Published online before print November 3, 2008, doi: 10.1161/HYPERTENSIONAHA.108.119404
(Hypertension. 2008;52:1030.)
© 2008 American Heart Association, Inc.
Original Articles |
Hydrochlorothiazide, but not Candesartan, Aggravates Insulin Resistance and Causes Visceral and Hepatic Fat Accumulation
The Mechanisms for the Diabetes Preventing Effect of Candesartan (MEDICA) Study
From the Departments of Medicine (J.W.E., B.C., M.K.S., K.O.) and Radiology (C.S.), Umeå University Hospital, Umeå, Sweden; Departments of Medicine (J.W.E., P-A.J., M.K.S.) and Radiology (L. Lönn), Sahlgrenska University Hospital, Gothenburg, Sweden; Departments of Medicine (A.H., L.K., L. Lind) and Radiology (H.A., L.J.), Uppsala University Hospital, Uppsala, Sweden; AstraZeneca R&D (J.W.E., L.J.), Mölndal, Sweden; and the Faculty of Health Sciences (L. Lönn), Rigshospitalet Umeå, Copenhagen, Denmark.
Correspondence to Jan W. Eriksson, Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, SE-41345 Gothenburg, Sweden. E-mail jan.eriksson{at}medic.gu.se
Treatment with angiotensin II receptor blockers is associated with lower risk for the development of type 2 diabetes mellitus compared with thiazide diuretics. The Mechanisms for the Diabetes Preventing Effect of Candesartan Study addressed insulin action and secretion and body fat distribution after treatment with candesartan, hydrochlorothiazide, and placebo. Twenty-six nondiabetic, abdominally obese, hypertensive patients were included in a multicenter 3-way crossover trial, and 22 completers (by predefined criteria; 10 men and 12 women) were included in the analyses. They underwent 12-week treatment periods with candesartan (C; 16 to 32 mg), hydrochlorothiazide (H; 25 to 50 mg), and placebo (P), respectively, and the treatment order was randomly assigned and double blinded. Intravenous glucose tolerance tests and euglycemic hyperinsulinemic (56 mU/m2 per minute) clamps were performed. Intrahepatic and intramyocellular and extramyocellular lipid content and subcutaneous and visceral abdominal adipose tissue were measured using proton magnetic resonance spectroscopy and MRI. Insulin sensitivity (M-value) was reduced following H versus C and P (6.07±2.05, 6.63±2.04, and 6.90±2.10 mg/kg of body weight per minute, mean±SD; P
0.01). Liver fat content was higher (P<0.05) following H than both P and C. The subcutaneous to visceral abdominal adipose tissue ratio was reduced following H versus C and P (P<0.01). Glycosylated hemoglobin, alanine aminotransferase, aspartate aminotransferase, and high-sensitivity C-reactive protein levels were higher (P<0.05) after H, but not C, versus P. There were no changes in body fat, intramyocellular lipid, extramyocellular lipid, or first-phase insulin secretion. Blood pressure was reduced similarly by C and H versus P. In conclusion, visceral fat redistribution, liver fat accumulation, low-grade inflammation, and aggravated insulin resistance were demonstrated after hydrochlorothiazide but not candesartan treatment. These findings can partly explain the diabetogenic potential of thiazides.
Key Words: insulin resistance • visceral obesity • liver fat • glucose clamp • magnetic resonance
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Hypertension 2008 52: 1009-1011.
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