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Intra-islet glucagon secretion and action in the regulation of glucose homeostasis.

Wang Q, Liang X, Wang S - Front Physiol (2013)

Bottom Line: In diabetes, however, while insulin secretion or action is insufficient, the production and secretion of glucagon are excessive, contributing to the development of diabetic hyperglycemia.Within an islet, intra-islet insulin, in cooperation with intra-islet GABA, suppresses glucagon secretion via direct modulation of α-cell intracellular signaling pathways involving Akt activation, GABA receptor phosphorylation and the receptor plasma membrane translocation, while intra-islet glucagon plays an important role in modulating β-cell function and insulin secretion.Therefore, deciphering the precise molecular mechanisms underlying glucagon secretion and action will facilitate our understanding of glucagon physiology, in particular, its role in regulating islet β-cell function, and hence the mechanisms behind glucose homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology and Metabolism, The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital Toronto, ON, Canada ; Department of Physiology, University of Toronto Toronto, ON, Canada ; Department of Medicine, University of Toronto Toronto, ON, Canada.

ABSTRACT
Glucagon, a key hormone in the regulation of glucose homeostasis, acts as a counter-regulatory hormone to insulin by promoting hepatic glucose output. Under normal conditions, insulin and glucagon operate in concert to maintain the glucose level within a narrow physiological range. In diabetes, however, while insulin secretion or action is insufficient, the production and secretion of glucagon are excessive, contributing to the development of diabetic hyperglycemia. Within an islet, intra-islet insulin, in cooperation with intra-islet GABA, suppresses glucagon secretion via direct modulation of α-cell intracellular signaling pathways involving Akt activation, GABA receptor phosphorylation and the receptor plasma membrane translocation, while intra-islet glucagon plays an important role in modulating β-cell function and insulin secretion. Defects in the insulin-glucagon fine-tuning machinery may result in β-cell glucose incompetence, leading to unsuppressed glucagon secretion and subsequent hyperglycemia, which often occur under extreme conditions of glucose influx or efflux. Therefore, deciphering the precise molecular mechanisms underlying glucagon secretion and action will facilitate our understanding of glucagon physiology, in particular, its role in regulating islet β-cell function, and hence the mechanisms behind glucose homeostasis.

No MeSH data available.


Related in: MedlinePlus

A model shows mechanisms underlying intra-islet hormonal regulation and their impact on liver glucose production. (1) Insulin, incorporation with GABA produced from β-cells suppresses glucagon secretion via membrane hyperpolarization. (2) Glucagon stimulates glucose-competent β-cell secretion and increases α-cell gene transcription via activation of CREB. (3) Glucagon increases its action in the liver on glucose production under glucagon stimulatory conditions. (4) Insulin increases the suppressive effect of insulin on hepatic glucose production by reducing gluconeogenesis and glycogenolysis. Insulin suppresses glucagon secretion via modulating KATP channels and repressing the proglucagon gene, as well as the effects of glucagon and insulin on a variety of organs and tissues are not shown.
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Figure 1: A model shows mechanisms underlying intra-islet hormonal regulation and their impact on liver glucose production. (1) Insulin, incorporation with GABA produced from β-cells suppresses glucagon secretion via membrane hyperpolarization. (2) Glucagon stimulates glucose-competent β-cell secretion and increases α-cell gene transcription via activation of CREB. (3) Glucagon increases its action in the liver on glucose production under glucagon stimulatory conditions. (4) Insulin increases the suppressive effect of insulin on hepatic glucose production by reducing gluconeogenesis and glycogenolysis. Insulin suppresses glucagon secretion via modulating KATP channels and repressing the proglucagon gene, as well as the effects of glucagon and insulin on a variety of organs and tissues are not shown.

