Up until recently, the prevailing dogma was that insulin secretion ceased within a couple of years after the diagnosis of type I diabetes, a clinical time period called the honeymoon. But a series of recent studies have established that release of C-peptide, which is the best measure of endogenous insulin production, can commonly persist for decades after disease onset. The release of C-peptide, even at low levels, is shown to have functional and clinical significance. For example, C-peptide levels >10 pmol/l are associated with fewer diabetes complications, id est, nephropathy, neuropathy, foot ulcers, and retinopathy. The diabetic population may also be heterogeneous in risk for fall in C-peptide, with early age of diabetes onset a risk factor for more rapid C-peptide decline. The persistence of insulin release for decades and its functional and clinical significance suggest that assays for C-peptide should be a regular part of diabetes management. Furthermore, patients with established diabetes should be eligible to participate in clinical trials of immune therapies since preservation of these low levels appears clinically important to prevent complications.

Abstract: TNF is a multifunctional cytokine involved in autoimmune disease pathogenesis that exerts its effects through two distinct TNF receptors, TNFR1 and TNFR2. While TNF- and TNFR1-deficient (but not TNFR2-deficient) mice show very similar phenotypes, the significance of TNFR2 signaling in health and disease remains incompletely understood. Recent studies implicated the importance of the TNF/TNFR2 axis in T regulatory (Treg) cell functions. To definitively ascertain the significance of TNFR2 signaling, we generated and validated doubly humanized TNF/TNFR2 mice, with the option of conditional inactivation of TNFR2. These mice carry a functional human TNF-TNFR2 (hTNF-hTNFR2) signaling module and provide a useful tool for comparative evaluation of TNF-directed biologics. Conditional inactivation of TNFR2 in FoxP3+ cells in doubly humanized TNF/TNFR2 mice down-regulated the expression of Treg signature molecules (such as FoxP3, CD25, CTLA-4, and GITR) and diminished Treg suppressive function in vitro. Consequently, Treg-restricted TNFR2 deficiency led to significant exacerbation of experimental autoimmune encephalomyelitis (EAE), accompanied by reduced capacity to control Th17-mediated immune responses. Our findings expose the intrinsic and beneficial effects of TNFR2 signaling in Treg cells that could translate into protective functions in vivo, including treatment of autoimmunity