Diabetes Research Centre2008 Abstracts
The accelerator hypothesis and increasing incidence of type 1 diabetes
Fourlanos S, Harrison LC, Colman PG
Pediatr Diabetes Curr Opin Endocrinol Diabetes Obes. 15:321-325 (2008)
PURPOSE OF REVIEW: To summarize the relevance of the 'accelerator hypothesis' to type 1 diabetes pathogenesis and examine if recent evidence supports the hypothesis. The 'accelerator hypothesis' proposes 'three processes in type 1 diabetes which variably accelerate the loss of beta cells through apoptosis: constitution, insulin resistance and autoimmunity'. RECENT FINDINGS: Insulin resistance is an independent risk factor for progression to clinical type 1 diabetes in people with islet autoimmunity. Higher bodyweight is also associated with type 1 diabetes development although no longitudinal studies have simultaneously assessed bodyweight and insulin resistance in preclinical diabetes. Currently, there is no evidence for the view that accelerated beta-cell apoptosis is due to insulin resistance in the pathogenesis of type 1 diabetes. SUMMARY: Insulin resistance accelerates development of type 1 diabetes in people with islet autoimmunity and insulin deficiency. The increasingly 'obesogenic' environment which promotes insulin resistance could account for the rising incidence of type 1 diabetes.
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The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes
Fourlanos S, Varney MD, Tait BD, Morahan G, Honeyman MC, Colman PG, Harrison LC
Diabetes Care. 31:1546-1549 (2008)
OBJECTIVE: The rising incidence of type 1 diabetes has been attributed to environment, implying a lesser role for genetic susceptibility. However, the rise could be accounted for by either more cases with classic high-risk genes or by cases with other risk genes. Separately, for any degree of genetic susceptibility, age at presentation may decrease in a permissive environment. To examine these possibilities, human leukocyte antigen (HLA) class II DRB1 genes known to confer risk for type 1 diabetes were analyzed in relation to year of birth and age at diagnosis over the last five decades. RESEARCH DESIGN AND METHODS: Caucasoid subjects (n = 462) diagnosed with type 1 diabetes before age 18 between 1950 and 2005 were DRB1 genotyped. RESULTS: Mean +/- SD age at diagnosis, 8.5 +/- 4.5 years, did not differ across decades. Recent diagnosis was associated with a lower proportion but unchanged incidence of the highest-risk DRB1 genotype DR3,4 (2000-2005, 28% vs. 1950-1969, 79%; P < 0.0001) and a higher proportion of lower-risk genotypes DR4,X and DR3,X (2000-2005, 48% vs. 1950-1969, 20%; P = 0.0002). The frequency of the DRX,X genotype was low (<or=3%) across decades. Recent birth was associated with a lower age at diagnosis for lower risk DR3,3 and DR4,4 (P < 0.0001) and DR4,X (P < 0.0001) and DR3,X (P = 0.015) genotypes but not for DR3,4. CONCLUSIONS: The rising incidence and decreasing age at diagnosis of type 1 diabetes is accounted for by the impact of environment on children with lower-risk HLA class II genes, who previously would not have developed type 1 diabetes in childhood.
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Vaccination against self to prevent autoimmune disease: the type 1 diabetes model.
Harrison LC
Immunol Cell Biol. 86:139-145 (2008).
Immune tolerance to self-antigens is physiological. Given a repertoire of self-reactive, potentially pathogenic lymphocytes, therapeutic options to diminish autoimmune disease risk include deletion, reduced activation or increased regulation of self-reactive lymphocytes by means that mimic or promote physiological mechanisms of immunity. Vaccination with self-antigen to promote self-antigen-specific tolerance, 'negative vaccination', may represent the most specific and potentially safest means of averting autoimmune disease. This strategy is therapeutically effective in inbred rodent models but its translation in humans has failed to meet expectations. This failure can be attributed to the use of suboptimal dosage regimens in end-stage disease, as well as other factors. This review focuses on vaccination against self-antigen in type 1 diabetes, an autoimmune disease unique in that individuals at risk can be identified years before clinical presentation. Moreover, the spontaneously diabetic non-obese diabetic mouse, which mimics human type 1 diabetes in many ways, has provided 'proof-of-concept' for negative vaccination. Recent trials of a nasal insulin vaccine in humans at risk of type 1 diabetes provide evidence of tolerance induction as a basis for clinical efficacy.
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Prospective evaluation of a protocol for reduced glucocorticoid replacement in transsphenoidal pituitary adenomectomy: prophylactic glucocorticoid replacement is seldom necessary
Wentworth JM, Gao N, Sumithran KP, Maartens NF, Kaye AH, Colman PG, Ebeling PR.
Clin Endocrinol (Oxf) 68:29-35 (2008).
BACKGROUND: Most pituitary surgery centres prescribe perioperative glucocorticoids to subjects undergoing transsphenoidal pituitary adenomectomy (TSA), despite reports suggesting this may be unnecessary. Evidence-based guidelines for glucocorticoid use in TSA have recently been published but there are no prospective studies of their utility. OBJECTIVE: To implement and assess a protocol for reduced glucocorticoid replacement for subjects undergoing TSA. DESIGN: Prospective and retrospective cohort study in an Australian pituitary surgery centre. PATIENTS AND MEASUREMENTS: Clinical and biochemical data for 56 TSAs performed for non-ACTH-secreting tumours between March 2004 and April 2006 were prospectively collected and compared with data for 47 TSAs performed between October 2001 and November 2003, before implementation of the protocol. In the prospective cohort, a postoperative days 1-3 morning serum cortisol threshold of 250 nmol/l (91 microg/dl) was used to guide long-term glucocorticoid requirement. RESULTS: Implementation of the protocol was associated with significant reductions in dose and duration of glucocorticoid treatment post TSA in 44 'low-risk' cases (no preoperative glucocorticoid use or evidence of pituitary apoplexy). In two low-risk cases, long-term glucocorticoid replacement was required despite postoperative cortisol greater than 250 nmol/l. Following the remaining 42 low-risk operations, glucocorticoid was not prescribed on hospital discharge on the basis of morning serum cortisol > 250 nmol/l and no clinical evidence of hypocortisolism. None of these 42 cases required glucocorticoid treatment for hypocortisolism following surgery. Short synacthen tests were performed in 35 of these subjects a minimum of 6 months after surgery and were normal. Use of the protocol was not associated with differences in postoperative complications. CONCLUSIONS: Reduced glucocorticoid replacement in TSA is safe and reduces patient exposure to glucocorticoids and their potential adverse events. The occurrence of hypocortisolism in two low-risk subjects with serum cortisol > 250 nmol/l highlights the importance of daily clinical assessment when using this protocol.
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