Summary
We have previously shown that the mRNA expression of muscle glycogen synthase is decreased in non-insulin-dependent diabetic (NIDDM) patients; the objective of the present protocol was to examine whether the gene expression of muscle glycogen synthase in NIDDM is affected by chronic sulphonylurea treatment. Ten obese patients with NIDDM were studied before and after 8 weeks of treatment with a weight-maintaining diet in combination with the sulphonylurea gliclazide. Gliclazide treatment was associated with significant reductions in HbA1c (p=0.01) and fasting plasma glucose (p=0.005) as well as enhanced beta-cell responses to an oral glucose load. During euglycaemic, hyperinsulinaemic clamp (2 mU · kg−1 · min−1) in combination with indirect calorimetry, a 35% (p=0.005) increase in whole-body insulin-stimulated glucose disposal rate, predominantly due to an increased non-oxidative glucose metabolism (p=0.02) was demonstrated in the gliclazide-treated patients when compared to pre-treatment values. In biopsies obtained from vastus lateralis muscle during insulin infusion, the half-maximal activation of glycogen synthase was achieved at a significantly lower concentration of the allosteric activator glucose 6-phosphate (p=0.01). However, despite significant increases in both insulin-stimulated non-oxidative glucose metabolism and muscle glycogen synthase activation in gliclazide-treated patients no changes were found in levels of glycogen synthase mRNA or immunoreactive protein in muscle. In conclusion, improved blood glucose control in gliclazide-treated obese NIDDM patients has no impact on the gene expression of muscle glycogen synthase.
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Abbreviations
- NIDDM:
-
Non-insulin-dependent diabetes mellitus
- GS:
-
glycogen synthase
- G6P:
-
glucose-6-phosphate
- OGTT:
-
oral glucose tolerance test
- AUC:
-
area under the curve
- HGO:
-
hepatic glucose output
- PCR:
-
polymerase chain reaction
- bp:
-
base pair
References
DeFronzo RA, Bonadonna R, Ferrannini E (1992) Pathogenesis of NIDDM. A balanced overview. Diabetes Care 15: 318–368
Kida Y, Esposito-Del Puente A, Bogardus C, Mott DM (1990) Insulin resistance is associated with reduced fasting and insulin-stimulated glycogen synthase phosphatase activity in human skeletal muscle. J Clin Invest 85: 476–481
Thorburn AW, Gumbiner B, Bulacan F, Brechtel G, Henry RR (1991) Multiple defects in muscle glycogen synthase activity contribute to reduced glycogen synthesis in non-insulin-dependent diabetes mellitus. J Clin Invest 87: 489–495
Vestergaard H, BjØrbÆk C, Andersen PH, Bak JF, Pedersen O (1991) Impaired expression of glycogen synthase mRNA in skeletal muscle of NIDDM patients. Diabetes 40: 1740–1745
Johnson AB, Argyraki M, Thow JC et al. (1991) Impaired activation of skeletal muscle glycogen synthase in non-insulin-dependent diabetes mellitus is unrelated to degree of obesity. Metabolism 40: 252–260
Kelley DE, Mandarino LJ (1990) Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in non-insulin-dependent diabetes mellitus. J Clin Invest 86: 1999–2007
Damsbo P, Vaag A, Hother-Nielsen O, Beck-Nielsen H (1991) Reduced glycogen synthase activity in skeletal muscle from obese patients with and without type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 34: 239–245
Johnson AB, Argyraki M, Thow JC, Broughton D, Jones IR, Taylor R (1990) Effects of intensive dietary treatment on insulin-stimulated skeletal muscle glycogen synthase activation and insulin secretion in newly presenting type 2 diabetic patients. Diabet Med 7: 420–428
Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG (1990) Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med 322: 223–228
Johnson AB, Argyraki M, Thow JC, Jones IR, Broughton D, Taylor R (1990) The effect of sulphonylurea therapy on skeletal muscle glycogen synthase activity and insulin secretion in newly presenting type 2 (non-insulin-dependent) diabetic patients. Diabetic Medicine 8: 243–253
Bak JF, MØller N, Schmitz O, Saaek A, Pedersen O (1992) In vivo insulin action and muscle glycogen synthase activity in type 2 (non- insulin-dependent) diabetes mellitus: effects of diet treatment. Diabetologia 35: 777–784
Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG (1985) The effect of insulin treatment on insulin secretion and insulin action in type 2 diabetes mellitus. Diabetes 34: 222–234
Beck-Nielsen H, Hother-Nielsen O, Pedersen O (1988) Mechanism of action of sulphonylureas with special reference to the extrapancreatic effect: an overview. Diabet Med 5: 613–620
Vestergaard H, Weinreb JE, Rosen AS, et al (1995) Sulphonylurea therapy improves glucose disposal without changing skeletal muscle GLUT4 levels in non-insulin-dependent diabetes mellitus subjects: a longitudinal study. J Clin Endocrinol Metab 80: 270–275
National Diabetes Data Group (1979) Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28: 1039–1057
DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol (Endocrinol Metab) 6(3):E214–E223
Vestergaard H, Lund S, Larsen FS, Bjerrum OJ, Pedersen O (1993) Glycogen synthase and phosphofructokinase protein and mRNA levels in skeletal muscle from insulin-resistant patients with non-insulin-dependent diabetes mellitus. J Clin Invest 91: 2342–2350
Steele R (1959) Influence of glucose loading and of injected insulin on hepatic glucose output. Ann NY Acad Sci 82: 420–430
Frayn KN (1983) Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol 55: 628–634
Wang AM, Doyle MV, Mark DF (1989) Quantitation of mRNA by polymerase chain reaction. Proc Natl Acad Sci USA 86: 9717–9721
Becker-André M, Hahlbrock K (1989) Absolute mRNA quantification using the polymerase chain reaction (PCR). A novel approach by a PCR aided transcript titration assay (PATTY). Nucleic Acids Res 17: 9437–9446
Mocharla H, Mocharla R, Hodes ME (1990) Coupled reverse transcription-polymerase chain reaction (RT-PCR) as a sensitive and rapid method for isozyme genotyping. Gene 93: 271–275
Siebert PD, Fukuda M (1985) Induction of cytoskeletal vimentin and actin gene expression by a tumor-promoting phorbol ester in human leukemic cell line K562. J Biol Chem 260: 3868–3874
Elder PK, French CL, Subramaniam M, Scmidt LJ, Getz MJ (1988) Evidence that the functional Β-actin gene is single copy in most mice and is associated with 5′ sequences capable of conferring serum- and cycloheximide-dependent regulation. Mol Cell Biol 8: 480–485
Schmidt EE, Merrill GF (1991) Changes in dihydrofolate reductase (DHFR) mRNA levels can account fully for changes in DHFR synthesis rates during terminal differentation in a highly amplified myogenic cell line. Mol Cell Biol 11: 3726–3734
Efstratiadis A, Kafatos FC, Maniatis T (1977) The primary structure of rabbit Β-globin mRNA as determined from cloned DNA. Cell 10: 571–585
Browner MF, Nakano K, Bang AG, Fletterick RJ (1989) Human muscle glycogen synthase cDNA sequence: a negatively charged protein with an asymmetric charge distribution. Proc Natl Acad Sci USA 86: 1443–1447
Bak JF, Pedersen O (1990) Exercise-enhanced activation of glycogen synthase in human skeletal muscle. Am J Physiol (Endocrinol Metab) 258:E957–E963
Andersen I, Hannibal S (1983) Analytical and economical optimization of a glucose method with immobilized enzymes. J Autom Chem 5: 188–192
Lanng S, Thorsteinsson B, RØder ME et al. (1993) Pancreas and gut hormone responses to oral glucose and intravenous glucagon in cystic fibrosis patients with normal, impaired, and diabetic glucose tolerance. Acta Endocrinol (Copenh) 128: 207–214
Heding LG (1975) Radioimmunological determination of human C-peptide in serum. Diabetologia 11: 541–548
Hother-Nielsen O, Schmitz O, Bak JF, Beck-Nielsen H (1987) Enhanced hepatic insulin sensitivity, but peripheral insulin resistance in patients with type 1 (insulin-dependent) diabetes. Diabetologia 30: 834–840
Itaya K, Michio U (1965) Colorimetric determination of free fatty acids in biological fluids. J Lipid Res 6: 16–20
Gray DS, Bray GA, Gemayel N, Kaplan K (1989) Effect of obesity on bioelectrical impedance. Am J Clin Nutr 50: 255–260
Jefferson LS (1980) Role of insulin in the regulation of protein synthesis (Lilly Lecture 1979). Diabetes 29: 487–496
O'Brien RM, Granner DK (1991) Regulation of gene expression by insulin. Biochem J 278: 609–619
Eriksson J, Franssila-Kullunki A, Ekstrand A, et al (1989) Early metabolic defects in persons at increased risk for non-insulin- dependent diabetes mellitus. N Engl J Med 321: 337–343
Schalin-JÄntti C, HÄrkönen M, Groop L (1992) Impaired activation of glycogen synthase in people at increased risk for developing NIDDM. Diabetes 41: 598–604
Villar-Palasi C (1991) Substrate specific activation by glucose 6-phosphate of the dephosphorylation of muscle glycogen synthase. Biochi Biophys Acta 1095: 261–267
Boden G, Jadali F, White J et al. (1991) Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. J Clin Invest 88: 960–966
Grunberger G, Ryan J, Gorden P (1982) Sulfonyureas do not affect insulin binding or glycemic control in insulin-dependent diabetics. Diabetes 31: 890–896
Ratzmann KP, Schulz B, Heinke P, Besch W (1984) Tolbutamide does not alter insulin requirement in type 1 (insulin-dependent) diabetes. Diabetologia 27: 8–12
Simonson DC, Ferrannini E, Bevilacqua S et al. (1984) Mechanism of improvement in glucose metabolism after glyburide therapy. Diabetes 33: 838–845
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Vestergaard, H., Lund, S., BjØrbÆk, C. et al. Unchanged gene expression of glycogen synthase in muscle from patients with NIDDM following sulphonylurea-induced improvement of glycaemic control. Diabetologia 38, 1230–1238 (1995). https://doi.org/10.1007/BF00422374
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DOI: https://doi.org/10.1007/BF00422374