title: Intensive insulin treatment induces insulin resistance in diabetic rats by impairing glucose metabolism-related mechanisms in muscle and liver.
abstract: Insulin replacement is the only effective therapy to manage hyperglycemia in type 1 diabetes mellitus (T1DM). Nevertheless, intensive insulin therapy has inadvertently led to insulin resistance. This study investigates mechanisms involved in the insulin resistance induced by hyperinsulinization. Wistar rats were rendered diabetic by alloxan injection, and 2 weeks later received saline or different doses of neutral protamine Hagedorn insulin (1.5, 3, 6, and 9 U/day) over 7 days. Insulinopenic-untreated rats and 6U- and 9U-treated rats developed insulin resistance, whereas 3U-treated rats revealed the highest grade of insulin sensitivity, but did not achieve good glycemic control as 6U- and 9U-treated rats did. This insulin sensitivity profile was in agreement with glucose transporter 4 expression and translocation in skeletal muscle, and insulin signaling, phosphoenolpyruvate carboxykinase/glucose-6-phosphatase expression and glycogen storage in the liver. Under the expectation that insulin resistance develops in hyperinsulinized diabetic patients, we believe insulin sensitizer approaches should be considered in treating T1DM.
authors: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Avenida Prof. Lineu Prestes, 1524, 05505-900 São Paulo (SP), Brazil. mokamoto@icb.usp.br
authors: Maristela Mitiko
authors: MM
authors: Okamoto
authors: Gabriel Forato
authors: GF
authors: Anhê
authors: Robinson
authors: R
authors: Sabino-Silva
authors: Milano Felipe dos Santos Ferreira
authors: MF
authors: Marques
authors: Helayne Soares
authors: HS
authors: Freitas
authors: Rosana Cristina Tieko
authors: RC
authors: Mori
authors: Karla Fabiana S
authors: KF
authors: Melo
authors: Ubiratan Fabres
authors: UF
authors: Machado
mesh_terms: D000496:Alloxan / Q000009:adverse effects; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000071161:Forkhead Box Protein O1
chemical_list: D000496:Alloxan; D051858:Forkhead Transcription Factors; D005947:Glucose; D051275:Glucose Transporter Type 4; D005952:Glucose-6-Phosphatase; D006003:Glycogen; D007004:Hypoglycemic Agents; D007328:Insulin; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; C495694:Slc2a4 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C069767:phosphoenolpyruvate carboxylase kinase