Deficiency in apolipoprotein A-I ablates the pharmacological effects of metformin on plasma glucose homeostasis and hepatic lipid deposition

Eleni A. Karavia, Aikaterini Hatziri, Christina Kalogeropoulou, Nikolaos I. Papachristou, Eva Xepapadaki, Caterina Constantinou, Anastasios Natsos, Peristera Ioanna Petropoulou, Shlomo Sasson, Dionysios J. Papachristou, Kyriakos E. Kypreos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Recently, we showed that deficiency in apolipoprotein A-I (ApoA-I) sensitizes mice to diet-induced obesity, glucose intolerance and NAFLD. Here we investigated the potential involvement of ApoA-I in the pharmacological effects of metformin on glucose intolerance and NAFLD development. Groups of apoa1-deficient (apoa1-/-) and C57BL/6 mice fed western-type diet were either treated with a daily dose of 300 mg/kg metformin for 18 weeks or left untreated for the same period. Then, histological and biochemical analyses were performed. Metformin treatment led to a comparable reduction in plasma insulin levels in both C57BL/6 and apoa1-/- mice following intraperitoneal glucose tolerance test. However, only metformin-treated C57BL/6 mice maintained sufficient peripheral insulin sensitivity to effectively clear glucose following the challenge, as indicated by a [3H]-2-deoxy-D-glucose uptake assay in isolated soleus muscle. Similarly, deficiency in ApoA-I ablated the effect of metformin on hepatic lipid deposition and NAFLD development. Gene expression analysis indicated that the effects of ApoA-I on metformin treatment may be independent of adenosine monophosphate-activated protein kinase (AMPK) activation and de novo lipogenesis. Interestingly, metformin treatment reduced mitochondrial oxidative phosphorylation function only in apoa1-/- mice. Our data show that the role of ApoA-I in diabetes extends to the modulation of the pharmacological actions of metformin, a common drug for the treatment of type 2 diabetes.

Original languageEnglish
Pages (from-to)76-85
Number of pages10
JournalEuropean Journal of Pharmacology
Volume766
DOIs
StatePublished - 5 Nov 2015

Bibliographical note

Publisher Copyright:
© 2015 Elsevier B.V.

Keywords

  • ApolipoproteinA-I
  • Glucose intolerance
  • HDL lipoprotein
  • Metformin
  • Nonalcoholic fattyliverdisease
  • Obesity

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