Career: Dr Sutherland has worked in industry with Glaxo Group Research, obtained his PhD under the supervision of Professor Sir Philip Cohen, at the University of Dundee, and studied under Professor Daryl K Granner, at Vanderbilt University, Tennessee. He has obtained personal Fellowships from the American Diabetes Association, the Wellcome Trust and Diabetes UK covering his work from 1994 to 2008. He has obtained personal research funding in excess of £10 million and contributes to undergraduate teaching in Life Sciences and the Medical Faculty.
Overview: The Sutherland lab has contributed to the understanding of insulin signalling mechanisms and regulation of gene transcription, most recently in human tissue. Major breakthroughs include establishing a major regulatory mechanism of the key protein kinase GSK3, demonstrating that GSK3 inhibition enhances insulin action in the liver and is a potential treatment for diabetes, identifying the signalling pathway by which insulin turns off hepatic glucose production, finding the mechanism by which the protein CRMP2 is modified to promote its accumulation into tangles in Alzheimer’s disease and finding new physiological functions for GSK3 and the CRMP family of proteins.
Current Focus: The lab continues to develop technology for the discovery of insulin sensitising drugs and biomarkers of metabolic dysfunction that would help identify people at high risk of developing Type 2 Diabetes and dementia. In recent years the lab has characterised molecular connections between Diabetes and Dementia that could explain the increased risk of Dementia in the diabetic population, and is investigating the impact of insulin resistance and obesity on heart disease, cancer, behaviour and the effectiveness of diabetes therapies.
Diabetes and Dementia
Funding: Diabetes UK and MRC
Insulin is the major hormone that prevents hyperglycemia after a meal. When insulin does not work properly prolonged hyperglycemia occurs (Diabetes), resulting in increased risk of heart disease, blindness, kidney failure, amputation, dementia and stroke. There are now more than 2 million people in the UK with diabetes. An understanding of the molecular aspects of insulin action will allow us to understand why diabetes occurs and how to develop strategies for prevention and cure, as well as prevent the complications of the disease. For example, insulin regulates the enzyme GSK3, which is closely linked to molecular development of neurodegenerative diseases such as Alzheimer's disease. Our group currently studies three aspects of insulin action.
1) Obesity, insulin resistance and molecular disease. In collaboration with our clinical colleagues at Ninewells Medical School we are establishing whether any of the molecules known to be important in the insulin regulation of gene expression are improperly regulated in human insulin resistance. This work led to the discovery of a novel insulin signalling mechanism. The human studies are generating new information on potential ‘biomarkers’ of early progression to diabetes, which should allow earlier and more efficacious intervention. In addition we are investigating whether obesity alters the activity of CDK5, and how that alters response to drugs used in diabetes. In particular we are establishing whether changes in CDK5 activity may underpin some of the increased risk of cancer in the obese population.
2) Insulin action and the brain. Perhaps surprisingly, insulin receptors are found throughout the brain. Interestingly, there is a higher incidence of Alzheimer’s disease in the diabetic population and it is proposed to be due to defective insulin action on the brain. We have identified a family of proteins regulated by insulin and shown that it is dysregulated in Alzheimer’s disease 13. These proteins (CRMPs) are targeted by GSK3 which is known to be upregulated in diabetes 14-16. Therefore abnormal activity of this family could explain part of the association between diabetes and Alzheimer’s disease. In collaboration with Professor Balfour and Dr Stewart at Ninewells we have identified a specific overnutrition-induced change in behavioural flexibility that is not prevented by the anti-diabetes drug metformin 17 18. In addition we are studying a new function of GSK3, the coordinated control of protein stability. This function provides the opportunity to develop new biomarkers of GSK3 which could have clinical utlity in the early diagnosis of dementia, as well as the molecular stratification of diabetes (to improve treatment and care).
3) The genetic contribution to drug response in diabetes. In collaboration with Professor Pearson and McCrimmon at Ninewells we are studying the biology behind the genetic contribution to response to the most common anti-diabetes therapy, metformin. We are investigating why gentic variation in 3 genes influences whether a person with diabetes would repsond to metformin and improve their blood glucose. The hope is this information will improve prescribing practice in diabetes, and may help find new therapies for those that can't use metformin.
