Diabetes Type 1
Type 1 diabetes (T1DM) or Insulin Dependent Diabetes Mellitus (IDDM) is one of the most common chronic diseases at childhood, affecting around one in 700 Australian children. More than 1000 children develop T1DM each year, and the incidence is increasing by 3% each year. The financial burden of T1DM is enormous, with a direct health expenditure of $180 million in 2001-2002 at Australia.
T1DM is a multifactorial and polygenic disease characterised by destruction of insulin-producing cells in the pancreatic islets with autoimmune features. Approximately 85% of patients have circulating islet cell antibodies, and the majority also have detectable anti-insulin antibodies before receiving insulin therapy. Most islet cell antibodies are directed against glutamic acid decarboxylase (GAD) within pancreatic beta-cells.
There are several existing lines of evidence demonstrating enteroviruses infection in patients at T1D onset and the temporal association between infection and development of islet autoantibodies in pre-diabetic children indicates enteroviruses have a role in the causal pathway to T1D in at least some cases. There is also suggestive evidence that enteroviruses contribute to other cases, either by direct infection and/or activation of beta-cell autoimmunity.
Enterovirus Infection and T1DM
Multiple factors are associated with T1DM in humans, including genetic predisposition and environmental agents, enteroviruses. We have previously reported higher rates of EV RNA in children at diagnosis of T1DM compared with non-diabetic controls (30% vs 4%), in keeping with other smaller studies. There is marked seasonal variation in beta-cell autoimmunity coinciding with the incidence of enterovirus infection. We and others have demonstrated that enterovirus infection often precedes the appearance of islet autoimmunity and manifestation of diabetic symptom. The most compelling evidence for a pivotal role of enteroviruses in T1DM is cases in which enteroviruses have been detected in pancreatic islets from T1DM patients or children who demonstrate markers of beta–cell autoimmunity. Enterovirus isolates obtained from these patients destroyed human islets and caused diabetes in laboratory animals and in vitro cellular models and cultured islets. While these data collectively support an important role for EV in T1DM pathogenesis, direct evidence for a causal association of enterovirus infection with disease development is still missing.
Of the over 90 known human enteroviruses, the 14 species linked to T1DM include Coxsackievirus A9 (CVA9), Coxsackieviruses B1 to B6 (CVB1-6), ECHO1, ECHO6, ECHO9, ECHO11, ECHO16, ECHO30 and Enterovirus71. The majority of these enteroviruses are from Human Enterovirus Group B, except Enterovirus 71 which is from Group A. These viruses are genetically similar and phylogenetically clustered, suggesting that only a certain group of these viruses may possess diabetogenic properties. In vitro, many of these enteroviruses cause cytolysis and impair the insulin-production of human pancreatic islets. Among different enterovirus, CVBs appear to be more active in destroying islets. Moreover, variants of CVB4 and ECHO30 have been shown to display very different infectivity and destructive effects on the islets. It is not fully understood how enteroviruses can cause beta-cell damage and whether different enteroviruses may act differently to induce the destructive effects. A critical unresolved question in T1D is how endogenous beta-cell antigens become immunogenic and whether environmental factors, such as viruses, initiate this process.
We hypothesise that T1D can result from enterovirus infection of pancreatic beta-cells, inducing production of pro-inflammatory cytokines and chemokines and cell death by apoptosis.
