When whole body
insulin-stimulated
glucose disposal rate is measured in man applying the euglycaemic, hyperinsulinaemic clamp technique it has been shown that approximately 75% of
glucose is taken up by skeletal muscle. After the initial transport step,
glucose is rapidly phosphorylated to
glucose-6-phosphate and routed into the major pathways of either
glucose storage as
glycogen or the glycolytic/
tricarboxylic acid pathway.
Glucose uptake in skeletal muscle involves-the activity of specific
glucose transporters and hexokinases, whereas,
phosphofructokinase and
glycogen synthase hold critical roles in
glucose oxidation/glycolysis and
glucose storage, respectively.
Glucose transporters and
glycogen synthase activities are directly and acutely stimulated by
insulin whereas the activities of hexokinases and
phosphofructokinase may primarily be allosterically regulated. The aim of the review is to discuss our present knowledge of the activities and gene expression of
hexokinase II (HKII),
phosphofructokinase (PFK) and
glycogen synthase (GS) in human skeletal muscle in states of altered
insulin-stimulated
glucose metabolism. My own experimental studies have comprised patients with disorders characterized by
insulin resistance like
non-insulin-dependent diabetes mellitus (
NIDDM) and
insulin-dependent diabetes mellitus (
IDDM) before and after therapeutic interventions, patients with
microvascular angina and patients with severe
insulin resistant
diabetes mellitus and congenital muscle fiber type disproportion
myopathy as well as athletes who are in a state of improved
insulin sensitivity. By applying the
glucose insulin clamp method in combination with nuclear magnetic resonance 31P spectroscopy to normoglycaemic or hyperglycaemic
insulin resistant subjects impairment of
insulin-stimulated
glucose transport and/or phosphorylation in skeletal muscle has been shown. In states characterized by
insulin resistance but normoglycaemia, the activity of HKII measured in needle revealed any genetic variability that contributes to explain the decreased muscle levels of GS
mRNA or the decreased activity and activation of muscle GS in
NIDDM patients and their
glucose tolerant but
insulin resistant relatives. Thus, the causes of impaired
insulin-stimulated
glycogen synthesis of skeletal muscle in normoglycaemic
insulin resistant subjects are likely to be found in the
insulin signalling network proximal to the GS
protein. In
insulin resistant diabetic patients the impact of these yet unknown abnormalities may be accentuated by the prevailing hyperglycaemia and hyperlipidaemia.
Endurance training in young healthy subjects results in improved
insulin-stimulated
glucose disposal rates, predominantly due to an increased
glycogen synthesis rate in muscle, which is paralleled by an increased total GS activity, increased GS
mRNA levels and enhanced
insulin-stimulated activation of GS. These changes are probably due to local contraction-dependent mechanisms. Likewise, one-legged exercise training has been reported to increase the basal concentration of muscle GS
mRNA in
NIDDM patients to a level similar to that seen in control subjects although
insulin-stimulated
glucose disposal rates remain reduced in
NIDDM patients. In the
insulin resistant states examined so far, basal and
insulin-stimulated
glucose oxidation rate at the whole body level and PFK activity in muscle are normal. In parallel, no changes have been found in skeletal muscle levels of PFK
mRNA and immunoreactive
protein in
NIDDM or
IDDM patients. In endurance trained subjects
insulin-stimulated whole body
glucose oxidation rate is often increased. However, depending on the intensity and frequency, physical exercise may induce an increased, a decreased or an unaltered level of muscle PFK activity. In athletes the muscle PFK
mRNA is similar to what is found in sedentary subjects whereas the immunoreactive PFK
protein concentration is decreased.