Diabetes Care Volume 37, June 2014
e141
Improvement of Electrophysiological Neuropathy After Islet Transplantation for Type 1 Diabetes: A 5-Year Prospective Study
Marie-Christine Vantyghem,1,2,3 Delphine Quintin,3 Robert Caiazzo,1,2,4 Clara Leroy,3 Violeta Raverdy,1,2,4 François Cassim,5 François Glowacki,6 Thomas Hubert,1,2 Valery Gmyr,1,2 Christian Noel,6 Julie Kerr-Conte,1,2 and François Pattou1,2,4
Diabetes Care 2014;37:e141–e142 | DOI: 10.2337/dc14-0320
as described (5). The main study end points were continuous 24-h mean blood pressure and 72-h continuous glucose monitoring (CGM), as well as electrophysiological and cardiovascular autonomic testing, pre-IT and yearly until 5 years post-IT. Ten of the 21 patients (48%) were insulin-independent 5 years postIT. Four patients lost their islet graft during follow-up, but were analyzed on an intention-to-treat basis. The metabolic and sensory parameters improved between 0 and 5 years: (median [interquartile range], respectively 0 vs. 5; A1c: 8.3 [7.3–8.9] vs. 6.9 [6.0–7.9]% or 67 [56–74] vs. 52 [42–63] mmol/mol, P , 0.01; fasting blood glucose: 237 [148–289] vs. 108 [98–139] mg/dL, P , 0.001; fasting/postprandial C-peptide: 0 [0–0] vs. 0.9 [0.5–2.0]/2.7 [0.6–3] ng/mL, P , 0.0001; CGM mean glucose and SD: 147 [129–198] vs. 126 [109–159] mg/dL, P 5 0.02 and 58 [43– 76] vs. 33 [15–55] mg/dL, P , 0.01; sensory NCV: 47.5 [40.4–53.3] vs. 41.2 [33.5–43.9] m/s, P , 0.01; and sensory action potentials: 5.5 [3.7–7.3] vs. 11.8 [5.8–14.5] mV, P , 0.01) (Fig. 1B, C, E, F). Moreover, the sensory parameters significantly improved over the 5-year posttransplantation period (Fig. 1A2D). The kidney (creatinine, Modification of Diet in Renal Disease, microalbuminuria) and
lipid parameters, mean 24-h blood pressure, and motor electrophysiological and CAN parameters did not vary significantly between pre- and 5 years post-IT. Enzyme conversion inhibitors and statins were added in one-third of patients between 0 and 5 years. Both sensory (r 5 20.28, P , 0.01) and motor (r 5 20.27, P , 0.01) action potentials and sensory and motor NCV (r 5 20.24, P 5 0.01 and r 5 20.34, P , 0.001, respectively) were negatively correlated with CGM mean glucose. Only sensory NCV were negatively correlated with CGM SD (r 5 20.19, P , 0.01). Motor action potentials and NCV were negatively correlated with tacrolimus (r 5 20.23, P 5 0.02 and r 5 20.25, P 5 0.01, respectively) and triglycerides (r 5 20.35, P , 0.001 and r 5 20.21, P 5 0.02, respectively). Motor action potentials were negatively correlated with mean systolic blood pressure (r 5 20.41, P , 0.0001). Half of the patients were insulinindependent at the 5-year assessment, a figure close to the results of pancreas transplantation. Sensory neuropathy improved 5 years after IT. The favorable effect of IT on peripheral neuropathy in association with CGM mean glucose was burdened with the deleterious consequences of tacrolimus, mainly on the
1
INSERM, U859 Biotherapies for Diabetes, Lille, France European Genomic Institute for Diabetes, Lille University, Lille, France 3 Department of Endocrinology and Metabolism, Lille University Hospital, Lille, France 4 Department of Endocrine Surgery, Lille University Hospital, Lille, France 5 Department of Clinical Neurophysiology, Lille University Hospital, Lille, France 6 Department of Nephrology and Transplantation, Lille University Hospital, Lille, France 2
Corresponding author: Marie-Christine Vantyghem,
[email protected]. Clinical trial reg. nos. NCT00446264 and NCT01123187, clinicaltrials.gov. © 2014 by the American Diabetes Association. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
eLETTERS – OBSERVATIONS
