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Fisiología en la secreción de glucagón

Fisiología en la secreción de glucagón

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REVIEWPhysiology of the pancreatic
a
-cell and glucagon secretion: role inglucose homeostasis and diabetes
Ivan Quesada, Eva Tudurı´, Cristina Ripoll
and
A´ngel Nadal
CIBER de Diabetes y Enfermedades Metabo´licas Asociadas (CIBERDEM) and Instituto de Bioingenierı´a, Universidad Miguel Herna´ndez, Avenida de laUniversidad 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 criticalrole in the regulation of glycaemia. This hormone counteractshypoglycaemia and opposes insulin actions by stimulatinghepatic glucose synthesis and mobilization, thereby increasingblood 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
-cellphysiology and the regulation of ion channels, electricalactivity, calcium signals and glucagon release. Our focus inthis review has been the multiple control levels that modulateglucagon secretion from glucose and nutrients to paracrineand neural inputs. Additionally, we have described theglucagon actions on glycaemia and energy metabolism, anddiscussed their involvement in the pathophysiology of diabetes. Finally, some of the present approaches for diabetestherapy related to
a
-cell function are also discussed in thisreview. A better understanding of the
a
-cell physiology isnecessary for an integral comprehension of the regulation of glucose homeostasis and the development of diabetes.
 Journal of Endocrinology 
(2008)
199,
5–19
Introduction
The principal level of control on glycaemia by the isletof Langerhans depends largely on the coordinatedsecretion of glucagon and insulin by
a
- and
b
-cellsrespectively. Both cell types respond oppositely to changesin blood glucose concentration: while hypoglycaemicconditions induce
a
-cell secretion,
b
-cells release insulinwhen glucose levels increase (Nadal
a
). Insulin and glucagon have opposite effectson glycaemia as well as on the metabolism of nutrients.Insulin acts mainly on muscle, liver and adipose tissuewith an anabolic effect, inducing the incorporationof glucose into these tissues and its accumulation asglycogen and fat. By contrast, glucagon induces acatabolic effect, mainly by activating liver glycogenolysisand gluconeogenesis, which results in the release of glucose to the bloodstream. An abnormal functionof these cells can generate failures in the control of glycaemia, which can lead to the development of diabetes(Dunning
. 2005). Actually, diabetes is associated withdisorders in the normal levels of both insulin andglucagon. An excess of glucagon plasma levels relativeto those of insulin can be determinant in the higher rate of hepatic glucose output, which seems to be criticalin maintaining hyperglycaemia in diabetic patients(Dunning
. 2005).Despite the importance of the
a
-cell and glucagonsecretion in the regulation of glycaemia and nutrienthomeostasis, little is known about the physiology of thesecells compared with the overwhelming information about
b
-cells. Several factors may explain this lack of informationabout glucagon secretion. First, the scarcity of this cellpopulation in islets of animal models such as mice and ratsalong with several technical limitations of conventionalmethods have made it more difficult to study
a
-cells than
b
-cells (Quoix
. 2007). Second, the lack of functionalidentification patterns has also been an important limitation in
a
-cell research. However, in recent years notable progress hasbeen made in the study of 
a
-cell function at the cellular andmolecular levels. This review attempts to describe recentadvances in
a
-cell physiology and the regulation of glucagonsecretion. Additionally, it focuses on the pathophysiology of these cells, their role in diabetes, as well as potentialtherapeutic strategies.
5
 Journal of Endocrinology 
(2008)
199,
519 DOI:10.1677/JOE-08-02900022–0795/08/0199–005
q
2008 Society for Endocrinology
Printed in Great Britain 
Online version via http://www.endocrinology-journals.org
 
