Projects per year
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.
Generating Evidence that RABEP2 is a Novel GSK3 Substrate that Represents a Single Therapeutic Target to Reduce Both Hyperglycemia and Microvascular Disease in Diabetes (joint with Glasgow Uni)
1/06/20 → 31/05/23
An Investigation of How Insulin Receptor Function Could Influence the Development of Insulin Resistance and Type 2 Diabestes
1/02/20 → 31/01/21
Reducing Glut2 throughout the body does not result in cognitive behaviour differences in aged male miceMorrice, N., van Aalten, L., McNeilly, A., McCrimmon, R. J., Pearson, E. R., Langston, R. & Sutherland, C., 16 Sep 2020, In : BMC Research Notes. 13, 1, p. 438 6 p., 438.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile7 Downloads (Pure)
Muha, V., Williamson, R., Hills, R., McNeilly, A., McWilliams, T. G., Alonso, J., Schimpl, M., Leney, A. C., Heck, A. J. R., Sutherland, C., Read, K., McCrimmon, R., Brooks, S. P. & van Aalten, D., 27 Nov 2019, In : Open Biology. 9, 11, p. 1-15 15 p.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile1 Citation (Scopus)77 Downloads (Pure)
Sutherland, C., 2 Jan 2019, In : British Journal of Hospital Medicine. 80, 1, p. 4-5 2 p.
Research output: Contribution to journal › Editorial › peer-review
Recruitment, Retainment, and Biomarkers of Response: A Pilot Trial of Lithium in Humans With Mild Cognitive ImpairmentDuthie, A., van Aalten, L., MacDonald, C., McNeilly, A., Gallagher, J., Geddes, J., Lovestone, S. & Sutherland, C., 28 Jun 2019, In : Frontiers in Molecular Neuroscience. 12, p. 1-16 16 p., 163.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile3 Citations (Scopus)107 Downloads (Pure)
Hayes, J. D. & Sutherland, C., Jan 2018, In : Biochemical Pharmacology. 147, p. 77-92 16 p.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile22 Citations (Scopus)211 Downloads (Pure)