Mentions: Activation of α-cell insulin receptor stimulates GABAAR phosphorylation at the β3 subunit, enhancing cell surface expression of the GABAAR and leading to α-cell hyperpolarization and subsequent suppression of glucagon secretion (Xu et al., 2006; Bansal and Wang, 2008) (Figure 1). In cultured clonal α-cells, GABAAR insertion into the plasma membrane is mediated by insulin signaling involving the activation of the PI3K/Akt signaling pathway. In isolated rat islets, treatment with glucose suppressed glucagon secretion, as a result of enhanced intra-islet insulin action on the α-cells; insulin signaling blockage in α-cells diminishes glucose-induced suppression of glucagon secretion (Xu et al., 2006). Therefore, the intra-islet insulin-Akt- GABAAR pathway is critical in the regulation of glucagon secretion and maintaining an appropriate insulin-to-glucagon ratio (Xu et al., 2006), which is essential for keeping the blood glucagon within a normal range. Remarkably, in a cellular model of “insulin resistance,” where high concentrations of glucose and insulin are exposed to α-cells to mimic hyperglycemia and hyperinsulinemia, subsequent applications of insulin fail to increase GABAAR on the cell surface and fail to inhibit glucagon secretion (Xu et al., 2006). These findings provide a molecular mechanism by which glucose-induced suppression of glucagon secretion is mediated by the intra-islet insulin-Akt-GABAAR pathway (Figure 1). Defects in this signaling pathway, referred to as α-cell insulin resistance (Larsson and Ahren, 2000; Xu et al., 2006), appear to be a major contributor to hyperglucagonemia and hyperglycemia in type 2 diabetes. Evidence supporting this notion is consistent with clinical observations that α-cell insulin resistance exaggerates glucagon responses to stimuli in type 2 diabetic patients (Tsuchiyama et al., 2007). This pathway may also provide a mechanistic explanation, at least in part, for hypoglycemia occurring in insulin-treated type 1 diabetic patients. The α-cells of these patients, due to a lack of suppression by endogenous insulin, were rendered hypersensitive to exogenous insulin (Bansal and Wang, 2008).


Intra-islet glucagon secretion and action in the regulation of glucose homeostasis.

Wang Q, Liang X, Wang S - Front Physiol (2013)

A model shows mechanisms underlying intra-islet hormonal regulation and their impact on liver glucose production. (1) Insulin, incorporation with GABA produced from β-cells suppresses glucagon secretion via membrane hyperpolarization. (2) Glucagon stimulates glucose-competent β-cell secretion and increases α-cell gene transcription via activation of CREB. (3) Glucagon increases its action in the liver on glucose production under glucagon stimulatory conditions. (4) Insulin increases the suppressive effect of insulin on hepatic glucose production by reducing gluconeogenesis and glycogenolysis. Insulin suppresses glucagon secretion via modulating KATP channels and repressing the proglucagon gene, as well as the effects of glucagon and insulin on a variety of organs and tissues are not shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539678&req=5

