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Calum Sutherland

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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 £5 million in the last 15 years, successfully supervised 9 PhD students, 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 poor insulin response that would help identify people at high risk of developing Type 2 Diabetes. 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.


Insulin Signalling and Disease

Funding: Diabetes UK, British Heart Foundation, Tenovus Scotland.

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. For example, insulin affects the production of over 100 proteins. Defects in the expression of one or more genes may contribute to the pathophysiology of diabetes and its complications 1-5. Our group currently studies three aspects of insulin action.

1) Insulin signaling in the liver.  We have identified the PDK1-PKB-GSK3 pathway as a key regulator of these genes, and an excellent target for pharmacological reduction of blood glucose levels 6-9. In addition, we have examined agents that mimic insulin action of these genes to identify novel glucose lowering pathways and therapeutic targets 10Finally using our knowledge of these systems we are developing cellular models to permit screening for novel anti-diabetic agents 11.

2) 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 12The human studies are generating new information on potential ‘biomarkers’ of early progression to diabetes, which should allow earlier and more efficacious intervention (Ruiz-Alcaraz et al 2013 in review). 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.

3) 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.

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