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

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. 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. Insulin resistance is a well-known complication of chronic kidney diseases (CKD).1.Rigalleau V. Gin H. Carbohydrate metabolism in uraemia.Curr Opin Clin Nutr Metab Care. 2005; 8: 463-469Crossref PubMed Scopus (53) Google Scholar, 2.Fliser D. Pacini G. Engelleiter R. et al.Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease.Kidney Int. 1998; 53: 1343-1347Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar, 3.Kobayashi S. Maesato K. Moriya H. et al.Insulin resistance in patients with chronic kidney disease.Am J Kidney Dis. 2005; 45: 275-280Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4.DeFronzo R.A. Smith D. Alvestrand A. Insulin action in uremia.Kidney Int. 1983; 24: S102-S114Google Scholar, 5.Alvestrand A. Mujagic M. Wajngot A. et al.Glucose intolerance in uremic patients: the relative contributions of impaired beta-cell function and insulin resistance.Clin Nephrol. 1989; 31: 175-183PubMed Google Scholar, 6.DeFronzo R.A. Alvestrand A. Smith D. et al.Insulin resistance in uremia.J Clin Invest. 1981; 67: 563-568Crossref PubMed Scopus (465) Google Scholar, 7.Deferrari G. Garibotto G. Robaudo C. et al.Glucose interorgan exchange in chronic renal failure.Kidney Int. 1983: S115-S120Google Scholar Although not clinically remarkable, insulin resistance appears to be strongly implicated in the pathogenesis of hypertension, accelerated atherosclerosis, and cardiovascular events.8.Chen J. Muntner P. Lee Ham L. et al.Insulin resistance and the risk of chronic kidney disease in nondiabetic US adults.J Am Soc Nephrol. 2003; 14: 469-477Crossref PubMed Scopus (314) Google Scholar, 9.Shinohara K. Shoji T. Emoto M. et al.Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease.J Am Soc Nephrol. 2002; 13: 1894-1900Crossref PubMed Scopus (315) Google Scholar, 10.Teta D. Insulin resistance as a therapeutic target for chronic kidney disease.J Ren Nutr. 2015; 25: 226-229Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Besides its effects on glucose and lipid metabolism, insulin also influences a number of metabolic pathways related to protein metabolism that lead to anabolic or anticatabolic effects.11.Tessari P. Cecchet D. Cosma A. et al.Insulin resistance of amino acid and protein metabolism in type 2 diabetes.Clin Nutr. 2011; 30: 267-272Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Particularly, even small increases in blood insulin levels, well within the physiological range, are associated with pronounced inhibition of protein breakdown.11.Tessari P. Cecchet D. Cosma A. et al.Insulin resistance of amino acid and protein metabolism in type 2 diabetes.Clin Nutr. 2011; 30: 267-272Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar An emergent hypothesis is that a resistance to the anabolic drive by insulin may contribute to loss of strength and muscle mass that are observed with the progression of CKD.12.Wang X.H. Mitch W.E. Mechanisms of muscle wasting in chronic kidney disease.Nat Rev Nephrol. 2014; 10: 504-516Crossref PubMed Scopus (358) Google Scholar,13.Deger S.M. Sundell M.B. Siew E.D. et al.Insulin resistance and protein metabolism in chronic hemodialysis patients.J Ren Nutr. 2013; 23: e59-e66Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar This hypothesis is supported by studies obtained in animal models of CKD. Bailey et al.14.Bailey J.L. Zheng B. Hu Z. et al.Chronic kidney disease causes defects in signalling through the insulin receptor substrate/phosphatidylinositol 3-kinase/Akt pathway: implications for muscle atrophy.J Am Soc Nephrol. 2006; 17: 1388-1394Crossref PubMed Scopus (195) Google Scholar have recently identified a series of abnormal postreceptor signaling changes in the insulin/insulin-like growth factor-1 pathway in the muscle of rats with CKD. These include the occurrence of functional abnormalities in the insulin receptor substrate/phosphatidylinositol 3-kinase (PI3K) cascade that decrease the phosphorylation of the downstream effector Akt. The low phosphorylated Akt activity has been shown to stimulate the expression of specific E3 ubiquitin conjugating enzymes, atrogin-1/MAFbx and MuRF1, to accelerate muscle protein degradation. Furthermore, a decrease in muscle PI3K activity per se activates Bax, leading to the stimulation of caspase-3 activity and increase protein degradation.12.Wang X.H. Mitch W.E. Mechanisms of muscle wasting in chronic kidney disease.Nat Rev Nephrol. 2014; 10: 504-516Crossref PubMed Scopus (358) Google Scholar, 14.Bailey J.L. Zheng B. Hu Z. et al.Chronic kidney disease causes defects in signalling through the insulin receptor substrate/phosphatidylinositol 3-kinase/Akt pathway: implications for muscle atrophy.J Am Soc Nephrol. 