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Am J Physiol Endocrinol Metab 295: E751-E761, 2008. First published July 22, 2008; doi:10.1152/ajpendo.90295.2008
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Insulin as a physiological modulator of glucagon secretion

Pritpal Bansal1 and Qinghua Wang1,2,3

1Department of Physiology, 2Department of Medicine, and 3Division of Endocrinology and Metabolism, Li Ka-Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada

Submitted 15 March 2008 ; accepted in final form 15 July 2008

ABSTRACT

Glucose homeostasis is regulated primarily by the opposing actions of insulin and glucagon, hormones that are secreted by pancreatic islets from β-cells and {alpha}-cells, respectively. Insulin secretion is increased in response to elevated blood glucose to maintain normoglycemia by stimulating glucose transport in muscle and adipocytes and reducing glucose production by inhibiting gluconeogenesis in the liver. Whereas glucagon secretion is suppressed by hyperglycemia, it is stimulated during hypoglycemia, promoting hepatic glucose production and ultimately raising blood glucose levels. Diabetic hyperglycemia occurs as the result of insufficient insulin secretion from the β-cells and/or lack of insulin action due to peripheral insulin resistance. Remarkably, excessive secretion of glucagon from the {alpha}-cells is also a major contributor to the development of diabetic hyperglycemia. Insulin is a physiological suppressor of glucagon secretion; however, at the cellular and molecular levels, how intraislet insulin exerts its suppressive effect on the {alpha}-cells is not very clear. Although the inhibitory effect of insulin on glucagon gene expression is an important means to regulate glucagon secretion, recent studies suggest that the underlying mechanisms of the intraislet insulin on suppression of glucagon secretion involve the modulation of KATP channel activity and the activation of the GABA-GABAA receptor system. Nevertheless, regulation of glucagon secretion is multifactorial and yet to be fully understood.

diabetes; hyperglycemia; {gamma}-aminobutyric acid; adenosine 5'-triphosphate-sensitive K+ channel

INSULIN AND GLUCAGON ARE PRIMARY ENDOCRINE FACTORS responsible for regulating the blood glucose levels (146). During periods of hyperglycemia (i.e., after meal ingestion), whereas insulin secretion is increased, glucagon secretion is reduced. Insulin promotes anabolism through facilitation of glucose transport in skeletal muscle and adipose tissue and stimulation of hepatic glycogen synthesis (41, 124). Glucagon protects the body against hypoglycemia to maintain an adequate level of blood glucose. This procedure is important particularly during fasting, because glucose is the primary fuel source of the central nervous system (146).

Glucagon Production and Secretion

Glucagon is a 29-amino acid peptide synthesized and secreted by pancreatic {alpha}-cells, which comprise ~20–30% of all islet cells (7, 23). The human proglucagon gene is a 9.4-kb sequence located on chromosome 2 (85), and translation of this gene in the pancreas, gut, and brain creates a precursor peptide (85) that is differentially processed by a set of prohormone covertases, depending on the cell type (70). In the {alpha}-cell, proglucagon is cleaved into glucagon by prohormone convertase 2 (120).

Both the insulin-producing β-cells and the glucagon-secreting {alpha}-cells are electrically excitable; however, each cell type features a unique set of ion channels (72, 89). Unlike in β-cells, {alpha}-cells are electrically silent in the presence of insulin-stimulatory glucose concentrations (56). Regulation of glucagon secretion is mediated by electrical machinery comprised of ion channels and is modulated by glucose and paracrine factors (Fig. 1). The {alpha}-cells contain a large tetrodotoxin (TTX)-sensitive Na+ current that inactivates at intermediate voltages (56, 119) and are equipped with two types, low-voltage activated (T-type) (56, 88) and high-voltage activated (L- or N-type) (11, 56, 88, 89, 95, 104, 156), of voltage-gated Ca2+ channels. T-type Ca2+ channels are partly responsible for initiation of the depolarization cascade that is required to elicit exocytosis (56, 72). Activated by the mild depolarization caused by activation of the T-type Ca2+ channel, the TTX-sensitive Na+ channel continues the depolarization cascade (56) to trigger the influx of Ca2+ ions via either the L-type (56) or N-type Ca2+ channel (55, 59, 95, 104), although in some cases blockade of the L-type Ca2+ channel has no effect on {alpha}-cell secretion (55, 95, 104). In comparison, pancreatic β-cells also express TTX-sensitive Na+ channels (20, 37, 54, 149), but they are half-maximally inactivated at a more negative voltage (Vh = –100 mV) (54, 89) compared with TTX-sensitive Na+ channels in {alpha}-cells (Vh = –47 mV) (56, 89). Mouse β-cells lack low-voltage-activated Ca2+ channels (89) and possess only L-, P/Q-, N-, and R-type Ca2+ channels (149), whereas a recent study using human β-cells found that they lack N- or R-type Ca2+ channels and express the T-type isoform (20). Rat β-cells express T- and L-type Ca2+ channels (6).


Figure 1
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  		Fig. 1. Electrical machinery of glucagon secretion in mouse {alpha}-cells. Glucagon secretion requires the initiation of a full depolarization cascade, which begins when T-type Ca2+ channels are activated and depolarize the cell to an intermediate membrane potential. The tetrodotoxin (TTX)-sensitive Na+ channels then open and allow an influx of Na+ ions to further depolarize the {alpha}-cell, leading to activation of the L- or N-type Ca2+ channels and generation of sustained Ca2+ influx that triggers the glucagon granule exocytosis. The cell membrane is repolarized by the opening of voltage-gated delayed rectifier K+ channels (KDR), and the depolarization cascade recurs (56, 95). The {alpha}-cell ATP-sensitive K+ (KATP) channel activity within a "narrow window" is critical for allowing the operation of this machinery; at low glucose concentrations, a subpopulation of the total number of KATP channels present on the {alpha}-cell is open and sets the membrane potential to –60 mV, causing activation of the T-type Ca2+ channels and subsequent depolarization cascades (56, 95). An elevation in glucose concentration and a rise in the intracellular ATP/ADP ratio results in a closure of the KATP channels (56, 61, 95) that depolarizes the {alpha}-cell membrane potential beyond the narrow window, causing voltage inactivation of ion channels involved in the depolarization cascade. Of note, in the rat {alpha}-cells the ATP/ADP ratio does not increase in high glucose conditions (35), whereas in isolated {alpha}-cells glucose-induced closure of KATP channels stimulates glucagon release (42, 104). Therefore, during hyperglycemia the paracrine modulators (i.e., insulin, Zn2+, and GABA) appear to be predominant in suppressing glucagon secretion presumably through either direct interference of the KATP channel activity (42, 61, 75, 87, 132) or the {alpha}-cell membrane potential (118, 153, 157). [Ca2+]i, intracellular free Ca2+ concentration.

 
Both {alpha}-cells and β-cells possess ATP-sensitive K+ (KATP) channels, which are weakly inwardly rectifying K+ channels that are gated by the intracellular levels of adenosine triphosphate (ATP) (121). The KATP channels set the resting membrane potential of the cell (17, 56, 72) and thus link the metabolic state of a cell to its electrophysiological activity. In the β-cells, a postprandially increased blood glucose concentration enhances glucose metabolism (i.e., increases the [ATP]i) (137). As a result, the KATP channels close, leading to membrane depolarization and subsequent activation of voltage-gated Ca2+ channels (137). The increased Ca2+ entry triggers insulin release (137). Both the {alpha}-cell and β-cell KATP channels are comprised of the SUR1 (sulphonylurea receptor) (138) and Kir6.2 (pore-forming) subunits (17, 138) yet were thought to be operated differently in the {alpha}-cells (61). Interestingly, it has been demonstrated by Olsen et al. (104) that the glucagon secretion pathway in isolated rat {alpha}-cells mimics the stimulus-secretion mechanism in β-cells. In these studies the authors found that prolonged treatment of 20 mM glucose causes closure of KATP channels and stimulates glucagon exocytosis (104). This effect is glycolysis dependent and mimicked by treatment with the KATP channel blocker tolbutamide (104). Similar results were obtained by Franklin et al. (42). Although one must be cautious when interpreting results from experiments on isolated {alpha}-cells because they are removed from any potential paracrine regulation from neighboring β-cells or somatostatin-secreting {delta}-cells, these findings suggest that glucose metabolism and increased ATP production in {alpha}-cells leads to KATP channel closure, {alpha}-cell membrane depolarization, and glucagon secretion (104). However, a biphasic effect of KATP channel activity on glucagon secretion has recently been demonstrated in isolated mouse islets, because low doses of tolbutamide stimulate glucagon secretion (95) while inhibiting glucagon secretion at high concentrations (61, 95). These findings suggest that a certain degree (i.e., narrow window) of {alpha}-cell KATP channel activity sets the {alpha}-cell membrane potential within a range that is critical for the operation of the machinery of glucagon secretion (Fig. 1). Nevertheless, the effects of modulating {alpha}-cell KATP channels are complex and yet to be fully understood. It is clear that the {alpha}-cell must be subject to a regulatory mechanism other than the direct action of glucose (i.e., paracrine or intraislet) to ensure that glucagon secretion is inhibited during hyperglycemia.

