood glucose compared to that in lean rats. Glucose-6-phosphatase and fructose-1,6-bisphosphatase activities in obese rats were increased 1.4-fold and 1.6-fold compared with lean rats. YM440 (300 mg/kg for 2 weeks) decreased 14C-incorporation into blood glucose by 29% in obese rats. Glucose-6-phosphatase but not fructose-1,6-bisphosphatase activity was reduced by YM440 and closely correlated with 14C-incorporation into blood glucose, indicating a key role for glucose-6-phosphatase in hepatic glucose output. These results suggest that the increased gluconeogenesis in obese rats is mainly due to the increased activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase and that YM440 suppresses hepatic glucose output by reducing glucose-6-phosphatase activity.

0 Bookmarks
 · 
44 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Thiazolidinediones constitute a family of antidiabetic drugs, and rosiglitasone (RSG) has an extensive usage in treating the complications of type 2 diabetes mellitus. Carvacrol (CVL), a monoterpenic phenol that occurs in many essential oils of the family Labiatae including Origanum, Satureja, Thymbra, Thymus, and Corydothymus species, possess a wide variety of pharmacological properties including antioxidant potential. We hypothesized that carvacrol in combination with RSG would prove beneficial to ameliorate the dysregulated carbohydrate metabolism in high-fat diet (HFD)-induced type 2 diabetic C57BL/6J mice. Mice were divided into six groups and fed HFD, for 10 weeks. CVL (20 mg/kg BW) and RSG (4 mg/kg BW) were administered post-orally, daily for 35 days. HFD mice showed an elevation in plasma glucose, insulin, glycosylated hemoglobin and a decrease in hemoglobin. The activities of carbohydrate metabolic enzymes such as glucose-6-phosphatase and fructose-1,6-bisphosphatase increased whereas glucokinase and glucose-6-phosphate dehydrogenase activities decreased in the liver of HFD mice. The activities of hepatic marker enzymes such as aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase increased in HFD mice. Combination of CVL and RSG prevented the above changes toward normalcy. Histopathological analysis of H&E stained pancreas was also in agreement with the biochemical findings. These major findings provide evidence that combination of CVL with RSG has better antidiabetic properties.
    Molecular and Cellular Biochemistry 09/2013; DOI:10.1007/s11010-013-1810-8 · 2.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Indole glucosinolates, present in cruciferous vegetables have been investigated for their putative pharmacological properties. The current study was designed to analyse whether the treatment of the indole glucosinolates-indole-3-carbinol (I3C) and its metabolite 3,3'-diindolylmethane (DIM) could alter the carbohydrate metabolism in high-fat diet (HFD)-induced C57BL/6J mice. The plasma glucose, insulin, haemoglobin (Hb), glycosylated haemoglobin (HbA1c), glycogen and the activities of glycolytic enzyme (hexokinase), hepatic shunt enzyme (glucose-6-phosphate dehydrogenase), gluconeogenic enzymes (glucose-6-phosphatase and fructose-1,6-bisphosphatase) were analysed in liver and kidney of the treated and HFD mice. Histopathological examination of liver and pancreases were also carried out. The HFD mice show increased glucose, insulin and HbA1c and decreased Hb and glycogen levels. The elevated activity of glucose-6-phosphatase and fructose-1,6-bisphosphatase and subsequent decline in the activity of glucokinase and glucose-6-phosphate dehydrogenase were seen in HFD mice. Among treatment groups, the mice administered with I3C and DIM, DIM shows decreased glucose, insulin and HbA1c and increased Hb and glycogen content in liver when compared to I3C, which was comparable with the standard drug metformin. The similar result was also obtained in case of carbohydrate metabolism enzymes; treatment with DIM positively regulates carbohydrate metabolic enzymes by inducing the activity of glucokinase and glucose-6-phosphate dehydrogenase and suppressing the activity of glucose-6-phosphatase and fructose-1,6-bisphosphatase when compared to I3C, which were also supported by our histopathological observations.
    Molecular and Cellular Biochemistry 09/2013; 385(1-2). DOI:10.1007/s11010-013-1808-2 · 2.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rosmarinic acid (RA) is a polyphenolic phytoconstituent found in many herbs of lamiacea species like rosemary, mint, thyme, basil, oregano. RA exhibits a wide array of benefecial and pharmacological properties including antioxidant, anti-microbial and anti-inflammatory. Oral administration of RA (100 mg/kg body weight) to high fat diet fed – low doses of STZ induced type 2 diabetic rats for 30 days established a significant (P < 0.05) decline in the levels of blood glucose, glycosylated hemoglobin, blood urea, serum uric acid and creatinine along with increase in plasma insulin level. Diminished activities of hepatospecific pathophysiological enzymes such as aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) were observed in diabetic rats administered with RA. Further, the altered activities of key carbohydrate metabolizing enzymes such as hexokinase, pyruvate kinase, glucose-6-phosphatase, fructose 1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase (P < 0.05) in the liver tissue of diabetic rats were significantly reverted to near normal levels upon treatment with RA. Also, RA administration to diabetic rats improved hepatic glycogen content suggesting the anti-hyperglycemic potential of RA in diabetic animals. The obtained results were compared with metformin, a standard oral hypoglycemic drug. Thus, the present findings indicate that RA is nontoxic and it can potentially maintain glycemic control and regulate the key enzymes of carbohydrate metabolism in experimental diabetic rats.
    07/2014; DOI:10.1016/j.bionut.2014.03.006