2006; 17: 1388-1394Crossref PubMed Scopus (195) Google Scholar, 15.Thomas S.S. Dong Y. Zhang L. et al.Signal regulatory protein-α interacts with the insulin receptor contributing to muscle wasting in chronic kidney disease.Kidney Int. 2013; 84: 308-316Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar It is interesting that metabolic acidosis, a common complication observed in patients with CKD, also interferes with insulin-induced intracellular signaling by suppressing PI3K activity in muscle, and thus increases protein degradation through an upregulation of the ubiquitin-requiring pathway.16.Rajan V. Mitch W.E. Ubiquitin, proteasomes and proteolytic mechanisms activated by kidney disease.Biochim Biophys Acta. 2008; 1782: 795-799Crossref PubMed Scopus (37) Google Scholar,17.Reaich D. Channon S.M. Scrimgeour C.M. et al.Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation.Am J Physiol. 1993; 265: E230-E235PubMed Google Scholar Despite initial controversial results obtained in human insulin-resistant states (see Tessari et al.11.Tessari P. Cecchet D. Cosma A. et al.Insulin resistance of amino acid and protein metabolism in type 2 diabetes.Clin Nutr. 2011; 30: 267-272Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar for review), a recent clinical study has shown that the anticatabolic response to insulin is blunted in obese insulin-resistant women.18.Chevalier S. Marliss E.B. Morais J.A. et al.Whole-body protein anabolic response is resistant to the action of insulin in obese women.Am J Clin Nutr. 2005; 82: 355-365PubMed Google Scholar Interestingly, patients with end-stage renal disease due to diabetic nephropathy have an accelerated loss of lean body mass as compared with nondiabetic patients,19.Pupim L.B. Flakoll P.J. Majchrzak K.M. et al.Increased muscle protein breakdown in chronic hemodialysis patients with type 2 diabetes mellitus.Kidney Int. 2005; 68: 1857-1865Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar suggesting that insulin resistance accelerates net catabolism. The evidence that insulin resistance also extends to protein metabolism in CKD is suggested by cross-sectional studies in which protein turnover was compared with basal insulin levels or with ‘static’ indexes of insulin resistance. Siew et al.20.Siew E.D. Pupim L.B. Majchrzak K.M. et al.Insulin resistance is associated with skeletal muscle protein breakdown in non-diabetic chronic hemodialysis patients.Kidney Int. 2007; 71: 146-152Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar observed that even lesser degrees of glucose intolerance in the absence of overt diabetes mellitus are associated with both increased whole-body and muscle protein breakdown, suggesting that protein metabolism is scarcely sensitive to basal insulin levels in uremia. In addition, when we studied muscle protein turnover in patients with CKD and metabolic acidosis, we observed that the inverse association between protein degradation and plasma insulin occurring in healthy subjects was lost in CKD patients.21.Garibotto G. Russo R. Sofia A. et al.Skeletal muscle protein synthesis and degradation in patients with chronic renal failure.Kidney Int. 1994; 45: 1432-1439Abstract Full Text PDF PubMed Scopus (132) Google Scholar However, in the few studies22.Alvestrand A. Defronzo R.A. Smith D. et al.Influence of hyperinsulinaemia on intracellular amino acid levels and amino acid exchange across splanchnic and leg tissues in uraemia.Clin Sci. 1988; 74: 155-163Crossref PubMed Scopus (49) Google Scholar,23.Castellino P. Luzi L. Giordano M. et al.Effects of insulin and amino acids on glucose and leucine metabolism in CAPD patients.J Am Soc Nephrol. 1999; 10: 1050-1058PubMed Google Scholar in which amino acid or protein metabolism was evaluated during the euglycemic hyperinsulinemic clamp (a ‘gold standard’ for the detection of insulin resistance), a normal antiproteolytic response to insulin was observed, even in the presence of metabolic acidosis with mean bicarbonate of 17 mmol/l.24.Reaich K.A. Graham K.A. Channon S.M. et al.Insulin-mediated changes in PD and glucose uptake after correction of acidosis in humans with J Google Scholar It is interesting that in studies the effects of insulin were tested in the high insulin physiological that is to insulin However, protein metabolism appears to be sensitive at increased to insulin R.A. et al.Insulin of protein and glucose metabolism in human forearm skeletal Clin Invest. PubMed Scopus Google Scholar the occurrence of defects in muscle response in be by the high insulin levels in different insulin levels to of the different to insulin of protein and glucose The present clinical the effects of different insulin levels on of its as glucose and protein metabolism, in the muscle of patients with nondiabetic CKD. We that the insulin response both protein and glucose