Calum Sutherland

+44 (0)1382 383098
Professor of Molecular Medicine

Bio

Biography

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.

Research

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 mechanismThe 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.

Publications

New developments for prevention of type 1 diabetes
12/2018, British Journal of Hospital Medicine
Research Output: Contribution To Journal > Editorial

A partnership with the proteasome
9/2017, Biochemical Pharmacology
Research Output: Contribution To Journal > Article

Rab-GTPase binding effector protein 2 (RABEP2) is a primed substrate for Glycogen Synthase kinase-3 (GSK3)
8/2017, Scientific Reports
Research Output: Contribution To Journal > Article

Proinsulin is stable at room temperature for 24 hours in EDTA
10/2016, PLoS ONE
Research Output: Contribution To Journal > Article

The effect of dietary intervention on the metabolic and behavioural impairments generated by short term high fat feeding in the rat
4/2016, Physiology & Behavior
Research Output: Contribution To Journal > Article

Regulation of the CNC-bZIP transcription factor Nrf2 by Keap1 and the axis between GSK-3 and β-TrCP
10/2016, Current Opinion in Toxicology
Research Output: Contribution To Journal > Review article

Heat Shock Factor 1 is a Substrate for p38 Mitogen-Activated Protein Kinases
6/2016, Molecular and Cellular Biology
Research Output: Contribution To Journal > Article

Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic response to metformin
6/2016, Nature Genetics
Research Output: Contribution To Journal > Letter

Investigation of salicylate hepatic responses in comparison with chemical analogues of the drug
1/2016, Biochimica et Biophysica Acta. Molecular Basis of Disease
Research Output: Contribution To Journal > Article

Phosphorylation of a splice variant of collapsin response mediator protein 2 in the nucleus of tumour cells links cyclin dependent kinase-5 to oncogenesis
5/2015, BMC Cancer
Research Output: Contribution To Journal > Article

View full profile on research portal

Activities

Diabetes UK Professional Conference 2013

Calum Sutherland (Participant)
13 Mar 201015 Mar 2016

Activity: Participating in or organising an event typesParticipation in conference

Activity Type: Attendance

Diabetes UK (External organisation)

Calum Sutherland (Member)
20102012

Activity: Membership typesMembership of external research organisation

Activity Type: Membership