Diabetes Research Centre2009 Abstracts
An evaluation of community-based resources for management of diabetes-related foot disorders in an Australian population
Bergin SM, Brand CA, Colman PG, Campbell DA
Aust Health Rev 33:671-8 (2009)
We aimed to evaluate service model configuration, service capacity and accessibility of diabetes-related footcare in an Australian community health setting. Eighty-eight community-based podiatry clinics were surveyed using the self-administered Footcare Provider Survey. Survey domains included communication, resources, service coordination and barriers to service provision. Sixty-nine from a possible 88 Victorian community podiatry clinics (78%) responded. Sixty-one (88%) provided ongoing care to individuals with diabetes-related foot disorders. Communication with vascular and orthopaedic specialists was reported to be readily available in 37% and 27% of cases respectively. Overall, communication with general practitioners was deemed readily available in 62% of cases. Just 39% of podiatrists statewide agreed overall resources were sufficient, with 26% agreeing staffing levels were adequate. Thirty-nine percent of community podiatrists used clinical care pathways, and onsite collaboration was deemed appropriate in just 30% of cases. Perceived barriers to provision of care included inadequate staffing and resources, lack of confidence from other health professionals in the podiatrists' ability to manage diabetes-related foot disorders, and lack of access to specialists.
[visit article page on Aust Health Rev website]
A questionnaire for determining prevalence of diabetes related foot disease (Q-DFD): construction and validation
Bergin SM, Brand CA, Colman PG, Campbell DA
J Foot Ankle Res 2:34 (2009).
ABSTRACT: BACKGROUND: Community based prevalence for diabetes related foot disease (DRFD) has been poorly quantified in Australian populations. The aim of this study was to develop and validate a survey tool to facilitate collection of community based prevalence data for individuals with DRFD via telephone interview. METHODS: Agreed components of DRFD were identified through an electronic literature search. Expert feedback and feedback from a population based construction sample were sought on the initial draft. Survey reliability was tested using a cohort recruited through a general practice, a hospital outpatient clinic and an outpatient podiatry clinic. Level of agreement between survey findings and either medical record or clinical assessment was evaluated. RESULTS: The Questionnaire for Diabetes Related Foot Disease (Q-DFD) comprised 12 questions aimed at determining presence of peripheral sensory neuropathy (PN) and peripheral vascular disease (PVD), based on self report of symptoms and/or clinical history, and self report of foot ulceration, amputation and foot deformity. Survey results for 38 from 46 participants demonstrated agreement with either clinical assessment or medical record (kappa 0.65, sensitivity 89.0%, and specificity 77.8%). Correlation for individual survey components was moderate to excellent. Inter and intrarater reliability and test re-test reliability was moderate to high for all survey domains. CONCLUSION: The development of the Q-DFD provides an opportunity for ongoing collection of prevalence estimates for DRFD across Australia.
[View free full-text article on J Foot Ankle Res website]
Immune characterization of an individual with an exceptionally high natural killer T cell frequency and her immediate family
Chan AC, Serwecinska L, Cochrane A, Harrison LC, Godfrey DI, Berzins SP
Clin Exp Immunol 156:238-245 (2009)
Natural killer T cells (NKT) are a regulatory subset of T lymphocytes whose frequency in peripheral blood is highly variable within the human population. Lower than normal NKT frequencies are associated with increased predisposition to a number of diseases, including type 1 diabetes and some forms of cancer, raising the possibility that an increased frequency may be protective. However, there is little or no understanding of how high NKT frequencies arise or, most importantly, whether the potential exists to boost and maintain NKT levels for therapeutic advantage. Here, we provide a detailed functional and phenotypic characterization of the NKT compartment of a human donor with NKT levels approximately 50 times greater than normal, including an analysis of NKT in her immediate family members. The study focuses upon the characteristics of this donor and her family, but demonstrates more broadly that the size and flexibility of the NKT niche is far greater than envisioned previously. This has important implications for understanding how the human NKT compartment is regulated, and supports the concept that the human NKT compartment might be expanded successfully for therapeutic benefit.
