title: Proinsulin maturation disorder is a contributor to the defect of subsequent conversion to insulin in β-cells.
abstract: Disproportionate hyperproinsulinemia is an indicator of β-cell dysfunction in diabetes and the basis underlying this abnormality remains obscure. Recently, we have found proinsulin is an aggregation-prone molecule inherent with a low relative folding rate and maintains a homeostatic balance of natively and plentiful non-natively folded states (i.e., proinsulin homeostasis, PIHO) in normal β-cells as a result of the integration of maturation and disposal processes. PIHO is susceptible to environmental and genetic influences. Perturbation of PIHO produces a number of toxic consequences with known association to β-cell failure in diabetes. To explore whether the perturbation of PIHO has a link to disproportionate hyperproinsulinemia, we investigated proinsulin conversion and the involved prohormone convertase 1/3 (PC1/3) and 2 (PC2) in mouse Ins2(+/Akita) islets/β-cells that preserve a primary PIHO disorder due to a mutation (C96Y) in the insulin 2 (Ins2) gene. Our metabolic-labeling studies found an increased ratio of proinsulin to insulin in the cellular or released proteins of Ins2(+/Akita) islets. Histological, metabolic-labeling, and RT-PCR analyses revealed decreases of the PC1/3 and PC2 immunoreactivities in the β-cells of Ins2(+/Akita) islets in spite of no declines of these two convertases at the transcriptional and translational levels. Immunoblot analyses in cloned Ins2(+/Akita) β-cells further confirmed the increased ratio of proinsulin to insulin despite the levels of PC1/3 and PC2 proteins were not reduced somehow. The findings demonstrate that the perturbation of PIHO results in defects in the subsequent conversion process of proinsulin and is a contributor to the occurrence of disproportionate hyperproinsulinemia in diabetes.
authors: Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA. jie.wang2@osumc.edu
authors: Jie
authors: J
authors: Wang
authors: Kwame
authors: K
authors: Osei
mesh_terms: D000818:Animals; D006946:Hyperinsulinism / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011384:Proinsulin / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D011384:Proinsulin