Does genetic variability in the fructosamine-3-kinase play a role in the progression of diabetic nephropathy, morbidity and mortality of diabetics?

Abstract

Meeting Abstract: 317 Background and aims: Fructosamines are products of non-enzymatic glycation formed in accelerated rate during hyperglycemia. As precursors of advanced glycation end-products (AGEs) fructosamines supposedly contribute to the development of glucotoxic injury. Mechanism of enzymatic deglycation of proteins in vivo by fructosamine-3-kinase (FN3K) was described recently. FN3K is a ubiquitous intracellular enzyme that phosphorylates fructosamines resulting in unstable fructosamine-3-phosphate, which subsequently spontaneously decomposes to inorganic phosphate, 3-deoxyglucosone and the unmodified amine. Recently, the -385A/G (rs3859206) and 900C/G (rs1056534) single nucleotide polymorphisms (SNPs) in the FN3K gene were found to have potential functional impact - association with FN3K enzyme activity in erythrocytes (genotypes -385AA and 900GG associated with lowest enzymatic activity). Fructosamine pathway may therefore represent either potentially protective metabolic process in hyperglycemia since degradation of fructosamines prevents formation of Lys-based AGEs or quite the reverse - harmful process - by formation of 3-deoxyglucosone as a potent mobile Arg-directed glycating agent. The aim was to study relationship between polymorphisms in FN3K gene, progression of diabetic nephropathy (DN) and cardiovascular morbidity and mortality of diabetics. Materials and methods: Study comprised a total of 420 T1DM or T2DM subject with variable stage of DN (i.e. normoalbuminuria, microalbuminuria, proteinuria or ESRD) prospectively followed for 45 [21 - 63] months (median [IQR]). Following end-points were considered: [1] renal (progression of DN by stage or reaching the ESRD), [2] major cardiovascular event (MCVE: nonfatal myocardial infarction or stroke, limb amputation), [3] cardiovascular mortality (CVM: fatal myocardial infarction, stroke or sudden death) and [4] all-cause mortality (AM). SNPs were genotyped by PCR with subsequent RFLP. Results: Progression of DN was reached in 16.5% of subjects, MCVE in 15.6%, CVM in 9.9% and ACM in 19.3%. Allele and genotype frequencies did not differ between DN stage groups (chi-square test). Using Kaplan-Meier time-to-event analysis significant effects were ascertained for the carrier state of the -385AA and 900GG genotype combinations and progression of DN, MCVE and CVM (all P<0.05, log-rank test). In all cases, group defined by the presence of at least one “low-activity” allele in both positions (i. e. -385AA or AG combined with 900GG or GC) were associated with significantly longer median of time to DN progression, MCVE and CVM. Conclusion: Interindividual variability in FN3K enzyme activity represents potentially significant genetic risk factor for the progression of DN and cardiovascular morbidity and mortality of diabetics. Based on our results, we can’t identify high FN3K deglycating activity as a protective factor, on the contrary higher rate of 3-deoxyglucosone formation may counterbalance putative protection by providing substrate for Arg-directed glycation and AGE formation. Supported by: NR 9443-3/2007 and Research grant from DANONE