'A partnership with the proteasome: the destructive nature of GSK3' Biochemical Pharmacology, vol. 147, pp. 77-92.
'Rab-GTPase binding effector protein 2 (RABEP2) is a primed substrate for Glycogen Synthase kinase-3 (GSK3)' Scientific Reports, vol. 7, 17682.
'Proinsulin is stable at room temperature for 24 hours in EDTA: A clinical laboratory analysis (ad APT 3)' PLo S ONE, vol. 12, no. 4, e0171716, pp. 1-6.
'The effect of dietary intervention on the metabolic and behavioural impairments generated by short term high fat feeding in the rat' Physiology & Behavior, vol. 167, pp. 100-109.
'Regulation of the CNC-b ZIP transcription factor Nrf2 by Keap1 and the axis between GSK-3 and β-Tr CP' Current Opinion in Toxicology, vol. 1, pp. 92-103.
'Heat Shock Factor 1 is a Substrate for p38 Mitogen-Activated Protein Kinases' Molecular and Cellular Biology, vol. 36, no. 18, pp. 2403-2417.
'Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic response to metformin' Nature Genetics, vol. 48, no. 9, pp. 1055-1059.
'Investigation of salicylate hepatic responses in comparison with chemical analogues of the drug' Biochimica et Biophysica Acta. Molecular Basis of Disease, vol. 1862, no. 8, pp. 1412-1422.
'Phosphorylation of a splice variant of collapsin response mediator protein 2 in the nucleus of tumour cells links cyclin dependent kinase-5 to oncogenesis' BMC Cancer, vol. 15, 885.
'Prolyl isomerase Pin1 regulates axon guidance by stabilizing CRMP2A selectively in distal axons' Cell Reports, vol. 13, no. 4, pp. 812-828.
'Dual regulation of transcription factor Nrf2 by Keap1 and by the combined actions of β-Tr CP and GSK-3' Biochemical Society Transactions, vol. 43, no. 4, pp. 611-620.
'Invited commentary on … Lithium treatment and risk for dementia in adults with bipolar disorder' British Journal of Psychiatry, vol. 207, no. 1, pp. 52-54.
'Hypertension fails to disrupt white matter integrity in young or aged Fisher (F44) Cyp1a1Ren2 transgenic rats' Journal of Cerebral Blood Flow and Metabolism, vol. 35, no. 2, pp. 188-192.
'High fat feeding is associated with stimulation of the hypothalamic-pituitary-adrenal axis and reduced anxiety in the rat' Psychoneuroendocrinology, vol. 52, pp. 272-280.
'The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver' Nature Communications, vol. 5, 4535.
'Neuronal deletion of GSK3beta increases microtubule speed in the growth cone and enhances axon regeneration via CRMP-2 and independently of MAP1B and CLASP2' BMC Biology, vol. 12, 47.
'CNP/c GMP signaling regulates axon branching and growth by modulating microtubule polymerization' Developmental Neurobiology, vol. 73, no. 9, pp. 673-687.
'Hormonal regulation of the Salt-inducible Kinase (SIK), a key mediator that controls hepatic gluconeogenesis' Diabetic Medicine, vol. 30, no. Suppl. 1, P577, pp. E2-E2.
'Hormonal regulation of the Salt-inducible Kinase (SIK), a key mediator that controls hepatic gluconeogenesis' Diabetes UK Professional Conference 2013, Manchester, United Kingdom, 13/03/13 - 15/03/13, .
'Obesity-Induced Insulin Resistance in Human Skeletal Muscle Is Characterised by Defective Activation of p42/p44 MAP Kinase' PLo S ONE, vol. 8, no. 2, e56928.
'Erratum to: A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin' Diabetologia, vol. 56, no. 1, pp. 230.
'A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin' Diabetologia, vol. 55, no. 11, pp. 3061-3070.
'Insulin resistance in the brain: An old-age or new-age problem?' Biochemical Pharmacology, vol. 84, no. 6, pp. 737-45.
'The role of ATM in response to metformin treatment and activation of AMPK reply' Nature Genetics, vol. 44, no. 4, pp. 361-362.
'Disordered insulin secretion in the development of insulin resistance and Type 2 diabetes' Diabetic Medicine, vol. 29, no. 8, pp. 972-979.