Physiological Role of Glucagon

Glucagon exerts a variety of biological actions via the activation of the glucagon receptor, which is a member of a subfamily of G protein-coupled receptors. Glucagon receptors are present in the islet β-cells and a wide array of tissues, including the liver, kidney, adipose tissue, brain, adrenal gland, duodenum, and heart (24). Glucagon has been shown to modulate heart muscle contractility (108), ghrelin secretion (5), and gastrointestinal motility (102), among other actions (Table 1). Most importantly, glucagon protects against hypoglycemia by stimulating net hepatic glucose production through promotion of glycogenolysis and gluconeogenesis and simultaneous inhibition of glycolysis and glycogenolysis (70, 146).


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  		Table 1. Effects of glucagon signaling in various organs

 
Generation of mouse models featuring a whole body knockout of the glucagon receptor gene (Gcgr–/–) has advanced our understanding of glucagon signaling and its roles in the regulation of glucose homeostasis. For instance, Gcgr–/– mice display reduced fasting blood glucose levels and improved glucose tolerance compared with the wild-type mice (50, 106). Interestingly, despite lacking glucagon action, these mice still retain their counterregulatory capacity since their glucose levels could be restored to the basal levels within 60 min during hypoglycemia induced by insulin injection (50). The clear counterregulatory mechanism functioning in the lack of glucagon action has yet to be determined; however, a remarkable increase in basal cAMP signaling in Gcgr–/– liver and enhanced responsiveness to epinephrine in the Gcgr–/– hepatocytes and white adipose tissues might be, in part, responsible for this compensation (50). The presence of marked {alpha}-cell hyperplasia in Gcgr–/– islets also suggests that glucagon signaling is required for the preservation of normal islet cell growth and function (50, 131). These islets also exhibit impaired insulin secretion when treated with insulin secretogogues such as arginine and carbachol, indicating that loss of glucagon signaling may impact the insulin secretion pathway (131). Interestingly, whole body insulin sensitivity in Gcgr–/– mice was enhanced as indicated by hyperinsulinemic euglycemic clamp studies (131), which may represent a compensatory mechanism for a reduction in β-cell function. Furthermore, one such compensatory pathway could be the elevation of glucagon-like peptide 1 (GLP-1) signaling as a consequence of increased production of the hormone by the {alpha}-cells in the face of whole body glucagon resistance (31, 50). GLP-1 is an insulinotropic hormone that exerts a variety of biological actions in mammals, including simulation of insulin secretion, promotion of β-cell growth, improvement of peripheral insulin sensitivity, and moderation of body weight gain (39). It is thus not surprising that the elevated levels of GLP-1 may explain why Gcgr–/– mice are protected against streptozotocin-induced β-cell destruction and high-fat diet-induced obesity (31). However, it is not clear whether the improved action of insulin on glucose clearance in Gcgr–/– mice is a result of direct glucagon action or indirect GLP-1 action on the insulin-sensitive tissues. It is important to note that the remarkable elevation of glucagon levels in the Gcgr–/– mice might have further facilitated the GLP-1 signaling, because glucagon can, although with reduced affinity and efficacy, bind and activate the GLP-1 receptor (32).

Hyperglucagonemia Causes Diabetic Hyperglycemia

Hyperglucagonemia has been established as a major contributor to the development of diabetic hyperglycemia (128, 143). A recent study using mice that were administered glucagon via osmotic minipump for 28 days showed that chronic hyperglucagonemia caused elevated blood glucose levels, impaired glucose tolerance, and glomerular abnormalities (91), symptoms that are representative of early-stage type 2 diabetes. Humans with type 2 diabetes have day-long plasma glucagon concentrations that are higher than normal (116), and this hyperglucagonemia causes inappropriate elevation of hepatic glucose output due to enhanced gluconeogenesis (48) and glycogenolysis (48, 127). Interestingly, clinical studies have demonstrated that challenge with glucagon results only in a transient and small rise in the glucose and insulin levels of healthy individuals (117). However, in insulin-withdrawn diabetes patients, the glycemic response to hyperglucagonemia is five to 15 times greater than in nondiabetic controls (128). These findings suggest that the action of glucagon is diabetogenic only under the conditions of insulin deficiency (117, 128, 143). Studies in human subjects with type 1 diabetes, a disease characterized by insufficient insulin production due to autoimmune destruction of the β-cells, have demonstrated that hyperglucagonemia could develop even after an oral glucose challenge (1, 145). However, administration of exogenous insulin in these patients is able to suppress excessive glucagon secretion induced by hyperglycemia (136) or other stimuli such as arginine (51). Therefore, the insulin action is essential to exert the suppressive effect of glucose on {alpha}-cells since, in its absence, glucose is unable to suppress glucagon release in vivo (58, 64). These studies provide an explanation underlying the observation of unsuppressed glucagon secretion in diabetes despite the presence of hyperglycemia, presumably due to relatively insufficient insulin levels in the internal environment of the islet or as a result of {alpha}-cell insulin resistance (68, 91, 141).

Intraislet Insulin Action on Glucagon Secretion

Actions of insulin are initiated by binding of the hormone to its receptor at the cell surface in insulin-responsive tissues, which activates a signaling complex through recruitment of adaptor molecules, including the insulin receptor substrate family. Upon tyrosine phosphorylation, these proteins interact with signaling molecules through their SH2 domains, which results in the activation of diverse signaling pathways, including phosphatidylinositol (PI) 3-kinase/Akt signaling and MAPK activation. These pathways act in a coordinated manner to regulate glucose transport, protein and lipid synthesis, and mitogenic responses (12).

Within the islets, the {alpha}-cells are major targets of insulin action. Studies on islet microvasculature have suggested that the {alpha}-cells lie downstream from the β-cells and are therefore presumably bathed by high concentrations of insulin (18). It is thought that the islet is arranged such that a core of β-cells is surrounded by a thin layer of {alpha}- and {delta}-cells (7, 18, 25, 84, 105). The directionality of microvascular perfusion within the islet has been investigated in perfused rat (125), dog (134), rhesus monkey (135), and human (133) pancreas by infusing insulin-neutralizing antibodies through the arterial and venous systems of the organ, representing anterograde and retrograde perfusion, respectively. The perfusate was then analyzed for pancreatic hormone secretions, using radioimmunoassays to determine the directional effects of abolishing insulin signaling on {alpha}- and {delta}-cell secretion. These "passive immunization" experiments demonstrated a β -> {alpha} -> {delta} directionality of islet blood flow and strongly suggested that intraislet insulin regulates hormone secretion from {alpha}-cells.

Consistent with an important role for insulin in the {alpha}-cell, insulin receptor and the insulin-signaling molecules are expressed highly in pancreatic {alpha}-cells (13, 71, 77, 107, 147) at levels that are similar to those in the hepatocytes (42). The insulin receptor plays a role in modulating {alpha}-cell function, as siRNA-mediated "knockdown" of the insulin receptor abolishes glucose-regulated glucagon secretion from the {alpha}-cells (36). Action of insulin on suppression of glucagon secretion has been demonstrated directly using cultured clonal glucagon-secreting {alpha}-cell lines, including {alpha}TC6 and In-R1-G9 cells (71, 77, 157). These studies have demonstrated that insulin-induced suppression of glucagon secretion could be blocked by the PI 3-kinase inhibitor wortmannin (71, 157) or ablation of Akt kinase activity using dominant negative approaches (157), suggesting that insulin-suppressed glucagon secretion is mediated by the PI 3-kinase-/Akt-dependent signaling pathway. Although results derived from clonal cell lines may not necessarily be representative of actual {alpha}-cell physiology, insulin also inhibits glucagon secretion in isolated rat islets treated with pyruvate, an intermediate of glycolysis that selectively stimulates glucagon secretion (69). The role of intraislet insulin in suppressing glucagon secretion from the {alpha}-cells has been illustrated further in studies using isolated rat and human islets and islet hormonal RIAs (157). In these studies, challenging islets with 20 mM glucose results in insulin secretion associated with suppressed glucagon secretion; however, blockade of insulin signaling by the PI 3-kinase inhibitor wortmannin prevents glucose from suppressing glucagon secretion, whereas the glucose-stimulated insulin secretion is not affected, indicating that the insulin-signaling pathway mediates the glucose-induced glucagon secretion in the islets (157). Studies in rat pancreata have shown that glucose-induced suppression of glucagon secretion is blocked in the presence of insulin-neutralizing antibodies (96), further supporting the physiological role of insulin in mediating glucose effect on the {alpha}-cells. These findings may provide a mechanism underlying the well-characterized push-pull phenomenon between the secretion of insulin and glucagon in response to glucose challenge (144) (Fig. 2). Thus, it is hypothesized that defects in the intraislet insulin-signaling pathway may contribute to the development of diabetic hyperglucagonemia and hyperglycemia, because {alpha}-cells with insulin resistance imposed by chronic treatment with high glucose and insulin displayed reduced insulin responsiveness, including blunted insulin-stimulated Akt phosphorylation and insulin-suppressed glucagon secretion in the {alpha}-cells (157). Therefore, it is conceivable that the postprandial hyperglucagonemia in type 2 diabetes may be due to the loss of intraislet postprandial suppression of glucagon secretion driven by insulin (144). This hypothesis has recently been verified by in vivo studies using pigs treated with or without alloxan (79, 100), a chemical that selectively destroys β-cells and causes diabetic hyperglycemia. Postprandial insulin secretion induced a suppression of glucagon secretion via inhibition of glucagon pulse mass (100); on the contrary, the postprandial insulin-driven suppression of glucagon secretion was lost in the pigs treated with alloxan, which caused a reduction of β-cell mass and a deficit in postprandial insulin secretion (100). Despite this, it has been shown that glucose can inhibit glucagon secretion at concentrations below that required to elicit insulin secretion (95, 104, 123), indicating that glucose may directly inhibit glucagon secretion in the {alpha}-cells.