Figure 1: A model shows mechanisms underlying intra-islet hormonal regulation and their impact on liver glucose production. (1) Insulin, incorporation with GABA produced from β-cells suppresses glucagon secretion via membrane hyperpolarization. (2) Glucagon stimulates glucose-competent β-cell secretion and increases α-cell gene transcription via activation of CREB. (3) Glucagon increases its action in the liver on glucose production under glucagon stimulatory conditions. (4) Insulin increases the suppressive effect of insulin on hepatic glucose production by reducing gluconeogenesis and glycogenolysis. Insulin suppresses glucagon secretion via modulating KATP channels and repressing the proglucagon gene, as well as the effects of glucagon and insulin on a variety of organs and tissues are not shown.
Mentions: Activation of α-cell insulin receptor stimulates GABAAR phosphorylation at the β3 subunit, enhancing cell surface expression of the GABAAR and leading to α-cell hyperpolarization and subsequent suppression of glucagon secretion (Xu et al., 2006; Bansal and Wang, 2008) (Figure 1). In cultured clonal α-cells, GABAAR insertion into the plasma membrane is mediated by insulin signaling involving the activation of the PI3K/Akt signaling pathway. In isolated rat islets, treatment with glucose suppressed glucagon secretion, as a result of enhanced intra-islet insulin action on the α-cells; insulin signaling blockage in α-cells diminishes glucose-induced suppression of glucagon secretion (Xu et al., 2006). Therefore, the intra-islet insulin-Akt- GABAAR pathway is critical in the regulation of glucagon secretion and maintaining an appropriate insulin-to-glucagon ratio (Xu et al., 2006), which is essential for keeping the blood glucagon within a normal range. Remarkably, in a cellular model of “insulin resistance,” where high concentrations of glucose and insulin are exposed to α-cells to mimic hyperglycemia and hyperinsulinemia, subsequent applications of insulin fail to increase GABAAR on the cell surface and fail to inhibit glucagon secretion (Xu et al., 2006). These findings provide a molecular mechanism by which glucose-induced suppression of glucagon secretion is mediated by the intra-islet insulin-Akt-GABAAR pathway (Figure 1). Defects in this signaling pathway, referred to as α-cell insulin resistance (Larsson and Ahren, 2000; Xu et al., 2006), appear to be a major contributor to hyperglucagonemia and hyperglycemia in type 2 diabetes. Evidence supporting this notion is consistent with clinical observations that α-cell insulin resistance exaggerates glucagon responses to stimuli in type 2 diabetic patients (Tsuchiyama et al., 2007). This pathway may also provide a mechanistic explanation, at least in part, for hypoglycemia occurring in insulin-treated type 1 diabetic patients. The α-cells of these patients, due to a lack of suppression by endogenous insulin, were rendered hypersensitive to exogenous insulin (Bansal and Wang, 2008).

Bottom Line: In diabetes, however, while insulin secretion or action is insufficient, the production and secretion of glucagon are excessive, contributing to the development of diabetic hyperglycemia.Within an islet, intra-islet insulin, in cooperation with intra-islet GABA, suppresses glucagon secretion via direct modulation of α-cell intracellular signaling pathways involving Akt activation, GABA receptor phosphorylation and the receptor plasma membrane translocation, while intra-islet glucagon plays an important role in modulating β-cell function and insulin secretion.Therefore, deciphering the precise molecular mechanisms underlying glucagon secretion and action will facilitate our understanding of glucagon physiology, in particular, its role in regulating islet β-cell function, and hence the mechanisms behind glucose homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology and Metabolism, The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital Toronto, ON, Canada ; Department of Physiology, University of Toronto Toronto, ON, Canada ; Department of Medicine, University of Toronto Toronto, ON, Canada.

ABSTRACT
Glucagon, a key hormone in the regulation of glucose homeostasis, acts as a counter-regulatory hormone to insulin by promoting hepatic glucose output. Under normal conditions, insulin and glucagon operate in concert to maintain the glucose level within a narrow physiological range. In diabetes, however, while insulin secretion or action is insufficient, the production and secretion of glucagon are excessive, contributing to the development of diabetic hyperglycemia. Within an islet, intra-islet insulin, in cooperation with intra-islet GABA, suppresses glucagon secretion via direct modulation of α-cell intracellular signaling pathways involving Akt activation, GABA receptor phosphorylation and the receptor plasma membrane translocation, while intra-islet glucagon plays an important role in modulating β-cell function and insulin secretion. Defects in the insulin-glucagon fine-tuning machinery may result in β-cell glucose incompetence, leading to unsuppressed glucagon secretion and subsequent hyperglycemia, which often occur under extreme conditions of glucose influx or efflux. Therefore, deciphering the precise molecular mechanisms underlying glucagon secretion and action will facilitate our understanding of glucagon physiology, in particular, its role in regulating islet β-cell function, and hence the mechanisms behind glucose homeostasis.

No MeSH data available.


Related in: MedlinePlus