INS and type 1 diabetes mellitus: As the expression and secretion of MANF has been reported to increase under ER-stress, elevated serum MANF level at the onset of T1D may reflect ER stress in the remaining β-cells, strained with increased demand for insulin production due to reduced β-cell mass27 in a chronically hyperglycemic environment, an aspect further impairing insulin secretion and causing increasing ER-stress28.