metabolism is blunted in the skeletal muscle of CKD patients with metabolic We tested an in which insulin levels were at different levels to a local of low or moderate exchange of glucose and protein turnover across forearm muscle were measured in the as well as in the hyperinsulinemic results that in patients with CKD the of skeletal muscle protein metabolism to to increased insulin levels is whereas the response to high insulin is the infusion of insulin (0.01 mU/kg per insulin was increased on the to and to in controls and CKD The of a insulin (0.035 mU/kg per min) increased insulin levels by the 7 to and to in controls and These insulin levels are to the Insulin levels measured in the were not during the study not insulin in patients with chronic kidney disease and in controls in the and during insulin infusion per basal basal basal basal basal basal basal basal basal basal basal basal basal in a Forearm blood was not significantly by the mU/kg per insulin infusion rates the insulin (0.035 mU/kg per a increase in forearm blood was observed in both controls and CKD blood per in patients with chronic kidney disease and in controls in the and during insulin infusion per basal basal basal basal basal in a The mU/kg per insulin infusion not in muscle glucose uptake in both patients and controls not The mU/kg per insulin infusion in increases of glucose uptake of in control subjects In the insulin-induced increase in forearm glucose uptake was impaired by in patients with CKD In the rates of protein degradation and net protein balance as a and in patients than controls. However, were not different between The net protein for are shown in In control the net protein balance observed in the was decreased by insulin infusion at both and mU/kg per and of (0.01 mU/kg per min) insulin infusion was observed in patients with CKD insulin infusion (0.035 mU/kg per net protein balance in patients to control subjects the effects of insulin on protein degradation. The mU/kg per insulin infusion a decrease of protein degradation in control subjects high suppression of protein degradation was observed in response to the insulin infusion rates degradation was not by insulin whereas a normal suppression was observed in response to the insulin infusion rates in CKD to was R.A. et al.Insulin of protein and glucose metabolism in human forearm skeletal Clin Invest. PubMed Scopus Google Scholar in muscle protein synthesis was observed at both insulin infusion rates in controls and CKD patients and the between net protein balance across the forearm and insulin the for the of insulin on muscle protein metabolism, the net balance of across the forearm was the plasma insulin the and infusion during insulin infusion. The is a to a In control subjects net protein balance decreased insulin of insulin of Thus, the of insulin at of μU/ml. was observed for CKD but for insulin between basal and the insulin response was to the The of insulin in patients with CKD to with the obtained in controls in the high insulin physiological are in with R.A. Smith D. Alvestrand A. Insulin action in uremia.Kidney Int. 1983; 24: S102-S114Google Scholar, 5.Alvestrand A. Mujagic M. Wajngot A. et al.Glucose intolerance in uremic patients: the relative contributions of impaired beta-cell function and insulin resistance.Clin Nephrol. 1989; 31: 175-183PubMed Google Scholar, 6.DeFronzo R.A. Alvestrand A. Smith D. et al.Insulin resistance in uremia.J Clin Invest. 1981; 67: 563-568Crossref PubMed Scopus (465) Google Scholar, metabolism in J Clin Nutr. Google Scholar the muscle response of glucose metabolism to insulin is blunted in CKD as a insulin of muscle protein metabolism is at insulin levels in the high than physiological This is in with studies on whole-body protein metabolism during euglycemic hyperinsulinemic K.A. Graham K.A. Channon S.M. et al.Insulin-mediated changes in PD and glucose uptake after correction of acidosis in humans with J Google Scholar, R.A. et al.Insulin of protein and glucose metabolism in human forearm skeletal Clin Invest. PubMed Scopus Google Scholar, metabolism in J Clin Nutr. Google Scholar the muscle response of protein metabolism to insulin in the low than physiological is impaired in patients with CKD. the results of study that in patients with CKD skeletal muscle protein metabolism is insulin resistant at low levels, whereas the of muscle protein metabolism to high insulin levels is studies have suggested that insulin resistance of glucose metabolism in is not of impaired insulin to its receptor but due to defects in intracellular signaling D. R.A. Insulin resistance in by Int. Full Text PDF PubMed Scopus Google R.A. et al.Glucose intolerance in of to glucose and tissue to Clin Invest. PubMed Scopus Google Scholar Insulin glucose uptake in skeletal muscle through the of the signaling a pathway that is in skeletal muscle in X.H. Mitch W.E. Mechanisms of muscle wasting in chronic kidney disease.Nat Rev Nephrol. 