Associations between circulating levels of FABP4 and TNF receptors are more evident in patients with type 2 diabetes mellitus than in patients with type 1 diabetes mellitus.

BACKGROUND: Fatty acid-binding protein 4 (FABP4) is an adipokine that plays significant roles in the development of insulin resistance and atherosclerosis. High levels of soluble tumor necrosis factor receptors (TNFRs) including TNFR1 and TNFR2 are associated with renal dysfunction and increased mortality in patients with diabetes mellitus (DM). However, the association between circulating levels of FABP4 and TNFRs remains unclear. METHODS: We investigated the associations of FABP4 with TNFRs and metabolic markers in Japanese patients with type 1 DM (T1DM, n=76, men/women: 31/45) and type 2 DM (T2DM, n=575, men/women: 312/263). RESULTS: FABP4 concentration was positively correlated with levels of TNFR1 and TNFR2 in both patients with T1DM and those with T2DM. Multivariable regression analyses showed that there were independent associations of FABP4 concentration with body mass index (BMI) and estimated glomerular filtration rate (eGFR) after adjustment of age and sex in both patients with T1DM and those with T2DM. FABP4 concentration was independently associated with circulating levels of TNFR1 and TNFR2 after adjustment of the confounders in patients with T2DM but not in those with T1DM. Similarly, levels of TNFR1 and TNFR2 were independently associated with FABP4 concentration after adjustment of age, sex, systolic blood pressure, duration of DM and levels of eGFR, high-density lipoprotein cholesterol and C-reactive protein in patients with T2DM but not in those with T1DM. CONCLUSION: FABP4 concentration is independently associated with levels of TNFRs in patients with DM, but the association is more evident in patients with T2DM than in those with T1DM.

Circulating TNF receptor levels are associated with estimated glomerular filtration rate even in healthy individuals with normal kidney function.

The association between serum tumor necrosis factor receptor (TNFRs: TNFR1, TNFR2) levels and estimated glomerular filtration rate (eGFR) observed in patients with diabetes has not been comprehensively tested in healthy subjects with normal kidney function. It also remains unclear whether TNFR levels differ by age and sex, and between healthy subjects and diabetics. We measured serum TNFR levels in 413 healthy subjects and 292 patients with type 2 diabetes. In healthy subjects, TNFR levels did not differ between men and women. Additionally, TNFR2, but not TNFR1, levels increased with age. In multivariate analysis, TNFR1 was associated only with cystatin C-based eGFR (eGFR-CysC), whereas TNFR2 was associated with systolic blood pressure in addition to eGFR-CysC. Both TNFRs were associated with lower eGFR (eGFR-Cys < 90 mL/min/1.73 m2) even after adjustment for relevant clinical factors. Upon combining healthy subjects and patients with diabetes, the presence of diabetes and elevated glycated hemoglobin level were significant factors in determining TNFR levels. TNFR levels were associated with eGFR-CysC, but were not affected by age and sex in healthy subjects with normal kidney function. TNFR levels in patients with diabetes appeared to be higher than in healthy subjects.

A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.

BACKGROUND: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. METHODS: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. RESULTS: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. CONCLUSIONS: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.