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Robert Semple

Wellcome Trust Senior Research Fellow in Clinical Science

Honorary Consultant Physician

Department of Clinical Biochemistry

Group members


Research Interests

Staff photo

My main interest is the pathophysiology of abnormal insulin action in human disease. I focus on the genetic, cellular and molecular basis of human genetic disorders of insulin action, 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. Our aim  is to, 1. Uncover novel candidate genes in which milder variation may contribute to the heritability of prevalent forms of insulin resistance 2. Gaining mechanistic insights into the link between insulin resistance and major pathologies such as diabetes, fatty liver disease, ovulatory dysfunction and cancer and 3. 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 disorders of phosphatidylinositol-3-kinase/AKT signalling, and on the links among impaired centrosomal function, DNA damage responses and severe insulin resistance.

I am funded by the Wellcome Trust, with additional support from the NIHR both through the Cambridge Biomedical Research Centre and the Rare Diseases Translational Research Collaboration.


Selected Publications


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


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


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 humaninduced pluripotent stem cells. J Clin Invest, 120(9):3127-36. PMID: 20739751. PMCID: PMC2929734.


Regan FM, Williams RM, McDonald, A, Umpleby AM, Acerini CL, O'Rahilly S, Hovorka R, Semple RK, Dunger DB. Treatment with Recombinant human insulin-like growth factor (rhIGF)-I/rhlGF binding protein 3 complex improves metabolic control in subjects with severe insulin resistance. (2010). J Clin Endocrinol Metab, 95(5):2113-22. PMID: 20233784.


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.


Semple RK, Cochran EK, Soos MA, Burling KA, Savage DB, Gorden P, O'Rahilly S. (2008). Plasma Adiponectin as a Marker of Insulin Receptor Dysfunction: Clinical Utility in Severe Insulin Resistance. Diabetes Care, 31(5):977-9. PMID: 18299442.


Semple RK, Halberg NH, Burling K, Soos MA, Schraw T, Luan J, Cochran EK, Dunger DB, Wareham NJ, Scherer PE, Gorden P, O'Rahilly S. (2007). Paradoxical elevation of high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies. Diabetes, 56(6):1712-7. PMID: 17325257. PMCID: PMC2253187.


Semple RK, Soos MA, Luan J, Mitchell CS, Wilson JC, Cochran EK, Gorden P, Chatterjee VKK, Wareham NJ, O'Rahilly S. (2006). Elevated plasma adiponectin in humans with genetically defective insulin receptors. J Clin Endocrinol Metab, 91(8):3219-23. PMID: 16705075.




Parker VER, Savage DB, O'Rahilly, Semple RK. (2011). Mechanistic Insights into Insulin Resistance in the Genetic Era. Diabetic Medicine, 28(12):1476-86. PMID: 21992440.


Semple RK, Savage DB, Cochran EK, Gorden P, O'Rahilly S. (2011). Genetic syndromes of severe insulin resistance. Endocr Rev, Epub ahead of print.


Savage DB, Semple RK. (2010). Recent Insights into Fatty Liver, Metabolic Dyslipidaemia and their Links to Insulin Resistance. Curr Opin Lipidol, 21(4):329-36. PMID: 20581678.