TY - JOUR
T1 - Deficiency in apolipoprotein A-I ablates the pharmacological effects of metformin on plasma glucose homeostasis and hepatic lipid deposition
AU - Karavia, Eleni A.
AU - Hatziri, Aikaterini
AU - Kalogeropoulou, Christina
AU - Papachristou, Nikolaos I.
AU - Xepapadaki, Eva
AU - Constantinou, Caterina
AU - Natsos, Anastasios
AU - Petropoulou, Peristera Ioanna
AU - Sasson, Shlomo
AU - Papachristou, Dionysios J.
AU - Kypreos, Kyriakos E.
N1 - Publisher Copyright:
© 2015 Elsevier B.V.
PY - 2015/11/5
Y1 - 2015/11/5
N2 - 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.
AB - 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.
KW - ApolipoproteinA-I
KW - Glucose intolerance
KW - HDL lipoprotein
KW - Metformin
KW - Nonalcoholic fattyliverdisease
KW - Obesity
UR - http://www.scopus.com/inward/record.url?scp=84944730284&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2015.09.040
DO - 10.1016/j.ejphar.2015.09.040
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C2 - 26420354
AN - SCOPUS:84944730284
SN - 0014-2999
VL - 766
SP - 76
EP - 85
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
ER -