The Effect of Graded Doses of Insulin on Total Glucose Uptake, Glucose Oxidation, and Glucose Storage in Man

Abstract

The dose-response relationship between plasma insulin concentration and total glucose uptake, glucose oxidation, and glucose storage was examined in 22 healthy young volunteers by employing the euglycemic insulin clamp technique in combination with indirect calorimetry. Insulin was infused at five rates to achieve steady-state hyperinsulinemic plateaus of 62 ± 4, 103 ± 5, 170 ± 10, 423 ± 16, and 1132 ± 47 μU/ml. With increasing plasma insulin concentrations within the physiologic range, there was a linear increase in glucose uptake with a half maximally effective insulin concentration of 72 μU/ml. Glucose uptake by all tissues of the body reached 80% of its maximum value (12.6 mg/kg · min) at a plasma insulin concentration of ∼200 μU/ml. In contrast to total glucose uptake, glucose oxidation plateaued more quickly, achieved a maximum rate of only 4.0 mg/kg · min, and displayed a lower half maximally effective insulin concentration of 40 μU/ml. The increase in glucose uptake with progressively increasing plasma insulin levels was primarily the result of an increase in glucose storage, with a half maximally effective insulin concentration of 105 μU/ml and maximum rate of 8.7 mg/kg · min. Glucose storage represented over 60–70% of total glucose uptake at all insulin concentrations. After achieving maximum rates of insulin-mediated glucose uptake (plasma insulin concentration = 1132 μU/ml), hyperglycemia (+125 mg/dl) was superimposed on hyperinsulinemia to further enhance glucose transport. Under these conditions, total glucose uptake (32.5 mg/kg · min, P < 0.001) was markedly augmented but no significant increase in glucose oxidation was observed. These results indicate a true saturation of the glucose oxidation pathway. With pro-gressively increasing doses of insulin, the glucose storage represents the major route of glucose disposal.

Inhibition of muscle glycogen synthase activity and non-oxidative glucose disposal during hypoglycaemia in normal man

“…The small difference in insulin levels (684 + 60 vs 756 _+ 30 pmol/1; p < 0.05) in our study cannot account for the pronounced suppression of glycogen synthase activity and non-oxidative glucose disposal [36,55]. However, the difference was slightly greater than would have been expected from suppression of endogenous insulin production, and could possibly reflect an elevated clearance of insulin during hypoglycaemia, even though this to our knowledge has not previously been described.…”

“…In a doseresponse study on the relationship between plasma insulin concentration and total Rd, Rd-ox and Rdnonox [55], Rd-nonox was found to represent the major route of glucose disposal during euglycaemic hyperinsulinaemia, and glucose oxidation was saturated at lower plasma insulin concentrations than glucose storage. In the present study hypoglycaemia especially compromised the route of Rd-nonox, a fact which seems logical, considering that insulin exerts its major influence here.…”

Peroxiredoxin 6, a Novel Player in the Pathogenesis of Diabetes

“…2/2 mice suggests that diminished insulin sensitivity could be located mainly at the skeletal muscle level, since ;80% of glucose uptake occurs in skeletal muscle during the test and PRDX6 is largely expressed in skeletal muscle (data not shown) (14).…”

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

“…Exercise-induced depletion of muscle glycogen can increase skeletal muscle insulin sensitivity and enhance glycemic control (Jensen et al 2011). Skeletal muscle is the major site for insulin-mediated glucose uptake in the postprandial state in humans (DeFronzo et al 1981, Thiebaud et al 1982. Skeletal muscle insulin resistance has been suggested as the primary defect in T2D and plays an essential role in the pathogenesis of the disease (DeFronzo & Tripathy 2009).…”