'Nrf2 is controlled by two distinct β-Tr CP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity' Oncogene, vol. 32, pp. 3765-3781.
'Models of Dementia: an introductory overview' Biochemical Society Transactions, vol. 39, pp. 851-856.
'Bioinformatic Prediction and Confirmation of beta-Adducin as a Novel Substrate of Glycogen Synthase Kinase 3' Journal of Biological Chemistry, vol. 286, no. 28, pp. 25274-25283.
'Identification of a Proline-rich Inositol Polyphosphate 5-Phosphatase (PIPP)center dot Collapsin Response Mediator Protein 2 (CRMP2) Complex That Regulates Neurite Elongation' Journal of Biological Chemistry, vol. 286, no. 26, pp. 23407-23418.
'Implications of genome wide association studies for the understanding of type 2 diabetes pathophysiology' Biochemical Pharmacology, vol. 81, no. 4, pp. 471-477.
'High fat feeding promotes simultaneous decline in insulin sensitivity and cognitive performance in a delayed matching and non-matching to position task' Behavioural Brain Research, vol. 217, no. 1, pp. 134-141.
'Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes' Nature Genetics, vol. 43, no. 2, pp. 117-120.
'CRMP2 Hyperphosphorylation is Characteristic of Alzheimer's Disease and not a Feature Common to Other Neurodegenerative Diseases' Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 615-625.
'What are the bona fide GSK3 substrates?' International Journal of Alzheimer's Disease, vol. 2011, pp. 1-23.
'Biguanide metformin acts on tau phosphorylation via m TOR/protein phosphatase 2A (PP2A) signaling' Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 50, pp. 21830-21835.
'Regulation of Tau-Dependent Toxicity by Brain Selective/SAD Kinases' Journal of Neurogenetics, vol. 24, pp. 12-12.
'Evidence that glycogen synthase kinase-3 isoforms have distinct substrate preference in the brain' Journal of Neurochemistry, vol. 115, no. 4, pp. 974-983.
'Generation, validation and humanisation of a novel insulin resistant cell model' Biochemical Pharmacology, vol. 80, no. 7, pp. 1042-1049.
'Dynamin I phosphorylation by GSK3 controls activity-dependent bulk endocytosis of synaptic vesicles' Nature Neuroscience, vol. 13, no. 7, pp. 845-U85.
'GSK3 beta Regulates Myelin-Dependent Axon Outgrowth Inhibition through CRMP4' Journal of Neuroscience, vol. 30, no. 16, pp. 5635-5643.
'All tangled up: tau-dependent neurodegeneration' Biochemist, vol. 32, no. 2, pp. 10-13.
'Dissecting insulin signaling pathways: individualised therapeutic targets for diagnosis and treatment of insulin resistant states' Endocrine, Metabolic and Immune Disorders - Drug Targets, vol. 9, no. 2, pp. 187-198.
'Increased CRMP2 Phosphorylation is Observed in Alzheimer's Disease: Does this Tell us Anything About Disease Development?' Current Alzheimer Research, vol. 6, no. 3, pp. 269-278.
'Filaggrin in the frontline: role in skin barrier function and disease' Journal of Cell Science, vol. 122, no. 9, pp. 1285-1294.
'Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status' American Journal of Physiology, Endocrinology and Metabolism, vol. 296, no. 5, pp. E1042-E1048.
'Leptin-dependent Phosphorylation of PTEN Mediates Actin Restructuring and Activation of ATP-sensitive K+ Channels' Journal of Biological Chemistry, vol. 284, no. 14, pp. 9331-9340.
'Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo' Biochemical Journal, vol. 418, pp. 665-671.
'Anaesthesia generates neuronal insulin resistance by inducing hypothermia' BMC Neuroscience, vol. 9, 100, pp. -.
'Relative resistance of Cdk5-phosphorylated CRMP2 to dephosphorylation' Journal of Biological Chemistry, vol. 283, no. 26, pp. 18227-18237.
'Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance' Molecular and Cellular Biology, vol. 28, no. 10, pp. 3258-3272.
'Novel procedure to investigate the effect of phosphorylation on protein complex formation in vitro and in cells' Biochemistry, vol. 47, no. 7, pp. 2153-2161.