Islet of Langerhans: cell architecture and function
Glucagon-secreting
a
-cells are one of the main endocrinecell populations that coexist in the islet of Langerhans alongwith insulin-secreting
b
-cells. The islet is further composedby other scarce secretory populations such as
d
- and poly-peptide releasing (PP)-cells, which release somatostatin andpancreatic polypeptide respectively. This multicellulastructure constitutes the endocrine unit of the pancreas andis responsible for the regulation of blood glucose homeostasis.Approximately one million islets are distributed throughout ahealthy adult human pancreas, representing 1 and 2% of thetotal mass of the organ. Each islet, with sizes varying from100 to 500
m
m, is made up of 1000–3000 cells. In mouseand rat islets,
b
-cells are the main population accounting for 60–80% of the total number of cells, while 15–20% are
a
-cells,
!
10% are
d
-cells and less than 1% correspond to thePP-cell population (Brelje
. 2005).The architecture of rodent islets is characterized by thelocation of 
b
-cells in the core and the non-
b
cells distributedin a mantle around the insulin-secreting cell population. Thiscellular distribution along with several studies on micro-circulation within the islet suggests that the order of paracrine interactions is from
b
- to
a
- and
d
-cells(Bonner-Weir 1991). The rich vascularization within the islet ensures a rapid sensing of plasma glucose levels by theseendocrine cells, allowing an appropriate secretory response.In human islets, however, there are important differencesin composition and spatial organization compared withrodents (Cabrera
. 2006). While the proportion of 
d
- andPP-cells are similar in the human islet,
b
-cells are lessabundant (48–59%) and the
a
-cell population reaches a33–46%, suggesting that glucagon secretion plays a majorole in humans (Cabrera
. 2006). These islet cellpopulations show a random distribution pattern, where themajority of 
b
-cells are in contact with non-
b
-cells,suggesting that paracrine interactions among differentpopulations may be more active (Cabrera
. 2006).Another divergence between human and rodent islets is theintercellular communication among the different populations.In mice,
b
-cells work as a syncytium in terms of electricalactivity and Ca
2
C
signalling due to the high level of couplingmediated by gap junctions of connexin36 (Gopel
. 2003). This coupling favoursa more vigorous insulin secretion (Vozzi
. 1995). Bycontrast, coupling can be found between several human
b
-cells in clusters within the same islet but not in the whole
b
-cell population (Quesada
b
). This kind of intercellular communication is probably the result of thehuman islet cytoarchitecture and its functional meaning isstill unknown (Cabrera
. 2006). Unlike
b
-cells,
a
- and
d
-cells from rodents and humans are not functionally coupledand work as independent units. In addition to nutrientsand paracrine signals, islet function is further regulated bysympathetic, parasympathetic and sensory nerves that godeeply into the islet (Ahren 2000). Thus, multiple regulationlevels determine hormone release from pancreatic islets.
Glucagon secretion by pancreatic
a
-cells
Stimulus-secretion coupling in
a
-cells: from ion channel activity toexocytosis
Pancreatic
a
-cells are equipped with a specific set of channelsthat generate action potentials of Na
C
and Ca
2
C
in theabsence or at low levels of glucose (Gromada
. 1997). Thiselectrical activity triggers Ca
2
C
signals and glucagonsecretion. Elevated glucose concentrations inhibit all theseevents. ATP-dependent K
C
(K
ATP
) channels play a funda-mental role in
a
-cells, such as they do in
b
-cells, since theycouple variations in extracellular glucose concentrations tochanges in membrane potential and electrical activity. Inintact rat
a
-cells, K
ATP
channels have a lower ATP sensitivity(
i
Z
0
.
94 mM) than the one observed in excised patches(
i
Z
16
m
. 2007), but avery similar one to the values recorded in mouse and rat intact
b
-cells. However, K
ATP
channels exhibit a higher ATPsensitivity in intact mouse
a
-cells (
i
Z
0
.
16 mM;Leung
.2005). Consequently, lower ATP concentrations are requiredto obtain the maximal inhibition of K
ATP
conductancecompared with mouse
b
-cells. Recent evidence has indicatedthat the densities of these channels are similar in mouse
a
- and
b
-cells (Leung
. 2005). The repolarization of actionpotentials is mediated by voltage-dependent K
C
channels.While delayed rectifying K
C
channels have been demon-strated in rat, mouse and guinea pig
a
-cells, a tetraethy-lammonium-resistant voltage-dependent K
C
current(A-current) has only been identified in mice (Barg
. 2005). Furthermore, tetrodotoxin-sensitiveNa
C
currents are fundamental for the generation of actionpotentials in these cells. Na
C
channels areactivated at voltagesabove
K
30 to
K
20 mV (Gopel
. 2000), and theiblockade by tetradotoxin leads to the inhibition of glucagonsecretion (Gromada
. 2007). Additionally,
a
-cells have a heterogeneouspresence of Ca
2
C
channel subtypes with different roles.While L and N channels have been reported in rat
a
-cells(Gromada
. 1997), mouse
a
-cells express L-, T-, N- andprobably R-type Ca
2
C
channels (Gopel
. 2007).The low voltage-activated T-type channels work as pace-makers in the initiation of action potentials in mice (Gopel
. 2000). They open around
K
60 mV, the action potentialinitiation threshold in
a
-cells. The high voltage-activated Land N channels open during action potentials when themembrane potential exceeds
K
40 to
K
30 mV. Althoughmost of the Ca
2
C
current goes through L-type channels in
a
-cells, the Ca
2
C
required forexocytosis at low-glucose levelsis mediated by N-type channels, and their blockade by
u
-conotoxin-GVIA inhibits glucagon secretion in these
I QUESADA
and others
.
Regulation of 
a
-cell and glucagon secretion 
6
 Journal of Endocrinology 
(2008)
199,
519 www.endocrinology-journals.org
 
