Prevalent role of the insulin receptor isoform A in the regulation of hepatic glycogen metabolism in hepatocytes and in mice.
In the postprandial state, the liver regulates glucose homeostasis by glucose uptake and conversion to glycogen and lipids. Glucose and insulin signalling finely regulate glycogen synthesis through several mechanisms. Glucose uptake in hepatocytes is favoured by the insulin receptor isoform A (IRA), rather than isoform B (IRB). Thus, we hypothesised that, in hepatocytes, IRA would increase glycogen synthesis by promoting glucose uptake and glycogen storage.



We addressed the role of insulin receptor isoforms on glycogen metabolism in vitro in immortalised neonatal hepatocytes. In vivo, IRA or IRB were specifically expressed in the liver using adeno-associated virus vectors in inducible liver insulin receptor knockout (iLIRKO) mice, a model of type 2 diabetes. The role of IR isoforms in glycogen synthesis and storage in iLIRKO was subsequently investigated.



In immortalised hepatocytes, IRA, but not IRB expression induced an increase in insulin signalling that was associated with elevated glycogen synthesis, glycogen synthase activity and glycogen storage. Similarly, elevated IRA, but not IRB expression in the livers of iLIRKO mice induced an increase in glycogen content.



We provide new insight into the role of IRA in the regulation of glycogen metabolism in cultured hepatocytes and in the livers of a mouse model of type 2 diabetes. Our data strongly suggest that IRA is more efficient than IRB at promoting glycogen synthesis and storage. Therefore, we suggest that IRA expression in the liver could provide an interesting therapeutic approach for the regulation of hepatic glucose content and glycogen storage.
Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid, 28040, Spain.|Mechanisms of Insulin Resistance (MOIR) Consortium, Comunidad de Madrid, Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Health Institute Carlos III (ISCIII), Spain.
Sabela
S
Diaz-Castroverde
Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid, 28040, Spain.
Selene
S
Baos
Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid, 28040, Spain.
María
M
Luque
Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain.
Marianna
M
Di Scala
Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain.
Gloria
G
González-Aseguinolaza
Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid, 28040, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Health Institute Carlos III (ISCIII), Spain.
Almudena
A
Gómez-Hernández
Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid, 28040, Spain.
Nuria
N
Beneit
Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid, 28040, Spain. oescriba@ucm.es.|Mechanisms of Insulin Resistance (MOIR) Consortium, Comunidad de Madrid, Madrid, Spain. oescriba@ucm.es.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Health Institute Carlos III (ISCIII), Spain, . oescriba@ucm.es.
Oscar
O
Escribano
Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid, 28040, Spain.|Mechanisms of Insulin Resistance (MOIR) Consortium, Comunidad de Madrid, Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Health Institute Carlos III (ISCIII), Spain.
Manuel
M
Benito
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism*; D024981:Glycogen Phosphorylase / Q000235:genetics / Q000378:metabolism*; D006006:Glycogen Synthase / Q000235:genetics / Q000378:metabolism*; D050261:Glycogenolysis; D022781:Hepatocytes; D008099:Liver / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*
D008112:Liver Glycogen; D020033:Protein Isoforms; D006003:Glycogen; D024981:Glycogen Phosphorylase; D006006:Glycogen Synthase; D011972:Receptor, Insulin; D005947:Glucose
Adeno-associated viruses; Glucose intolerance; Glycogen metabolism; Insulin receptor isoforms; Liver; Type 2 diabetes mellitus