Selected Publications:
Craig ME, Nair S, Stein H, Rawlinson WD. Viruses and Diabetes: a new look at an old story (Invited review). Pediatric Diabetes, 14, 149-58, 2013
Han M, Craig ME. Autologous Cord Blood – A New Direction for Prevention of Type 1 Diabetes? Medical Journal of Australia, 199:288-90, 2013
Penno MA, Couper JJ, Craig ME, Colman PG, Rawlinson WD, Cotterill AM, Jones TW, Harrison LC. Environmental determinants of islet autoimmunity (ENDIA): a pregnancy to early life cohort study in children at-risk of type 1 diabetes. BMC Pediatrics, 13(1), 124, 2013
Nair S, Akil A, Craig ME. Enterovirus infection, ?-cell apoptosis and type 1 diabetes. Microbiology Australia: 34(3): 153-6, September 2013
Craig ME, Donaghue KC. Detection and prevention of diabetic nephropathy in type 1 diabetes. Diabetes Management Journal 26:6-8, 2013
Cho YH, Craig ME, Donaghue KC. Puberty as an accelerator for diabetes complications. Pediatric Diabetes (in press)
Islam S, Abraham A, Donaghue KC, Chan AK, Lloyd M, Srinivasan S, Craig ME. Plateau of adiposity in Australian children diagnosed with type 1 diabetes – a 20 year study. Diabetic Medicine (in press)
Basha J, Iwasenko J, Robertson P, Craig ME, Rawlinson WD. Congenital cytomegalovirus (CMV) infection is associated with high maternal socioeconomic status and corresponding low maternal CMV seropositivity. Journal of Paediatrics and Child Health (in press)
Poon M, Craig ME, Kaur H, Cusumano J, Sasongo MB, Wong T, Donaghue KC. Vitamin D Deficiency Is Not Associated with Changes in Retinal Geometric Parameters in Young People with Type 1 Diabetes. Journal of Diabetes Research 280691. doi: 10.1155/2013/280691. Epub Jul 7, 2013
Shun C, Phelan H, Donaghue KC, Twigg SM, Craig ME. Thyroid autoimmunity in type 1 diabetes – systematic review and meta-analysis. Diabetic Medicine Sep 16, 2013. doi: 10.1111/dme.12318. [Epub ahead of print]
Pham-Short A, Donaghue KC, Ambler GR, Chan AK, Hing S, Cusumano J, Craig ME. Early elevation of albumin excretion rate is associated with poor gluten free diet adherence in young people with coeliac disease and diabetes. Diabetic Medicine Sep 30. 2013 doi: 10.1111/dme.12329. [Epub ahead of print]
Cho YH, Craig ME, Srinivasan S, Benitez-Aguirre P, Mitchell P, Jopling T, Donaghue KC. Heart rate variability in pubertal girls with type 1 diabetes: its relationship with glycaemic control, insulin resistance and hyperandrogenism. Clin Endocrinol (Oxf). 2013 May 7. doi: 10.1111/cen.12238. [Epub ahead of print]
Marcovecchio ML, Woodside J, Jones TW, Daneman D, Neil A, Prevost T, Dalton RN, Deanfield J, Dunger D, on behalf of the AdDIT Investigators. Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT): Urinary screening and baseline biochemical and cardiovascular assessments. Diabetes Care 2013 Nov 6. [Epub ahead of print]
Deal CL, Tony M, Höybye C, Allen DB, Tauber M, Christiansen JS; 2011 Growth Hormone in Prader-Willi Syndrome Clinical Care Guidelines Workshop Participants. J Clin Endocrinol Metab. 98(6):E1072-87. doi: 10.1210/jc.2012-3888, 2013. Epub 2013 Mar 29. Review.
Craig ME, Tran F. Type 2 diabetes in childhood. Conquest Diabetes Australia. Winter 2013
Craig ME: Autoimmune risk in type 1 diabetes Diabetes Connect, 18 Winter 2013
Tang M, Donaghue KC, Cho YH, Craig ME: Autonomic neuropathy in young people with type 1 diabetes: a systematic review. Paediatric Diabetes, 14:249-38, 2013
Naing Z, Rayner B, Killikulangara A, Vunnam K, Leach S, McIver S, Scott GM, Craig ME, Lui K, Rawlinson WD. Prevalence of viruses in stool of premature neonates at a Neonatal Intensive Care Unit. Journal of Paediatrics and Child Health, Mar;49(3):E221-6. doi: 10.1111/jpc.12113, 2013
Klocker A, Phelan H, Twigg SW, Craig ME. Blood ?-hydroxybutyrate versus urine acetoacetate testing for the prevention and management of diabetic ketoacidosis in people with type 1 diabetes: a systematic review. Diabetic Medicine. Diabet Med. 2013 Jul;30(7):818-24. doi: 10.1111/dme.12136.
Hamilton ST, Scott G, Naing Z, Iwasenko J, Hall B, Graf N, Arbuckle S, Craig ME, Rawlinson WD. Human Cytomegalovirus-Induces Cytokine Changes in the Placenta with Implications for Adverse Pregnancy Outcomes. PLoS One, 7(12):e52899. doi: 10.1371/journal.pone.00528992012
Cameron FJ, Cotterill A, Couper JJ, Craig ME, Davis EA, Donaghue KC, Jones TW King B, Sheil B,. Care for children and adolescents with diabetes in Australia and New Zealand: have we achieved the defined goals? Journal of Pediatrics and Child Health, in press doi:10.1111/jpc.12145
The Australian National Adult Insulin Pump Working Group: Provision of Quality Care for Adults with Type 1 diabetes requiring insulin pump therapy. Infusystems Asia: 8(1):1-6, 2013
Maguire A, Ambler GR, Craig ME. Short stature in children: when is further evaluation and referral required. Endocrinology Today, 2(1): 6-13, 2013
Scheermeyer E, Hughes I, Harris M, Ambler G, Crock P, Verge CF, Craig ME, Bergman P, Werther G, van Driel M, Davies P, Choong CSY. Response to GH treatment in PWS: auxological criteria versus genetic diagnosis. Journal of Paediatrics and Child Health, in press (accepted 15/04/2013)
Cho YH, Craig ME, Srinivasan S, Benitez-Aguirre P, Mitchell P, Joplin T, Donaghue KC. Heart rate variability in pubertal girls with type 1 diabetes: its relationship with glycemic control, insulin resistance and hyperandrogenism. Clinical Endocrinology (Oxf), May 7. doi: 10.1111/cen.12238, 2013. [Epub ahead of print]
Rana M, Munns CF, Selvadurai H, Briody J, Craig ME. The impact of dysglycaemia on bone mineral accrual in young people with Cystic Fibrosis. Clinical Endocrinology (Oxf); 78(1), 36-42, 2013
Lv J, Perkovic V, Foote CV, Craig ME, Craig JC, Strippoli GF. Antihypertensive agents for preventing diabetic kidney disease. Cochrane Database of Systematic Reviews 2012, Issue 4. CD004136. DOI:10.1002/14651858.CD004136.pub2.
