Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor gamma co-activator 1

• Published in: Diabetologia Vol. 48; no. 6; pp. 1173 - 1179
• Main Authors: AL-KHALILI, L, FORSGREN, M, KANNISTO, K, ZIERATH, J. R, LÖNNQVIST, F, KROOK, A
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.06.2005; Springer Nature B.V
• Subjects: Adult; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; Antidiabetics; Biological and medical sciences; Biopsy; Cells, Cultured; Diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Fundamental and applied biological sciences. Psychology; Glucose; Glucose - pharmacology; Glucose Transporter Type 4; Glycogen - biosynthesis; Homeostasis; Humans; Insulin - pharmacology; Insulin resistance; Kinases; Male; Medical sciences; Medicin och hälsovetenskap; Metabolism; Metformin - pharmacology; Middle Aged; Monosaccharide Transport Proteins - genetics; Muscle Fibers, Skeletal - cytology; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Muscle Proteins - genetics; Muscle, Skeletal - cytology; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Musculoskeletal system; Physiology; Reference Values; Regulation; Ribonucleotides - pharmacology; RNA, Messenger - genetics; Striated muscle. Tendons; Thiazolidinediones - pharmacology; Transcription factors; Transcription Factors - genetics; Vertebrates: osteoarticular system, musculoskeletal system; Endocrinopathy; Human; MEF2; GLUT1; Pancreatic hormone; Metformin PGC1; Glycogen; Diabetes mellitus; Thiazolidinedione derivatives; Biosynthesis; Gene expression; Striated muscle; Insulin; Human skeletal muscle; Glycogen synthesis; Biguanides; Activator; Rosiglitazone; AICAR; Metformin; GLUT4; Biological receptor
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-005-1741-3

The aim of this study was to determine the effect of several antidiabetic agents on insulin-stimulated glycogen synthesis, as well as on mRNA expression. Cultured primary human skeletal myotubes obtained from six healthy subjects were treated for 4 or 8 days without or with glucose (25 mmol/l), insulin (400 pmol/l), rosiglitazone (10 micromol/l), metformin (20 micromol/l) or the AMP-activated kinase activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) (200 micromol/l). After this, insulin-stimulated glycogen synthesis was determined. mRNA levels of the glucose transporters GLUT1 and GLUT4, the peroxisomal proliferator activator receptor gamma (PPAR gamma) co-activator 1 (PGC1) and the myocyte-specific enhancer factors (MEF2), MEF2A, MEF2C and MEF2D were determined using real-time PCR analysis after 8 days exposure to the various antidiabetic agents. Insulin-stimulated glycogen synthesis was significantly increased in cultured human myotubes treated with insulin, rosiglitazone or metformin for 8 days, compared with non-treated cells. Furthermore, an 8-day exposure of myotubes to 25 mmol/l glucose impaired insulin-stimulated glycogen synthesis. In contrast, treatment with AICAR was without effect on insulin-mediated glycogen synthesis. Exposure to insulin, rosiglitazone or metformin increased mRNA expression of PGC1 and GLUT4, while AICAR or 25 mmol/l glucose treatment increased GLUT1 mRNA expression. Metformin also increased mRNA expression of the MEF2 isoforms. Enhanced insulin-stimulated glycogen synthesis in human skeletal muscle cell culture coincides with increased GLUT4 and PGC1 mRNA expression following treatment with various antidiabetic agents. These data show that chronic treatment of human myotubes with insulin, metformin or rosiglitazone has a direct positive effect on insulin action and mRNA expression.