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Akt/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes.

Mackenzie RW, Elliott BT - Diabetes Metab Syndr Obes (2014)

Bottom Line: Treatments reducing hyperglycemia and the secondary complications that result from these dysfunctions are being sought after.Novel evidence suggesting a reduction in IP7 production via IP6K1 inhibition represents an exciting therapeutic avenue in the treatment of insulin resistance.However, this treatment does not seem to improve peripheral insulin resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Human and Health Sciences, Facility of Science and Technology, University of Westminster, London, UK.

ABSTRACT
Type 2 diabetes is a metabolic disease categorized primarily by reduced insulin sensitivity, β-cell dysfunction, and elevated hepatic glucose production. Treatments reducing hyperglycemia and the secondary complications that result from these dysfunctions are being sought after. Two distinct pathways encourage glucose transport activity in skeletal muscle, ie, the contraction-stimulated pathway reliant on Ca(2+)/5'-monophosphate-activated protein kinase (AMPK)-dependent mechanisms and an insulin-dependent pathway activated via upregulation of serine/threonine protein kinase Akt/PKB. Metformin is an established treatment for type 2 diabetes due to its ability to increase peripheral glucose uptake while reducing hepatic glucose production in an AMPK-dependent manner. Peripheral insulin action is reduced in type 2 diabetics whereas AMPK signaling remains largely intact. This paper firstly reviews AMPK and its role in glucose uptake and then focuses on a novel mechanism known to operate via an insulin-dependent pathway. Inositol hexakisphosphate (IP6) kinase 1 (IP6K1) produces a pyrophosphate group at the position of IP6 to generate a further inositol pyrophosphate, ie, diphosphoinositol pentakisphosphate (IP7). IP7 binds with Akt/PKB at its pleckstrin homology domain, preventing interaction with phosphatidylinositol 3,4,5-trisphosphate, and therefore reducing Akt/PKB membrane translocation and insulin-stimulated glucose uptake. Novel evidence suggesting a reduction in IP7 production via IP6K1 inhibition represents an exciting therapeutic avenue in the treatment of insulin resistance. Metformin-induced activation of AMPK is a key current intervention in the management of type 2 diabetes. However, this treatment does not seem to improve peripheral insulin resistance. In light of this evidence, we suggest that inhibition of IP6K1 may increase insulin sensitivity and provide a novel research direction in the treatment of insulin resistance.

No MeSH data available.


Related in: MedlinePlus

Insulin and contraction signaling pathways during GLUT-4 recruitment and translocation.Note: Data from Sakamoto et al.14Abbreviations: IRS, insulin receptor substrate; PI3-K, class IA phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PDK1, phosphoinositide-dependent protein kinase-1; Akt, serine/threonine protein kinase; AS160, 160 kDa Akt substrate; GLUT-4, glucose transporter 4; GSV, GLUT-4 storage vesicle; Rab-GAP, Rab-GTPase-activating protein; Rab-GDP, guanosine-50-diphosphate-loaded Rab; Rab-GTP, guanosine-50-triphosphate-loaded Rab; CaMKK, Ca2+/calmodulin-dependent protein kinase kinase; LKB1, Serine/threonine kinase 11; STRAD, putative kinase; MO25, mouse protein 25/scaffold protein; AMPK, 5′-monophosphate-activated protein kinase; Thr172, phosphorylated AMPKα at threonine 172; AMP, adenosine monophosphate; ATP, adenosine triphosphate; P, phosphorylated site.
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f1-dmso-7-055: Insulin and contraction signaling pathways during GLUT-4 recruitment and translocation.Note: Data from Sakamoto et al.14Abbreviations: IRS, insulin receptor substrate; PI3-K, class IA phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PDK1, phosphoinositide-dependent protein kinase-1; Akt, serine/threonine protein kinase; AS160, 160 kDa Akt substrate; GLUT-4, glucose transporter 4; GSV, GLUT-4 storage vesicle; Rab-GAP, Rab-GTPase-activating protein; Rab-GDP, guanosine-50-diphosphate-loaded Rab; Rab-GTP, guanosine-50-triphosphate-loaded Rab; CaMKK, Ca2+/calmodulin-dependent protein kinase kinase; LKB1, Serine/threonine kinase 11; STRAD, putative kinase; MO25, mouse protein 25/scaffold protein; AMPK, 5′-monophosphate-activated protein kinase; Thr172, phosphorylated AMPKα at threonine 172; AMP, adenosine monophosphate; ATP, adenosine triphosphate; P, phosphorylated site.

Mentions: When forming an understanding of the progression of this disease, it is important to recognize two points. First, peripheral glucose uptake into skeletal muscle (the main disposal site for glucose) can be promoted via two distinct pathways, ie, insulin-dependent mechanisms resulting in recruitment and activation of Akt/PKB and contraction-mediated stimulation22 or hypoxia-mediated stimulation23 of AMPK (Figure 1). It has been consistently shown that PI3 kinase is necessary for insulin-stimulated but not for contraction-stimulated glucose uptake,24–27 while Akt2 knockout mice demonstrate normal basal and contraction-stimulated glucose uptake.28 Indeed, glucose transport is additive when either hypoxia or contractile activity are coupled with insulin, whereas hypoxia and contractile activity are not.29,30 In support of this is the observation that wortmannin, a selective inhibitor of PI3 kinase, completely blocks insulin-stimulated glucose transport but has no effect on contraction-mediated or hypoxia-mediated 2-deoxy-D-glucose uptake in rat skeletal muscle.25


Akt/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes.

