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Horm Metab Res 2004; 36(11/12): 787-794
DOI: 10.1055/s-2004-826165
Original
© Georg Thieme Verlag KG Stuttgart · New York

New Insights Concerning the Glucose-dependent Insulin Secretagogue Action of Glucagon-like Peptide-1 in Pancreatic β-Cells

G.  Holz1
  • 1 Department of Physiology and Neuroscience, New York University School of Medicine, USA
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Publikationsverlauf

Received 7 July 2004

Accepted after revision 18 August 2004

Publikationsdatum:
18. Januar 2005 (online)

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Erratum zu diesem Artikel:

New Insights Concerning the Glucose-dependent Insulin Secretagogue Action of Glucagon-like Peptide-1 in Pancreatic β-CellsHorm Metab Res 2005; 37(02): 126
DOI: 10.1055/s-2005-861314

Abstract

The GLP-1 receptor is a Class B heptahelical G-protein-coupled receptor that stimulates cAMP production in pancreatic β-cells. GLP-1 utilizes this receptor to activate two distinct classes of cAMP-binding proteins: protein kinase A (PKA) and the Epac family of cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs). Actions of GLP-1 mediated by PKA and Epac include the recruitment and priming of secretory granules, thereby increasing the number of granules available for Ca2+-dependent exocytosis. Simultaneously, GLP-1 promotes Ca2+ influx and mobilizes an intracellular source of Ca2+. GLP-1 sensitizes intracellular Ca2+ release channels (ryanodine and IP3 receptors) to stimulatory effects of Ca2+, thereby promoting Ca2+-induced Ca2+ release (CICR). In the model presented here, CICR activates mitochondrial dehydrogenases, thereby upregulating glucose-dependent production of ATP. The resultant increase in cytosolic [ATP]/[ADP] concentration ratio leads to closure of ATP-sensitive K+ channels (K-ATP), membrane depolarization, and influx of Ca2+ through voltage-dependent Ca2+ channels (VDCCs). Ca2+ influx stimulates exocytosis of secretory granules by promoting their fusion with the plasma membrane. Under conditions where Ca2+ release channels are sensitized by GLP-1, Ca2+ influx also stimulates CICR, generating an additional round of ATP production and K-ATP channel closure. In the absence of glucose, no ”fuel” is available to support ATP production, and GLP-1 fails to stimulate insulin secretion. This new ”feed-forward” hypothesis of β-cell stimulus-secretion coupling may provide a mechanistic explanation as to how GLP-1 exerts a beneficial blood glucose-lowering effect in type 2 diabetic subjects.

Key words

Glucose · GLP-1 · cAMP · PKA · Epac · Insulin secretion

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G. G. Holz, Ph. D.

Associate Professor · Department of Physiology and Neuroscience

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