Signaling cross talk between growth hormone (GH) and insulin-like growth factor-I (IGF-I) in pancreatic islet β-cells

Mol Endocrinol. 2011 Dec;25(12):2119-33. doi: 10.1210/me.2011-1052. Epub 2011 Oct 27.

Abstract

Dysfunction and destruction of pancreatic islet β-cells is a hallmark of diabetes. Better understanding of cell signals regulating β-cell growth and antiapoptosis will allow development of therapeutic strategies for diabetes by preservation and expansion of β-cell mass. GH and IGF-I share a complicated physiological relationship and have both been implicated in β-cell function. GH and IGF-I exert their biological effects through binding to respective receptors (GHR and IGF-IR) and subsequently engaging downstream signaling pathways. However, their collaborative roles in modulation of β-cell mass and the underlying molecular mechanisms remain poorly understood. In this study, we demonstrate that cultured β-cells are appealing systems for investigating potential GH-IGF-I signaling cross talk. We uncover that GH specifically promotes formation of a protein complex containing GHR, Janus kinase 2 (a nonreceptor kinase coupled to GH/GHR signaling), and IGF-IR. More importantly, GH and IGF-I synergistically activate both signal transducer and activator of transcription 5 and Akt pathways. Concomitantly, β-cells proliferate more robustly and are better protected from serum deprivation-induced apoptosis when exposed to GH and IGF-I in combination vs. GH or IGF-I alone. The augmented proliferative effects by GH and IGF-I are confirmed in isolated islets. Taken together, our findings strongly suggest that there exists a novel signaling relationship between GH/GHR and IGF-I/IGF-IR systems in β-cells, i.e. IGF-IR may serve as a proximal component of GH/GHR signaling, contributing to enhancement of β-cell mass and function. In support of this, IGF-IR knockdown in β-cells resulted in the desensitization of acute GH-induced signal transducer and activator of transcription 5 activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Enzyme Activation
  • Gene Knockdown Techniques
  • Growth Hormone / pharmacology
  • Growth Hormone / physiology*
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor I / physiology*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / physiology*
  • Janus Kinase 2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Protein Multimerization
  • RNA Interference
  • Rats
  • Receptor Cross-Talk*
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*
  • Receptors, Somatotropin / metabolism*
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction

Substances

  • Receptors, Somatotropin
  • STAT5 Transcription Factor
  • insulin-like growth factor-1, mouse
  • Insulin-Like Growth Factor I
  • Growth Hormone
  • Receptor, IGF Type 1
  • Jak2 protein, mouse
  • Janus Kinase 2