conditions (Gromada
. 2007). However, in the presence of cAMP-elevating agents, L channels are the major conduit for Ca
2
C
. 1997).A model to explain the glucose regulation of electricalactivity in mouse
a
-cells has been postulated in the light of recent studies (Fig. 1). At low-glucose levels, the activity of K
ATP
channels renders a membrane potential of about
K
60 mV. At this voltage, T-type channels open, whichdepolarize the membrane potential to levels where Na
C
andN-type Ca
2
C
channels are activated, leading to regenerativeaction potentials (Gromada
.2007). Ca
2
C
entry through N-type channels inducesglucagon secretion. The repolarization of action potentialsis mediated by the flowing of K
C
A-currents. At low-glucoseconcentrations, this electrical activity triggers oscillatoryCa
2
C
signals in both human and mouse
a
-cells in intactislets (Nadal
b
;Fig. 2).However, the increase in extracellular glucose levels rises thecytosolic ATP/ADP ratio which blocks K
ATP
channels,depolarizing
a
-cells to a membrane potential range wherethe channels involved in action potentials become inactivated(Gromada
. 2007). As aconsequence, electrical activity, Ca
2
C
signals and glucagonsecretion are inhibited (Figs 1 and 2). Thus, glucagon releasefrom
a
-cells is mainly supported by an intermediate K
ATP
channel activity that maintains a membrane potential rangeable to sustain regenerative electrical activity (MacDonald
.2007). A similar model has been also proposed for human
a
-cells (MacDonald
. 2007). Nevertheless, this schemehas been argued by some reports indicating that glucose maybe hyperpolarizing rather than depolarizing (Liu
. 2006). It has also been proposed thatglucose would inhibit glucagon secretion by suppressinga depolarizing Ca
2
C
store-operated current independentof K
ATP
channels (Liu
. 2007).In rat
a
-cells, the activity of K
ATP
channels at low-glucoseconcentrations also keeps the membrane potential at about
K
60 mV, where spontaneous Na
C
and Ca
2
C
actionpotentials are produced (Gromada
. 1997). However, incontrast to the situation in mice, the stimulus-secretioncoupling in rat
a
-cells is similar to that of 
b
-cells. That is,elevations of extracellular glucose levels increase theintracellular ATP/ADP ratio, blocking K
ATP
channels anddepolarizing the membrane potential, which stimulates Ca
2
C
Figure 1
Schematic model for glucose-dependent regulation of glucagon secretion in the mouse
a
-cell. Glucose is incorporatedinto the
a
-cell by the transporter SLC2A1. At low-glucoseconcentrations, the moderate activity of K
ATP
channels situates the
a
-cell membrane potential in a range that allows the opening of voltage-dependent T- and N-type Ca
2
C
channels and voltage-dependent Na
C
channels. Their activation triggers actionpotentials, Ca
2
C
influx and exocytosis of glucagon granules. Theopening of A-type K
C
channels is necessary for action potentialrepolarization. However, high-glucose concentrations elevate theintracellular ATP/ADP ratio, blocking K
ATP
channels and depolar-izing the membrane potential to a range where the inactivation of voltage-dependent channels takes place. This results in theinhibitionof electricalactivity, Ca
2
C
influxand glucagon secretion.The function of L-type channels predominates when cAMP levelsare elevated. See text for further details.
Figure 2
Opposite Ca
2
C
signalling patterns in
a
- and
b
-cells inresponse to glucose. At low-glucose concentrations (0
.
5 mM),electrical activity triggers oscillatory Ca
2
C
signals in
a
-cells thatlead to glucagon release. Elevation of glucose levels (11 mM)inhibits all these events. By contrast, 11 mM glucose stimulateCa
2
C
signalling and insulin secretion in
b
-cells. Both fluorescencerecords were obtained by confocal microscopy from two cellswithin an intact mouse islet. Inset shows a thin optical section(
w
6
m
m) of a mouse islet loaded with the Ca
2
C
-sensitivefluorescent probe Fluo-3.
Regulation of 
a
-cell and glucagon secretion 
.
I QUESADA
and others 7
www.endocrinology-journals.org
Journal of Endocrinology 
(2008)
199,
5–19

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