Yeung WC, Al-Shabeeb A, Pang CN, Wilkins MR, Catteau J, Howard NJ, Rawlinson WD, Craig ME. Children with islet autoimmunity and enterovirus infection demonstrate a distinct cytokine profile. Diabetes, 61(6): 1500-8, 2012. PMID: 22474026
Benitez-Aguirre PZ, Sasongko MB, Craig ME, Jenkins AJ, Cusumano J, Cheung N, Wong TY, Donaghue KC. Retinal vascular geometry predicts incident renal dysfunction in young people with type 1 diabetes. Diabetes Care. 35(3):599-604, 2012
Cho YH, Besser R, Craig ME. Highlights from the Highlights from the 37th Annual Meeting for ISPAD, Miami. Pediatric Diabetes, Feb;13(1):124-31, 2012
Benitez-Aguirre PZ, Craig ME, Jenkins AJ, Gallego PH, Cusumano J, Duffin AC, Donaghue KC. Plantar fascia thickness is associated with persistent retinopathy and renal dysfunction: A longitudinal study from adolescence to adulthood. Journal of Diabetes Science and Technology, 1;6(2):348-55, 2012
Balzer B, Graham C, Craig ME, Selvadurai H, Donaghue KC, Brand-Miller J, Steinbeck K. Low glycaemic index dietary interventions in youth with cystic fibrosis: a systematic review and discussion of the clinical implications. Nutrients, 4(4), 286-296; 2012 doi:10.3390/nu4040286 2012
Pham A, Donaghue KC, Ambler GR, Chan AK, Craig ME: Coeliac disease in type 1 diabetes from 1990 – 2009: higher incidence in young children after longer diabetes duration. Diabetic Medicine, 29(9), 286-9, 2012
Phelan H, Twigg S, Craig ME. Type 1 diabetes is different: Key messages from the guidelines. Endocrinology Today, 1(1):8-16, 2012
Phelan H, Craig ME, Twigg S. Type 1 Diabetes is Different: Recommendations from the National Evidence-based Clinical Care Guidelines for Type 1 Diabetes in Children, Adolescents and Adults 2011. Diabetes Management Journal, 32-33, 2012
Claessen FM, Donaghue K, Craig ME. Consistently high incidence of diabetic ketoacidosis in children with newly diagnosed type 1 diabetes. Med J Aust. 2012 Aug 20;197(4):216.