The consequences of islet transplantation (IT) on neuropathy remain unclear, especially since neurotoxic effects of tacrolimus have been reported (1). The restoration of a euglycemic state in the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications study and through alone or combined whole pancreas transplantation has been shown to halt the progression of diabetic neuropathy (2). A significant improvement of a nerve conduction velocity (NCV) score compared with baseline was observed after IT-after-kidney (IAK), without any difference from a control group of nine kidney-only transplanted patients (3). No significant improvement of NCV was noticed 3 years after IT-alone (ITA) in a crossover study compared with intensive medical therapy (4). There has been no study of cardiac autonomic neuropathy (CAN) after IT and the results after kidney-pancreas transplantation are discordant. The aim of our study is to describe the evolution of neuropathy after IT. This single-arm, 5-year prospective, longitudinal study included 21 type 1 diabetic patients who underwent IT (13 ITA, 8 IAK) in a single center. Immunosuppression was induced by interleukin-2 receptor antibodies and maintained with tacrolimus and sirolimus
e142
Diabetes Care Volume 37, June 2014
Neuropathy After Islet Transplantation
Figure 1—Evolution in 21 patients over 5 years after IT of the motor and sensory NCVs (A) and action potentials (D) (Friedman test for repeated measures; effect of time, P 5 0.02 for sensory and 0.95 for motor NCVs; P 5 0.004 for sensory and 0.228 for motor action potentials). Pretransplantation (PreTx) and 5-year posttransplantation (5y) individual values of the motor and sensory NCVs (B, C) and action potentials (E, F) (Wilcoxon signed rank paired test).
motor component. Low-dose tacrolimus and tight glucose, triglycerides, and blood pressure control are recommended.
Acknowledgments. The authors thank Mrs. J. Ratziu from ProZ.com Translator (wwa@proz .com), who edited the English. Funding. This study was supported by the French Ministry of Health (PHRC 2001, 2008, and 2009), the European Community (Fond Europe´ en de De´ veloppement Re´ gional), Conseil R´egional du Nord-Pas-de-Calais (IFR 114, Institut de M´edecine Pr´edictive et de Recherche Th´erapeutique), and Groupement Inter-hospitalier G4 (Amiens, Caen, Lille, Rouen). Our team is also part of the European FP7 and supported by JDRF, the Soci´et´e Francophone du Diab`ete, the Association de Recherche pour le Diab`ete, and the Agence de la Biom´edecine. Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Author Contributions. M.-C.V. wrote the manuscript and researched data. D.Q. and V.R. researched data. R.C., C.L., F.C., F.G., and V.G. were deeply involved in the follow-up of the patients. T.H., C.N., and J.K.-C. contributed to discussion. F.P. reviewed and edited the manuscript and contributed to discussion. M.C.-V. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. This work was accepted as an oral communication at the 73rd Scientific Sessions of the American Diabetes Association, Chicago, IL, 21225 June 2013, and as a poster at the 49th Annual European Association for the Study of Diabetes Meeting, Barcelona, Spain, 23227 September 2013.
References 1. Arnold R, Pussell BA, Pianta TJ, Lin CS, Kiernan MC, Krishnan AV. Association between calcineurin inhibitor treatment and peripheral
nerve dysfunction in renal transplant recipients. Am J Transplant 2013;13:2426–2432 2. Martin CL, Albers JW, Pop-Busui R; DCCT/ EDIC Research Group. Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care 2014;37:31–38 3. Del Carro U, Fiorina P, Amadio S, et al. Evaluation of polyneuropathy markers in type 1 diabetic kidney transplant patients and effects of islet transplantation: neurophysiological and skin biopsy longitudinal analysis. Diabetes Care 2007;30:3063–3069 4. Thompson DM, Meloche M, Ao Z, et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation 2011;91:373–378 5. Vantyghem MC, Kerr-Conte J, Arnalsteen L, et al. Primary graft function, metabolic control, and graft survival after islet transplantation. Diabetes Care 2009;32:1473–1478
