Kidney International, Vol. 68 (2005), pp. 2396–2397

EDITORIAL

Diabetes, a cause of progressive sarcopenia in dialysis patients?

Pupim et al [1] have identified diabetes as a risk factor forloss of lean body mass in incident dialysis patients. Leanbody mass is composed of body cell mass and extracellu-lar fluid. The most vulnerable compartment within bodycell mass is skeletal muscle. Changes in muscle mass areaccompanied by changes in physical function marked bydecreased strength and mobility. Because muscle masstends to decline continuously with increasing vintageamong dialysis patients, finding an approachable mecha-nism to halt or slow the decline could have significant im-pact on patient function. Because insulin resistance anddiabetes can be approached therapeutically, recognitionthat diabetes imposes independent and significant risk totissue wasting presents opportunities both for interven-tion and to probe mechanism. The magnitude of loss oflean body mass, a mean of 3.4 kg/year, if continued lin-early, would lead to substantial sarcopenia. Malnutrition,defined by low serum albumin and prealbumin, are gener-ally observed among diabetic dialysis patients. However,the magnitude of loss of lean body mass observed hereis not reflected in cross-sectional measurements of ureavolume of distribution or anthopometric measures of leanbody mass by others [2, 3]. In the HEMO study, there wasno difference in urea volume of distribution at baselineamong a prevalent dialysis patient population [2]. Whilethis measure may not be quantitatively as precise as otherdirect measures of lean body mass, the lack of differencebetween nondiabetic and diabetic patients would suggestthat ongoing differences in loss of lean body mass such asobserved during the first year of treatment are unlikelyto continue in a linear fashion.

Chronic renal failure is accompanied both by alter-ations in plasma protein composition and by loss of leanbody mass, which may be an outcome either of inadequatenutritional intake or inflammation or a combination ofboth processes. In longitudinal studies, a decline in phaseangle measured by bioimpedance is associated with bothnutritional factors, and inflammation [4], as are changesin creatinine, a reporter of muscle mass [5]. Experimen-tal models of diabetes in the rat are indeed associatedwith decreased muscle protein synthesis and increased

Key words: diabetes, inflammation, proteinuria, muscle, nutrition.

C© 2005 by the International Society of Nephrology

catabolism [6], suggesting that diabetes either by theseor other mechanisms may affect muscle mass. Truncalobesity, a component of the metabolic syndrome, is asso-ciated with increased TNFa and IL-6 levels in type 2 di-abetics without renal failure and is associated with lowerbody cell mass [7], providing a potential mechanistic link.Activity of NFjB by the inflammatory cascade leads tomuscle protein catabolism [8] and impairs repair mecha-nisms [9], leading to loss of muscle mass. While diabeticpatients in the current study indeed had a greater fat mass,the authors found no association between a single cross-sectional measurement of CRP and subsequent changesin lean body mass. If this is the metabolic pathway link-ing diabetes to accelerated loss of lean body mass, themechanism would require uncoupling between a randommeasure of CRP and the plasma levels of these cytokines.Alternatively, a single measurement of cytokine activa-tion may be inadequate in this patient population becauseof the great variability in inflammation. This incident dial-ysis cohort of diabetic patients also had significantly moreurinary protein loss than the nondiabetic subjects. In-deed, urinary protein was well within the nephrotic range.This also presents a potential confounding variable be-cause liver protein synthesis increases in response to uri-nary protein loss with no change in over all body aminoacid economy [10]. The amino acids in proteins lost inthe urine, mostly generated in the liver, clearly must bereplaced by amino acids coming from other tissue stores.The most likely candidate is muscle. While the diabeticpatients may have come to dialysis with greater expan-sion of extracellular fluid than the nondiabetic patients,the authors established that muscle mass, as estimated bycreatinine generation, was not significantly different be-tween diabetic and nondiabetic patients, making such aconfounding effect unlikely. Gastroparesis or other fac-tors associated with diabetes may also have contributed tothe disproportionate loss of lean body mass in the diabet-ics; however, the loss of lean body mass was not accom-panied by a decrease in fat mass as well. Indeed, bodycomposition changed to that of increasing adiposity inthe dialysis patients. Recognizing that diabetes may bean independent variable associated with the rather pro-found loss of lean body mass opens the question of mech-anism, and potentially provides an option of interventionwith PPARc agonists to directly approach mechanisms

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of insulin resistance in this especially vulnerable cohortwithin this already high-risk pool of patients.

GEORGE A. KAYSEN

Davis, California

Correspondence to George A. Kaysen, University of California Davis,Genome and Biomedical Sciences Facility, 451 East Health Sciences Dr.,Suite 6300, Davis, CA 95616.E-mail: gakaysen@ucdavis.edu

REFERENCES

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FOR NUTRITION IN DIALYSIS (FSG-ND): Malnutrition in hemodialysisdiabetic patients: Evaluation and prognostic influence. Kidney Int62:593–601, 2002

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5. KAYSEN GA, CHERTOW GM, ADHIKARLA R, et al: Inflammationand dietary protein intake exert competing effects on serum albu-min and creatinine in hemodialysis patients. Kidney Int 60:333–340,2001

6. RODRIGUEZ T, ALVAREZ B, BUSQUETS S, et al: The increased skeletalmuscle protein turnover of the streptozotocin diabetic rat is as-sociated with high concentrations of branched-chain amino acids.Biochem Mol Med 61:87–94, 1997

7. PEDERSEN M, BRUUNSGAARD H, WEIS N, et al: Circulating levels ofTNF-alpha and IL-6-relation to truncal fat mass and muscle massin healthy elderly individuals and in patients with type-2 diabetes.Mech Ageing Dev 124:495–502, 2003

8. DENIS C, GUTTRIDGE DC, MAYO MW, et al: NF-jB–induced loss ofMyoD messenger RNA: Possible role in muscle decay and cachexia.Science 289:2363–2366, 2000

9. LANG CH, FROST RA, NAIRN AC, et al: TNF-alpha impairs heart andskeletal muscle protein synthesis by altering translation initiation.Am J Physiol Endocrinol Metab 282:E336–E347, 2002

10. DE SAIN-VAN DER VELDEN MG, DE MEER K, et al: Nephrotic protein-uria has no net effect on total body protein synthesis: measurementswith (13)C valine. Am J Kidney Dis 35:1149–1154, 2000