Kiefer DG, Keeler LC, Rust O, Chow SS, Craig ME, Peltier MR, Vintzileos AM, Rawlinson WD, Hanna N. Amniotic fluid inflammatory score is associated with pregnancy outcome in patients with mid trimester short cervix. Am J Obstet Gynecol. 206(1) 68 e1-6, 2012
Nucci AM, Becker DJ, Virtanen SM, Cuthbertson D, Softness B, Huot C, Wasikowa R, Dosch HM, Åkerblom HK, Knip M, The TRIGR Study Group. Growth differences between North American and European children at risk for type 1 diabetes. Paediatric Diabetes, 13(5): 425-31, 2012
Craig ME, Donaghue KC, Cameron FJ, Silink M. Change of HbA1c reporting to the new SI units. Medical Journal of Australia. 195 (9):514, 2011
Scott GM, Chow SSW, Craig ME, Pang CN, Hall B, Wilkins MR, Jones CA, Lloyd AR, Rawlinson WD. Cytomegalovirus infection during pregnancy with materno-fetal transmission induces a pro-inflammatory cytokine bias in placenta and amniotic fluid. Journal of Infectious Diseases, 205(8):1305-10, 2012
Yeung G, Rawlinson WD, Craig ME. Enterovirus Infection and Type 1 Diabetes Mellitus – A systematic review of molecular studies. British Medical Journal 342:d35 doi:10.1136/bmj.d35 2011
Downie E, Craig ME, Hing S, Cusumano J, Chan AK, Donaghue KC. Continued reduction in the prevalence of retinopathy in adolescents with type 1 diabetes – role of insulin therapy and glycemic control. Diabetes Care 34:2368–2373, 2011
Cho H, Craig ME, Hing S, Gallego PH, Poon M, Chan A, Donaghue KC. Microvascular complications assessment in adolescents with 2- 5 years duration of Type 1 diabetes from 1990-2006. Pediatric Diabetes 12(8), 682-9, 2011
Benitez-Aguirre P, Craig ME, Sasongko MB, Jenkins AJ, Wong TY, Wang JJ, Cheung N, Donaghue KC Retinal vascular geometry predicts incident retinopathy in young people with type 1 diabetes: a prospective cohort study from adolescence. Diabetes Care 34(7); 1622-7, 2011
Kaur H, Donaghue KC, Chan AK, Benitez-Aguirre P, Hing S, Lloyd M, Cusumano J, Pryke A, Craig ME. Vitamin D deficiency is associated with retinopathy in children and adolescents with type 1 diabetes. Diabetes Care 34:1400–1402, 2011
Iwasenko JM, Howard J, Arbuckle S, Graf N, Hall B, Craig ME, Rawlinson WD. CMV infection is detected frequently in stillbirths, in association with fetal thrombotic vasculopathy. Journal of Infectious Diseases 203(11);1526-33, 2011
Tran F, Nguyen HT, Vu DC, Bui TP, Can NT, Nguyen KN, Huynh LT, Nguyen KP, Nguyen VT, Tran HM, Tran D, Hoang TD, Harkin N, Armstrong K, Jameson K, Pham A, Cowell CT, Craig ME. Glycemic Control in Children with Neonatal Diabetes and Type 1 Diabetes in Vietnam. International Health, 3 (3), 188-92, 2011
TRIGR Study Group. Akerblom HK, Krischer J, Virtanen SM, Berseth C, Becker D, Dupré J, Ilonen J, Trucco M, Savilahti E, Koski K, Pajakkala E, Fransiscus M, Lough G, Bradley B, Koski M, Knip M. The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study: recruitment, intervention and follow-up. Diabetologia. 54(3):627-633, 2011
Knip M, Virtanen SM, Becker D, Dupré J, Krischer JP, Åkerblom HK; TRIGR Study Group. Early feeding and risk of type 1 diabetes: experiences from the Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR). Am J Clin Nutr 94(6 Suppl):1814S-1820S, 2011
Hameed S, Ellard S, Woodhead HJ, Neville KA, Walker JA, Craig ME, Armstrong T, Yu L, Eisenbath G, Hattersley AT, Verge CF. Persistently autoantibody negative (pan) type 1 diabetes mellitus in children. Pediatric Diabetes 2011 May;12(3 Pt 1):142-9.
Rana M, Munns CF, Selvadurai H, Simonds S, Cooper P, Woodhead HJ, Hameed S, Verge CF, Lafferty AR, Crock PA, Craig ME. Increased detection of Cystic Fibrosis Related Diabetes in Australia. Arch Dis Child 96(9):823-6, 2011
Craig ME, Donaghue KC, Cameron FJ, Silink M. Change of HbA1c reporting – targets for children and adolescents (letter). Medical Journal of Australia, doi: 10.5694/mja11.10583, 2011
Garnett SJ, Srinivasan S, Birt S, Ambler G, Lawrie E, Cowell CT, Craig ME. Evaluation of glycemic status in young people with clinical insulin resistance; fasting glucose, fasting insulin or an OGTT? Clinical Endocrinology (Oxf). 2010 72(4), 475-480
Nair S, Leung K-C, Rawlinson WD, Naing Z, Craig ME. Enterovirus Infection induces Cytokine and Chemokine Expression in Insulin Producing Cells. Journal of Medical Virology 82(11):1950-7, 2010
Warne GL, Armstrong KL, Faunce TA, Wilcken BM, Boneh A, Geelhoed E, Craig ME: The case for newborn screening for congenital adrenal hyperplasia in Australia. Medical Journal of Australia 192:107, 2010
Craig ME, Wong C. Diabetic Ketoacidosis: an update. Medical Observer, 29-31, June 2010
Rana M, Munns CF, Selvadurai H, Donaghue KC, Craig ME. Cystic Fibrosis Related Diabetes in Children-Gaps in the Evidence? Nature Clinical Practice Endocrinology and Metabolism, 6(7):371-8, 2010
