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Glucose-dependent insulinotropic polypeptide signaling in pancreatic β-cells and adipocytes.

McIntosh CH, Widenmaier S, Kim SJ - J Diabetes Investig (2012)

Bottom Line: Recent studies have shown that inhibition of the kinase apoptosis signal-regulating kinase 1 (ASK1) by GIP plays a key role in reducing mitochondria-induced apoptosis in β-cells through protein kinase B (PKB)-mediated pathways, and that GIP-induced post-translational modification of voltage- dependent K(+) (Kv) channels also contributes to its prosurvival role.Through regulation of gene expression, GIP tips the balance between pro- and anti-apoptotic members of the B-cell lymphoma-2 (Bcl-2) protein family towards β-cell survival.GIP also plays important roles in the differentiation of pre-adipocytes to adipocytes, and in the regulation of lipoprotein lipase expression and lipogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Physiological Sciences and the Diabetes Research Group, Life Sciences Institute University of British Columbia, Vancouver, BC, Canada.

ABSTRACT
Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin to be identified. In addition to stimulating insulin secretion, GIP plays regulatory roles in the maintenance, growth and survival of pancreatic islets, as well as impacting on adipocyte function. The current review focuses on the intracellular signaling pathways by which GIP contributes to the regulation of β-cell secretion and survival, and adipocyte differentiation and lipogenesis. Studies on signaling underlying the insulinotropic actions of the incretin hormones have largely been carried out with glucagon-like peptide-1. They have provided evidence for contributions by both protein kinase A (PKA) and exchange protein directly activated by cyclic adenosine monophosphate (EPAC2), and their probable role in GIP signaling is discussed. Recent studies have shown that inhibition of the kinase apoptosis signal-regulating kinase 1 (ASK1) by GIP plays a key role in reducing mitochondria-induced apoptosis in β-cells through protein kinase B (PKB)-mediated pathways, and that GIP-induced post-translational modification of voltage- dependent K(+) (Kv) channels also contributes to its prosurvival role. Through regulation of gene expression, GIP tips the balance between pro- and anti-apoptotic members of the B-cell lymphoma-2 (Bcl-2) protein family towards β-cell survival. GIP also plays important roles in the differentiation of pre-adipocytes to adipocytes, and in the regulation of lipoprotein lipase expression and lipogenesis. These events involve interactions between GIP, insulin and resistin signaling pathways. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00196.x, 2012).

No MeSH data available.


Related in: MedlinePlus

 Signaling pathways proposed to be involved in proximal events in glucose‐dependent insulinotropic polypeptide (GIP)‐mediated potentiation of glucose‐induced insulin secretion. (a) Evidence has been presented supporting roles for both protein kinase A (PKA) and cyclic adenosine monophosphate (cAMP)‐activated guanine nucleotide exchange factor (cAMP‐GEF)/exchange protein directly activated by cAMP (Epac) in the modulation of adenosine triphosphate (ATP)‐sensitive K+ (KATP) channels. Dissociation of cAMP‐Epac2 from sulfonulurea receptor 1 (SUR1) binding has been proposed to activate phospholipase C‐ε (PLCε) through Ras‐related protein 1 (Rap1), resulting in phosphatidylinositol 4,5 bisphosphate (PIP2) metabolism and inhibition of adenosine triphosphate‐sensitive channel subunit, Kir6.2, membrane depolarization and activation of voltage‐dependent Ca2+ channels (VDCC). (b) Diacylglycerol‐activated PKCε potentiates calcium‐induced calcium release through ryanodine receptors and phosphatidylinositol trisphosphate (IP3) stimulates Ca2+ release from IP3 sensitive endoplasmic reticulum (ER) Ca2+ stores. PKA might act to sensitize the Ca2+ release channels (based on references 15, 20, 31, 36). AC, adenylyl cyclase; CAM, calmodulin; Gαs, stimulatory G protein α‐subunit, IP3R, inositol trisphosphate receptor; P, phosphate; RyR, ryanodine receptor; SERCA, sarco(endo)plasmic reticulum Ca2+‐ATPase.
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f1:  Signaling pathways proposed to be involved in proximal events in glucose‐dependent insulinotropic polypeptide (GIP)‐mediated potentiation of glucose‐induced insulin secretion. (a) Evidence has been presented supporting roles for both protein kinase A (PKA) and cyclic adenosine monophosphate (cAMP)‐activated guanine nucleotide exchange factor (cAMP‐GEF)/exchange protein directly activated by cAMP (Epac) in the modulation of adenosine triphosphate (ATP)‐sensitive K+ (KATP) channels. Dissociation of cAMP‐Epac2 from sulfonulurea receptor 1 (SUR1) binding has been proposed to activate phospholipase C‐ε (PLCε) through Ras‐related protein 1 (Rap1), resulting in phosphatidylinositol 4,5 bisphosphate (PIP2) metabolism and inhibition of adenosine triphosphate‐sensitive channel subunit, Kir6.2, membrane depolarization and activation of voltage‐dependent Ca2+ channels (VDCC). (b) Diacylglycerol‐activated PKCε potentiates calcium‐induced calcium release through ryanodine receptors and phosphatidylinositol trisphosphate (IP3) stimulates Ca2+ release from IP3 sensitive endoplasmic reticulum (ER) Ca2+ stores. PKA might act to sensitize the Ca2+ release channels (based on references 15, 20, 31, 36). AC, adenylyl cyclase; CAM, calmodulin; Gαs, stimulatory G protein α‐subunit, IP3R, inositol trisphosphate receptor; P, phosphate; RyR, ryanodine receptor; SERCA, sarco(endo)plasmic reticulum Ca2+‐ATPase.

