Abstract
Over-expression of phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15) causes insulin resistance by interacting with the D4 domain of phospholipase D1 (PLD1). Indeed, the disruption of this association restores insulin sensitivity in cultured cells over-expressing PED/PEA-15. Whether the displacement of PLD1 from PED/PEA-15 improves insulin sensitivity in vivo has not been explored yet. In this work we show that treatment with a recombinant adenoviral vector containing the human D4 cDNA (Ad-D4) restores normal glucose homeostasis in transgenic mice overexpressing PED/PEA-15 (Tg ped/pea-15) by improving both insulin sensitivity and secretion. In skeletal muscle of these mice, D4 over-expression inhibited PED/PEA-15-PLD1 interaction, decreased Protein Kinase C alpha activation and restored insulin induced Protein Kinase C zeta activation, leading to amelioration of insulin-dependent glucose uptake. Interestingly, Ad-D4 administration improved insulin sensitivity also in high-fat diet treated obese C57Bl/6 mice. We conclude that PED/PEA-15-PLD1 interaction may represent a novel target for interventions aiming at improving glucose tolerance.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenoviridae / genetics
-
Animals
-
Apoptosis Regulatory Proteins
-
Diet, High-Fat / adverse effects
-
Gene Expression Regulation
-
Genetic Therapy*
-
Genetic Vectors
-
Glucose / metabolism
-
Humans
-
Insulin / metabolism*
-
Insulin Resistance / genetics*
-
Insulin Secretion
-
Mice
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
Obesity / etiology
-
Obesity / genetics
-
Obesity / metabolism*
-
Obesity / therapy
-
Phospholipase D / genetics*
-
Phospholipase D / metabolism
-
Phosphoproteins / genetics*
-
Phosphoproteins / metabolism
-
Protein Binding
-
Protein Kinase C / genetics
-
Protein Kinase C / metabolism
-
Protein Kinase C-alpha / genetics
-
Protein Kinase C-alpha / metabolism
-
Protein Structure, Tertiary
-
Signal Transduction
-
Transgenes
Substances
-
Apoptosis Regulatory Proteins
-
Insulin
-
Pea15 protein, mouse
-
Phosphoproteins
-
protein kinase C zeta
-
Protein Kinase C
-
Protein Kinase C-alpha
-
Phospholipase D
-
phospholipase D1
-
Glucose
Grants and funding
This study was supported in part by the European Community’s FP6 PREPOBEDIA (201681), the European Foundation for the Study of Diabetes (EFSD), the Associazione Italiana per la Ricerca sul Cancro (AIRC) and by the Ministero dell’Università e della Ricerca Scientifica (grants PRIN and FIRB-MERIT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.