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

MacKenzie, R. and Elliott, B. 2014. Akt/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 7, pp. 55-67. doi:10.2147/DMSO.S48260

TitleAkt/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes
TypeJournal article
AuthorsMacKenzie, R. and Elliott, B.
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 Ca2+/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.

Keywordstype 2 diabetes, insulin resistance, Akt/PKB, 5′-monophosphate-activated protein kinase
JournalDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy
Journal citation7, pp. 55-67
ISSN1178-7007
Year2014
PublisherDove Medical Press Ltd.
Publisher's versiondmso-7-055.pdf
Digital Object Identifier (DOI)doi:10.2147/DMSO.S48260
Web address (URL)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928478/
Publication dates
Published13 Feb 2014
LicenseCC BY-NC 3.0

Related outputs

Effects of upper-body, lower-body, or combined resistance training on the ratio of follistatin and myostatin in middle-aged men
Bagheri, R., Rashidlamir, A., Motevalli, M., Elliott, B., Mehrabani, J. and Wong, A. 2019. Effects of upper-body, lower-body, or combined resistance training on the ratio of follistatin and myostatin in middle-aged men. European Journal of Applied Physiology. 119 (9), p. 1921–1931. doi:10.1007/s00421-019-04180-z

Short-Term Exercise Training Inconsistently Influences Basel Testosterone in Older Men: A Systematic Review and Meta-Analysis
Hayes, L. and Elliott, B. 2019. Short-Term Exercise Training Inconsistently Influences Basel Testosterone in Older Men: A Systematic Review and Meta-Analysis. Frontiers in Physiology. 9 (1878). doi:10.3389/fphys.2018.01878

The Effect of Omega-3 Supplementation on Exercise-Induced Muscle Damage
Kyriakidou, Y., Wood, C., Elliott, B. and Dolci, A. 2018. The Effect of Omega-3 Supplementation on Exercise-Induced Muscle Damage. Europhysiology 2018. London 14 - 16 Sep 2018 The Physiological Society.

Activin subfamily peptides predict chronological age in humans
Barrios-Silva, L., Parnell, M., Shinwari, Z., Chaudhary, G., Xenofontos, T, van Bekhoven, A., McArthur, S. and Elliott, B. 2018. Activin subfamily peptides predict chronological age in humans. Physiological Report. 6 (17), p. e13823. doi:10.14814/phy2.13823

Differing Effects of Younger and Older Human Plasma on C2C12 Myocytes in Vitro
Kalampouka, I., van Bekhoven, A. and Elliott, B. 2018. Differing Effects of Younger and Older Human Plasma on C2C12 Myocytes in Vitro. Frontiers in Physiology. 9 (152), pp. 1-7. doi:10.3389/fphys.2018.00152

High intensity exercise decreases IP6K1 muscle content & improves insulin sensitivity in glucose intolerant individuals
Naufahu, J., Elliott, B., Markiv, A., Dunning-Foreman, P., McGrady, M., Howard, D., Watt, P.W. and Mackenzie, R.W.A. 2018. High intensity exercise decreases IP6K1 muscle content & improves insulin sensitivity in glucose intolerant individuals. Journal of Clinical Endocrinology and Metabolism. 103 (4), pp. 1479-1490. doi:10.1210/jc.2017-02019

PhytoCloud: A gamified Mobile Web Application to modulate diet and physical activity of women with breast cancer
Economou, D., Dwek, M., Elliott, B., Ramezanian Kalahroudi, M. and Azimi, T. 2017. PhytoCloud: A gamified Mobile Web Application to modulate diet and physical activity of women with breast cancer. IEEE 30th International Symposium on Computer-Based Medical Systems. Thessaloniki, Greece 22 Jun - 24 Sep 2017 IEEE . doi:10.1109/CBMS.2017.164

Lifelong exercise, but not short-term high-intensity interval training, increases GDF11, a marker of successful aging: a preliminary investigation
Elliott, B., Herbert, P., Sculthorpe, N., Grace, F., Stratton, D. and Hayes, L. 2017. Lifelong exercise, but not short-term high-intensity interval training, increases GDF11, a marker of successful aging: a preliminary investigation. Physiological Report. 5 (13), p. e13343. doi:10.14814/phy2.13343

Circulating myostatin is reduced with aging in humans but not altered by short-term, high intensity training
Elliott, B., Shinwari, Z.B., Altayar, Z., Barrios, L., Chaudhary, G.A., Hanifa, E., Parnell, M., Xenofontos, T., Sculthorpe, N., Herbert, P., Grace, F. and Hayes, L. 2016. Circulating myostatin is reduced with aging in humans but not altered by short-term, high intensity training. Physiology 2016. Dublin, Ireland 29 2016 - 31 Jul 2017 The Physiological Society.