Mentions: Both GIP and GLP‐1 have been shown to stimulate adenylyl cyclase (AC) through a stimulatory G protein (Gs) coupled process resulting in increased cyclic adenosine monophosphate (cAMP)20,21, and this is considered to be the major signaling pathway involved in their potentiation of glucose‐induced insulin secretion. Although GIP‐stimulated insulin secretion is glucose‐dependent, cAMP production and subsequent activation of downstream signaling modules are not22,23. As discussed further below, synergistic interaction between glucose and incretin action occurs when Ca2+ fluxes are increased through modulation of KATP channels and VDCC, as well as through release from the endoplasmic reticulum (Figure 1)15,17,24. Type VIII AC has been proposed to act as a ‘coincidence detector’ of signals from glucose and cAMP17, as it is activated by both Ca2+‐calmodulin and Gαs25. Ca2+‐calmodulin also modulates the activity of phosphodiesterase (PDE) 1C, and synergistic interactions between Gαs and Ca2+‐calmodulin have been suggested to drive synchronous, in‐phase oscillations of cAMP and Ca2+24,26.


Glucose-dependent insulinotropic polypeptide signaling in pancreatic β-cells and adipocytes.

McIntosh CH, Widenmaier S, Kim SJ - J Diabetes Investig (2012)

 Signaling pathways proposed to be involved in proximal events in glucose‐dependent insulinotropic polypeptide (GIP)‐mediated potentiation of glucose‐induced insulin secretion. (a) Evidence has been presented supporting roles for both protein kinase A (PKA) and cyclic adenosine monophosphate (cAMP)‐activated guanine nucleotide exchange factor (cAMP‐GEF)/exchange protein directly activated by cAMP (Epac) in the modulation of adenosine triphosphate (ATP)‐sensitive K+ (KATP) channels. Dissociation of cAMP‐Epac2 from sulfonulurea receptor 1 (SUR1) binding has been proposed to activate phospholipase C‐ε (PLCε) through Ras‐related protein 1 (Rap1), resulting in phosphatidylinositol 4,5 bisphosphate (PIP2) metabolism and inhibition of adenosine triphosphate‐sensitive channel subunit, Kir6.2, membrane depolarization and activation of voltage‐dependent Ca2+ channels (VDCC). (b) Diacylglycerol‐activated PKCε potentiates calcium‐induced calcium release through ryanodine receptors and phosphatidylinositol trisphosphate (IP3) stimulates Ca2+ release from IP3 sensitive endoplasmic reticulum (ER) Ca2+ stores. PKA might act to sensitize the Ca2+ release channels (based on references 15, 20, 31, 36). AC, adenylyl cyclase; CAM, calmodulin; Gαs, stimulatory G protein α‐subunit, IP3R, inositol trisphosphate receptor; P, phosphate; RyR, ryanodine receptor; SERCA, sarco(endo)plasmic reticulum Ca2+‐ATPase.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4020726&req=5