Convergence of leptin and insulin signaling networks in obesity. in J Harvey & DJ Withers (eds), Neurobiology of obesity. Cambridge University Press, Cambridge, pp. 127-163.
Measuring GSK3 expression and activity in cells. in E Vincan (ed.), Wnt signaling: pathway methods and mammalian models. Methods in Molecular Biology, vol. 468, Humana Press, pp. 45-65.
Insulin action gene regulation. in Mechanisms of Insulin Action: Medical Intelligence Unit. Springer New York, pp. 110-132.
'Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer's disease progression' Journal of Neurochemistry, vol. 103, no. 3, pp. 1132-1144.
'Characterization of a protein kinase B inhibitor in vitro and in insulin-treated liver cells' Diabetes, vol. 56, no. 9, pp. 2218-2227.
'Differential proteomics analysis of synaptic proteins identifies potential cellular targets and protein mediators of synaptic neuroprotection conferred by the slow Wallerian degeneration (Wld(s)) gene' Molecular & Cellular Proteomics, vol. 6, no. 8, pp. 1318-1330.
'5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men' Diabetes, vol. 56, no. 8, pp. 2078-2084.
'Molecular connexions between dementia and diabetes' Neuroscience and Biobehavioral Reviews, vol. 31, no. 7, pp. 1046-1063.
'A temporal switch in the insulin-signalling pathway that regulates hepatic IGF-binding protein-1 gene expression' Journal of Molecular Endocrinology, vol. 37, no. 2, pp. 227-237.
'Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo' Journal of Biological Chemistry, vol. 281, no. 24, pp. 16591-16598.
'Functional characterisation of the regulation of CAAT enhancer binding protein alpha by GSK-3 phosphorylation of Threonines 222/226' BMC Molecular Biology, vol. 7, 14, pp. -.
'A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration' Biochemical Journal, vol. 392, pp. 345-352.
'Constitutive activation of GSK3 down-regulates glycogen synthase abundance and glycogen deposition in rat skeletal muscle cells' Journal of Biological Chemistry, vol. 280, no. 10, pp. 9509-9518.
'AMP-activated protein kinase mediates phenobarbital induction of CYP2B gene expression in hepatocytes and a newly derived human hepatoma cell line' Journal of Biological Chemistry, vol. 280, no. 6, pp. 4367-4373.
'Deficiency of PDK1 in liver results in glucose intolerance, impairment of insulin-regulated gene expression and liver failure' Biochemical Journal, vol. 385, no. 3, pp. 639-648.
'Analysis of hepatic gene transcription in mice expressing insulin-insensitive GSK3' Biochemical Journal, vol. 392, no. 3, pp. 633-639.
'Leptin and insulin stimulation of signalling pathways in arcuate nucleus neurones: PI3K dependent actin reorganization and K-ATP channel activation' BMC Neuroscience, vol. 5, 54, pp. -.
'GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons' Journal of Biological Chemistry, vol. 279, no. 48, pp. 50176-50180.
'Glycogen synthase kinase-3 regulates IGFBP-1 gene transcription through the thymine-rich insulin response element' BMC Molecular Biology, vol. 5, 15, pp. -.
'Tumour necrosis factor a decreases glucose-6-phosphatase gene expression by activation of nuclear factor k B' Biochemical Journal, vol. 382, pp. 471-479.
'The aminoguanidine carboxylate BVT.12777 activates ATP-sensitive K+ channels in the rat insulinoma cell line, CRI-G1' BMC Clinical Pharmacology, vol. 4, no. 17.
'Different mechanisms are used by insulin to repress three genes that contain a homologous thymine-rich insulin response element' FEBS Letters, vol. 549, no. 1-3, pp. 72-76.
'Insulin regulation of insulin-like growth factor-binding protein-1 gene expression is dependent on the mammalian target of rapamycin, but independent of ribosomal S6 kinase activity' Journal of Biological Chemistry, vol. 277, no. 12, pp. 9889-9895.
'Insulin regulation of hepatic insulin-like growth factor-binding protein-1 (IGFBP-1) gene expression and mammalian target of rapamycin (m TOR) signalling is impaired by the presence of hydrogen peroxide' Biochemical Journal, vol. 365, pp. 537-545.