Complete and Voluntary Starvation of 50 days
Elliott, B., Mina, A. and Ferrier, C. 2016. Complete and Voluntary Starvation of 50 days. Clinical Medical Insights: Case Reports. 2016:9, pp. 67-70. doi:10.4137/CCRep.S39776

The role of acute ambient hypoxia in the regulation of myostatin
Elliott, B. 2015. The role of acute ambient hypoxia in the regulation of myostatin. PhD thesis University of Westminster Biomedical Sciences

Wearable technology in academia: the use of Google Glass in the life sciences
Elliott, B. and Sukan, A. 2015. Wearable technology in academia: the use of Google Glass in the life sciences. Compass: Journal of Learning & Teaching . 6 (10).

Acute hypoxia reduces plasma myostatin independent of hypoxic dose
Elliott, B., Simonson, T.S., Getting, S.J., Renshaw, D., Wagner Peter, D. and MacKenzie, R. 2015. Acute hypoxia reduces plasma myostatin independent of hypoxic dose. 8th International Conference on Cachexia, Sarcopenia and Muscle Wasting. Paris 04 - 06 Dec 2015 The Society on Sarcopenia, Cachexia and Wasting Disorders.

Serum ferritin levels are correlated with total adiposity, but not BMI in obese males
Zariwala, M., Kosicka, A., MacKenzie, R. and Renshaw, D. 2014. Serum ferritin levels are correlated with total adiposity, but not BMI in obese males. Society for Endocrinology BES 2014. Liverpool, UK 24 - 27 Mar 2014 BioScientifica Ltd.. doi:10.1530/endoabs.34.P255

What range of methods is available to evaluate the implementation and impact of complex environmental policies on complex systems?
Fagan-Watson, B., Watson, T., Elliott, B., Vanner, R., Shaw, Ben and Morris, S. 2014. What range of methods is available to evaluate the implementation and impact of complex environmental policies on complex systems? A report to the Department for Environment, Food and Rural Affairs. Policy Studies Institute. Defra, London.

Acute hypoxia alters myotube size in vitro and myostatin signalling in vivo
Elliott, B., Renshaw, D., Getting, S.J., Watt, P.W. and MacKenzie, R. 2014. Acute hypoxia alters myotube size in vitro and myostatin signalling in vivo. FASEB. San Diego Jul 2015 Federation of American Societies for Experimental Biology.

The role of acute hypoxia in skeletal muscle atrophy
Elliott, B., Renshaw, D., Getting, S.J., Watt, P., Howard, D. and MacKenzie, R. 2014. The role of acute hypoxia in skeletal muscle atrophy. Physiology. London 30 Jun 2014 The Physiological Society.

Attenuation of plasma annexin A1 in human obesity
Kosicka, A., Cunliffe, AD., MacKenzie, R., Zariwala, M., Perretti, M., Flower, R.J. and Renshaw, D. 2013. Attenuation of plasma annexin A1 in human obesity. FASEB Journal. 27 (1), pp. 1-11. doi:10.1096/fj.12-213728

The effect of hypoxia and work intensity on insulin resistance in type 2 diabetes
MacKenzie, R., Elliott, B., Maxwell, N.S., Brickley, G. and Watt, P.W. 2012. The effect of hypoxia and work intensity on insulin resistance in type 2 diabetes. Journal of Clinical Endocrinology & Metabolism. 97 (1), pp. 155-62. doi:10.1210/jc.2011-1843

Intermittent Exercise with and without Hypoxia Improves Insulin Sensitivity in Individuals with Type 2 Diabetes
MacKenzie, R., Maxwell, N.S., Castle, P.C., Elliot, B., Brickley, G., Watt, P.W. and Elliott, B. 2012. Intermittent Exercise with and without Hypoxia Improves Insulin Sensitivity in Individuals with Type 2 Diabetes. Journal of Clinical Endocrinology & Metabolism. 97 (4), pp. 46-55. doi:10.1210/jc.2011-2829

The Central Role of Myostatin in Skeletal Muscle and Whole Body Homeostasis
Elliott, B., Renshaw, D., Getting, S.J. and MacKenzie, R. 2012. The Central Role of Myostatin in Skeletal Muscle and Whole Body Homeostasis. Acta Physiologica. 205 (3), pp. 324-40. doi:10.1111/j.1748-1716.2012.02423.x

Voluntary resistance running wheel activity pattern and skeletal muscle growth in rats
Legerlotz, K., Elliott, B., Guillemin, B. and Smith, H. 2008. Voluntary resistance running wheel activity pattern and skeletal muscle growth in rats. Experimental Physiology. 93 (6), pp. 754-62. doi:10.1113/expphysiol.2007.041244

Permalink - https://westminsterresearch.westminster.ac.uk/item/qwz94/akt-pkb-activation-and-insulin-signaling-a-novel-insulin-signaling-pathway-in-the-treatment-of-type-2-diabetes


Share this
Tweet
Email