My main interest is in the pathophysiology of abnormal insulin action in human disease. In particular, I aim 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. I am particularly interested in disorders that couple these metabolic disturbances to abnormal growth. 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. Particular interest in the lab at the moment is focussed on:
- Human disorders caused by mosaic genetic activation of class 1A phosphatidylinositol-3-kinase/AKT/mTOR signalling (Rachel Knox, Leena De Silva, Ralitsa Madsen)
- Human diseases caused by mutations in PIK3R1-encoded regulatory subunits of phosphatidylinositol-3-kinase (Albert Kwok, Patsy Tomlinson)
- Links between multiple symmetrical lipomatosis and mutations in MFN2 (Nuno Rocha, David Bulger)
- Novel aspects of insulin signalling (Gemma Brierley, David Bulger)
- Developing novel diagnostic strategies and therapies for patients with insulin receptor mutations, or antibodies interfering with insulin action (Gemma Brierley, David Church)
- Links between impaired DNA replication and damage responses and severe insulin resistance (Jian Hua Chen, Nuno Rocha, Yukai Wang)
Support across many projects is provided by Conny Gewert and Julie Harris
My main funding comes from the Wellcome Trust, with important additional support from the NIHR through the Cambridge Biomedical Research Centre and the Rare Diseases Translational Research Collaboration, from Diabetes UK and from The Diabetes Research and Wellness Foundation.
Huang-Doran I, Tomlinson P, Payne F, Gast A, Sleigh A, Bottomley W, Harris J, Daly A, Rocha N, Rudge S, Clark J, Kwok A, Romeo S, McCann E, Müksch B, Dattani M, Zucchini S, Wakelam M, Foukas LC, Savage DB, Murphy R, O’Rahilly S, Barroso I, Semple RK Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations J.Clin.Inv (Insight) (in press, 2016). PMID:27766312. PMCID:PMC5070960.
Chen JH, Segni M, Payne F, Huang-Doran I, Sleigh A, Adams C; UK10K Consortium, Savage DB, O’Rahilly S, Semple RK, Barroso I. Truncation of POC1A associated with short stature and extreme insulin resistance. J Mol Endocrinol. 2015 Oct;55(2):147-58. 2015 Oct;55(2):147-58. PMID:26336158. PMCID: PMC4722288.
Payne F, Colnaghi R, Rocha N, Seth A, Harris J, Carpenter G, Bottomley W, Wheeler E, Wong S, Saudek V, Savage DB, O’Rahilly S, Carel J-C, Barroso I, O’Driscoll M, Semple RK Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance J.Clin.Inv 2014 Sep 2;124(9):4028-38. PMID: 25105364. PMCID: PMC4151221.
Lindhurst MJ, Parker VE, Payne F, Sapp JC, Rudge S, Harris J, Witkowski AM, Zhang Q, Groeneveld MP, Scott CE, Daly A, Huson SM, Tosi LL, Cunningham ML, Darling TN, Geer J, Gucev Z, Sutton VR, Tziotzios C, Dixon AK, Helliwell T, O’Rahilly S, Savage DB, Wakelam MJ, Barroso I, Biesecker LG, Semple RK. (2012). Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA.Nat Genet, 2012 Jun 24;44(8):928-33. PMID: 22729222. PMCID: PMC3461408.
Hussain K, Challis B, Rocha N, Payne F, Minic M, Thompson A, Daly A, Scott C, Harris J, Smillie BJ, Savage DB, Ramaswami U, De Lonlay P, O’Rahilly S, Barroso I, Semple RK. (2011). An Activating Mutation of AKT2 and Human Hypoglycemia. Science,2011 Oct 28;334(6055). PMID: 21979934. PMCID:PMC3204221.
Raffan E, Soos MA, Rocha N, Tuthill A, Thomsen AR, Hyden CS, Gregory JW, Hindmarsh P, Dattani M, Cochran E, Al Kaabi J, Gorden P, Barroso I, Morling N, O’Rahilly S, Semple RK. (2011). Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling. Diabetologia, 54(5):1057-65.PMID: 21318406. PMCID: PMC3071941.
Huang-Doran I, Bicknell LS, Finucane FM, Rocha N, Porter KM, Tung YCL, MOPD Study Groupe, Szekeres F, Krook A, Nolan JJ, O’Driscoll M, Bober M, O’Rahilly S, Jackson Ap, Semple RK. (2011). Genetic Defects in Human Pericentrin Are Associated With Severe Insulin Resistance and Diabetes Mellitus. Diabetes, Jan 26 [Epub ahead of print]. PMID: 21270239. PMCID:PMC3046854.
Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang-Doran I, Griffin J, Ahrlund-Richter L, Skepper J, Semple RK, Weber A, Lomas DA, Vallier L. (2010). Modelling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest, 120(9):3127-36. PMID: 20739751. PMCID: PMC2929734.
Semple RK, Sleigh A, Murgatroyd PR, Adams C, Bluck L, Jackson S, Vottero A, Kanabar D, Charlton-Menys V, Durrington P, Soos MA, Carpenter TA, Lomas DJ, Cochran EK, Gorden P, O’Rahilly S, Savage DB. (2009). Dyslipidaemia hepatic steatosis and selective post-receptor insulin resistance: insights from humans with insulin receptor and post-receptor signalling defects. J Clin Invest, 119(2):315-22.PMID: 19164855. PMCID: PMC2631303.
Topaloglu AK, Reinmann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Imamoglu S, Akalin S, Yuksel B, O’Rahilly S, Semple RK. (2009). Loss of function mutations in TAC3 or TACR3, encoding neurokinin B and its receptor, produce hypogonadotropic hypogonadism in humans. Nat Genet, 41(3):354-8. PMID: 19079066. PMCID:PMC4312696.