title: 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.
abstract: 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.
authors.affiliation: Departments of Medicine, Umeå University Hospital, Umeå, Sweden. jan.eriksson@medic.gu.se
authors.forename: Jan W
authors.initials: JW
authors.lastname: Eriksson
authors.forename: Per-Anders
authors.initials: PA
authors.lastname: Jansson
authors.forename: Bo
authors.initials: B
authors.lastname: Carlberg
authors.forename: Anders
authors.initials: A
authors.lastname: Hägg
authors.forename: Lisa
authors.initials: L
authors.lastname: Kurland
authors.forename: Maria K
authors.initials: MK
authors.lastname: Svensson
authors.forename: Håkan
authors.initials: H
authors.lastname: Ahlström
authors.forename: Conny
authors.initials: C
authors.lastname: Ström
authors.forename: Lars
authors.initials: L
authors.lastname: Lönn
authors.forename: Kristina
authors.initials: K
authors.lastname: Ojbrandt
authors.forename: Lars
authors.initials: L
authors.lastname: Johansson
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
mesh_terms: D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001562:Benzimidazoles / Q000008:administration & dosage*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D001823:Body Composition; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced* / Q000175:diagnosis / Q000517:prevention & control; D004232:Diuretics / Q000008:administration & dosage / Q000009:adverse effects*; D005234:Fatty Liver / Q000139:chemically induced / Q000473:pathology; D005260:Female; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage / Q000009:adverse effects*; D006946:Hyperinsulinism; D006973:Hypertension / Q000188:drug therapy*; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D013777:Tetrazoles / Q000008:administration & dosage*
chemical_list: D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004232:Diuretics; D013777:Tetrazoles; D006852:Hydrochlorothiazide; C081643:candesartan