Increased expression and activity of 11beta-HSD-1 in diabetic islets and prevention with troglitazone.
To determine if increased local production of glucocorticoids by the pancreatic islets might play a role in the spontaneous noninsulin-dependent diabetes mellitus of obesity, we compared islet 11beta-HSD-1 mRNA and activity in islets of obese prediabetic and diabetic Zucker Diabetic Fatty (ZDF) (fa/fa) rats and lean wild-type (+/+) controls. In diabetic rat islets, both mRNA and enzymatic activity of the enzyme were increased in proportion to the hyperglycemia. Troglitazone (TGZ) treatment, beginning at 6 weeks of age, prevented the hyperglycemia, the hyperlipidemia, and the increase in 11beta-HSD-1. To determine if the metabolic abnormalities had caused the 11beta-HSD-1 increase, prediabetic islets were cultured in high or low glucose or in 2:1 oleate:palmitate for 3 days. Neither nutrient enhanced the expression of 11beta-HSD-1. We conclude that 11beta-HSD-1 expression and activity are increased in islets of diabetic, but not prediabetic ZDF rats, and that TGZ prevents both the increase in 11beta-HSD-1 and the diabetes.
Duplomb
Laurence
L
Gifford Laboratories, Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Lee
Young
Y
Wang
May-Yun
MY
Park
Byung H
BH
Takaishi
Kiyosumi
K
Agarwal
Anil K
AK
Unger
Roger H
RH
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D002839:Chromans / Q000494:pharmacology*; D003480:Cushing Syndrome / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000517:prevention & control*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007515:Islets of Langerhans / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D019301:Oleic Acid / Q000494:pharmacology; D010168:Palmitates / Q000494:pharmacology; D010641:Phenotype; D011241:Prednisone / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
D002839:Chromans; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D020738:Leptin; D010168:Palmitates; D012333:RNA, Messenger; D045162:Thiazolidinediones; D019301:Oleic Acid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000077288:Troglitazone; D005947:Glucose; D011241:Prednisone