Urine levels of 5-aminoimidazole-4-carboxamide riboside (AICAR) in patients with type 2 diabetes
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5-Aminoimidazole-4-carboxamide riboside (AICAR) is an endogenous activator of AMPK, a central regulator of energy homeostasis. Loss and/or reduction of AMPK signaling plays an important role in the development of insulin resistance in type 2 diabetes. The loss of AMPK in diabetes could be due to a loss of AICAR. The aim of this study was to characterize urine levels of AICAR in diabetes and determine whether an association exists with respect to late complications, e.g., retinopathy, nephropathy and neuropathy.
Urine AICAR was measured by liquid chromatography tandem mass spectrometry in 223 patients consisting of 5 healthy controls, 63 patients with pre-diabetes, 29 patients with newly diagnosed type 2 diabetes and 126 patients with long-standing type 2 diabetes. For statistical analyses, nonparametric Kruskal–Wallis test, one-way ANOVA and multivariate regression analysis were performed to investigate the associations of urinary AICAR excretion within different groups and different clinical parameters.
The mean urine AICAR for all 223 patients was 694.7 ± 641.1 ng/ml. There was no significant difference in urine AICAR between the control and patients with diabetes (592.3 ± 345.1 vs. 697.1 ± 646.5 ng/ml). No association between any of the biochemical and/or clinical parameters measured and urine AICAR was found, with the exception of age of patient (R = − 0.34; p < 0.01) and estimated glomerular filtration rate (R = 0.19; p = 0.039). These results were confirmed additionally by linear regression analysis.
Clinical diabetes is not associated with a change in endogenous AICAR levels. Loss of AICAR may therefore not be a mechanism by which AMPK signaling is reduced in diabetes.
KeywordsDiabetes Late diabetic complications Urine analysis AICAR AMPK
Albumin to creatinine ratio
AMP-activated protein kinase
Body mass index
Neuropathy symptom score (NSS)
Neuropathy disability score (NDS)
The authors would like thank Kathrin Schmidt for her excellent technical assistance.
MM and PPN designed the study, interpreted data and drafted the manuscript. JBG contributed substantially in the acquisition of data and revised the manuscript critically for important intellectual content. SK contributed substantially in the analysis and interpretation of data and preparing the tables and figures. CR revised the manuscript critically for important intellectual content. THF contributed substantially to the interpretation of data and revised the manuscript elaborately. JGO established the AICAR measurement, interpreted the data and revised the manuscript for important intellectual content. All authors read and approved the final manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
This study was supported by the DFG (CRC1118 to MM, CR, THF & PPN).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
Urine samples were obtained from three studies that have been approved by the Ethics Committee Heidelberg (S-245/2013, S-232-2013, S-383/2016) that have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
All patients gave their written consent prior to their inclusion in the studies.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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