title: Combined intervention with pioglitazone and n-3 fatty acids in metformin-treated type 2 diabetic patients: improvement of lipid metabolism.
abstract: BACKGROUND
  The marine n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exert numerous beneficial effects on health, but their potency to improve treatment of type 2 diabetic (T2D) patients remains poorly characterized. We aimed to evaluate the effect of a combination intervention using EPA + DHA and the insulin-sensitizing drug pioglitazone in overweight/obese T2D patients already treated with metformin.
  
  
  METHODS
  In a parallel-group, four-arm, randomized trial, 69 patients (66 % men) were assigned to 24-week-intervention using: (i) corn oil (5 g/day; Placebo), (ii) pioglitazone (15 mg/day; Pio), (iii) EPA + DHA concentrate (5 g/day, containing ~2.8 g EPA + DHA; Omega-3), or (iv) pioglitazone and EPA + DHA concentrate (Pio& Omega-3). Data from 60 patients were used for the final evaluation. At baseline and after intervention, various metabolic markers, adiponectin and cytokines were evaluated in serum using standard procedures, EPA + DHA content in serum phospholipids was evaluated using shotgun lipidomics and mass spectrometry, and hyperinsulinemic-euglycemic clamp and meal test were also performed. Indirect calorimetry was conducted after the intervention. Primary endpoints were changes from baseline in insulin sensitivity evaluated using hyperinsulinemic-euglycemic clamp and in serum triacylglycerol concentrations in fasting state. Secondary endpoints included changes in fasting glycemia and glycated hemoglobin (HbA1c), changes in postprandial glucose, free fatty acid and triacylglycerol concentrations, metabolic flexibility assessed by indirect calorimetry, and inflammatory markers.
  
  
  RESULTS
  Omega-3 and Pio& Omega-3 increased EPA + DHA content in serum phospholipids. Pio and Pio& Omega-3 increased body weight and adiponectin levels. Both fasting glycemia and HbA1c were increased by Omega-3, but were unchanged by Pio& Omega-3. Insulin sensitivity was not affected by Omega-3, while it was improved by Pio& Omega-3. Fasting triacylglycerol concentrations and inflammatory markers were not significantly affected by any of the interventions. Lipid metabolism in the meal test and metabolic flexibility were additively improved by Pio& Omega-3.
  
  
  CONCLUSIONS
  Besides preventing a modest negative effect of n-3 fatty acids on glycemic control, the combination of pioglitazone and EPA + DHA can be used to improve lipid metabolism in T2D patients on stable metformin therapy.
  
  
  BACKGROUND
  EudraCT number 2009-011106-42.
authors.affiliation: Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Veleba
authors.affiliation: Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Kopecky
authors.affiliation: Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Janovska
authors.affiliation: Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Kuda
authors.affiliation: Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Olga
authors.initials: O
authors.lastname: Horakova
authors.affiliation: Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Malinska
authors.affiliation: Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Kazdova
authors.affiliation: Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Olena
authors.initials: O
authors.lastname: Oliyarnyk
authors.affiliation: Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Vojtech
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authors.lastname: Skop
authors.affiliation: Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Jaroslava
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authors.lastname: Trnovska
authors.affiliation: Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Milan
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authors.lastname: Hajek
authors.affiliation: Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Antonin
authors.initials: A
authors.lastname: Skoch
authors.affiliation: Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Flachs
authors.affiliation: Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Kristina
authors.initials: K
authors.lastname: Bardova
authors.affiliation: Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Rossmeisl
authors.affiliation: Human Development & Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Josune
authors.initials: J
authors.lastname: Olza
authors.affiliation: Human Development & Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Gabriela Salim
authors.initials: GS
authors.lastname: de Castro
authors.affiliation: Human Development & Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Calder
authors.affiliation: Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic ; Department of Mathematical Analysis and Applications of Mathematics, Faculty of Science, Palacky University, Olomouc, Czech Republic.
authors.forename: Alzbeta
authors.initials: A
authors.lastname: Gardlo
authors.affiliation: Department of Mathematical Analysis and Applications of Mathematics, Faculty of Science, Palacky University, Olomouc, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Fiserova
authors.affiliation: Department of Physical Performance, Norwegian School of Sport Sciences, Oslo, Norway.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Jensen
authors.affiliation: Silentia AS, Svelvik, Norway.
authors.forename: Morten
authors.initials: M
authors.lastname: Bryhn
authors.affiliation: Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Kopecky
authors.affiliation: Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Terezie
authors.initials: T
authors.lastname: Pelikanova
keywords: Docosahexaenoic acid; Eicosapentaenoic acid; Humans; Hyperinsulinemic-euglycemic clamp; Indirect calorimetry; Meal test