Growth factor control of pancreatic islet regeneration and function

Abstract

Type 1 and type 2 diabetes mellitus together are predicted to affect over 300 million people worldwide by the year 2020. A relative or absolute paucity of functional β-cells is a central feature of both types of disease, and identifying the pathways that mediate the embryonic origin of new β-cells and mechanisms that underlie the proliferation of existing β-cells are major efforts in the fields of developmental and islet biology. A poor secretory response of existing β-cells to nutrients and hormones and the defects in hormone processing also contribute to the hyperglycemia observed in type 2 diabetes and has prompted studies aimed at enhancing β-cell function. The factors that contribute to a greater susceptibility in aging individuals to develop diabetes is currently unclear and may be linked to a poor turnover of β-cells and/or enhanced susceptibility of β-cells to apoptosis. This review is an update on the recent work in the areas of islet/β-cell regeneration and hormone processing that are relevant to the pathophysiology of the endocrine pancreas in type 1, type 2 and obesity-associated diabetes.

Figure 1

Regulation of G1/S transition by growth factor (insulin and IGF-I) signaling in β-cells. Knockout mice (black square) or transgenic mice (grey circle) for some genes involved in this signaling pathway have been described to develop diabetes (see details and references in part 2). IGF: insulin-like growth factor; IR: insulin receptor; IGF-IR insulin-like growth factor 1 receptor; IRS: insulin receptor substrate; Akt: v-akt murine thymoma viral oncogene homolog; MDM2: mouse double minute 2; TGF-β: transforming growth factor, beta; Smad: Small mothers against decapentaplegic homolog; GSK3: glycogen synthase kinase 3; FoxO-1: forkhead box O1; FoxM1: forkhead box M1; CDK4: cyclin-dependent kinase 4; Pdx1: pancreatic and duodenal homeobox 1; cmyc: cellular myelocytomatosis oncogene; pRb: retinoblastoma 1; E2F 1/2: E2F transcription factor 1/2;

Figure 2

Schematic Representation of proinsulin processing in pancreatic β-cells. The major pathway (accounting for >90% of processing) is represented in bold fonts. PC1: prohormone convertase 1/3; PC2: prohormone convertase 2; CPH: carboxypeptidease H or E. Arg: Arginine; Lys: Lysine.

Figure 3

Effects of disruption of genes coding for processing enzymes on proinsulin processing. The major phenotypes are described. Block transition is in bold and main intermediate in these mice is circled. PC1: Prohormone convertase 1/3; PC2: Prohormone convertase 2; CPE: carboxypeptidase E or H. IPGTT: intra-peritoneal glucose tolerance test

Figure 4

Schematic representation of proglucagon processing in different tissues. Vertical lines indicate positions of basic amino acids at typical cleavage sites and numbers indicate amino acid positions. GRPP: glicentin related pancreatic polypeptide, IP-1 or 2: Intervening peptide 1 or 2, adapted from (209). R: abbreviation Arginine; K: abbreviation Lysine; PC: Prohormone convertase; CPH or CPE: carboxypeptidase H or E.