PRADER-WILLI SYNDROME AND GENETIC FORMS OF DIABETES
Whilst our laboratory has a broad interest in the pathophysiology of obesity, insulin resistance and type 2 diabetes, this particular research group focuses on the rarer metabolic diseases which are caused by known single gene variants or known genetic regions.
Prader-Willi syndrome (PWS) is one of the most common known genetic obesity disorders; it causes individuals with the disease to have an insatiable appetite, which often leads to the development of morbid obesity. The syndrome has two separate, opposite phases – infants born with PWS find it difficult to feed and are often underweight; then, as children and adults, they eat voraciously and rapidly gain weight if their food intake is not strictly controlled. The transition between the two phases generally takes place around 2-6 years of age. People with PWS have other problems including poor muscle development, sleep disorders and behavioural difficulties, and many also experience co-morbidities such as cardiovascular disease.
There is currently no pharmacological treatment for excessive appetite in PWS. The only way that this appetite can be controlled is through constant vigilance, behavioural restraints and environmental modifications such as locked fridges and cupboards. Many adults with PWS would be able to live more independently if there were effective appetite treatments.
Garvan established the Clinical PWS Research Group in 2006, and has since then become one of the biggest research groups in this field. It has conducted very informative clinical research in several areas of PWS, helping to understand the physiological basis for the insatiable appetite and to develop treatments to combat it, as well as investigating underlying mechanisms of cardiovascular disease.
Our own research has demonstrated that there is no inherent problem in metabolic rate in adults with PWS, suggesting that increased appetite is the main driver of obesity in this disease (Purtell et al., 2015). To investigate appetite, we investigated how hormone released from the gut after eating can influence the balance of hunger and fullness differently in people with PWS compared to healthy people (Purtell et al., 2011). Since these hormone pathways are so important in PWS, we then tested a hormone-like drug and found that a single injection was successful in causing increased fullness in people with PWS, a hugely promising finding (Sze et al., 2011). This published proof-of-principle study has now been taken into the next stage of development towards a therapy for PWS in a clinical trial in the US. We have also identified two things that are related to increased cardiovascular risk in this syndrome: increased low-grade inflammation (Viardot et al., 2010) and a problem in the autonomic nervous system regulating the cardiovascular system (Purtell et al., 2013).
We have several new projects underway in PWS research, working towards understanding how critical low muscle mass is for bone strength as well as understanding the link between eating and inflammation in people with PWS. Importantly, we are commencing a study testing a novel therapy to reduce appetite, testing also for possible benefits to behaviour and cognition. Finding potential treatments for PWS relies heavily on private family donations. Garvan is extremely grateful to those who are enabling us to tackle this challenging area of work.
Monogenic Forms of Diabetes
Diabetes represents a major health and economic burden to Australia. Diabetes can be classified into a number of different types, most common being type 1 and type 2 diabetes. Because genetic testing is not available in Australia, it is estimated that many are wrongly classified into either of these categories, and may actually have an undiagnosed form of monogenic diabetes. These monogenic forms of diabetes are estimated to be up to 5% of all diabetes patients, compared to 10% of type 1 diabetes and 85% of type 2 diabetes. Importantly, these patients require treatments that differ from standard regimens, and if undiagnosed, suboptimal management can lead to worse clinical outcomes. Therefore, introducing affordable genetic testing is essential. Current clinical diagnostic algorithms propose sequential testing of the most likely affected genes by conventional methods, which is slow, expensive, and delivers only rarely a genetic diagnosis. The recent drop in cost of whole genome sequencing (WGS) means that it is now an attractive tool in the diagnosis of patients with mutations in known monogenic disease genes, and also adds an opportunity to identify new disease genes in mutation-negative patients. These new genes could be used to identify subgroups within type 1 or 2 diabetes which have a distinct metabolic defect and might respond differently to the standard medication, enabling us to individualise the treatment for these patients.
The aim of our work is to test the performance of WGS in the diagnosis of monogenic forms of diabetes in a tertiary referral hospital. This will allow us to tailor the treatment of these newly identified patients according to their gene mutations and to prospectively assess whether the genetic diagnosis changes treatment outcomes and health costs over the following 12 months. In mutation-negative patients we will have the opportunity to further explore and identify new genes and variants underlying the yet undiscovered monogenic forms of diabetes or specific subgroups of type 1 and type 2 diabetes patients.
