ABSTRACT
The present study was performed to compare glucocorticoid levels in obese KKA (y) and ob/ob mice with those in normal C57BL/6J mice, and the effect of high-fat diet on glucocorticoids in KKA (y) and ob/ob mice. Liver, mesenteric and epididymal adipose tissue corticosterone and 11-dehydrocorticosterone concentrations as well as circulating corticosterone concentrations were measured. The KKA (y) and ob/ob mice displayed elevated serum corticosterone levels compared to normal mice, 2.0 to 2.8-fold in KKA (y), and 11 to 16-fold in ob/ob mice. Liver corticosterone levels were 3.0 to 5.1 and 6.2 to 8.1-fold, and 11-dehydrocorticosterone levels were 3.4 to 3.6 and 6.7 to 8.2-fold higher in KKA (y) and ob/ob mice compared to normal mice. Mesenteric adipose tissue corticosterone levels were 2.7 to 4.2-fold higher, and 11-dehydrocorticosterone levels were 2 to 4-fold higher in ob/ob than in KKA (y) mice. Epididymal adipose tissue corticosterone levels were 3.0 to 6.2-fold higher, and 11-dehydrocorticosterone levels were 1.8 to 2.0-fold higher in ob/ob than in KKA (y) mice. Circulating, hepatic, and mesenteric and epididymal adipose tissue glucocorticoid concentrations were low in the normal C57BL/6J mouse, high in the ob/ob mouse, and intermediate in the KKA (y) mouse. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA levels were doubled in ob/ ob compared to KKA (y) mice in all three tissues. Glucocorticoid concentrations correlated with 11beta-HSD1 mRNA levels. High-fat diet had no effect on the tissue glucocorticoid concentrations.
Subject(s)
Adipose Tissue/metabolism , Corticosterone/analogs & derivatives , Diet/adverse effects , Dietary Fats/adverse effects , Liver/metabolism , 11-beta-Hydroxysteroid Dehydrogenases/biosynthesis , Adipose Tissue/drug effects , Animals , Blood Glucose/metabolism , Chromatography, Liquid , Corticosterone/metabolism , Diabetes Mellitus/genetics , Diabetes Mellitus/metabolism , Epididymis/drug effects , Epididymis/metabolism , Insulin/blood , Liver/drug effects , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Obese , RNA, Messenger/biosynthesis , Radioimmunoassay , Reverse Transcriptase Polymerase Chain Reaction , Spectrometry, Mass, Electrospray IonizationABSTRACT
AIMS/HYPOTHESIS: Current pharmacological treatments for Type II (non-insulin-dependent) diabetes mellitus have various limitations. New treatments are needed to reduce long-term risks for diabetic complications and mortality. We tested a new principle for lowering blood glucose. It is well known that glucocorticoids in excess cause glucose intolerance and insulin resistance. The enzymes 11beta-hydroxysteroid dehydrogenase type 1 and type 2 inter-convert inactive and active glucocorticoids, thereby playing a major role in local modulation of agonist concentration and activation of corticosteroid receptors in target tissues. It has been hypothesized that selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases excessive hepatic glucose production in hyperglycemia and diabetes. BVT.2733 is a new, small molecule, non-steroidal, isoform-selective inhibitor of mouse 11beta-hydroxysteroid dehydrogenase type 1. The aim of the present study is to test if selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 lowers blood glucose concentrations in a hyperglycaemic and hyperinsulinaemic mouse model. METHODS: BVT.2733 was given to spontaneously hyperglycaemic KKA(y) mice for 7 days using subcutaneous osmotic mini-pumps. RESULTS: BVT.2733 lowered hepatic PEPCK and glucose-6-phosphatase mRNA, blood glucose and serum insulin concentrations compared with vehicle treated mice. In contrast, hepatic 11beta-hydroxysteroid dehydrogenase type 1 mRNA, liver function marker enzyme expression (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatases), daily food intake and body weight were not altered by the treatment. CONCLUSION/INTERPRETATION: These results suggest that a selective inhibitor of human 11beta-hydroxysteroid dehydrogenase type 1 can become a new approach for lowering blood glucose concentrations in Type II diabetes.
Subject(s)
Blood Glucose/metabolism , Enzyme Inhibitors/pharmacology , Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Hyperglycemia/blood , Piperazines/pharmacology , Sulfonamides/pharmacology , Thiazoles/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 1 , Animals , Base Sequence , DNA Primers , Hydroxysteroid Dehydrogenases/genetics , Hyperglycemia/enzymology , Liver/drug effects , Liver/enzymology , Male , Mice , Phosphoenolpyruvate Carboxykinase (GTP)/genetics , Polymerase Chain Reaction , RNA, Messenger/geneticsABSTRACT
It is established that insulin-like growth factor I (IGF-I) influences cell differentiation and proliferation. Less is known, however, if such changes also influence the flow of nutrients from the intestinal lumen to the portal circulation. In the present study, we tested if IGF-I treatment (0.3 mg IGF-I/24 hr and kg) during 7 days affects the porto-arterial concentration differences of amino acids and glucose in piglets. Two routes of administration, oral and intraperitoneal, were compared. Following the IGF-I treatment, a bolus of nutrients was administered to the proximal duodenum and the porto-arterial concentration differences of amino acids and glucose were determined. We found that intraperitoneal administration of IGF-I significantly increased the difference in concentration between portal and arterial plasma for amino acids, whereas no such effect was seen with glucose. This might suggest that IGF-I has a specific effect on amino acid transporters in the intestinal wall. The same dose of IGF-I given orally did not exhibit the same effect on the absorption of amino acid as the animals which were given the peptide intraperitoneally.