Figure 2
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  		Fig. 2. The reciprocal response of insulin ({square}) and glucagon ({circ}) to changes in glucose concentration in the perfused dog pancreas (144). Figure is reproduced from the article by Dr. R. H. Unger (144) with permission from the author.

 
Hypoglycemia is a serious acute complication in type 1 diabetic patients undergoing intensive insulin therapy (33). Defects in glucose counterregulation have been attributed to tonic inhibition of {alpha}-cell activity due to intraislet hyperinsulinemia (9), which prevents a decrement in intraislet insulin during hypoglycemia that would normally act as the switch for {alpha}-cells to secrete glucagon (114). This "switch-off" hypothesis has been supported by studies in rats rendered diabetic via treatment with the β-cell-selective toxin streptozotocin (159) as well as by using isolated rat and human islets (65) and a rat model of spontaneous type 1 diabetes (161). These studies demonstrated that cessation of exogenous insulin administration prior to induction of hypoglycemia produces a glucagon secretory response that would otherwise be absent during continuous insulin infusion (65, 159, 161). A clincal study in nondiabetic humans attributed a 30% decrease in the counterregulatory glucagon response to hypoglycemia after somatostatin infusion was administered to abolish any decrement in intraislet insulin during hypoglycemia (57), indicating that there may be other mechanisms involved in triggering glucagon secretion in humans. However, the specificity of the switch-off hypothesis has become broad, since a recent study has suggested that a decrease in the intraislet concentration of Zn2+ and not insulin is the switch required to trigger glucagon secretion during hypoglycemia in rats (160). The effects of Zn2+ on {alpha}-cell function are discussed later in this review, but these results highlight the importance of β-cell secretory products on {alpha}-cell glucagon secretion.

Intraislet Insulin Modulates {alpha}-Cell KATP Channels

Insulin's action as a negative regulator of glucagon secretion may involve diverse machineries, including modulating the {alpha}-cell KATP channel activity. As mentioned above, glucagon secretion requires {alpha}-cell depolarization to trigger the release of glucagon-containing granules. Conversely, hyperpolarization of the {alpha}-cell as a consequence of KATP channel activation can block glucagon secretion (61). Insulin has been shown to activate KATP channels in hypothalamic neurons in rats (132) and isolated mouse β-cells (75), resulting in membrane hyperpolarization and cessation of electrical activity (75, 132). Interestingly, a recent study showed that, in isolated mouse β-cells, glucose could directly enhance KATP channel conductance by upregulating KATP channel plasma membrane localization (158). Furthermore, it has also been demonstrated that activation of ERK2 enhanced the activity of KATP channels in HEK-293 cells transiently transfected with the KATP channels through phosphorylation of the Kir6.2 subunit, leading to a decrease in ATP sensitivity (92). It is interesting to note that ERK2 is a component in the Ras-MAPK pathway that is activated by insulin (139). Since the Ras-MAPK pathway is PI 3-kinase independent, it is plausible that insulin modulates KATP channel function via PI 3-kinase-dependent and/or -independent pathways.

Treatment of isolated rat {alpha}-cells with insulin can also transiently enhance KATP-mediated currents (42), suggesting that insulin-mediated suppression of glucagon secretion from the {alpha}-cells could occur via modulation of KATP currents. Interestingly, this effect is not blocked by wortmannin (42), which suggests the potential involvement of nonclassical PI 3-kinases in glucagon secretory competence. Studies in transgenic mice expressing green fluorescent protein under the control of the mouse insulin promoter, which facilitates differentiation between β-cells and non-β-cells within the pancreatic islet (89), have characterized the KATP channels in {alpha}-cells to be five times more sensitive to intracellular ATP-mediated channel inhibition than β-cell KATP channels, although the densities of KATP channels found in both cell types are equal (89). In isolated {alpha}-cells from mice expressing insulin promoter-green fluorescent protein, insulin markedly reduces the sensitivity of KATP channels to ATP in a wortmannin-sensitive fashion (87). Interestingly, although glucose can dose-dependently modulate the intracellular [ATP] in the β-cells, glucose has no effect on (35) or increases the intracellular [ATP] less efficiently in {alpha}-cells compared with β-cells (69). Therefore, it is conceivable that glucose-induced suppression of glucagon secretion could occur through insulin-mediated desensitization of {alpha}-cell KATP channels to ATP inhibition, increasing channel activity and causing the {alpha}-cell to become hyperpolarized. It is of great interest to further determine how insulin precisely reduces the {alpha}-cell KATP channel sensitivity and its downstream cascades.

Intraislet Insulin Promotes GABAergic Inhibition of Glucagon Secretion

{gamma}-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian central nervous system and is synthesized from glutamic acid by glutamic acid decarboxylase (82). Three types of the GABA receptor (GABAR) have been identified: type A GABAR (GABAAR), a heteropentameric ligand-gated Cl– channel that is antagonized by the compound bicuculline (93); GABABR, a heterodimeric G protein-coupled receptor (19, 28); and GABACR, which is also a ligand-gated Cl– channel; however, it is bicuculline insensitive, homopentameric, and active at lower concentrations of GABA than GABAAR (28). Activation of GABAAR results in membrane hyperpolarization as a consequence of an inward Cl– flux (78). Although GABAergic signaling is an essential regulatory component of neural excitability accounting for 20–30% of all synaptic signaling in the mammalian brain (154), GABA also modulates the endocrine function of the pancreas (43, 74). Pancreatic β-cells contain high concentrations of GABA (21, 46, 140) and glutamic acid decarboxylase (45, 53). GABA is localized in both synaptic-like microvesicles (21) and the insulin-containing large dense core vesicles (22, 44) within the β-cells. The functional GABAARs are expressed in both {alpha}-cells (63, 118) and β-cells (38).

The GABA-GABAAR system has been suggested to negatively regulate glucagon secretion (118, 153). GABA administered to isolated mouse and rat islets, as well as to perfused rat pancreas, can inhibit the release of glucagon (52), whereas inhibition of the GABAAR by bicuculline (47, 118) or SR95531 (153) prevents GABA-mediated suppression of glucagon secretion from the {alpha}-cells but does not affect the insulin secretion (157). However, although controversial (47), the release of GABA from the β-cells does not appear to be stimulated by glucose (130, 151, 155), or the increase in GABA release by high glucose may be too small to detect (118). However, the failure to detect an increase in GABA release from the β-cells in response to increased glucose concentrations does not exclude the possibility that there is an increase in the responsiveness of GABAARs on {alpha}-cells. Evidence supporting this idea is the finding that GABAARs can be phosphorylated directly by Akt, the important insulin-signaling molecule, resulting in translocation of the receptors from intracellular pools to the cell surface (152). Furthermore, a recent study also suggested that, at postreceptor levels, glucose can modulate GABAAR activity through increasing cell surface abundance of the GABAARs (8). Consistent with the role of insulin in modulating GABAergic signaling in the central nervous system (148, 150, 152), insulin enhances inhibitory GABA currents in clonal glucagon-secreting {alpha}-cells and isolated rat {alpha}-cells upon phosphorylation of the β-subunit of GABAAR and plasma membrane recruitment of the GABAARs by insulin (157). The rapid regulation of neurotransmitter receptor numbers in the postsynaptic domain by direct receptor phosphorylation is an important means of modulating synaptic plasticity (30, 152). Increasing cell surface abundance of GABAARs in pancreatic {alpha}-cells, as a result of direct modulation by glucose or indirectly by insulin, in response to increased glucose concentrations may be a major mechanism underlying glucose-induced suppression of glucagon secretion. This conception is in accord with a recent study using a well-designed in situ patch-clamp recording technique that illustrates that GABA released from the β-cells could diffuse across the islet interstitium to activate GABAARs in neighboring cells (153). It is interesting to note that, in vitro, high glucose concentrations stimulate glucagon secretion from isolated rat {alpha}-cells via the glucose-sensing pathway as used by the β-cells (104), further emphasizing the crucial importance of islet paracrine signaling in the regulation of glucagon release in vivo. The intraislet insulin pathway and these modulators appear to constitute precise regulatory networks that operate to regulate glucagon release and, hence, to control glucose homeostasis. Given that in diabetic individuals, insulin deficiency is associated with elevated glucagon levels, which rapidly return to normal with insulin treatment, it is possible that defects in this pathway may contribute to diabetic hyperglucagonemia and subsequent hyperglycemia. This pathway may also partly explain that type 1 diabetic hypoglycemia that occurs in insulin-treated patients may be due to a lack of suppression by endogenous insulin that may potentially render the {alpha}-cells hypersensitive to the suppression induced by exogenous insulin (9).

Insulin Suppresses Glucagon Gene Expression

Transcriptional regulation of the glucagon gene by insulin appears to be an important way to regulate glucagon production and secretion. The inhibitory effects of insulin on glucagon biosynthesis are mediated through a downregulaton of proglucagon gene expression (29, 109, 110) that requires activation of PI 3-kinase and Akt (126). The insulin response element that mediates insulin effects on glucagon gene transcription is located in the proximal promoter region of the proglucagon gene (111), and several proteins have been identified to act in trans with this region to facilitate insulin-induced transcriptional alterations (49, 111, 126). Furthermore, it has recently been identified that FoxO1, a member of the forkhead transcription factor family, is required for the regulation of proglucagon gene expression by insulin by direct binding of FoxO1 to a forkhead consensus binding site in the preproglucagon gene promoter region (99). In vitro studies in clonal glucagon-secreting cells have demonstrated that insulin induced nuclear exclusion of FoxO1 and a subsequent reduction in proglucagon gene transcription. Experiments employing direct-site mutagenesis and RNA interference have also demonstrated that diminishment of FoxO1 binding eliminated transcriptional regulation by glucose or insulin, whereas FoxO1 silencing abolished the acute regulation by insulin, but not glucose, of glucagon secretion. (99). Therefore, these studies further support that intraislet insulin is a key modulator of {alpha}-cell function. However, this transcriptional regulation may be more critical for long-term maintenance of {alpha}-cell glucagon content instead of for short-term responses to changes in blood glucose levels.