Polyviou T, MacDougall K, Chambers ES, Viardot A, Psichas A, Jawaid S, HC Harris, Edwards CA, Simpson L, Murphy KG, Zac-Varghese SEK, Blundell JE, Dhillo WS, Bloom SR, Frost GS, Preston T, Tedford MC, Morrison DJ. Randomised clinical study: inulin short chain fatty acid esters for targeted delivery of short chain fatty acids to the human colon. Alimentary Pharmacology & Therapeutics, 2016 Jul [e-pub ahead of print].
Lam T, Hoffman DM, Cukier K, Darnell D, Greenfield JR, Harrison N, Tien-Ming Hng, Morrow AF, Cheung NW. Temporal HbA1c patterns amongst patients with type 2 diabetes: Data from the S4S-DINGO-Diabetes Informatics Group. Diab Res Clin Pract, 2016 116: 159-164.
Purtell L, Viardot A, Campbell J. Vitamin D levels in primary growth hormone deficiency disorder Prader-Willi syndrome. Endocrine, 2016 Aug;53(2):619-20.
Purtell L*, Viardot A*, Sze L, Loughnan G, Steinbeck K, Sainsbury A, Herzog H, Smith A, Campbell LV. Postprandial metabolism in adults with Prader-Willi syndrome. Obesity, 2015 Jun;23(6):1159-65.
Chambers ES*, Viardot A*, Psichas A*, Morrison DJ*, Kevin G. Murphy, Sagen E.K. Zac-Varghese, Kenneth MacDougall, Tom Preston, Catriona Tedford, Graham S. Finlayson, John E. Blundell, Jimmy D. Bell, E. Louise Thomas, Shahrul Mt-Isa, Deborah Ashby, Glen R.Gibson, Sofia Kolida, Waljit S. Dhillo, Stephen R. Bloom, Wayne Morley, Stuart Clegg, Gary Frost. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut, 2015 Nov;64(11):1744-54.
Frost G , Sleeth ML, Arisoylu MA, Lizarbe B, Cerdan S, Brody L, Anastasovska J, Ghourab S, Hankir M, Zhan S, Carling D, Swan J, Gibson G, Viardot A, Morrison D, Thomas EL, Bell JD. The short chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nature Communications. 2014 Apr 29;5:3611.
Samaras K, Viardot A, Botelho NK, Jenkins A, Lord RV. Immune cell-mediated inflammation and the early improvements in glucose metabolism after gastric banding surgery. Diabetologia, 2013 Dec;56(12):2564-72
Tan TM, Field BCT, McCullough KA, Troke RC, Chambers ES, Salem V, Maffe JG, Baynes KCR, De Silva A, Viardot A, Alsafi A, Frost GS, Ghatei MA, Bloom SR. Co-administration of glucagon-like peptide-1 (GLP-1) during glucagon infusion in man results in increased energy expenditure and amelioration of hyperglycaemia. Diabetes. 2013; 62(4):1131-8.
Purtell L, Jenkins A, Viardot A, Herzog H, Sainsbury A, Smith A, Loughnan G, Steinbeck K, Campbell LV, Sze L. Postprandial cardiac autonomic function in Prader-Willi syndrome. Clin Endocrinol (Oxf). 2013 Jul;79(1):128-33.
Viardot A, Heilbronn L, Samocha-Bonet D, Mackay F, Campbell LV, Samaras K. Obesity is associated with activated and insulin resistant immune cells. Diabetes/Metabolism Research and Reviews 2012; 28(5):447-54.
Samaras K, Viardot A, Lee PN, Jenkins A, Botelho NK, Bakopanos A, Lord RV, Hayward CS. Reduced arterial stiffness after weight loss in obese type 2 diabetes and impaired glucose tolerance: the role of immune cell activation and insulin resistance. Diabetes and Vascular Disease Research 2012; 10(1): 40-48.
Chambers E, Guess N, Viardot A, Frost G. Dietary starch and fibre: potential benefits to body weight and glucose metabolism. Review. Diabetes Management 2011; Vol. 1, No. 5, Pages 521-528.
Purtell L, Sze L, Loughnan G, Smith E, Herzog H, Sainsbury A, Steinbeck K, Campbell LV, Viardot A. In adults with Prader-Willi syndrome, elevated ghrelin levels are more consistent with hyperphagia than high PYY and GLP-1 levels. Neuropeptides 2011 Aug; 45(4):301-7.
Sze L, Purtell L, Jenkins A, Loughnan G, Smith E, Herzog H, Sainsbury A, Steinbeck K, Campbell LV, Viardot A. Effects of a single dose of exenatide on appetite, gut hormones, and glucose homeostasis in adults with Prader-Willi syndrome. JCEM 2011Aug; 96(8):E1314-9.
