Overview

My overarching interest is in the causes and consequences of abnormal insulin action in human disease. I aim ultimately to gain insights into the nature and mechanisms of "common" insulin resistance, and into potentially modifiable mechanisms linking it to major diseases such as type 2 diabetes, fatty liver, dyslipidaemia, subfertility and cancer. To achieve this, my lab focuses on the genetic, cellular and molecular basis of extreme human disorders of insulin action, whether genetic or antibody-mediated, and ranging from severe insulin resistance to spontaneous non insulin-dependent hypoglycaemia. Many of the conditions we study feature primary abnormalities either the insulin receptor (INSR) or downstream phosphatidylinositol-3-kinase (PI3K).  As well as undertaking mechanistically informative studies of relevance to common disease, I have a major translational interest in improving diagnostic pathways and therapy for patients with these rare disorders. Core approaches include physiological phenotyping of humans with rare genetic syndromes, dissection of insulin action in primary cells from affected patients ex vivo, and identification of causative genetic defects using hypothesis-led and non hypothesis-driven genetic approaches.

Specific Interests

The modern pandemic of obesity-related diseases has its origins in chronic positive energy balance driven by easy availability of energy dense foot and increasingly sedentary lifestyles.  However the risk of disease in this environment is not uniform, and many lines of evidence suggest that heritable aspects of adipose tissue behaviour are critical in determining risk of metabolic complications of obesity. This means that understanding how adipose tissue adapts or maladapts to sustained caloric burdens through processes involving hyperplasia, hypertrophy and remodelling of topography is central to understanding disease propensity.  This is the first focus of my research programme, concentrating on rare human single gene disorders that we have discovered implicating unsuspected cellular defects (e.g. in DNA replication/repair or mitochondrial network function) in pathological adipose remodelling and insulin resistance.   

Insulin resistance is generally defined be attenuating of the blood glucose-lowering effect of insulin, however insulin exerts cellular actions via a complex signalling network that may function differently among different insulin-responsive tissues.  It has long been recognised that “insulin resistance” could in principle be patchy or incomplete, and supporting this we have observed that human genetic defects in proximal insulin signalling cause insulin resistance subphenotypes that differ from “common” insulin resistance, uncoupling fatty liver, dyslipidaemia and suppressed plasma adiponectin from very severe systemic insulin resistance.   The second focus of my programme is on understanding the nature of pandemic insulin resistance, and the mechanisms linking it to disease, by focusing on such human monogenic examples of perturbed insulin signalling (e.g. mutations in INSR or PIK3R1), and asking which pathologies are linked to lack of insulin action, and which instead are caused by the “toxic” effects of compensatory hyperinsulinaemia.

Related to the above line of research, I am also interested in novel translational approaches to lethal recessive insulin receptoropathy, and with my collaborator Prof Kenneth Siddle (Cambridge) my lab is investigating the potential of monoclonal anti-INSR antibodies to circumvent insulin signalling defects in extreme infantile forms of insulin resistance.

The final line of my laboratory’s work relates not to mutations causing loss of function of insulin/PI3K/AKT signalling, but rather to mutations conferring gain of function.  Such mutations, especially but not exclusively in PIK3CA, when occurring postzygotically, lead to a range of debilitating human overgrowth disorders that we and others have named the PIK3CA-related overgrowth spectrum.  Over the past few years we have assembled a large cohort of affected patients, have studied genotype-correlations, have undertaken a pilot therapeutic study, and are now focusing on disease modelling in human induced pluripotent stem cell-based models.

My main funding comes from the Wellcome Trust, with important additional support from Diabetes UK, and, for continuing studies in Cambridge, where I retain visiting scientist status, from the NIHR through the Cambridge Biomedical Research Centre.