Mackenzie RW, Elliott BT - Diabetes Metab Syndr Obes (2014)

Insulin and contraction signaling pathways during GLUT-4 recruitment and translocation.Note: Data from Sakamoto et al.14Abbreviations: IRS, insulin receptor substrate; PI3-K, class IA phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PDK1, phosphoinositide-dependent protein kinase-1; Akt, serine/threonine protein kinase; AS160, 160 kDa Akt substrate; GLUT-4, glucose transporter 4; GSV, GLUT-4 storage vesicle; Rab-GAP, Rab-GTPase-activating protein; Rab-GDP, guanosine-50-diphosphate-loaded Rab; Rab-GTP, guanosine-50-triphosphate-loaded Rab; CaMKK, Ca2+/calmodulin-dependent protein kinase kinase; LKB1, Serine/threonine kinase 11; STRAD, putative kinase; MO25, mouse protein 25/scaffold protein; AMPK, 5′-monophosphate-activated protein kinase; Thr172, phosphorylated AMPKα at threonine 172; AMP, adenosine monophosphate; ATP, adenosine triphosphate; P, phosphorylated site.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928478&req=5

f1-dmso-7-055: Insulin and contraction signaling pathways during GLUT-4 recruitment and translocation.Note: Data from Sakamoto et al.14Abbreviations: IRS, insulin receptor substrate; PI3-K, class IA phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PDK1, phosphoinositide-dependent protein kinase-1; Akt, serine/threonine protein kinase; AS160, 160 kDa Akt substrate; GLUT-4, glucose transporter 4; GSV, GLUT-4 storage vesicle; Rab-GAP, Rab-GTPase-activating protein; Rab-GDP, guanosine-50-diphosphate-loaded Rab; Rab-GTP, guanosine-50-triphosphate-loaded Rab; CaMKK, Ca2+/calmodulin-dependent protein kinase kinase; LKB1, Serine/threonine kinase 11; STRAD, putative kinase; MO25, mouse protein 25/scaffold protein; AMPK, 5′-monophosphate-activated protein kinase; Thr172, phosphorylated AMPKα at threonine 172; AMP, adenosine monophosphate; ATP, adenosine triphosphate; P, phosphorylated site.
Mentions: When forming an understanding of the progression of this disease, it is important to recognize two points. First, peripheral glucose uptake into skeletal muscle (the main disposal site for glucose) can be promoted via two distinct pathways, ie, insulin-dependent mechanisms resulting in recruitment and activation of Akt/PKB and contraction-mediated stimulation22 or hypoxia-mediated stimulation23 of AMPK (Figure 1). It has been consistently shown that PI3 kinase is necessary for insulin-stimulated but not for contraction-stimulated glucose uptake,24–27 while Akt2 knockout mice demonstrate normal basal and contraction-stimulated glucose uptake.28 Indeed, glucose transport is additive when either hypoxia or contractile activity are coupled with insulin, whereas hypoxia and contractile activity are not.29,30 In support of this is the observation that wortmannin, a selective inhibitor of PI3 kinase, completely blocks insulin-stimulated glucose transport but has no effect on contraction-mediated or hypoxia-mediated 2-deoxy-D-glucose uptake in rat skeletal muscle.25

Bottom Line: Treatments reducing hyperglycemia and the secondary complications that result from these dysfunctions are being sought after.Novel evidence suggesting a reduction in IP7 production via IP6K1 inhibition represents an exciting therapeutic avenue in the treatment of insulin resistance.However, this treatment does not seem to improve peripheral insulin resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Human and Health Sciences, Facility of Science and Technology, University of Westminster, London, UK.

ABSTRACT
Type 2 diabetes is a metabolic disease categorized primarily by reduced insulin sensitivity, β-cell dysfunction, and elevated hepatic glucose production. Treatments reducing hyperglycemia and the secondary complications that result from these dysfunctions are being sought after. Two distinct pathways encourage glucose transport activity in skeletal muscle, ie, the contraction-stimulated pathway reliant on Ca(2+)/5'-monophosphate-activated protein kinase (AMPK)-dependent mechanisms and an insulin-dependent pathway activated via upregulation of serine/threonine protein kinase Akt/PKB. Metformin is an established treatment for type 2 diabetes due to its ability to increase peripheral glucose uptake while reducing hepatic glucose production in an AMPK-dependent manner. Peripheral insulin action is reduced in type 2 diabetics whereas AMPK signaling remains largely intact. This paper firstly reviews AMPK and its role in glucose uptake and then focuses on a novel mechanism known to operate via an insulin-dependent pathway. Inositol hexakisphosphate (IP6) kinase 1 (IP6K1) produces a pyrophosphate group at the position of IP6 to generate a further inositol pyrophosphate, ie, diphosphoinositol pentakisphosphate (IP7). IP7 binds with Akt/PKB at its pleckstrin homology domain, preventing interaction with phosphatidylinositol 3,4,5-trisphosphate, and therefore reducing Akt/PKB membrane translocation and insulin-stimulated glucose uptake. Novel evidence suggesting a reduction in IP7 production via IP6K1 inhibition represents an exciting therapeutic avenue in the treatment of insulin resistance. Metformin-induced activation of AMPK is a key current intervention in the management of type 2 diabetes. However, this treatment does not seem to improve peripheral insulin resistance. In light of this evidence, we suggest that inhibition of IP6K1 may increase insulin sensitivity and provide a novel research direction in the treatment of insulin resistance.

No MeSH data available.


Related in: MedlinePlus