Unexpectedly High and Difficult-to-Explain Regenerative Capacity in an 82-Year-Old Patient with Insulin-Requiring Type 2 Diabetes and End-Stage Renal Disease

Abstract

Background/Objectives: The case we present is part of a large study that we conducted on hemodialysis patients with type 2 diabetes mellitus (T2DM) and which set the following objectives: studying changes in the intestinal microbiota, innate and acquired immune response capacity, and tissue regeneration. Methods: (1) For the genetic study of the gut microbiota, special techniques that are not based on cultivation were used since most of the species in the intestinal flora are not cultivable. (2) The immunological study had two targets: innate immunity (inflammation) and adaptive immunity (we chose to address the cellular immune response because, unlike the humoral one, it is insufficiently studied in this category of associated pathologies). As markers for innate immunity (inflammation), the following were determined: IL-6, sIL-6R, IL-1β, TNFα, IL-10, and NGAL. TNFβ/LTα was determined as a marker for adaptive immunity (the cellular immune response). (3) The study of tissue regeneration capacity was performed using NT-3 (this is the first study to do so) and VEGFβ (another marker that is scarce in this category of patients) as markers. All the aforementioned compounds were determined from serum samples, utilizing Merck Millipore ELISA kits for IL-6, IL-1β, IL-10, NT-3, and VEGF β, and Elabscience ELISA kits for IL-6R, TNFα, TNFβ, and NGAL. Results: We were very surprised to find unexpected immunological changes and tissue regenerative capacity in one of the patients studied, an 82-year-old female patient diagnosed with insulin-dependent T2DM with multiple complications, including end-stage renal disease (ESRD). The patient showed a huge capacity for tissue regeneration, combined with amplification of immunological capacity, in comparison to patients in the same group (T2DM and ESRD) and to those in the control group (ESRD). Thus, extremely elevated serum concentrations of IL-1β, IL-6, IL-10, and TNF-β, as well as the tissue regeneration indicators NT-3 and VEGFβ, were obtained in comparison to all other members of the patient group. At the same time, serum levels of the soluble IL-6 receptor (sIL6-R) and TNFα were greatly reduced compared to the test group's mean. Conclusions: All the data obtained during our research were corroborated with those from the specialized literature and entitle us to support the hypothesis that the cause of these unexpected behaviors is the genetically conditioned overproduction (possibly acquired post-infection) of IL-6, along with its predominant anti-inflammatory and pro-regenerative signaling through the membrane-bound receptor IL-6R.

Keywords: end-stage renal disease; inflammatory cytokines; neurotrophin-3; type 2 diabetes mellitus; vascular endothelial growth factor beta.

Figure 1

Relative abundance of (A) Betaproteobacteria, (B) Gammaproteobacteria, and (C) Enterobacteriaceae in patients with T2DM and ESRD. * p < 0.05, **** p < 0.0001 vs. control; Mann–Whitney test. ESRD, end-stage renal disease; T2DM, type 2 diabetes mellitus [8].

Figure 2

Relative abundance of (A) Clostridium leptum, (B) Clostridium coccoides, and (C) Butyricicoccus in patients with T2DM and ESRD. * p < 0.05 vs. control; Mann–Whitney test. ESRD, end-stage renal disease; T2DM, type 2 diabetes mellitus.

Figure 3

Relative abundance of (A) Aspergillus spp., (B) Saccharomyces spp., and (C) Candida spp. in patients with T2DM and ESRD. * p < 0.05, *** p < 0.0001 vs. control; Mann–Whitney test. ESRD, end-stage renal disease; T2DM, type 2 diabetes mellitus.

Figure 4

The mean value of IL-6 serum levels in the test group vs. the value obtained in the 82-year-old patient (left); the mean value of sIL-6R serum levels in the test group vs. the value obtained in the studied patient (right).

Figure 5

The difference between interleukin 6 (IL-6) and IL-6 soluble receptor (sIL-6R) serum levels.

Figure 6

The mean value of IL-1β serum levels in the test group vs. the value obtained in the 82-year-old patient (left); the mean value of sIL-6R serum levels in the test group vs. the value obtained in the studied patient (right).

Figure 7

The mean value of IL-10 serum levels in the test group vs. the value obtained in the 82-year-old patient (left); the test group’s mean NGAL serum level vs. the value obtained in the studied patient (right).

Figure 8

The extremely high serum level of TNFβ (LTα) in the 82-year-old patient vs. the test group’s mean value.

Figure 9

The mean value of NT-3 serum levels in the test group vs. the value obtained in the 82-year-old patient (left); the mean of the test group’s VEGFβ serum level vs. the value obtained in the studied patient (right).