[Visit article page on Clin Exp Immunol website]
Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes.
Couper JJ, Beresford S, Hirte C, Baghurst PA, Pollard A, Tait BD, Harrison LC, Colman PG
Diabetes Care. 32:94-99 (2009)
OBJECTIVE: In a prospective birth cohort study, we followed infants who had a first-degree relative with type 1 diabetes to investigate the relationship between early growth and infant feeding and the risk of islet autoimmunity. RESEARCH DESIGN AND METHODS: Infants with a first-degree relative with type 1 diabetes were identified during their mother's pregnancy. Dietary intake was recorded prospectively to determine duration of breast-feeding and age at introduction of cow's milk protein, cereals, meat, fruit, and vegetables. At 6-month reviews, length (or height) and weight, antibodies to insulin, GAD65, the tyrosine phosphatase-like insulinoma antigen, and tissue transglutaminase were measured. Islet autoimmunity was defined as persistent elevation of one or more islet antibodies at consecutive 6-month intervals, including the most recent measure, and was the primary outcome measure. RESULTS: Follow-up of 548 subjects for 5.7 +/- 3.2 years identified 46 children with islet autoimmunity. Weight z score and BMI z score were continuous predictors of risk of islet autoimmunity (adjusted hazard ratios 1.43 [95% CI 1.10-1.84], P = 0.007, and 1.29 [1.01-1.67], P = 0.04, respectively). The risk of islet autoimmunity was greater in subjects with weight z score >0 than in those with weight z score < or =0 over time (2.61 [1.26-5.44], P = 0.01). Weight z score and BMI z score at 2 years and change in weight z score between birth and 2 years, but not dietary intake, also predicted risk of islet autoimmunity. CONCLUSIONS: Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes.
[View free full-text article on Diabetes Care website]
Depression is greater in non-English speaking hospital outpatients with type 2 diabetes
Graco M, Berlowitz DJ, Fourlanos S, Sundram S
Diabetes Res Clin Pract 83:e51-e53 (2009).
This study aimed to compare the prevalence of depression and anxiety in English (ES) and non-English speaking (NES) hospital outpatients with type 2 diabetes. Overall, depression and/or anxiety were present in 31% of patients. The prevalence of depression was significantly higher in NES than ES patients (p=0.03)..
[View article page on Diab Res Clin Pract website]
Congenital rubella, diabetes and HLA
Honeyman MC, Harrison LC
Diabetologia 52:371-372 (2009).
To the Editor: In a recent Editorial, Edwin Gale reviewed the congenital rubella syndrome (CRS) and the postulated role of viruses in type 1 diabetes, pulling together most of the literature that links congenital rubella and diabetes [1]. He concluded that the case appears sound for type 2 diabetes, but is at most only suggestive for type 1 diabetes. However, he did not reveal the whole story, in particular, the evidence for HLA associations with diabetes in CRS...
[View article page on Diabetologia website]
Alternative and additional mechanisms to the hygiene hypothesis.
Honeyman MC, Harrison LC
In: Progress in Inflammation Research: The Hygiene Hypothesis and Darwinian Medicine (Rook GAW, Ed) Birkhauser, Basel, 279-298 (2009).
The rising incidence of allergic and autoimmune diseases is occurring on a background of genes selected for strong immune responses. Possible mechanisms for selection and changed environmental factors that impact on immune response genes are discussed. Reduced exposure of infants to infections is discussed elsewhere in the volume. Here we consider the role of delayed exposure to infections as well as additional factors that could promote chronic immuno-inflammatory diseases. These include changes in the amount of food consumed, dietary composition, sleep reduction and lower energy expenditure due to reduced exercise and thermoneutrality of the built environment. Any or all of these may result in obesity, which is a proinflammatory state. Increases in air pollution and psychological stress and, finally, insufficiency of vitamin D, are discussed, as these may also shift immune responsiveness towards a proinflammarory state.
The A-chain of insulin is a hot-spot for CD4+ T cell epitopes in human type 1 diabetes
Mannering SI, Pang SH, Williamson NA, Naselli G, Reynolds EC, O'Brien-Simpson NM, Purcell AW, Harrison LC.