Regulation of Glucagon Secretion is Multifactoral

Although the intraislet insulin-mediated suppression of glucagon secretion plays an important role in modulating glucagon secretion via mechanisms involving protein-protein interactions, signal transduction, receptor translocation, and transcriptional regulation (Fig. 3), it should be noted that factors other than intraislet insulin, such as Zn2+, may also influence glucagon secretion from {alpha}-cells. Insulin molecules are complexed with Zn2+ ions to permit stable storage of insulin within large dense core vesicles (81). Zn2+ is coreleased with insulin from the β-cells (113) and may be an important inhibitor of glucagon secretion (42, 69). Upon liberation, Zn2+ is transported into the {alpha}-cells via Ca2+ channels and Zn2+ transporters (62). Zn2+ has been shown to inhibit pyruvate-stimulated glucagon secretion in perfused rat pancreas (69), reduce the release of glucagon in isolated {alpha}-cells when incubated in the absence of glucose (42), and inhibit glucagon release from {alpha}TC6 cells as well as mouse islets at low glucose concentrations (62). Also, a recent study in rats has found that a decrement in intraislet Zn2+ is required for a normal glucagon secretory response to hypoglycemia (160). Zn2+ may inhibit glucagon secretion by binding directly to two histidine residues on the SUR1 subunit (10) of the KATP channel and enhancing their activity (42, 112), as it has been reported to enhance KATP channel-mediated current in clonal rat β-cells (16); however, studies in mouse {alpha}-cells have shown no effect of Zn2+ on KATP channels (62, 87). These findings potentially explain why ZnCl2 has no effect on intracellular Ca2+ oscillations or glucagon secretion in isolated mouse {alpha}-cells in the absence of glucose (115), since mouse {alpha}-cells express fewer KATP channels than rat {alpha}-cells (11, 115).


Figure 3
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  		Fig. 3. Proposed mechanisms of intraislet insulin suppression of glucagon secretion. Insulin secreted from β-cells acts in a paracrine manner to activate the insulin-signaling cascade in {alpha}-cells. This has 3 main consequences: 1) activation of KATP channels, 2) enhancement of type A GABA receptor (GABAAR)-mediated GABA current, and 3) inhibition of proglucagon gene transcription. First, insulin decreases the {alpha}-cell KATP channel sensitivity to ATP inhibition in a phosphatidylinositol 3-kinase-dependent manner, causing an increase in the efflux of K+ ions from the {alpha}-cell and hyperpolarizing the {alpha}-cell membrane potential. The resultant cessation of action potentials prevents an increase in cytosolic [Ca2+] and inhibits glucagon secretion. Second, activation of the insulin receptor (IR) promotes membrane translocation of GABAAR and enhances GABA-mediated Cl– influx. The {alpha}-cell membrane potential becomes hyperpolarized, and glucagon secretion is suppressed. Finally, insulin inhibits proglucagon gene transcription, possibly representing a long-term mechanism for regulating {alpha}-cell function. Other modulators of {alpha}-cell glucagon secretion, including Zn2+ and somatostatin, are not shown.

 
Furthermore, there are a number of reported regulators/modulators that may participate in the process of glucagon secretion. Among them are sympathetic and parasympathetic nerves (4), somatostatin (27), ghrelin (122), L-glutamate (142), and GLP-1 (97). However, L-glutamate (40, 86) and GLP-1 (103) are also known to stimulate insulin secretion, which suggests that, in vivo, the effects of these molecules on the {alpha}-cells may be indirectly caused by raising intraislet insulin concentrations. For a thorough and up-to-date review of the effects these substances have on {alpha}-cells, refer to Ref. 60.

Conclusion

As a counterregulatory hormone for insulin, glucagon plays a critical role in maintaining glucose homeostasis. Glucagon increases hepatic glucose output by enhancing glycogenolysis and gluconeogenesis in the liver. In diabetic subjects, abnormal secretion of not only insulin but also glucagon leads to hyperglucagonemia and altered insulin-to-glucagon ratios, which predominantly contribute to diabetic hyperglycemia. Given that insulin is a physiological suppressor of glucagon secretion, understanding the precise molecular mechanism of glucagon secretion by intraislet insulin may facilitate our effort to develop strategies to combat diabetic hyperglycemia and to prevent hypoglycemia in insulin-treated patients.

GRANTS

Researchers in Dr. Wang's laboratory are supported by grants from the Canadian Institute for Health Research (CIHR), Canadian Diabetes Association (CDA), and Juvenile Diabetes Research Foundation. Q. Wang was a CDA Scholar and is presently supported by the New Investigator Program from CIHR.

ACKNOWLEDGMENTS

We thank L. Ding, J. Zhang, and Dr. K. Chen for the credit in artwork.

FOOTNOTES


Address for reprint requests and other correspondence: Q. Wang, Dept. of Medicine, Univ. of Toronto, St. Michael's Hospital, 30 Bond St., Rm. 7005, Toronto, ON, Canada M5B 1W8 (e-mail: qinghua.wang{at}utoronto.ca)

