NMR studies of muscle glycogen synthesis in insulin-resistant offspring of parents with non-insulin-dependent diabetes mellitus immediately after glycogen-depleting exercise.

Abstract

To examine the impact of insulin resistance on the insulin-dependent and insulin-independent portions of muscle glycogen synthesis during recovery from exercise, we studied eight young, lean, normoglycemic insulin-resistant (IR) offspring of individuals with non-insulin-dependent diabetes mellitus and eight age-weight matched control (CON) subjects after plantar flexion exercise that lowered muscle glycogen to -25% of resting concentration. After '20 min of exercise, intramuscular glucose 6-phosphate and glycogen were simultaneously monitored with 31P and 13C NMR spectroscopies. The postexercise rate of glycogen resynthesis was nonlinear. Glycogen synthesis rates during the initial insulin independent portion (0-1 hr of recovery) were similar in the two groups (IR, 15.5 ± 1.3 mM/hr and CON, 15.8 + 1.7 mM/hr); however, over the next 4 hr, insulin-dependent glycogen synthesis was significantly reduced in the IR group [IR, 0.1 + 0.5 mM/hr and CON, 2.9 ± 0.2 mM/hr; (P ' 0.001)]. After exercise there was an initial rise in glucose 6-phosphate concentrations that returned to baseline after the first hour of recovery in both groups. In summary, we found that following muscle glycogen-depleting exercise, IR offspring of parents with non-insulin-dependent diabetes mellitus had (i) normal rates of muscle glycogen synthesis during the insulin-independent phase of recovery from exercise and (ii) severely diminished rates of muscle glycogen synthesis during the subsequent recovery period (2-5 hr), which has previously been shown to be insulin-dependent in normal CON subjects. These data provide evidence that exercise and insulin stimulate muscle glycogen synthesis in humans by different mechanisms and that in the IR subjects the early response to stimulation by exercise is normal.After intense exercise that depletes muscle glycogen concentrations to <35 mM glycogen, resynthesis proceeds in an approximately biphasic manner in both animal and human skeletal muscles (1-4). In normal healthy humans, there is an initial phase of rapid glycogen resynthesis (12-30 mM/hr) lasting -45 min that is insulin independent (1). The subsequent period of glycogen resynthesis (beyond -35 mM glycogen) is much slower (-3 mM/hr) and insulin dependent (5).Exercise and insulin are both known to stimulate muscle glucose uptake and subsequent glycogen synthesis in an independent and additive manner (6-10). Under resting conditions, the effect of insulin stimulation on glycogen synthesis has been compared in healthy control (CON) subjects and in subjects with non-insulin-dependent diabetes mellitus (NIDDM) by 13C NMR (11). In both CON subjects and NIDDM subjects placed under hyperglycemic-hyperinsulinemic conditions, the major pathway of insulin-dependent glucose metabolism was muscle glycogen synthesis (11). However, in the NIDDM subjects the rate of muscle glycogen synthesis was significantly impaired (11).31P NMR has been used to measure concentrations of glucose 6-phosphate (G6P), an intermediate of glycogen synthesis, under hyperglycemic-...

NMR of glycogen in exercise

“…Since the initial intense glycogen-depleting exercise study demonstrated that in normal healthy human subjects there was an early phase of rapid glycogen resynthesis (12-30 mmol/l per h) lasting approximately 45 min that was insulin independent and a subsequent period of glycogen resynthesis (above approximately 35 mmol glycogen/l) that was much slower (approximately 3 mmol/l per h) and insulin dependent (Price et al 1994a), a second exercise study compared control subjects with the insulin-resistant offspring of parents with non-insulin-dependent diabetes mellitus (NIDDM; Price et al 1996). During the insulinindependent portion of recovery from glycogen-depleting exercise the glycogen recovery rates were not significantly different between the control and the insulin-resistant groups (Fig.…”

Differential aetiology and impact of phosphoinositide 3-kinase (PI3K) and Akt signalling in skeletal muscle on in vivo insulin action

“…Defective insulinstimulated glucose uptake in muscle is associated with impaired muscle membrane glucose transport [2,3] and reduced muscle glycogen synthase activity [2,[4][5][6][7], which in turn may both result from impaired insulin signalling.…”

Overexpression of Peroxisome Proliferator-activated Receptor γ Coactivator-1α Down-regulates GLUT4 mRNA in Skeletal Muscles

“…These effects might be related to increased numbers of mitochondria and the GLUT4 isoform of the glucose transporter in skeletal muscles, respectively. GLUT4, the insulin-responsive glucose transporter, is expressed in skeletal muscles, heart, and adipose tissues, and the number of GLUT4 on plasma membrane becomes a rate-limiting step for whole-body glucose clearance under physiological conditions (3)(4)(5). Thus, exercise training modifies the skeletal muscle to metabolize more fatty acids and glucose.…”