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.

Pancreatic loss of Mig6 alters murine endocrine cell fate and protects functional beta cell mass in an STZ-induced model of diabetes

“…The regulation of endocrine cell fate and the mechanisms that protect BCM in diabetes remain poorly understood. EGFR signaling stimulates beta cell formation and expansion [9,14,47], and thus has been explored as a therapeutic target for the treatment of diabetes [11,12,48,49]. However, successes in pre-clinical models have failed to translate to human diabetes.…”

“…One beta cell mitogen is epidermal growth factor (EGF). Acting via its cognate receptor, EGFR, the mitogen EGF was found to aid in establishing BCM in rodents [9], and upregulation of EGF/EGFR signaling was associated with beta cell expansion [10][11][12][13][14]. Conversely, inhibition of EGFR has been documented to potentiate beta cell stress and death [15] Thus, in principle activating and sustaining EGFR signaling could be beneficial for fortifying functional BCM.…”

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].…”

A Network Pharmacology Approach to Investigate the Mechanism of Erjing Prescription in Type 2 Diabetes

“…AKT1 was indirectly activated by insulin and other growth factors [36]. Inhibition of EGFR or HB-EGF intercepted the proliferative response to HB-EGF and glucose in rat islets [37]. MiR-133 may be an effective target for the treatment of diabetic nephropathy via the MAPK/ERK pathway [38].…”