REFERENCES

  1. Aguilar-Parada E, Eisentraut AM, Unger RH. Pancreatic glucagon secretion in normal and diabetic subjects. Am J Med Sci 257: 415–419, 1969.[Web of Science][Medline]
  2. Ahloulay M, Dechaux M, Hassler C, Bouby N, Bankir L. Cyclic AMP is a hepatorenal link influencing natriuresis and contributing to glucagon-induced hyperfiltration in rats. J Clin Invest 98: 2251–2258, 1996.[Web of Science][Medline]
  3. Ahloulay M, Dechaux M, Laborde K, Bankir L. Influence of glucagon on GFR and on urea and electrolyte excretion: direct and indirect effects. Am J Physiol Renal Fluid Electrolyte Physiol 269: F225–F235, 1995.[Abstract/Free Full Text]
  4. Ahren B. Autonomic regulation of islet hormone secretion—implications for health and disease. Diabetologia 43: 393–410, 2000.[CrossRef][Web of Science][Medline]
  5. Arafat AM, Perschel FH, Otto B, Weickert MO, Rochlitz H, Schofl C, Spranger J, Mohlig M, Pfeiffer AF. Glucagon suppression of ghrelin secretion is exerted at hypothalamus-pituitary level. J Clin Endocrinol Metab 91: 3528–3533, 2006.[Abstract/Free Full Text]
  6. Ashcroft FM, Rorsman P. Electrophysiology of the pancreatic beta-cell. Prog Biophys Mol Biol 54: 87–143, 1989.[CrossRef][Medline]
  7. Baetens D, Malaisse-Lagae F, Perrelet A, Orci L. Endocrine pancreas: three-dimensional reconstruction shows two types of islets of langerhans. Science 206: 1323–1325, 1979.[Abstract/Free Full Text]
  8. Bailey SJ, Ravier MA, Rutter GA. Glucose-dependent regulation of gamma-aminobutyric acid (GABA A) receptor expression in mouse pancreatic islet alpha-cells. Diabetes 56: 320–327, 2007.[Abstract/Free Full Text]
  9. Banarer S, McGregor VP, Cryer PE. Intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response. Diabetes 51: 958–965, 2002.[Abstract/Free Full Text]
  10. Bancila V, Cens T, Monnier D, Chanson F, Faure C, Dunant Y, Bloc A. Two SUR1-specific histidine residues mandatory for zinc-induced activation of the rat KATP channel. J Biol Chem 280: 8793–8799, 2005.[Abstract/Free Full Text]
  11. Barg S, Galvanovskis J, Gopel SO, Rorsman P, Eliasson L. Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells. Diabetes 49: 1500–1510, 2000.[Abstract]
  12. Bevan P. Insulin signalling. J Cell Sci 114: 1429–1430, 2001.[Abstract/Free Full Text]
  13. Bhathena SJ, Oie HK, Gazdar AF, Voyles NR, Wilkins SD, Recant L. Insulin, glucagon, and somatostatin receptors on cultured cells and clones from rat islet cell tumor. Diabetes 31: 521–531, 1982.[Abstract]
  14. Billington CJ, Bartness TJ, Briggs J, Levine AS, Morley JE. Glucagon stimulation of brown adipose tissue growth and thermogenesis. Am J Physiol Regul Integr Comp Physiol 252: R160–R165, 1987.[Abstract/Free Full Text]
  15. Billington CJ, Briggs JE, Link JG, Levine AS. Glucagon in physiological concentrations stimulates brown fat thermogenesis in vivo. Am J Physiol Regul Integr Comp Physiol 261: R501–R507, 1991.[Abstract/Free Full Text]
  16. Bloc A, Cens T, Cruz H, Dunant Y. Zinc-induced changes in ionic currents of clonal rat pancreatic β-cells: activation of ATP-sensitive K+ channels. J Physiol 529: 723–734, 2000.[Abstract/Free Full Text]
  17. Bokvist K, Olsen HL, Høy M, Gotfredsen CF, Holmes WF, Buschard K, Rorsman P, Gromada J. Characterisation of sulphonylurea and ATP-regulated K+ channels in rat pancreatic A-cells. Pflugers Arch 438: 428–436, 1999.[CrossRef][Web of Science][Medline]
  18. Bonner-Weir S, Orci L. New perspectives on the microvasculature of the islets of Langerhans in the rat. Diabetes 31: 883–889, 1982.[Abstract]
  19. Bowery NG. GABAB receptor: a site of therapeutic benefit. Curr Opin Pharmacol 6: 37–43, 2006.[CrossRef][Web of Science][Medline]
  20. Braun M, Ramracheya R, Bengtsson M, Zhang Q, Karanauskaite J, Partridge C, Johnson PR, Rorsman P. Voltage-gated ion channels in human pancreatic beta-cells: electrophysiological characterization and role in insulin secretion. Diabetes 57: 1618–1628, 2008.[CrossRef][Web of Science][Medline]
  21. Braun M, Wendt A, Birnir B, Broman J, Eliasson L, Galvanovskis J, Gromada J, Mulder H, Rorsman P. Regulated exocytosis of GABA-containing synaptic-like microvesicles in pancreatic beta-cells. J Gen Physiol 123: 191–204, 2004.[Abstract/Free Full Text]
  22. Braun M, Wendt A, Karanauskaite J, Galvanovskis J, Clark A, MacDonald PE, Rorsman P. Corelease and differential exit via the fusion pore of GABA, serotonin, and ATP from LDCV in rat pancreatic beta cells. J Gen Physiol 129: 221–231, 2007.[Abstract/Free Full Text]
  23. Brissova M, Fowler MJ, Nicholson WE, Chu A, Hirshberg B, Harlan DM, Powers AC. Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J Histochem Cytochem 53: 1087–1097, 2005.[Abstract/Free Full Text]
  24. Burcelin R, Li J, Charron MJ. Cloning and sequence analysis of the murine glucagon receptor-encoding gene. Gene 164: 305–310, 1995.[CrossRef][Web of Science][Medline]
  25. Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci USA 103: 2334–2339, 2006.[Abstract/Free Full Text]
  26. Carr-Locke DL, Gregg JA, Aoki TT. Effects of exogenous glucagon on pancreatic and biliary ductal and sphincteric pressures in man demonstrated by endoscopic manometry and correlation with plasma glucagon. Dig Dis Sci 28: 312–320, 1983.[CrossRef][Web of Science][Medline]
  27. Cejvan K, Coy DH, Efendic S. Intra-islet somatostatin regulates glucagon release via type 2 somatostatin receptors in rats. Diabetes 52: 1176–1181, 2003.[Abstract/Free Full Text]
  28. Chebib M, Johnston GA. The ‘ABC’ of GABA receptors: a brief review. Clin Exp Pharmacol Physiol 26: 937–940, 1999.[CrossRef][Web of Science][Medline]
  29. Chen L, Komiya I, Inman L, McCorkle K, Alam T, Unger RH. Molecular and cellular responses of islets during perturbations of glucose homeostasis determined by in situ hybridization histochemistry. Proc Natl Acad Sci USA 86: 1367–1371, 1989.[Abstract/Free Full Text]
  30. Collingridge GL, Isaac JT, Wang YT. Receptor trafficking and synaptic plasticity. Nat Rev Neurosci 5: 952–962, 2004.[CrossRef][Web of Science][Medline]
  31. Conarello SL, Jiang G, Mu J, Li Z, Woods J, Zycband E, Ronan J, Liu F, Roy RS, Zhu L, Charron MJ, Zhang BB. Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia. Diabetologia 50: 142–150, 2007.[CrossRef][Web of Science][Medline]
  32. Creutzfeldt W, Ebert R. The Enteroinsular Axis. In: The Pancreas: Biology, Pathobiology, and Disease, edited by Go VLW, DiMagno EP, Gardner JD, Lebenthal E, Reber HA, and Scheele GA. New York: Raven, 1993, chapt. 40, p. 769–788.
  33. Cryer PE, Fisher JN, Shamoon H. Hypoglycemia. Diabetes Care 17: 734–755, 1994.[Web of Science][Medline]
  34. Delahousse M, Mercier O, Bichara M, Paillard M, Leviel F, Assan R. Glucagon inhibits urinary acidification in the rat. Am J Physiol Renal Fluid Electrolyte Physiol 254: F762–F769, 1988.[Abstract/Free Full Text]
  35. Detimary P, Dejonghe S, Ling Z, Pipeleers D, Schuit F, Henquin JC. The changes in adenine nucleotides measured in glucose-stimulated rodent islets occur in beta cells but not in alpha cells and are also observed in human islets. J Biol Chem 273: 33905–33908, 1998.[Abstract/Free Full Text]
  36. Diao J, Asghar Z, Chan CB, Wheeler MB. Glucose-regulated glucagon secretion requires insulin receptor expression in pancreatic alpha-cells. J Biol Chem 280: 33487–33496, 2005.[Abstract/Free Full Text]
  37. Donatsch P, Lowe DA, Richardson BP, Taylor P. The functional significance of sodium channels in pancreatic beta-cell membranes. J Physiol 267: 357–376, 1977.[Abstract/Free Full Text]
  38. Dong H, Kumar M, Zhang Y, Gyulkhandanyan A, Xiang YY, Ye B, Perrella J, Hyder A, Zhang N, Wheeler M, Lu WY, Wang Q. Gamma-aminobutyric acid up- and downregulates insulin secretion from beta cells in concert with changes in glucose concentration. Diabetologia 49: 697–705, 2006.[CrossRef][Web of Science][Medline]
  39. Drucker DJ. The biology of incretin hormones. Cell Metab 3: 153–165, 2006.[CrossRef][Web of Science][Medline]
  40. Eto K, Yamashita T, Hirose K, Tsubamoto Y, Ainscow EK, Rutter GA, Kimura S, Noda M, Iino M, Kadowaki T. Glucose metabolism and glutamate analog acutely alkalinize pH of insulin secretory vesicles of pancreatic β-cells. Am J Physiol Endocrinol Metab 285: E262–E271, 2003.[Abstract/Free Full Text]
  41. Ferrannini E, Galvan AQ, Gastaldelli A, Camastra S, Sironi AM, Toschi E, Baldi S, Frascerra S, Monzani F, Antonelli A, Nannipieri M, Mari A, Seghieri G, Natali A. Insulin: new roles for an ancient hormone. Eur J Clin Invest 29: 842–852, 1999.[CrossRef][Web of Science][Medline]
  42. Franklin I, Gromada J, Gjinovci A, Theander S, Wollheim CB. Beta-cell secretory products activate alpha-cell ATP-dependent potassium channels to inhibit glucagon release. Diabetes 54: 1808–1815, 2005.[Abstract/Free Full Text]