Tam CS*, Viardot A*, Clément K, Tordjman J, Tonks K, Greenfield JR, Campbell LV, Samocha-Bonet D, Heilbronn LK. Short-term overfeeding may induce peripheral insulin resistance without altering subcutaneous adipose tissue macrophages in humans. Diabetes 2010; 59(9):2164-70.
Samocha-Bonet D, Campbell LV, Viardot A, Freund J, Tam CS, Greenfield JR, Heilbronn LK. A family history of type 2 diabetes increases risk factors associated with overfeeding. Diabetologia 2010; 53(8):1700-8.
Viardot A, Lord RV, Samaras K. The effects of weight loss and gastric banding on the innate and adaptive immune system in type 2 diabetes and pre-diabetes. JCEM 2010; 95(6):2845-50.
Viardot A, Sze L, Purtell L, Sainsbury A, Loughnan G, Smith E, Herzog H, Steinbeck K, Campbell LK. Prader-Willi syndrome is associated with activation of the innate immune system independently of central adiposity and insulin resistance. JCEM 2010 Jul;95(7):3392-9.
Viardot A, Heilbronn LK, Gregersen S, Herzog H, Campbell LV. Abnormal postprandial PYY response in insulin sensitive nondiabetic subjects with a strong family history of type 2 diabetes. Int J Obes (Lond). 2008; 32(6):943-8.
Viardot A, Grey ST, Mackay F, Chisholm D. Potential anti-inflammatory role of insulin via the preferential polarization of effector T cells towards a T-helper 2 phenotype. Endocrinology 2007; 148 (1):346-53
Viardot A. Metabolism and appetite regulation in PWS. 3rd Asia Pacific Prader-Willi Syndrome Conference. 11-12 April 2015.
Viardot A, Taylor J, Cooper L, Chudleigh A, Greenfield JR, Campbell LV. Diabetes outreach clinic for the homeless: A model for improved care and outcomes? Oral presentation at the Annual Scientific Meeting of the Australian Diabetes Society (ADS) & Australian Diabetes Educators Association (ADEA); August 28-30, 2013; Sydney.
Purtell L, Viardot A, Sze L, Loughnan G, Smith A, Herzog H, Sainsbury A, Steinbeck K, Campbell LV (2013) Postprandial metabolic profile in adults with Prader-Willi syndrome. 8th International Prader-Willi Syndrome Organization Conference Cambridge.
Purtell L, Campbell LV, Jenkins A, Loughnan G, Steinbeck K, Viardot A (2013) Evidence of low-grade inflammation in adults with Prader-Willi syndrome. 8th International Prader-Willi Syndrome Organization Conference Cambridge.
Purtell L, Viardot A, Jenkins A, Sze L, Loughnan G, Steinbeck K, Campbell LV (2013) Lean mass has a stronger association with bone mineral density than fat mass does in adults with Prader-Willi syndrome. 8th International Prader-Willi Syndrome Organization Conference Cambridge.
Viardot A. Gut hormones – pathophysiology and therapeutical potential for treatment of hyperphagia in Prader-Willi syndrome. Invited oral presentation at the 2nd Asian/Pacific PWS Conference, Sydney, March 10-11, 2012
Purtell L, Sze L, Loughnan G, Smith A, Herzog H, Sainsbury A, Steinbeck K, Campbell LV, Viardot A (2011) Impaired postprandial cardiac autonomic function in Prader-Willi syndrome. Prader-Willi Syndrome Association Conference Orlando.
Campbell L (2011) Byetta: pilot study of a potential new treatment for Prader-Willi Syndrome. Australian Prader-Willi Symposium Sydney.
Viardot A, Sze L, Purtell L, Loughnan G, Smith E, Herzog H, Sainsbury A, Steinbeck K, Campbell LV. Exenatide lowers postprandial glycaemia and increases satiety without side effects in Prader-Willi syndrome. Oral presentation at the 46th EASD Annual Meeting, 20 - 24 September 2010, Stockholm, Sweden.
Viardot A, Sze L, Purtell L, Loughnan G, Smith E, Herzog H, Sainsbury A, Steinbeck K, Campbell LV. Exenatide (Byetta®) increases postprandial fullness without side effects in Prader-Willi syndrome - a pilot study. Oral presentation at the 7th International Prader-Willi Syndrome Organisation Conference; 20-23 May 2010, Taipei, Taiwan.