'Antagonistic effects of phorbol esters on insulin regulation of insulin-like growth factor-binding protein-1 (IGFBP-1) but not glucose-6-phosphatase gene expression' Biochemical Journal, vol. 359, no. 3, pp. 611-619.
'Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphoenolpyruvate carboxykinase gene expression' Diabetes, vol. 50, no. 5, pp. 937-946.
'NF-kappa B inhibits glucocorticoid and c AMP-mediated expression of the phosphoenolpyruvate carboxykinase gene' Journal of Biological Chemistry, vol. 275, no. 41, pp. 31847-31856.
'The molecular physiology of hepatic nuclear factor 3 in the regulation of gluconeogenesis' Journal of Biological Chemistry, vol. 275, no. 19, pp. 14717-14721.
'5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase' Diabetes, vol. 49, no. 6, pp. 896-903.
'Dominant negative forms of Akt (protein kinase B) and atypical protein kinase Cλ do not prevent insulin inhibition of phosphoenolpyruvate carboxykinase gene transcription' Journal of Biological Chemistry, vol. 274, no. 30, pp. 21305-21312.
'Activation of the Ras mitogen-activated protein kinase ribosomal protein kinase pathway is not required for the repression of phosphoenolpyruvate carboxykinase gene transcription by insulin' Journal of Biological Chemistry, vol. 273, no. 6, pp. 3198-3204.
'Oxidative and chemical stress mimic insulin by selectively inhibiting the expression of phosphoenolpyruvate carboxykinase in hepatoma cells' Diabetes, vol. 46, no. 1, pp. 17-22.
'New connections in the regulation of PEPCK gene expression by insulin [and discussion]' Philosophical Transactions of the Royal Society B - Biological Sciences, vol. 351, no. 1336, pp. 191-199.
'Insulin regulation of phosphoenolpyruvate carboxykinase gene expression does not require activation of the Ras mitogen-activated protein kinase signaling pathway' Journal of Biological Chemistry, vol. 271, no. 4, pp. 1890-1897.
'Analysis of the signaling pathway involved in the regulation of hexokinase II gene transcription by insulin' Journal of Biological Chemistry, vol. 271, no. 28, pp. 16690-16694.
'Phosphatidylinositol 3-Kinase, but not p70/p85 ribosomal S6 protein kinase, is required for the regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene expression by insulin: dissociation of signaling pathways for insulin and phorbol ester regulation of PEPCK gene expression' Journal of Biological Chemistry, vol. 270, no. 26, pp. 15501-15506.
'The α-isoform of glycogen synthase kinase-3 from rabbit skeletal muscle is inactivated by p70 S6 kinase or MAP kinase-activated protein kinase-1 in vitro' FEBS Letters, vol. 338, no. 1, pp. 37-42.
'Inactivation of glycogen-synthase kinase-3-beta by phosphorylation: new kinase connections in insulin and growth-factor signaling' Biochemical Journal, vol. 296, no. 1, pp. 15-19.
'Inactivation of glycogen synthase kinase-3β by phosphorylation: New kinase connections in insulin and growth-factor signalling' Biochemical Journal, vol. 296, no. 1, pp. 15-19.
'Identification of insulin-stimulated protein kinase-1 as the rabbit equivalent of rskmo-2: identification of two threonines phosphorylated during activation by mitogen-activated protein kinase' European Journal of Biochemistry, vol. 212, no. 2, pp. 581-588.
'Phosphorylation and activation of human tyrosine hydroxylase in vitro by mitogen-activated protein (MAP) kinase and MAP-kinase-activated kinases 1 and 2' European Journal of Biochemistry, vol. 217, no. 2, pp. 715-722.
'Dissection of the protein kinase cascades involved in insulin and nerve growth factor action' Biochemical Society Transactions, vol. 20, no. 3, pp. 671-674.
'Esterification and absorption of cholesterol: in vitro and in vivo observations in the rat' Biochimica et Biophysica Acta (BBA)/Lipids and Lipid Metabolism, vol. 1003, no. 2, pp. 213-216.
Diabetes UK Professional Conference 2013
Activity: Participation in conference
Diabetes UK (External organisation)
Activity: Membership of external research organisation