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Activin B receptor ALK7 is a negative regulator of pancreatic beta-cell function

Philippe Bertolino1, Rebecka Holmberg, Eva Reissmann

  • 1Division of Molecular Neurobiology, Department of Neuroscience, Karolinska Institutet, S-17177 Stockholm, Sweden.

Proceedings of the National Academy of Sciences of the United States of America
|May 16, 2008
PubMed

Insights

Mice lacking the ALK7 receptor developed hyperinsulinemia and impaired glucose tolerance, indicating ALK7 negatively regulates insulin secretion. Activin B signaling through ALK7 is crucial for controlling pancreatic islet function.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Signaling

Background:

  • The transforming growth factor (TGF)-beta superfamily receptor ALK7 is expressed in pancreatic islets, but its physiological role remains unclear.
  • Understanding ALK7's function is crucial for deciphering pancreatic islet regulation and potential therapeutic targets for metabolic disorders.

Purpose of the Study:

  • To investigate the physiological function of the ALK7 receptor in pancreatic islets.
  • To elucidate the role of ALK7 in regulating insulin secretion and glucose homeostasis.

Main Methods:

  • Utilized mutant mice lacking the ALK7 receptor (Alk7-/-) to study age-dependent metabolic phenotypes.
  • Analyzed insulin secretion, glucose tolerance, liver steatosis, and islet morphology in wild-type and mutant mice.
  • Investigated the effects of activins A and B on calcium (Ca2+) signaling in islet cells.

Main Results:

  • Alk7-/- mice exhibited progressive hyperinsulinemia, reduced insulin sensitivity, liver steatosis, impaired glucose tolerance, and islet enlargement.
  • Mutant islets demonstrated enhanced insulin secretion under sustained glucose stimulation, suggesting ALK7 negatively regulates this process.
  • Activin B, but not activin A, signaling through ALK7 was found to decrease glucose-stimulated Ca2+ influx in beta-cells, while activin A increased it, revealing an antagonism.

Conclusions:

  • ALK7 negatively regulates glucose-stimulated insulin secretion in pancreatic beta-cells, primarily by mediating the inhibitory effects of activin B on Ca2+ signaling.
  • The ALK7-activin B pathway plays a significant role in maintaining functional plasticity and homeostasis within pancreatic islets.
  • Dysregulation of the ALK7-activin B pathway may contribute to the pathogenesis of metabolic disorders characterized by hyperinsulinemia and impaired glucose tolerance.

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