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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
Department of Medicine, Umeå University Hospital, Umeå, Sweden; Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden; AstraZeneca R&D, Mölndal, Sweden.
Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Medicine, Umeå University Hospital, Umeå, Sweden.
Department of Medicine, Uppsala University Hospital, Uppsala, Sweden.
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2008 (English)In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 52, no 6, p. 1030-1037Article in journal (Refereed) Published
Abstract [en]

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/m(2) 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<or=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.

Place, publisher, year, edition, pages
American Heart Association , 2008. Vol. 52, no 6, p. 1030-1037
Keywords [en]
insulin resistance, visceral obesity, liver fat, glucose clamp, magnetic resonance
National Category
Medical and Health Sciences Endocrinology and Diabetes Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:oru:diva-69404DOI: 10.1161/HYPERTENSIONAHA.108.119404ISI: 000261031400011PubMedID: 18981327OAI: oai:DiVA.org:oru-69404DiVA, id: diva2:1254515
Funder
Swedish Research CouncilSwedish Diabetes Association
Note

Research funders:

AstraZeneca Sweden

AstraZeneca R&D

Available from: 2018-10-09 Created: 2018-10-09 Last updated: 2024-01-16Bibliographically approved

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