Antidiabetic effects of 11beta-HSD1 inhibition in a mouse model of combined diabetes, dyslipidaemia and atherosclerosis.
OBJECTIVE
11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is considered to contribute to the aetiology of the metabolic syndrome, and specific inhibitors have begun to emerge as treatments for insulin resistance and other facets of the syndrome, including atherosclerosis. Given the role of glucocorticoids and 11beta-HSD1 in the anti-inflammatory response and the involvement of inflammation in the development of atherosclerosis, 11beta-HSD1 inhibition may exacerbate atherosclerosis. Our aim was to investigate in vivo the effects of a specific 11beta-HSD1 inhibitor (2922) on atherosclerosis while assessing glucose homeostasis.


METHODS
We conducted a 12-week study administering 2922 (at three doses, 3, 10 and 100 mg/kg body weight) in Ldlr 3KO (Ldlr(-/-)Apob(100/100)Lep(ob/ob)) mice, a genetic model of obesity, insulin resistance, dyslipidaemia and atherosclerosis. Rosiglitazone and simvastatin were used to test the responsiveness of our model in both types of therapy.


RESULTS
2922 was effective in reducing 11beta-HSD1 activity in inguinal adipose tissue (>90% for 100 mg/kg) and was efficacious in improving glucose homeostasis at doses > or =10 mg/kg. Plasma insulin, blood glucose, glucose tolerance and homeostatic model assessment indices were all improved in mice treated with 2922 (100 mg/kg) compared with control animals. Despite an improvement in these parameters, no differences were observed in body weight, adipose or lean tissue masses in the 2922-treated mice. Interestingly, circulating lipids, proinflammatory cytokines and atherosclerosis were unaltered in response to 2922, although a small reduction in LDL cholesterol was detected.


CONCLUSIONS
Importantly, 11beta-HSD1 inhibition leads to improved glucose metabolism and does not result in a worsening of atherosclerotic lesion area, yet retained antidiabetic potential in the face of multiple severe metabolic aberrations. This study reinforces the potential use of 11beta-HSD1 inhibitors in patients with the metabolic syndrome without negatively impacting atherosclerosis.
Lloyd
D J
DJ
Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA 91320, USA. dlloyd@amgen.com
Helmering
J
J
Cordover
D
D
Bowsman
M
M
Chen
M
M
Hale
C
C
Fordstrom
P
P
Zhou
M
M
Wang
M
M
Kaufman
S A
SA
Véniant
M M
MM
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D050197:Atherosclerosis / Q000150:complications / Q000188:drug therapy; D001786:Blood Glucose / Q000032:analysis; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000150:complications / Q000188:drug therapy; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000188:drug therapy*; D051379:Mice; D018345:Mice, Knockout; D000077154:Rosiglitazone; D019821:Simvastatin / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone; D002784:Cholesterol; D019821:Simvastatin; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1