Clin Exp Immunol 156:226-231 (2009).
Type 1 diabetes (T1D) is caused by T cell-mediated destruction of the pancreatic insulin-producing beta cells. While the role of CD4(+) T cells in the pathogenesis of T1D is accepted widely, the epitopes recognized by pathogenic human CD4(+) T cells remain poorly defined. None the less, responses to the N-terminal region of the insulin A-chain have been described. Human CD4(+) T cells from the pancreatic lymph nodes of subjects with T1D respond to the first 15 amino acids of the insulin A-chain. We identified a human leucocyte antigen-DR4-restricted epitope comprising the first 13 amino acids of the insulin A-chain (A1-13), dependent upon generation of a vicinal disulphide bond between adjacent cysteines (A6-A7). Here we describe the analysis of a CD4(+) T cell clone, isolated from a subject with T1D, which recognizes a new HLR-DR4-restricted epitope (KRGIVEQCCTSICS) that overlaps the insulin A1-13 epitope. This is a novel epitope, because the clone responds to proinsulin but not to insulin, T cell recognition requires the last two residues of the C-peptide (Lys, Arg) and recognition does not depend upon a vicinal disulphide bond between the A6 and A7 cysteines. The finding of a further CD4(+) T cell epitope in the N-terminal A-chain region of human insulin underscores the importance of this region as a target of CD4(+) T cell responses in human T1D.
[View article page on Clin Exp Immunol website]
Glycaemic impact of patient-led use of sensor-guided pump therapy in type 1 diabetes: a randomised controlled trial
O'Connell MA, Donath S, O'Neal DN, Colman PG, Ambler GR, Jones TW, Davis EA, Cameron FJ.
Diabetologia 52:1250-1257 (2009).
AIMS/HYPOTHESIS: The objective of this study was to assess the impact of patient-led sensor-guided pump management on glycaemic control, and compare the effect with that of standard insulin pump therapy. METHODS: An open multicentre parallel randomised controlled trial was conducted at five tertiary diabetes centres. Participants aged 13.0-40.0 years with well-controlled type 1 diabetes were randomised 1:1 to either study group for 3 months. Randomisation was carried out using a central computer-generated schedule. Participants in the intervention group used sensor-guided pump management; no instructive guidelines in interpreting real-time data were provided ('patient-led' use). Participants in the control group continued their original insulin pump regimen. Continuous glucose monitoring (CGM) and HbA(1c) level were used to assess outcomes. The primary outcome was the difference in the proportion of time in the target glycaemic range during the 3 month study period (derived from CGM, target range 4-10 mmol/l). Secondary outcomes were difference in HbA(1c), time in hypoglycaemic (< or =3.9 mmol/l) and hyperglycaemic (> or =10.1 mmol/l) ranges and glycaemic variability. RESULTS: Sixty-two participants were recruited and randomised; 5/31 and 2/31 withdrew from intervention and control groups, respectively, leaving 26/31 and 29/31 for the intention-to-treat analyses. When adjusted for baseline values, the mean end-of-study HbA(1c) was 0.43% lower in the intervention group compared with the control group (95% CI 0.19 to 0.75%; p = 0.009). No difference was observed in CGM-derived time in target (measured difference 1.72; 95% CI -5.37 to 8.81), hypoglycaemic (0.54; 95% CI -3.48 to 4.55) or hyperglycaemic (-2.18; 95% CI -10.0 to 5.69) range or in glycaemic variability (-0.29; 95% CI -0.34 to 0.28). Within the intervention group, HbA(1c) was 0.51% lower in participants with sensor use > or =70% compared with participants with sensor use <70% (95% CI -0.98 to -0.04, p = 0.04). Five episodes of device malfunction occurred. CONCLUSIONS/INTERPRETATION: Individuals established on insulin pump therapy can employ sensor-guided pump management to improve glycaemic control. An apparent dose-dependent effect of sensor usage was noted; however, frequent use of this technology (> or =70%) was not universally acceptable. Trial registration: ACTRN12606000049572.