  43. Franklin IK, Wollheim CB. GABA in the endocrine pancreas: its putative role as an islet cell paracrine-signalling molecule. J Gen Physiol 123: 185–190, 2004.[Free Full Text]
  44. Gammelsaeter R, Froyland M, Aragon C, Danbolt NC, Fortin D, Storm-Mathisen J, Davanger S, Gundersen V. Glycine, GABA and their transporters in pancreatic islets of Langerhans: evidence for a paracrine transmitter interplay. J Cell Sci 117: 3749–3758, 2004.[Abstract/Free Full Text]
  45. Garry DJ, Appel NM, Garry MG, Sorenson RL. Cellular and subcellular immunolocalization of L-glutamate decarboxylase in rat pancreatic islets. J Histochem Cytochem 36: 573–580, 1988.[Abstract]
  46. Garry DJ, Sorenson RL, Elde RP, Maley BE, Madsen A. Immunohistochemical colocalization of GABA and insulin in beta-cells of rat islet. Diabetes 35: 1090–1095, 1986.[Abstract]
  47. Gaskins HR, Baldeon ME, Selassie L, Beverly JL. Glucose modulates gamma-aminobutyric acid release from the pancreatic beta TC6 cell line. J Biol Chem 270: 30286–30289, 1995.[Abstract/Free Full Text]
  48. Gastaldelli A, Baldi S, Pettiti M, Toschi E, Camastra S, Natali A, Landau BR, Ferrannini E. Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study. Diabetes 49: 1367–1373, 2000.[Abstract]
  49. Gauthier BR, Schwitzgebel VM, Zaiko M, Mamin A, Ritz-Laser B, Philippe J. Hepatic nuclear factor-3 (HNF-3 or Foxa2) regulates glucagon gene transcription by binding to the G1 and G2 promoter elements. Mol Endocrinol 16: 170–183, 2002.[Abstract/Free Full Text]
  50. Gelling RW, Du XQ, Dichmann DS, Romer J, Huang H, Cui L, Obici S, Tang B, Holst JJ, Fledelius C, Johansen PB, Rossetti L, Jelicks LA, Serup P, Nishimura E, Charron MJ. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci USA 100: 1438–1443, 2003.[Abstract/Free Full Text]
  51. Gerich JE, Tsalikian E, Lorenzi M, Schneider V, Bohannon NV, Gustafson G, Karam JH. Normalization of fasting hyperglucagonemia and excessive glucagon responses to intravenous arginine in human diabetes mellitus by prolonged infusion of insulin. J Clin Endocrinol Metab 41: 1178–1180, 1975.[Abstract/Free Full Text]
  52. Gilon P, Bertrand G, Loubatieres-Mariani MM, Remacle C, Henquin JC. The influence of gamma-aminobutyric acid on hormone release by the mouse and rat endocrine pancreas. Endocrinology 129: 2521–2529, 1991.[Abstract/Free Full Text]
  53. Gilon P, Tappaz M, Remacle C. Localization of GAD-like immunoreactivity in the pancreas and stomach of the rat and mouse. Histochemistry 96: 355–365, 1991.[CrossRef][Web of Science][Medline]
  54. Gopel S, Kanno T, Barg S, Galvanovskis J, Rorsman P. Voltage-gated and resting membrane currents recorded from B-cells in intact mouse pancreatic islets. J Physiol 521: 717–728, 1999.[Abstract/Free Full Text]
  55. Gopel S, Zhang Q, Eliasson L, Ma XS, Galvanovskis J, Kanno T, Salehi A, Rorsman P. Capacitance measurements of exocytosis in mouse pancreatic alpha-, beta- and delta-cells within intact islets of Langerhans. J Physiol 556: 711–726, 2004.[Abstract/Free Full Text]
  56. Gopel SO, Kanno T, Barg S, Weng XG, Gromada J, Rorsman P. Regulation of glucagon release in mouse alpha-cells by KATP channels and inactivation of TTX-sensitive Na+ channels. J Physiol 528: 509–520, 2000.[Abstract/Free Full Text]
  57. Gosmanov NR, Szoke E, Israelian Z, Smith T, Cryer PE, Gerich JE, Meyer C. Role of the decrement in intraislet insulin for the glucagon response to hypoglycemia in humans. Diabetes Care 28: 1124–1131, 2005.[Abstract/Free Full Text]
  58. Greenbaum CJ, Havel PJ, Taborsky GJ Jr, Klaff LJ. Intra-islet insulin permits glucose to directly suppress pancreatic A cell function. J Clin Invest 88: 767–773, 1991.[Web of Science][Medline]
  59. Gromada J, Bokvist K, Ding WG, Barg S, Buschard K, Renstrom E, Rorsman P. Adrenaline stimulates glucagon secretion in pancreatic A-cells by increasing the Ca2+ current and the number of granules close to the L-type Ca2+ channels. J Gen Physiol 110: 217–228, 1997.[Abstract/Free Full Text]
  60. Gromada J, Franklin I, Wollheim CB. Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev 28: 84–116, 2007.[Abstract/Free Full Text]
  61. Gromada J, Ma X, Hoy M, Bokvist K, Salehi A, Berggren PO, Rorsman P. ATP-sensitive K+ channel-dependent regulation of glucagon release and electrical activity by glucose in wild-type and SUR1–/– mouse alpha-cells. Diabetes 53, Suppl 3: S181–S189, 2004.[Abstract/Free Full Text]
  62. Gyulkhandanyan AV, Lu H, Lee SC, Bhattacharjee A, Wijesekara N, Fox JE, MacDonald PE, Chimienti F, Dai FF, Wheeler MB. Investigation of transport mechanisms and regulation of intracellular Zn2+ in pancreatic alpha-cells. J Biol Chem 283: 10184–10197, 2008.[Abstract/Free Full Text]
  63. Hales TG, Tyndale RF. Few cell lines with GABAA mRNAs have functional receptors. J Neurosci 14: 5429–5436, 1994.[Abstract]
  64. Hamaguchi T, Fukushima H, Uehara M, Wada S, Shirotani T, Kishikawa H, Ichinose K, Yamaguchi K, Shichiri M. Abnormal glucagon response to arginine and its normalization in obese hyperinsulinaemic patients with glucose intolerance: importance of insulin action on pancreatic alpha cells. Diabetologia 34: 801–806, 1991.[CrossRef][Web of Science][Medline]
  65. Hope KM, Tran PO, Zhou H, Oseid E, LeRoy E, Robertson RP. Regulation of alpha-cell function by the beta-cell in isolated human and rat islets deprived of glucose: the "switch-off" hypothesis. Diabetes 53: 1488–1495, 2004.[Abstract/Free Full Text]
  66. Huypens P, Ling Z, Pipeleers D, Schuit F. Glucagon receptors on human islet cells contribute to glucose competence of insulin release. Diabetologia 43: 1012–1019, 2000.[CrossRef][Web of Science][Medline]
  67. Inokuchi A, Oomura Y, Nishimura H. Effect of intracerebroventricularly infused glucagon on feeding behavior. Physiol Behav 33: 397–400, 1984.[CrossRef][Medline]
  68. Ipp E. Impaired glucose tolerance: the irrepressible alpha-cell? Diabetes Care 23: 569–570, 2000.[Free Full Text]
  69. Ishihara H, Maechler P, Gjinovci A, Herrera PL, Wollheim CB. Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells. Nat Cell Biol 5: 330–335, 2003.[CrossRef][Web of Science][Medline]
  70. Jiang G, Zhang BB. Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab 284: E671–E678, 2003.[Abstract/Free Full Text]
  71. Kaneko K, Shirotani T, Araki E, Matsumoto K, Taguchi T, Motoshima H, Yoshizato K, Kishikawa H, Shichiri M. Insulin inhibits glucagon secretion by the activation of PI3-kinase in In-R1-G9 cells. Diabetes Res Clin Pract 44: 83–92, 1999.[CrossRef][Web of Science][Medline]
  72. Kanno T, Gopel SO, Rorsman P, Wakui M. Cellular function in multicellular system for hormone-secretion: electrophysiological aspect of studies on alpha-, beta- and delta-cells of the pancreatic islet. Neurosci Res 42: 79–90, 2002.[CrossRef][Web of Science][Medline]
  73. Katayama T, Shimamoto S, Oda H, Nakahara K, Kangawa K, Murakami N. Glucagon receptor expression and glucagon stimulation of ghrelin secretion in rat stomach. Biochem Biophys Res Commun 357: 865–870, 2007.[CrossRef][Web of Science][Medline]
  74. Kawai Unger RH. Effects of gamma-aminobutyric acid on insulin, glucagon, and somatostatin release from isolated perfused dog pancreas. Endocrinology 113: 111–113, 1983.[Abstract/Free Full Text]
  75. Khan FA, Goforth PB, Zhang M, Satin LS. Insulin activates ATP-sensitive K(+) channels in pancreatic beta-cells through a phosphatidylinositol 3-kinase-dependent pathway. Diabetes 50: 2192–2198, 2001.[Abstract/Free Full Text]
  76. Kirsch JR, D'Alecy LG. Glucagon stimulates ketone utilization by rat brain slices. Stroke 15: 324–328, 1984.[Abstract/Free Full Text]
  77. Kisanuki K, Kishikawa H, Araki E, Shirotani T, Uehara M, Isami S, Ura S, Jinnouchi H, Miyamura N, Shichiri M. Expression of insulin receptor on clonal pancreatic alpha cells and its possible role for insulin-stimulated negative regulation of glucagon secretion. Diabetologia 38: 422–429, 1995.[Web of Science][Medline]
  78. Kittler JT, Moss SJ. Modulation of GABAA receptor activity by phosphorylation and receptor trafficking: implications for the efficacy of synaptic inhibition. Curr Opin Neurobiol 13: 341–347, 2003.[CrossRef][Web of Science][Medline]
  79. Kjems LL, Kirby BM, Welsh EM, Veldhuis JD, Straume M, McIntyre SS, Yang D, Lefebvre P, Butler PC. Decrease in beta-cell mass leads to impaired pulsatile insulin secretion, reduced postprandial hepatic insulin clearance, and relative hyperglucagonemia in the minipig. Diabetes 50: 2001–2012, 2001.[Abstract/Free Full Text]
  80. Kolanowski J, Salvador G, Desmecht P, Henquin JC, Crabbe J. Influence of glucagon on natriuresis and glucose-induced sodium retention in the fasting obese subject. Eur J Clin Invest 7: 167–175, 1977.[CrossRef][Web of Science][Medline]