2014; 10: 504-516Crossref PubMed Scopus (358) Google D. V. Sofia A. et and are in the skeletal muscle of patients with chronic kidney disease.Kidney Int. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar In study the response to insulin of glucose metabolism in the muscle of CKD patients was impaired at insulin levels of levels that are observed after a are in with was shown by Alvestrand et A. Mujagic M. Wajngot A. et al.Glucose intolerance in uremic patients: the relative contributions of impaired beta-cell function and insulin resistance.Clin Nephrol. 1989; 31: 175-183PubMed Google Scholar observed a of glucose uptake by tissues at high insulin levels in uremic results are also in with was shown recently by et T. A. T. et metabolic response to a and in patients with chronic kidney 2011; PubMed Scopus Google Scholar observed a insulin response hemodialysis patients are to normal blood glucose levels after a has been associated with an response cardiovascular disease and mortality in patients with diabetes mellitus and is an in uremic T. A. T. et metabolic response to a and in patients with chronic kidney 2011; PubMed Scopus Google Scholar In insulin has both anabolic the presence of amino acid and anticatabolic effects.11.Tessari P. Cecchet D. Cosma A. et al.Insulin resistance of amino acid and protein metabolism in type 2 diabetes.Clin Nutr. 2011; 30: 267-272Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar that in the physiological of insulin whole-body protein and muscle et al.Insulin-mediated of body protein effects on leucine metabolism in Clin Invest. PubMed Scopus Google Scholar, P. R. S. et of effects of insulin on leucine in J Google Scholar, Z. T. et al.Insulin of protein metabolism in Nutr 1999; Google Scholar However, the mechanisms by which insulin muscle protein degradation are in In insulin decreases the activity of the pathway through changes in the phosphorylation of of the signaling M. C. A. et the ubiquitin and skeletal muscle Full Text Full Text PDF PubMed Scopus Google Scholar In rats is evidence that Akt activity phosphorylation of the of et of through phosphorylation during and its by 2008; PubMed Scopus Google E.D. G. et of the by 1999; PubMed Scopus Google Scholar and the of of the the ubiquitin muscle and that are to the control of muscle protein S. et of ubiquitin for skeletal muscle PubMed Scopus Google Scholar In when muscle protein in association with intracellular signaling were studied in response to insulin, decreases in the of protein and the not of were a for the in insulin-induced muscle et between the effects of amino acids and insulin on ubiquitin and protein turnover in human J 2008; PubMed Scopus Google Scholar It is interesting that metabolic acidosis the activity of different caspase-3 and the that increase muscle protein degradation.12.Wang X.H. Mitch W.E. Mechanisms of muscle wasting in chronic kidney disease.Nat Rev Nephrol. 2014; 10: 504-516Crossref PubMed Scopus (358) Google Scholar insulin and acidosis to target in an the signaling pathway in muscle, as also shown in a muscle S. et insulin receptor 3-kinase signaling in muscle on J Physiol. PubMed Scopus Google Scholar In we to study insulin of protein metabolism in CKD patients with acidosis in acidosis has been shown to increase protein V. Mitch W.E. Ubiquitin, proteasomes and proteolytic mechanisms activated by kidney disease.Biochim Biophys Acta. 2008; 1782: 795-799Crossref PubMed Scopus (37) Google Scholar,17.Reaich D. Channon S.M. Scrimgeour C.M. et al.Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation.Am J Physiol. 1993; 265: E230-E235PubMed Google Scholar an that is by bicarbonate A. B. et of bicarbonate on muscle protein in patients J Kidney Dis. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar In addition, acidosis decreases insulin of glucose K.A. Graham K.A. Channon S.M. et al.Insulin-mediated changes in PD and glucose uptake after correction of acidosis in humans with J Google Scholar Besides acidosis, different of CKD as S.S. Dong Y. 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Sofia A. et al.Skeletal muscle protein synthesis and degradation in patients with chronic renal failure.Kidney Int. 1994; 45: 1432-1439Abstract Full Text PDF PubMed Scopus (132) Google Scholar The net forearm balance for was as and are the arterial and The forearm protein breakdown by of was as in which and in arterial and The local of of which the muscle protein synthesis was are as the of the mean or the in between patients and the and of were arterial with was using the The of insulin on the response was using of for the effects high and insulin and and were to the between was with the This study was supported by the and by the of