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REVIEW
Physiology of the pancreatic a-cell and glucagon secretion: role in
glucose homeostasis and diabetes
ngel Nadal
Ivan Quesada, Eva Tudur, Cristina Ripoll and A
CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM) and Instituto de Bioingeniera, Universidad Miguel Hernandez, Avenida de la
Universidad s/n, 03202 Elche, Spain
(Correspondence should be addressed to I Quesada; Email: ivanq@umh.es)
Abstract
The secretion of glucagon by pancreatic a-cells plays a critical
role in the regulation of glycaemia. This hormone counteracts
hypoglycaemia and opposes insulin actions by stimulating
hepatic glucose synthesis and mobilization, thereby increasing
blood glucose concentrations. During the last decade,
knowledge of a-cell physiology has greatly improved,
especially concerning molecular and cellular mechanisms.
In this review, we have addressed recent findings on a-cell
physiology and the regulation of ion channels, electrical
activity, calcium signals and glucagon release. Our focus in
this review has been the multiple control levels that modulate
Introduction
DOI: 10.1677/JOE-08-0290
Online version via http://www.endocrinology-journals.org
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Figure 3 Paracrine signalling in the a-cell. See text for details. ADCY, adenylate cyclase; AMPA-R,
a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; GABA, g-aminobutyric acid;
GLP1, glucagon-like peptide-1; GRM, metabotrophic glutamate receptor; PKA, protein kinase A;
SSTR2, somatostatin receptor-2.
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Glucagon receptor
Glucagon physiological and pathophysiological
actions and its role in diabetes
Glucagon synthesis
The preproglucagon-derived peptides glucagon, GLP1 and
GLP2, are encoded by the preproglucagon gene, which is
expressed in the central nervous system, intestinal L-cells and
pancreatic a-cells. A post-translational cleavage by prohormone convertases (PC) is responsible for the maturation of
the preproglucagon hormone that generates all these peptides
(Mojsov et al. 1986). The different expression of PC subtypes
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Figure 4 The role of glucagon and the glucagon receptor in the liver. Glucagon signalling regulates positively (C) or
negatively (K) the multiple steps of the hepatic glucose metabolism. This modulation affects the expression and/or the
activity of several enzymes of glucose metabolism. See text for details. ADCY, Adenylate cyclase; CREB, cAMP response
element binding; F(1,6)P2, fructose-1,6-bisphosphate; F(2,6)P2, fructose-2,6-bisphosphate; F-6-P, fructose 6-phosphate;
FBP1, fructose-1,6-bisphosphatase; FBP2, fructose-2,6-bisphosphatase; G-1-P, glucose 1-phosphate; G-6-P, glucose
6-phosphate; G6PC, glucose-6-phosphatase; GP, glycogen phosphorylase; GS, glycogen synthase; IP3, inositol
1,4,5-trisphosphate; OAA, oxaloacetate; PC, pyruvate carboxylase; PEP, phosphoenolpyruvate; PCK2, phosphoenolpyruvate carboxykinase; PFKM, phosphofructokinase-1; PPARGC1A, peroxisome proliferators-activated receptor-g
coactivator-1; PIP2, phosphatidylinositol 4,5-bisphosphate; PKLR, pyruvate kinase; PLC, phospholipase C; Pyr, pyruvate.
Dashed lines: red, inhibition; blue, stimulation.
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Conclusions
Pancreatic a-cells and glucagon secretion are fundamental
components of the regulatory mechanisms that control glucose
homeostasis. However, a-cell physiology has remained elusive
compared with the overwhelming information about insulin
secretion and the b-cell. In recent years, however, several groups
have initiated intensive efforts to understand a-cell physiology
and identified essential pieces of its stimulus-secretion coupling.
Additionally, important aspects of the regulation of a-cell
metabolism and the control of glucagon expression are being
elucidated. All of this information will favour an overall
comprehension of the a-cell function and its role in glucose
homeostasis. Nevertheless, more research is required to understand the a-cell behaviour, not only in healthy subjects but in
pathological conditions as well. In conclusion, since the
malfunction of the glucagon secretory response is involved in
diabetes and its complications, a complete understanding of the
a-cell will allow for a better design of therapeutic approaches for
the treatment of this disease.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived
as prejudicing the impartiality of the research reported.
Funding
This work was supported by grants from the Ministerio de Educacion y
Ciencia (BFU2007-67607 and PCI2005-A7-0131 to I Q; BFU2005-01052
to A N). CIBERDEM is an initiative of the Instituto de Salud Carlos III.
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