  81. Kristiansen LH, Rungby J, Sondergaard LG, Stoltenberg M, Danscher G. Autometallography allows ultrastructural monitoring of zinc in the endocrine pancreas. Histochem Cell Biol 115: 125–129, 2001.[CrossRef][Web of Science][Medline]
  82. Krnjevic K. How does a little acronym become a big transmitter? Biochem Pharmacol 68: 1549–1555, 2004.[CrossRef][Web of Science][Medline]
  83. Krzeski R, Czyzyk-Krzeska MF, Trzebski A, Millhorn DE. Centrally administered glucagon stimulates sympathetic nerve activity in rat. Brain Res 504: 297–300, 1989.[CrossRef][Web of Science][Medline]
  84. Ku SK, Lee HS, Lee JH. An immunohistochemical study on the pancreatic endocrine cells of the C57BL/6 mouse. J Vet Sci 3: 327–333, 2002.[Medline]
  85. Lefebvre PJ. Glucagon and its family revisited. Diabetes Care 18: 715–730, 1995.[Web of Science][Medline]
  86. Lehtihet M, Honkanen RE, Sjoholm A. Glutamate inhibits protein phosphatases and promotes insulin exocytosis in pancreatic beta-cells. Biochem Biophys Res Commun 328: 601–607, 2005.[CrossRef][Web of Science][Medline]
  87. Leung YM, Ahmed I, Sheu L, Gao X, Hara M, Tsushima RG, Diamant NE, Gaisano HY. Insulin regulates islet alpha-cell function by reducing KATP channel sensitivity to adenosine 5'-triphosphate inhibition. Endocrinology 147: 2155–2162, 2006.[CrossRef][Web of Science][Medline]
  88. Leung YM, Ahmed I, Sheu L, Tsushima RG, Diamant NE, Gaisano HY. Two populations of pancreatic islet alpha-cells displaying distinct Ca2+ channel properties. Biochem Biophys Res Commun 345: 340–344, 2006.[CrossRef][Web of Science][Medline]
  89. Leung YM, Ahmed I, Sheu L, Tsushima RG, Diamant NE, Hara M, Gaisano HY. Electrophysiological characterization of pancreatic islet cells in the mouse insulin promoter-green fluorescent protein mouse. Endocrinology 146: 4766–4775, 2005.[CrossRef][Web of Science][Medline]
  90. Li XC, Carretero OA, Shao Y, Zhuo JL. Glucagon receptor-mediated extracellular signal-regulated kinase 1/2 phosphorylation in rat mesangial cells: role of protein kinase A and phospholipase C. Hypertension 47: 580–585, 2006.[Abstract/Free Full Text]
  91. Li XC, Liao TD, Zhuo JL. Long-term hyperglucagonaemia induces early metabolic and renal phenotypes of Type 2 diabetes in mice. Clin Sci (Lond) 114: 591–601, 2007.
  92. Lin YF, Chai Y. Functional modulation of the ATP-sensitive potassium channel by extracellular signal-regulated kinase-mediated phosphorylation. Neuroscience 152: 371–380, 2008.[CrossRef][Web of Science][Medline]
  93. Luscher B, Keller CA. Regulation of GABAA receptor trafficking, channel activity, and functional plasticity of inhibitory synapses. Pharmacol Ther 102: 195–221, 2004.[CrossRef][Web of Science][Medline]
  94. Ma X, Zhang Y, Gromada J, Sewing S, Berggren PO, Buschard K, Salehi A, Vikman J, Rorsman P, Eliasson L. Glucagon stimulates exocytosis in mouse and rat pancreatic alpha-cells by binding to glucagon receptors. Mol Endocrinol 19: 198–212, 2005.[Abstract/Free Full Text]
  95. MacDonald PE, De Marinis YZ, Ramracheya R, Salehi A, Ma X, Johnson PR, Cox R, Eliasson L, Rorsman P. A K ATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans. PLoS Biol 5: e143, 2007.[CrossRef][Medline]
  96. Maruyama H, Hisatomi A, Orci L, Grodsky GM, Unger RH. Insulin within islets is a physiologic glucagon release inhibitor. J Clin Invest 74: 2296–2299, 1984.[Web of Science][Medline]
  97. Matsumura T, Itoh H, Watanabe N, Oda Y, Tanaka M, Namba M, Kono N, Matsuyama T, Komatsu R, Matsuzawa Y. Glucagonlike peptide-1(7–36)amide suppresses glucagon secretion and decreases cyclic AMP concentration in cultured In-R1-G9 cells. Biochem Biophys Res Commun 186: 503–508, 1992.[CrossRef][Web of Science][Medline]
  98. Mazzocchi G, Gottardo L, Aragona F, Albertin G, Nussdorfer GG. Glucagon inhibits ACTH-stimulated cortisol secretion from dispersed human adrenocortical cells by activating unidentified receptors negatively coupled with the adenylate cyclase cascade. Horm Metab Res 32: 265–268, 2000.[Web of Science][Medline]
  99. McKinnon CM, Ravier MA, Rutter GA. FoxO1 is required for the regulation of preproglucagon gene expression by insulin in pancreatic alphaTC1–9 cells. J Biol Chem 281: 39358–39369, 2006.[Abstract/Free Full Text]
  100. Meier JJ, Kjems LL, Veldhuis JD, Lefebvre P, Butler PC. Postprandial suppression of glucagon secretion depends on intact pulsatile insulin secretion: further evidence for the intraislet insulin hypothesis. Diabetes 55: 1051–1056, 2006.[Abstract/Free Full Text]
  101. Mercier O, Bichara M, Delahousse M, Prigent A, Leviel F, Paillard M. Effects of glucagon on H+-HCOFormula transport in Henle's loop, distal tubule, and collecting ducts in the rat. Am J Physiol Renal Fluid Electrolyte Physiol 257: F1003–F1014, 1989.[Abstract/Free Full Text]
  102. Mochiki E, Suzuki H, Takenoshita S, Nagamachi Y, Kuwano H, Mizumoto A, Itoh Z. Mechanism of inhibitory effect of glucagon on gastrointestinal motility and cause of side effects of glucagon. J Gastroenterol 33: 835–841, 1998.[CrossRef][Web of Science][Medline]
  103. Mojsov S, Weir GC, Habener JF. Insulinotropin: glucagon-like peptide I (7–37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest 79: 616–619, 1987.[Web of Science][Medline]
  104. Olsen HL, Theander S, Bokvist K, Buschard K, Wollheim CB, Gromada J. Glucose stimulates glucagon release in single rat alpha-cells by mechanisms that mirror the stimulus-secretion coupling in beta-cells. Endocrinology 146: 4861–4870, 2005.[CrossRef][Web of Science][Medline]
  105. Orci L, Unger RH. Functional subdivision of islets of Langerhans and possible role of D cells. Lancet 2: 1243–1244, 1975.[Web of Science][Medline]
  106. Parker JC, Andrews KM, Allen MR, Stock JL, McNeish JD. Glycemic control in mice with targeted disruption of the glucagon receptor gene. Biochem Biophys Res Commun 290: 839–843, 2002.[CrossRef][Web of Science][Medline]
  107. Patel YC, Amherdt M, Orci L. Quantitative electron microscopic autoradiography of insulin, glucagon, and somatostatin binding sites on islets. Science 217: 1155–1156, 1982.[Abstract/Free Full Text]
  108. Peterson CD, Leeder JS, Sterner S. Glucagon therapy for beta-blocker overdose. Drug Intell Clin Pharm 18: 394–398, 1984.[Abstract]
  109. Philippe J. Insulin regulation of the glucagon gene is mediated by an insulin-responsive DNA element. Proc Natl Acad Sci USA 88: 7224–7227, 1991.[Abstract/Free Full Text]
  110. Philippe J. Glucagon gene transcription is negatively regulated by insulin in a hamster islet cell line. J Clin Invest 84: 672–677, 1989.[Web of Science][Medline]
  111. Philippe J, Morel C, Cordier-Bussat M. Islet-specific proteins interact with the insulin-response element of the glucagon gene. J Biol Chem 270: 3039–3045, 1995.[Abstract/Free Full Text]
  112. Prost AL, Bloc A, Hussy N, Derand R, Vivaudou M. Zinc is both an intracellular and extracellular regulator of KATP channel function. J Physiol 559: 157–167, 2004.[Abstract/Free Full Text]
  113. Qian WJ, Aspinwall CA, Battiste MA, Kennedy RT. Detection of secretion from single pancreatic beta-cells using extracellular fluorogenic reactions and confocal fluorescence microscopy. Anal Chem 72: 711–717, 2000.[Medline]
  114. Raju B, Cryer PE. Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans. Diabetes 54: 757–764, 2005.[Abstract/Free Full Text]
  115. Ravier MA, Rutter GA. Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic alpha-cells. Diabetes 54: 1789–1797, 2005.[Abstract/Free Full Text]
  116. Reaven GM, Chen YD, Golay A, Swislocki AL, Jaspan JB. Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 64: 106–110, 1987.[Abstract/Free Full Text]
  117. Rizza R, Verdonk C, Miles J, Service FJ, Gerich J. Effect of intermittent endogenous hyperglucagonemia on glucose homeostasis in normal and diabetic man. J Clin Invest 63: 1119–1123, 1979.[CrossRef][Web of Science][Medline]
  118. Rorsman P, Berggren PO, Bokvist K, Ericson H, Mohler H, Ostenson CG, Smith PA. Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels. Nature 341: 233–236, 1989.[CrossRef][Web of Science][Medline]
  119. Rorsman P, Hellman B. Voltage-activated currents in guinea pig pancreatic alpha 2 cells. Evidence for Ca2+-dependent action potentials. J Gen Physiol 91: 223–242, 1988.[Abstract/Free Full Text]
  120. Rouille Y, Kantengwa S, Irminger JC, Halban PA. Role of the prohormone convertase PC3 in the processing of proglucagon to glucagon-like peptide 1. J Biol Chem 272: 32810–32816, 1997.[Abstract/Free Full Text]
