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Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM

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We investigated the response of the glucose transport system to insulin, in the presence of ambient glucose concentrations, in isolated skeletal muscle from seven patients with non-insulin-dependent diabetes mellitus (NIDDM) (age, 55±3 years, BMI 27.4±1.8 kg/m2) and seven healthy control subjects (age, 54±3 years, BMI 26.5±1.1 kg/m2). Insulin-mediated whole body glucose utilization was similar between the groups when studied in the presence of ambient glucose concentrations (approximately 10 mmol/l for the NIDDM patients and 5 mmol/l for the control subjects). Samples were obtained from the vastus lateralis muscle, by means of an open muscle biopsy procedure, before and after a 40-min insulin infusion. An increase in serum insulin levels from 54±12 to 588±42 pmol/l, induced a 1.6±0.2-fold increase in glucose transporter protein (GLUT4) in skeletal muscle plasma membranes obtained from the control subjects (p<0.05), whereas no significant increase was noted in plasma membrane fractions prepared from NIDDM muscles, despite a similar increase in serum insulin levels. At concentrations of 5 mmol/l 3-O-methylglucose in vitro, insulin (600 pmol/l) induced a 2.2-fold (p<0.05) increase in glucose transport in NIDDM muscles and a 3.4-fold (p<0.001) increase in the control muscles. Insulin-stimulated 3-O-methylglucose transport was positively correlated with whole body insulin-mediated glucose uptake in all participants (r=0.78,p<0.001) and negatively correlated with fasting plasma glucose levels in the NIDDM subjects (r=0.93,p<0.001). Muscle fibre type distribution and capillarization were similar between the groups. Our results suggest that insulin-stimulated glucose transport in skeletal muscle from patients with NIDDM is down-regulated in the presence of hyperglycaemia. The increased flux of glucose as a consequence of hyperglycaemia may result in resistance to any further insulin-induced gain of GLUT4 at the level of the plasma membrane.

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Abbreviations

NIDDM:

Non-insulin-dependent diabetes mellitus

GLUT4:

insulin-regulatable glucose transporter protein

KHB:

Krebs-Heinsleit bicarbonate buffer

HEPES:

N-2-hydroxyethyl-piperazine-N-2-ethanesulphonic acid

BSA:

bovine serum albumin

ATPase:

adenosine triphosphatase

PMSF:

phenylemthylsulphonyl fluoride.

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Authors and Affiliations

  1. Department of Clinical Physiology, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden

    J. R. Zierath, E. Odegaard Wahlström & H. Wallberg-Henriksson

  2. Division of Cell Biology, The Hospital for Sick Children, Toronto, Canada

    L. He, A. Gumà & A. Klip

Authors
  1. J. R. Zierath
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  2. L. He
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  3. A. Gumà
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  4. E. Odegaard Wahlström
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  5. A. Klip
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  6. H. Wallberg-Henriksson
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Zierath, J.R., He, L., Gumà, A. et al. Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM. Diabetologia 39, 1180–1189 (1996). https://doi.org/10.1007/BF02658504

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