Decreased insulin sensitivity and muscle enzyme activity in elderly subjects

Abstract

Abstract. Skeletal muscle glycogen deposition, and the activation of muscle glycogen synthase and pyruvate deh y drogenase during a hyerinsulinaemic euglycaemic clamp have been measured in six young and six elderly males matched for body mass index, physical activity and diet. Clamp glucose requirement (insulin, 0.1 U kg-' h-') was significantly lower in the older subjects (8.0f0.4 mg kg-' min-I) than in younger subjects (10.5f0.6 mg kg-' min-I, P<0.02). Although the older subjects had a 6.5% decrease in lean body mass, clamp glucose requirement expressed per unit of lean body mass was also significantly decreased in the older subjects (10.2f0.5 vs. 12.4f0.6 mg kg-* min-I, P<O.O5). The increase in muscle glycogen with the clamp was decreased by 33% in the older subjects (elderly: 13.1 f 1.3 mg g-' protein, young: 19.6f2.2 mg g-' protein; P < 0.05), and was strongly correlated with clamp glucose requirement (r =0*72, P < 0.01). Glucose-6-phosphate independent glycogen synthase activity increased significantly between fasting and the end of the clamps in both groups ( P < 0.001), but was lower at the end of the clamp in the older subjects (P < 0.05). Glycogen synthase activity at the end of the clamp correlated with both clamp glucose requirement (r =0.83, P < 0.01) and muscle glycogen deposition (r = 0.73, P < 0.01). Skeletal muscle pyruvate dehydrogenase activity increased significantly between fasting and end of clamp in the young subjects (P < 0.05) but not in the elderly males. Pyruvate dehydrogenase activity at the end of the clamp, however, did not differ between the two groups and was not related to clamp glucose requirement. Thus the impaired glucose handling of the elderly may be related to decreased insulin action on muscle and muscle enzymes.

Multiple defects in muscle glycogen synthase activity contribute to reduced glycogen synthesis in non-insulin dependent diabetes mellitus.

“…When a defect in insulin's ability to activate glycogen synthase has been reported previously, it has usually been accompanied by a corresponding reduced rate of glucose uptake into insulin-sensitive tissues (e.g., 7,[12][13][14][15][16]. This association has lead to the suggestion that a causal relationship exists between insulin-stimulation ofglycogen synthase and glucose uptake (7,13,14).…”

“…Although impaired muscle glycogen synthase activity in response to insulin has been well documented in a number of insulin-resistant states (7,(12)(13)(14)(15)(16)(17), little is known about the nature or extent of these defects. In a previous study carried out during steadystate glucose clamp conditions and insulin levels of 300 pmol/ liter, we documented that muscle glycogen synthase activity (expressed as fractional velocity) was reduced by 40% in NIDDM but could be normalized by increasing insulin levels fourfold ( 17).…”

“…In animals, diabetes induced by streptozotocin, alloxan, or pancreatectomy has been shown to blunt the ability of insulin to promote glucose incorporation into glycogen (8,9) as well as the ability ofinsulin to lower the sensitivity of the enzyme for G6P (10, 1 1). A number of recent studies conducted in human subjects have also documented reduced glycogen synthase activity in insulinresistant states including NIDDM (7,(12)(13)(14)(15)(16)(17). However, the nature and extent ofthe glycogen synthase defect in muscle and its role in reduced glycogen formation in NIDDM has not yet been clearly elucidated.…”

Mechanism of Increased Plasma Glucose Levels after Oral Glucose Ingestion in Normal-Weight Middle-Aged Subjects

“…This has already been reported in conditions of both normal [11,30] and high [12] glycemia, although it was not yet clear whether the defect concerns oxidative or non-oxidative glucose disposal. Franssila-Kallunki et al [8] found a negative correlation between age and non-oxidative glucose disposal, and Kruszynska et al [11] linked the reduction in insulin-mediated glucose uptake with a lower activity of muscular glycogen synthase. Comparing subjects differing in age at similar rates of glucose uptake, the defect only involved glucose oxidation [5], with no change in glycogen synthase activity [9].…”

“…This decrease (-8% of body weight) was near the 10-14% decrease in more aged groups studied by skinfold thickness [13], hydrostatic weighing [6] or isotopic techniques [5]. Age-related reductions in FFM-normalized glucose uptake have been reported during clamps [11], but not during OGTTs, probably because the higher glucose level compensates for the defect in utilization. The subtle differences after normalization might have reached significance if we had studied more subjects, or older subjects.…”