The balance between proinsulin biosynthesis and insulin secretion: where can imbalance lead?
Insulin is stored in pancreatic beta-cells in beta-granules. Whenever insulin is secreted in response to a nutrient secretagogue, there is a complementary increase in proinsulin biosynthesis to replenish intracellular insulin stores. This specific nutrient regulation of proinsulin biosynthesis is predominately regulated at the translational level. Recently, a highly conserved cis-element in the 5'-untranslated region (UTR) of preproinsulin mRNA, named ppIGE, has been identified that is required for specific translational regulation of proinsulin biosynthesis. This ppIGE is also found in the 5'-UTR of certain other translationally regulated beta-granule protein mRNAs, including the proinsulin processing endopeptidases, PC1/3 and PC2. This provides a mechanism whereby proinsulin processing is adaptable to changes in proinsulin biosynthesis. However, relatively few beta-granules undergo secretion, with most remaining in the storage pool for approximately 5 days. Aged beta-granules are retired by intracellular degradation mechanisms, either via crinophagy and/or autophagy, as another long-term means of maintaining beta-granule stores at optimal levels. When a disconnection between insulin production and secretion arises, as may occur in type 2 diabetes, autophagy further increases to maintain beta-granule numbers. However, if this increased autophagy becomes chronic, autophagia-mediated cell death occurs that could then contribute to beta-cell loss in type 2 diabetes.
Uchizono
Y
Y
Comprehensive Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, The University of Chicago, Chicago, IL 60637, USA.
Alarcón
C
C
Wicksteed
B L
BL
Marsh
B J
BJ
Rhodes
C J
CJ
D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D011384:Proinsulin / Q000096:biosynthesis*; D045664:Proprotein Convertase 1 / Q000378:metabolism; D045706:Proprotein Convertase 2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D007328:Insulin; D012333:RNA, Messenger; D011384:Proinsulin; D045664:Proprotein Convertase 1; D045706:Proprotein Convertase 2