Increased circulating concentrations of mesencephalic astrocyte-derived neurotrophic factor in children with type 1 diabetes

Abstract

Mesencephalic astrocyte-derived neurotrophic factor (MANF) was recently shown to be essential for the survival and proliferation of pancreatic β-cells in mice, where deletion of MANF resulted in diabetes. The current study aimed at determining whether the concentration of circulating MANF is associated with the clinical manifestation of human type 1 diabetes (T1D). MANF expression in T1D or MANF levels in serum have not been previously studied. We developed an enzyme-linked immunosorbent assay (ELISA) for MANF and measured serum MANF concentrations from 186 newly diagnosed children and adolescents and 20 adults with longer-term T1D alongside with age-matched controls. In healthy controls the mean serum MANF concentration was 7.0 ng/ml. High MANF concentrations were found in children 1–9 years of age close to the diagnosis of T1D. The increased MANF concentrations were not associated with diabetes-predictive autoantibodies and autoantibodies against MANF were extremely rare. Patients with conspicuously high MANF serum concentrations had lower C-peptide levels compared to patients with moderate MANF concentrations. Our data indicate that increased MANF concentrations in serum are associated with the clinical manifestation of T1D in children, but the exact mechanism behind the increase remains elusive.

Circulating mesencephalic astrocyte-derived neurotrophic factor is increased in newly diagnosed prediabetic and diabetic patients, and is associated with insulin resistance

“…In contrast, MANF deficiency leads to progressive loss of β-cell, thereby resulting in diabetes mellitus due to reduced β-cell proliferation and enhanced β-cell apoptosis. Furthermore, it was reported that increased circulating MANF levels were associated with the clinical manifestation of type 1 diabetes in children 1-9 years of age [14]. These results suggest that MANF is regulated by ER stress and is involved in the pathogenesis of diabetes.…”

MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

“…Although MANF was not completely deleted from all pancreatic b-cells in MIP-1Cre ERT ::Manf fl/fl (TMX) mice, we demonstrate that lack of MANF in the adult b-cells results in reduced expression of b-cell-specific genes and poor b-cell survival and proliferation, leading to hyperglycemia and diabetes. The above results strongly argue against a systemic effect of circulating MANF in rescuing b-cells and clearly demonstrates that local expression of MANF is required to maintain the b-cell phenotype in mice (56,57). Furthermore, MANF expression in pancreatic exocrine acinar cells did not protect MANF-deficient adult b-cells.…”

High fat diet disrupts endoplasmic reticulum calcium homeostasis in the rat liver

“…MANF is an ER-localized protein that is secreted upon ER stress [33] and implicated as a marker and therapeutic of neurodegeneration [34–36]. Recently MANF’s potential as a disease biomarker has been investigated in both type I diabetes and kidney disease [37, 38]. Both found increased levels of MANF in serum and urine in disease-associated samples, respectively.…”