f1:  Signaling pathways proposed to be involved in proximal events in glucose‐dependent insulinotropic polypeptide (GIP)‐mediated potentiation of glucose‐induced insulin secretion. (a) Evidence has been presented supporting roles for both protein kinase A (PKA) and cyclic adenosine monophosphate (cAMP)‐activated guanine nucleotide exchange factor (cAMP‐GEF)/exchange protein directly activated by cAMP (Epac) in the modulation of adenosine triphosphate (ATP)‐sensitive K+ (KATP) channels. Dissociation of cAMP‐Epac2 from sulfonulurea receptor 1 (SUR1) binding has been proposed to activate phospholipase C‐ε (PLCε) through Ras‐related protein 1 (Rap1), resulting in phosphatidylinositol 4,5 bisphosphate (PIP2) metabolism and inhibition of adenosine triphosphate‐sensitive channel subunit, Kir6.2, membrane depolarization and activation of voltage‐dependent Ca2+ channels (VDCC). (b) Diacylglycerol‐activated PKCε potentiates calcium‐induced calcium release through ryanodine receptors and phosphatidylinositol trisphosphate (IP3) stimulates Ca2+ release from IP3 sensitive endoplasmic reticulum (ER) Ca2+ stores. PKA might act to sensitize the Ca2+ release channels (based on references 15, 20, 31, 36). AC, adenylyl cyclase; CAM, calmodulin; Gαs, stimulatory G protein α‐subunit, IP3R, inositol trisphosphate receptor; P, phosphate; RyR, ryanodine receptor; SERCA, sarco(endo)plasmic reticulum Ca2+‐ATPase.
Mentions: Both GIP and GLP‐1 have been shown to stimulate adenylyl cyclase (AC) through a stimulatory G protein (Gs) coupled process resulting in increased cyclic adenosine monophosphate (cAMP)20,21, and this is considered to be the major signaling pathway involved in their potentiation of glucose‐induced insulin secretion. Although GIP‐stimulated insulin secretion is glucose‐dependent, cAMP production and subsequent activation of downstream signaling modules are not22,23. As discussed further below, synergistic interaction between glucose and incretin action occurs when Ca2+ fluxes are increased through modulation of KATP channels and VDCC, as well as through release from the endoplasmic reticulum (Figure 1)15,17,24. Type VIII AC has been proposed to act as a ‘coincidence detector’ of signals from glucose and cAMP17, as it is activated by both Ca2+‐calmodulin and Gαs25. Ca2+‐calmodulin also modulates the activity of phosphodiesterase (PDE) 1C, and synergistic interactions between Gαs and Ca2+‐calmodulin have been suggested to drive synchronous, in‐phase oscillations of cAMP and Ca2+24,26.

Bottom Line: Recent studies have shown that inhibition of the kinase apoptosis signal-regulating kinase 1 (ASK1) by GIP plays a key role in reducing mitochondria-induced apoptosis in β-cells through protein kinase B (PKB)-mediated pathways, and that GIP-induced post-translational modification of voltage- dependent K(+) (Kv) channels also contributes to its prosurvival role.Through regulation of gene expression, GIP tips the balance between pro- and anti-apoptotic members of the B-cell lymphoma-2 (Bcl-2) protein family towards β-cell survival.GIP also plays important roles in the differentiation of pre-adipocytes to adipocytes, and in the regulation of lipoprotein lipase expression and lipogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Physiological Sciences and the Diabetes Research Group, Life Sciences Institute University of British Columbia, Vancouver, BC, Canada.

ABSTRACT
Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin to be identified. In addition to stimulating insulin secretion, GIP plays regulatory roles in the maintenance, growth and survival of pancreatic islets, as well as impacting on adipocyte function. The current review focuses on the intracellular signaling pathways by which GIP contributes to the regulation of β-cell secretion and survival, and adipocyte differentiation and lipogenesis. Studies on signaling underlying the insulinotropic actions of the incretin hormones have largely been carried out with glucagon-like peptide-1. They have provided evidence for contributions by both protein kinase A (PKA) and exchange protein directly activated by cyclic adenosine monophosphate (EPAC2), and their probable role in GIP signaling is discussed. Recent studies have shown that inhibition of the kinase apoptosis signal-regulating kinase 1 (ASK1) by GIP plays a key role in reducing mitochondria-induced apoptosis in β-cells through protein kinase B (PKB)-mediated pathways, and that GIP-induced post-translational modification of voltage- dependent K(+) (Kv) channels also contributes to its prosurvival role. Through regulation of gene expression, GIP tips the balance between pro- and anti-apoptotic members of the B-cell lymphoma-2 (Bcl-2) protein family towards β-cell survival. GIP also plays important roles in the differentiation of pre-adipocytes to adipocytes, and in the regulation of lipoprotein lipase expression and lipogenesis. These events involve interactions between GIP, insulin and resistin signaling pathways. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00196.x, 2012).

No MeSH data available.


Related in: MedlinePlus