Insulin sensitivity of muscle protein metabolism is altered in patients with chronic kidney disease and metabolic acidosis

Abstract

An emergent hypothesis is that a resistance to the anabolic drive by insulin may contribute to loss of strength and muscle mass in patients with chronic kidney disease (CKD). We tested whether insulin resistance extends to protein metabolism using the forearm perfusion method with arterial insulin infusion in 7 patients with CKD and metabolic acidosis (bicarbonate 19 mmol/l) and 7 control individuals. Forearm glucose balance and protein turnover (²H-phenylalanine kinetics) were measured basally and in response to insulin infused at different rates for 2 h to increase local forearm plasma insulin concentration by approximately 20 and 50 μU/ml. In response to insulin, forearm glucose uptake was significantly increased to a lesser extent (-40%) in patients with CKD than controls. In addition, whereas in the controls net muscle protein balance and protein degradation were decreased by both insulin infusion rates, in patients with CKD net protein balance and protein degradation were sensitive to the high (0.035 mU/kg per min) but not the low (0.01 mU/kg per min) insulin infusion. Besides blunting muscle glucose uptake, CKD and acidosis interfere with the normal suppression of protein degradation in response to a moderate rise in plasma insulin. Thus, alteration of protein metabolism by insulin may lead to changes in body tissue composition which may become clinically evident in conditions characterized by low insulinemia.

Figure 1

The effect of insulin on forearm skeletal muscle glucose uptake in patients with chronic kidney disease (CKD) (n=7) and controls (n=7). The 0.035 mU/kg per min insulin infusion rate resulted in significant increases of glucose uptake of ∼3–4-fold in control subjects. The effect of local insulin was reduced by ~40% in patients with CKD. Values are mean±s.e.m. ^aStatistically significant differences (P⩽0.02) between basal and insulin-infused periods. ^bStatistically significant differences (P⩽0.03) between patients with CKD and controls.

Figure 2

Effect of insulin at 0.01 and 0.035 mU/kg per min on forearm muscle net protein balance. (a, b) In control subjects, the negative net protein balance observed in the basal, postabsorptive state was markedly decreased by insulin at both 0.01 (n=5) and 0.035 mU/kg per min (n=7). (a) Contrariwise, no effect of low-dose (0.01 mU/kg per min) insulin infusion was observed in patients with chronic kidney disease (CKD) (n=5). (b) At higher insulin infusion rates (0.035 mU/kg per min) net protein balance declined in patients (n=7) similarly to control subjects. Values are mean±s.e.m. ^aStatistically significant differences (P⩽0.01 or less) between basal and insulin-infused periods. ^bStatistically significant differences (P⩽0.03 or less) between patients with CKD and controls.

Figure 3

Effect of insulin at 0.01 and 0.035 mU/kg/min on forearm muscle protein degradation. (a) In control subjects the 0.01 mU/kg per min insulin infusion produced a significant ~31–34% decrease of protein degradation while it was only modestly influenced in patients with chronic kidney disease (CKD) (n=5); (b) A similar suppression of protein degradation in response to the higher insulin infusion rates was observed in control subjects (n=7) and patients with CKD (n=7). Values are mean±s.e.m. ^aStatistically significant differences (P⩽0.01) between basal and insulin-infused periods.

Figure 4

Effect of insulin at 0.01 and 0.035 mU/kg per min on forearm muscle protein synthesis. (a, b) No change in muscle protein synthesis was observed at both insulin infusion rates in controls and patients with chronic kidney disease (CKD). NS, nonsignificant.

Figure 5

Dose–response relationships between net protein balance across the forearm and insulin levels. To determine the dose–response characteristics for the effect of insulin on muscle protein metabolism, the net balance of phenylalanine across the forearm was plotted versus the corresponding steady-state plasma insulin concentrations (only the 100 and 120 min infusion data point considered) during insulin infusion. The fitted curve is a nonlinear least squares best fit to a logarithmic function. In control subjects, net protein balance decreased steeply from −17 nmol/min per 100 ml in the basal, postabsorptive state to −8 nmol/min per 100 ml when insulin concentrations were raised to 30 μU/ml. With further increases in insulin concentrations to ~100 μU/ml, net protein balance decreased only to −5 nmol/min per 100 ml. Thus, the maximal effect of insulin occurred at insulin concentrations between 15 and 30 μU/ml. In CKD patients the insulin response was shifted downward with higher net protein balance at moderate hyperinsulinemia. The curve of insulin sensitivity of protein balance in patients with chronic kidney disease (CKD) overlapped with the same curve obtained in controls in the high insulin physiological range.

Figure 6

The design of the study.

Figure 7

Plasma mass percent enrichment (MPE) of phenylalanine at study time points. CKD, chronic kidney disease.