[View article page on Diabetologia website]
Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial
Rajamani K, Colman PG, Li LP, Best JD, Voysey M, D'Emden MC, Laakso M, Baker JR, Keech AC; FIELD study investigators.
Lancet 373:1780-1788 (2009).
BACKGROUND: Amputations in people with type 2 diabetes mellitus substantially impair their quality of life and impose high costs on health-care systems. Our aim was to assess the effect of fenofibrate on amputation events in a large cohort of patients with type 2 diabetes. METHODS: In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, 9795 patients aged 50-75 years with type 2 diabetes were randomly assigned by computer-generated randomisation sequence to receive fenofibrate 200 mg per day (n=4895) or matching placebo (n=4900) for 5 years' duration. Information about non-traumatic amputation-a prespecified tertiary endpoint of the study-was routinely gathered. Clinicians who were masked to treatment allocation adjudicated amputations as minor or major (below or above the ankle, respectively). Amputations were also classified on the basis of whether or not large-vessel disease was present in the limb, to distinguish those related to large-artery atherosclerosis from those predominantly related to microvascular disease. Analysis was by intention to treat (ITT). The FIELD study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481. FINDINGS: All 9795 patients were included in the ITT population. 115 patients had one or more non-traumatic lower-limb amputations due to diabetes. Previous cardiovascular disease, microvascular disease, previous non-traumatic amputation or skin ulcer, smoking, and longer duration of diabetes were more frequent in patients who had amputations during the trial than in those who had other cardiovascular events or in those who had neither event (all p<0.001 for three-way comparison). Mean lipid concentrations differed between patients who had on-study amputations and those who had other cardiovascular events or neither event, but by no more than 0.2 mmol/L. The risks of first amputation (45 vs 70 events; hazard ratio [HR] 0.64, 95% CI 0.44-0.94; p=0.02) and minor amputation events without known large-vessel disease (18 vs 34 events; 0.53, 0.30-0.94; p=0.027) were lower for patients assigned to fenofibrate than for patients assigned to placebo, with no difference between groups in risk of major amputations (24 vs 26 events; 0.93, 0.53-1.62; p=0.79). INTERPRETATION: Classic markers of macrovascular and microvascular risk were associated with lower extremity amputations in patients with type 2 diabetes. Treatment with fenofibrate was associated with a lower risk of amputations, particularly minor amputations without known large-vessel disease, probably through non-lipid mechanisms. These findings could lead to a change in standard treatment for the prevention of diabetes-related lower-limb amputations. FUNDING: Laboratoires Fournier SA (now part of Solvay Pharmaceuticals) and National Health and Medical Research Council of Australia.
[View free full-text on Lancet website]
Reappraising the stereotypes of diabetes in the modern diabetogenic environment
Wentworth JM, Fourlanos S, Harrison L
Nat Rev Endocrinol 5:483-489 (2009)
The prevailing concentration of blood glucose is a result of the integrated regulation of insulin secretion and insulin action. Nevertheless, the classic stereotypes of diabetes are dichotomous: type 1 diabetes mellitus (T1DM) is attributed to impaired insulin secretion, and type 2 diabetes mellitus (T2DM) is primarily attributed to impaired insulin action (insulin resistance). The available evidence indicates that this view is overly simplistic. Impaired insulin secretion (beta-cell dysfunction) is also a feature of T2DM, and insulin resistance is also a risk factor for the development of T1DM. Moreover, with the increasing incidence of T2DM and T1DM in both developed and developing countries, attributed to environmental factors, the existence of 'hybrid' diabetes types that have clinical and pathogenetic features of both conditions is becoming clearly evident. A common thread across the spectrum of diabetes might be the activation of innate immunological and inflammatory pathways by a proinflammatory environment, which leads to beta-cell dysfunction in T2DM, insulin resistance in both T2DM and T1DM, and enhanced adaptive immunity that kills beta cells in T1DM. Embracing a holistic view of the diabetes syndrome will help us to understand the environmental basis for the epidemic of diabetes and improve preventative strategies.
[view article page on Nat Rev Endocrinol website]