Purtell L, Sze L, Loughnan G, Smith E, Herzog H, Sainsbury A, Steinbeck K, Campbell L, Viardot A (2010) PWS hyperphagia is not due to impaired GLP-1 or PYY secretion. 7th International Prader-Willi Syndrome Organization Conference Taipei, Taiwan.
Viardot A. Hyperphagia and obesity in Prader-Willi syndrome. Invited speaker at the International Fellow Symposium, Garvan Institute of Medical Research; 14 December 2009; Sydney, Australia.
Purtell L, Sze L, Loughnan G, Smith E, Herzog H, Sainsbury A, Steinbeck K, Campbell L, Viardot A (2010) Critical role for ghrelin, but not PYY or GLP-1, in Prader-Willi syndrome hyperphagia. Australian and New Zealand Obesity Society Annual Meeting Sydney..
Purtell L (2009) PWS at Garvan - a research update. Seminar on Prader-Willi Syndrome Sydney.
Viardot A, Sze L, Purtell L, Sainsbury A, Loughnan G, Smith E, Herzog H, Steinbeck K, Campbell L (2009) Prader-Willi syndrome is associated with activation of the innate immune system independently of central adiposity and insulin resistance. Endocrine Society of Australia and Society of Reproductive Biology Annual Scientific Meeting Adelaide.
Viardot A, Samocha-Bonet D, Greenfield JR, Campbell LV, Heilbronn LK. Weight gain in humans induces insulin resistance in absence of systemic and adipose tissue inflammation. Oral presentation at the Annual Scientific Meeting of the European Association for the Study of Diabetes (EASD); September 30 October 2, 2009; Vienna, Austria.
Viardot A, Samocha-Bonet D, Greenfield JR, Campbell LV, Heilbronn LK. Experimental weight gain induces insulin resistance in absence of adipose tissue inflammation in humans. Oral presentation at the Annual Scientific Meeting of the Australian Diabetes Society (ADS) & Australian Diabetes Educators Association (ADEA); August 26-28, 2009; Adelaide, South Australia.
Viardot A, Samocha-Bonet D, Heilbronn LK, Campbell LV. The role of immune activation in insulin sensitive non-diabetic subjects with a strong family history of type 2 diabetes. Abstract at the Annual Scientific Meeting of the Australian Diabetes Society (ADS) & Australian Diabetes Educators Association (ADEA); August 26-28, 2009; Adelaide, South Australia.
Viardot A, Purtell L, Herzog H, Sainsbury A, Loughnan G, Steinbeck KS, Campbell LV. Prader-Willi syndrome is associated with activation of the innate immune system independently from central adiposity and insulin resistance. Abstract at the Annual Scientific Meeting of the Endocrine Society Australia (ESA); August 24-26, 2009; Adelaide, South Australia.
Viardot A, Heilbronn LK, Samocha-Bonet D, Mackay F, Campbell LV, Samaras K. Pro-inflammatory T-lymphocytes linking insulin resistance and adipose tissue inflammation in obesity and type 2 diabetes. Abstract at the Keystone Symposium for Type 2 Diabetes, January 20-25, 2009, Banff, Canada.
Viardot A, Gregersen S, Heilbronn LK, Herzog H, Campbell LV. Postprandial PYY response is blunted in non-diabetic subjects with a strong family history of type 2 diabetes. Oral presentation at the 90th annual meeting of the Endocrine Society, 15-18 June 2008, San Francisco, CA.
Viardot A. The role of appetite regulating hormones in Prader-Willi syndrome. Oral presentation at the 1st Asian/Pacific PWS Conference, Te Papa National Museum, Wellington, March 1-2, 2008.
Viardot A, Samaras K, Heilbronn LK, Mackay F, Campbell LV. Weight Gain And Insulin Resistance Promote T Cell Polarization Towards A Type 1-T Helper Cell Phenotype. A Trigger For Auto-Immune Diabetes? Abstract at the 90th annual meeting of the Endocrine Society, 15-18 June 2008, San Francisco, CA
Viardot A, Herzog H, Campbell LV. Has gut-derived hormone PYY 3-36 a causative role in hyperphagia and obesity in Prader-Willi syndrome? Abstract at the IPWSO Scientific Conference in Cluj-Napoca, Romania, June 21-22, 2007
Viardot A, Mackay F, Campbell LV. PYY 3-36 Has Anti-Inflammatory Effects on T-Lymphocytes. Is There a Role in Inflammation in Obesity and T2D? Poster at the 89th annual meeting of the Endocrine Society, 2-5 June 2007, Toronto, CA
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