Islet prohormone processing in health and disease

Abstract

Biosynthesis of peptide hormones by pancreatic islet endocrine cells is a tightly orchestrated process that is critical for metabolic homeostasis. Like neuroendocrine peptides, insulin and other islet hormones are first synthesized as larger precursor molecules that are processed to their mature secreted products through a series of proteolytic cleavages, mediated by the prohormone convertases Pc1/3 and Pc2, and carboxypeptidase E. Additional posttranslational modifications including C-terminal amidation of the β-cell peptide islet amyloid polypeptide (IAPP) by peptidyl-glycine α-amidating monooxygenase (Pam) may also occur. Genome-wide association studies (GWAS) have showed genetic linkage of these processing enzymes to obesity, β-cell dysfunction, and type 2 diabetes (T2D), pointing to their important roles in metabolism and blood glucose regulation. In both type 1 diabetes (T1D) and T2D, and in the face of metabolic or inflammatory stresses, islet prohormone processing may become impaired; indeed elevated proinsulin:insulin (PI:I) ratios are a hallmark of the β-cell dysfunction in T2D. Recent studies suggest that genetic or acquired defects in proIAPP processing may lead to the production and secretion of incompletely processed forms of proIAPP that could contribute to T2D pathogenesis, and additionally that impaired processing of both PI and proIAPP may be characteristic of β-cell dysfunction in T1D. In islet α-cells, the prohormone proglucagon is normally processed to bioactive glucagon by Pc2 but may express Pc1/3 under certain conditions leading to production of GLP-1(7-36 ). A better understanding of how β-cell processing of PI and proIAPP, as well as α-cell processing of proglucagon, are impacted by genetic susceptibility and in the face of diabetogenic stresses, may lead to new therapeutic approaches for improving islet function in diabetes.

Gut-Proglucagon-Derived Peptides Are Essential for Regulating Glucose Homeostasis in Mice

“…Nevertheless, some (Mojsov et al, 1990), but not all (Galsgaard et al, 2018;Larraufie et al, 2019), studies report small amounts of GLP-1(7-36)amide in the normal rat or mouse pancreas and both pancreatic GLP-1 and Pcsk1 expression were increased in the rat pancreas following induction of experimental diabetes with streptozotocin (Nie et al, 2000). A considerable body of subsequent evidence is now consistent with the production of islet GLP-1 in the context of experimental pancreatic inflammation, diabetes, and aging (Chen et al, 2018;Ellingsgaard et al, 2011;Habener and Stanojevic, 2017). Our current findings further support the concept of pancreatic GLP-1 production by demonstrating low but detectable levels of active GLP-1 in the mouse and human pancreas.…”

The making of insulin in health and disease

“…Next, the exopeptidase carboxypeptidase E/H (CPE) removes the dibasic residues R55-R56 at the C-terminal end of the B chain ( Fig. 1) [70,71]. Although impaired proinsulin conversion with elevated proinsulin secretion is a hallmark of type 2 [73] and type 1 diabetes [74,75], genetic variants affecting the junction between the C-peptide and the A chain, such as replacement of R89 [50] (Fig.…”

Spatial and transcriptional heterogeneity of β-cell neogenesis revealed by a time-resolved reporter system

“…Unbiased annotation revealed six distinct clusters in more differentiated β cells ( Figure 6A, 6B). The trajectory given by Monocle showed one directional development toward GR Scg2 cells expressing Scg2, a member of the chromogranin family, and carboxypeptidase E (Cpe), which is an key enzyme for proinsulin processing ( Figure 6C, 6D) 31 .…”