HB-EGF Signaling Is Required for Glucose-Induced Pancreatic β-Cell Proliferation in Rats

Abstract

The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced β-cell proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) in the β-cell proliferative response to glucose, a β-cell mitogen and key regulator of β-cell mass in response to increased insulin demand. We show that exposure of isolated rat and human islets to HB-EGF stimulates β-cell proliferation. In rat islets, inhibition of EGFR or HB-EGF blocks the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in rat islets blocks β-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels are increased in β-cells in response to glucose in a carbohydrate-response element–binding protein (ChREBP)–dependent manner. In addition, chromatin immunoprecipitation studies identified ChREBP binding sites in proximity to the HB-EGF gene. Finally, inhibition of Src family kinases, known to be involved in HB-EGF processing, abrogated glucose-induced β-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in β-cell compensation to increased metabolic demand.

Pronounced proliferation of non-beta cells in response to beta-cell mitogens in isolated human islets of Langerhans

“…We recently demonstrated that the EGF receptor ligand HB-EGF exerts mitogenic activity on human β cells 22 . In the present study we substantiated these findings by showing that β cells proliferate in response to HB-EGF in the majority of human islet batches in both intact and dispersed islets.…”

“…Unfortunately, our knowledge of the factors controlling human β-cell proliferation is much more limited 13 – 15 . Although human β cells respond to glucose 16 – 18 , fatty acids 12 , serpinB1 7 , dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitors including harmine 19 – 21 , and heparin-binding epidermal growth factor-like growth factor (HB-EGF) 22 , proliferation rates are very low compared to rodents and published data on the efficacy of human β-cell mitogens are often highly variable 23 .…”

Multi-Omics Data Analysis Uncovers Molecular Networks and Gene Regulators for Metabolic Biomarkers

“…Further, high levels of TG, high levels of low-density lipoprotein, and low levels of HDL were found in patients with T2DM [ 50 , 51 , 52 ]. One unique pathway involved, EGFR signaling, has been implicated in glucose homeostasis by regulating beta-cell proliferation in response to increased metabolic demand [ 53 ]. Notably, EGFR signaling is associated with IGF-IR expression and IGF-I secretion in cancer cells [ 54 , 55 ], contributing to cancer cell growth and poor survival; thus, dual targeting at EGFR and the IGF/IR axis has been suggested to be a promising therapeutic strategy for overcoming drug-acquired resistance in several cancer types, such as lung adenocarcinoma, head and neck squamous cell and colorectal carcinomas, and glioblastoma [ 55 , 56 , 57 , 58 ].…”

Associations of myeloperoxidase, interleukin-17A and heparin-binding EGF-like growth factor levels with in-stent restenosis after percutaneous coronary intervention: a single-centre case–control study in China

“…No analysis was made specifically in patients with and without diabetes. Nevertheless, there is already a wealth of literature about the close correlation between those biomarkers and diabetes [37][38][39][40][41][42][43] and between diabetes and ISR. [44][45][46][47][48] Additional studies are required to evaluate the precise molecular roles of MPO, IL-17A and HB-EGF in ISR.…”