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Robert Semple

Wellcome Trust Senior Research Fellow in Clinical Science

Honorary Consultant Physician

Department of Clinical Biochemistry

rks16@cam.ac.uk

Group members

 

Research Interests

Staff photo

My main interest is in the pathophysiology of abnormal insulin action in human disease. In particular, I would like 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 diabees, fatty liver, dyslipidaemia, subfertility and cancer. In an attempt to achieve this, the 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 disorders involving gain or loss of function of phosphatidylinositol-3-kinase/AKT signalling, on the links among impaired centrosomal function, DNA damage responses and severe insulin resistance, and on developing novel diagnostic strategies and therapies for patients with insulin receptor mutations, or antibodies interfering with insulin action.

 

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. Funding was also received from the Society for Endocrinology for a summer studentship.

 

Selected Publications

 

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

 

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.

  

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. 

 

Reviews

 

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. PMID: 21536711.

 

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.