  121. Sakura H, Ammala C, Smith PA, Gribble FM, Ashcroft FM. Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel subunit expressed in pancreatic beta-cells, brain, heart and skeletal muscle. FEBS Lett 377: 338–344, 1995.[CrossRef][Web of Science][Medline]
  122. Salehi A, Dornonville de la Cour C, Håkanson R, Lundquist I. Effects of ghrelin on insulin and glucagon secretion: a study of isolated pancreatic islets and intact mice. Regul Pept 118: 143–150, 2004.[CrossRef][Web of Science][Medline]
  123. Salehi A, Vieira E, Gylfe E. Paradoxical stimulation of glucagon secretion by high glucose concentrations. Diabetes 55: 2318–2323, 2006.[Abstract/Free Full Text]
  124. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414: 799–806, 2001.[CrossRef][Web of Science][Medline]
  125. Samols E, Stagner JI, Ewart RB, Marks V. The order of islet microvascular cellular perfusion is B—A—D in the perfused rat pancreas. J Clin Invest 82: 350–353, 1988.[Web of Science][Medline]
  126. Schinner S, Barthel A, Dellas C, Grzeskowiak R, Sharma SK, Oetjen E, Blume R, Knepel W. Protein kinase B activity is sufficient to mimic the effect of insulin on glucagon gene transcription. J Biol Chem 280: 7369–7376, 2005.[Abstract/Free Full Text]
  127. Shah P, Vella A, Basu A, Basu R, Schwenk WF, Rizza RA. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 85: 4053–4059, 2000.[Abstract/Free Full Text]
  128. Sherwin RS, Fisher M, Hendler R, Felig P. Hyperglucagonemia and blood glucose regulation in normal, obese and diabetic subjects. N Engl J Med 294: 455–461, 1976.[Abstract]
  129. Shimatsu A, Kato Y, Matsushita N, Ohta H, Kabayama Y, Imura H. Glucagon-induced somatostatin release from perifused rat hypothalamus: calcium dependency and effect of cysteamine treatment. Neurosci Lett 37: 285–289, 1983.[CrossRef][Web of Science][Medline]
  130. Smismans A, Schuit F, Pipeleers D. Nutrient regulation of gamma-aminobutyric acid release from islet beta cells. Diabetologia 40: 1411–1415, 1997.[CrossRef][Web of Science][Medline]
  131. Sorensen H, Winzell MS, Brand CL, Fosgerau K, Gelling RW, Nishimura E, Ahren B. Glucagon receptor knockout mice display increased insulin sensitivity and impaired beta-cell function. Diabetes 55: 3463–3469, 2006.[Abstract/Free Full Text]
  132. Spanswick D, Smith MA, Mirshamsi S, Routh VH, Ashford ML. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci 3: 757–758, 2000.[CrossRef][Web of Science][Medline]
  133. Stagner JI, Samols E. The vascular order of islet cellular perfusion in the human pancreas. Diabetes 41: 93–97, 1992.[Abstract]
  134. Stagner JI, Samols E, Bonner-Weir S. Beta—alpha—delta pancreatic islet cellular perfusion in dogs. Diabetes 37: 1715–1721, 1988.[Abstract]
  135. Stagner JI, Samols E, Koerker DJ, Goodner CJ. Perfusion with anti-insulin gamma globulin indicates a B to A to D cellular perfusion sequence in the pancreas of the rhesus monkey, Macaca mulatta. Pancreas 7: 26–29, 1992.[Web of Science][Medline]
  136. Starke A, Imamura T, Unger RH. Relationship of glucagon suppression by insulin and somatostatin to the ambient glucose concentration. J Clin Invest 79: 20–24, 1987.[Web of Science][Medline]
  137. Straub SG, Sharp GW. Glucose-stimulated signaling pathways in biphasic insulin secretion. Diabetes Metab Res Rev 18: 451–463, 2002.[CrossRef][Web of Science][Medline]
  138. Suzuki M, Fujikura K, Inagaki N, Seino S, Takata K. Localization of the ATP-sensitive K+ channel subunit Kir6.2 in mouse pancreas. Diabetes 46: 1440–1444, 1997.[Abstract]
  139. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7: 85–96, 2006.[CrossRef][Web of Science][Medline]
  140. Taniguchi H, Okada Y, Seguchi H, Shimada C, Seki M, Tsutou A, Baba S. High concentration of gamma-aminobutyric acid in pancreatic beta cells. Diabetes 28: 629–633, 1979.[Abstract]
  141. Tsuchiyama N, Takamura T, Ando H, Sakurai M, Shimizu A, Kato K, Kurita S, Kaneko S. Possible role of alpha-cell insulin resistance in exaggerated glucagon responses to arginine in type 2 diabetes. Diabetes Care 30: 2583–2587, 2007.[Abstract/Free Full Text]
  142. Uehara S, Muroyama A, Echigo N, Morimoto R, Otsuka M, Yatsushiro S, Moriyama Y. Metabotropic glutamate receptor type 4 is involved in autoinhibitory cascade for glucagon secretion by alpha-cells of islet of Langerhans. Diabetes 53: 998–1006, 2004.[Abstract/Free Full Text]
  143. Unger RH. Role of glucagon in the pathogenesis of diabetes: the status of the controversy. Metabolism 27: 1691–1709, 1978.[CrossRef][Web of Science][Medline]
  144. Unger RH. Glucagon physiology and pathophysiology in the light of new advances. Diabetologia 28: 574–578, 1985.[Web of Science][Medline]
  145. Unger RH, Aguilar-Parada E, Muller WA, Eisentraut AM. Studies of pancreatic alpha cell function in normal and diabetic subjects. J Clin Invest 49: 837–848, 1970.[Web of Science][Medline]
  146. Unger RH, Orci L. Physiology and pathophysiology of glucagon. Physiol Rev 56: 778–826, 1976.[Free Full Text]
  147. Velloso LA, Carneiro EM, Crepaldi SC, Boschero AC, Saad MJ. Glucose- and insulin-induced phosphorylation of the insulin receptor and its primary substrates IRS-1 and IRS-2 in rat pancreatic islets. FEBS Lett 377: 353–357, 1995.[CrossRef][Web of Science][Medline]
  148. Vetiska SM, Ahmadian G, Ju W, Liu L, Wymann MP, Wang YT. GABAA receptor-associated phosphoinositide 3-kinase is required for insulin-induced recruitment of postsynaptic GABAA receptors. Neuropharmacology 52: 146–155, 2007.[CrossRef][Web of Science][Medline]
  149. Vignali S, Leiss V, Karl R, Hofmann F, Welling A. Characterization of voltage-dependent sodium and calcium channels in mouse pancreatic A- and B-cells. J Physiol 572: 691–706, 2006.[Abstract/Free Full Text]
  150. Wan Q, Xiong ZG, Man HY, Ackerley CA, Braunton J, Lu WY, Becker LE, MacDonald JF, Wang YT. Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature 388: 686–690, 1997.[CrossRef][Web of Science][Medline]
  151. Wang C, Kerckhofs K, Van de Casteele M, Smolders I, Pipeleers D, Ling Z. Glucose inhibits GABA release by pancreatic β-cells through an increase in GABA shunt activity. Am J Physiol Endocrinol Metab 290: E494–E499, 2006.[Abstract/Free Full Text]
  152. Wang Q, Liu L, Pei L, Ju W, Ahmadian G, Lu J, Wang Y, Liu F, Wang YT. Control of synaptic strength, a novel function of Akt. Neuron 38: 915–928, 2003.[CrossRef][Web of Science][Medline]
  153. Wendt A, Birnir B, Buschard K, Gromada J, Salehi A, Sewing S, Rorsman P, Braun M. Glucose inhibition of glucagon secretion from rat alpha-cells is mediated by GABA released from neighboring beta-cells. Diabetes 53: 1038–1045, 2004.[Abstract/Free Full Text]
  154. Whiting PJ, Bonnert TP, McKernan RM, Farrar S, Le BB, Heavens RP, Smith DW, Hewson L, Rigby MR, Sirinathsinghji DJ, Thompson SA, Wafford KA. Molecular and functional diversity of the expanding GABA-A receptor gene family. Ann NY Acad Sci 868: 645–653, 1999.[CrossRef][Web of Science][Medline]
  155. Winnock F, Ling Z, De Proft R, Dejonghe S, Schuit F, Gorus F, Pipeleers D. Correlation between GABA release from rat islet β-cells and their metabolic state. Am J Physiol Endocrinol Metab 282: E937–E942, 2002.[Abstract/Free Full Text]
  156. Xia F, Leung YM, Gaisano G, Gao X, Chen Y, Fox JE, Bhattacharjee A, Wheeler MB, Gaisano HY, Tsushima RG. Targeting of voltage-gated K+ and Ca2+ channels and soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins to cholesterol-rich lipid rafts in pancreatic alpha-cells: effects on glucagon stimulus-secretion coupling. Endocrinology 148: 2157–2167, 2007.[CrossRef][Web of Science][Medline]
  157. Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, Liu S, Wendt A, Deng S, Ebina Y, Wheeler MB, Braun M, Wang Q. Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system. Cell Metab 3: 47–58, 2006.[CrossRef][Web of Science][Medline]
  158. Yang SN, Wenna ND, Yu J, Yang G, Qiu H, Yu L, Juntti-Berggren L, Kohler M, Berggren PO. Glucose recruits K(ATP) channels via non-insulin-containing dense-core granules. Cell Metab 6: 217–228, 2007.[CrossRef][Web of Science][Medline]
  159. Zhou H, Tran PO, Yang S, Zhang T, LeRoy E, Oseid E, Robertson RP. Regulation of alpha-cell function by the beta-cell during hypoglycemia in Wistar rats: the "switch-off" hypothesis. Diabetes 53: 1482–1487, 2004.[Abstract/Free Full Text]
  160. Zhou H, Zhang T, Harmon JS, Bryan J, Robertson RP. Zinc, not insulin, regulates the rat alpha-cell response to hypoglycemia in vivo. Diabetes 56: 1107–1112, 2007.[CrossRef][Web of Science][Medline]
  161. Zhou H, Zhang T, Oseid E, Harmon J, Tonooka N, Robertson RP. Reversal of defective glucagon responses to hypoglycemia in insulin-dependent autoimmune diabetic BB rats. Endocrinology 148: 2863–2869, 2007.[CrossRef][Web of Science][Medline]



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