Diabetes Research Centre2004 Abstracts
Insulin resistance is a risk factor for progression to type 1 diabetes
Fourlanos S, Narendran P, Byrnes GB Colman PG Harrison LC
Diabetologia 47:1661-1667 (2004)
AIMS/HYPOTHESIS: Glucose homeostasis is determined by an interplay between insulin secretion and insulin action. In type 1 diabetes, autoimmune destruction of pancreatic beta cells leads to impaired insulin secretion. However, the contribution of impaired insulin action (insulin resistance) to the development of type 1 diabetes has received little attention. We investigated whether insulin resistance was a risk factor for progression to type 1 diabetes.
METHODS: Islet-antibody-positive first-degree relatives of type 1 diabetes probands were followed for 4.0 years (median). Insulin secretion was measured as first-phase insulin response (FPIR) to intravenous glucose. Insulin resistance was estimated by homeostasis model assessment of insulin resistance (HOMA-R). We compared subjects who progressed (n=43) and subjects who did not progress (n=61) to diabetes, including 21 pairs matched for age, sex, islet antibodies and FPIR.
RESULTS: Progressors had higher insulin resistance relative to insulin secretion at baseline (median HOMA-R : FPIR 0.033 vs 0.013, p<0.0001). According to Cox proportional hazards analysis, islet antibody number, FPIR, fasting plasma glucose, fasting serum insulin, HOMA-R and log(HOMA-R : FPIR) were each predictive of progression to diabetes. However, log(HOMA-R : FPIR) (hazard ratio 2.57 per doubling, p<0.001) was the only metabolic variable independently associated with progression. In the matched comparison, progressors had higher fasting glucose, fasting insulin, HOMA-R and HOMA-R : FPIR, both at baseline and during the follow-up pre-clinical phase.
CONCLUSIONS/INTERPRETATION: Relatives positive for islet antibodies who progress most rapidly to diabetes have a subtle disturbance of insulin-glucose homeostasis years before the onset of symptoms, distinguished by greater insulin resistance for their level of insulin secretion. Taking steps to reduce this insulin resistance could therefore delay the development of type 1 diabetes.
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Pancreatic beta-cell function and immune responses to insulin following administration of intranasal insulin to humans at-risk for type 1 diabetes
Harrison LC, Honeyman MC, Steele C, Stone NL, Sarugeri E, Bonifacio E, Couper JJ, Colman PG
Diabetes Care 27:2348-2355 (2004)
OBJECTIVE: Mucosal administration of insulin retards development of autoimmune diabetes in the nonobese diabetic mouse model. We conducted a double-blind crossover study in humans at risk for type 1 diabetes to determine if intranasal insulin was safe, in particular did not accelerate beta-cell destruction, and could induce immune effects consistent with mucosal tolerance.
RESEARCH DESIGN AND METHODS: A total of 38 individuals, median age 10.8 years, with antibodies to one or more pancreatic islet antigens (insulin, GAD65, or tyrosine phosphatase-like insulinoma antigen 2) were randomized to treatment with intranasal insulin (1.6 mg) or a carrier solution, daily for 10 days and then 2 days a week for 6 months, before crossover. The primary outcome was beta-cell function measured as first-phase insulin response (FPIR) to intravenous glucose at 0, 6, and 12 months and then yearly; the secondary outcome was immunity to islet antigens, measured monthly for 12 months.
RESULTS: No local or systemic adverse effects were observed. Diabetes developed in 12 participants with negligible beta-cell function at entry after a median of 1.1 year. Of the remaining 26, the majority had antibodies to two or three islet antigens and FPIR greater than the first percentile at entry, as well as beta-cell function that generally remained stable over a median follow-up of 3.0 years. Intranasal insulin was associated with an increase in antibody and a decrease in T-cell responses to insulin.
CONCLUSIONS: Results from this pilot study suggest that intranasal insulin does not accelerate loss of beta-cell function in individuals at risk for type 1 diabetes and induces immune changes consistent with mucosal tolerance to insulin. These findings justify a formal trial to determine if intranasal insulin is immunotherapeutic and retards progression to clinical diabetes.
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Prevention of type 1 diabetes
Harrison LC, Fourlanos S, Every A, Honeyman MC, Steptoe RJ, Martinez NR, Jensen KP, Funda DP, Mannering SI, Colman PG, Narendran P
In: International Textbook of Diabetes Mellitus (Ferranini E, Zimmet P, De fronzo R and Keen H, Eds). John Wiley & Sons, Chichester, UK. 3rd Ed, 115, pp1879-1898 (2004)
Insulin-dependent or type 1 diabetes (T1D) results from the selective destruction of β cells in the islets of the pancreas,with consequent insulin deficiency and chronic hyperglycemia that may lead to complications involving primarily small blood vessels and nerves. T1D is considered to be an autoimmune disease triggered by environmental agents in genetically susceptible individuals, which in most cases begins months to years before loss of β-cell function heralds symptoms of hyperglycemia. The pathogenesis of T1D has been reviewed elsewhere and will not be reiterated here except insofar as necessary to justify therapeutic approaches to the prevention of T1D. The ideal approach to T1D prevention would be primary prevention directed at the triggering events that initiate disease in genetically at-risk individuals. Secondary prevention, once the disease has been initiated, is directed at subverting pathogenic immunity and its effects on the β cell.
Although the focus in T1D is on β-cell pathology and insulin deficiency, it is important to consider that blood glucose control reflects both insulin secretion and insulin action. T1D often presents clinically at times of “insulin resistance,” e.g. puberty, and insulin resistance could accelerate the rate of progression to clinical disease. Therefore, agents that promote insulin action might also be considered for the secondary prevention of T1D. The nonobese diabetic (NOD) mouse is a model of T1D that has contributed enormously to our understanding of the pathogenesis of the disease, and to our expectation that it is preventable. The NOD mouse develops spontaneous, autoimmune β-cell destruction that depends on activation of the innate immune cells followed by islet-reactive T cells. The cellular immune infiltrate of the islets (insulitis) in NOD mice is more florid than that revealed from the limited number of autopsies performed on humans dying soon after diagnosis and diabetes occurs predominantly in females. Otherwise, the NOD mouse has features in common with human T1D, including polygenic inheritance dominated by specific genes within the major histocompatibility complex (MHC), autoimmunity to (pro)insulin, glutamic acid decarboxylase (GAD), and probably tyrosine phosphatase-like insulinoma antigen IA-2, transfer of disease by bone marrow, and a preclinical stage of disease prior to hyperglycemia. A variety of immune and other interventions substantially reduce the incidence of diabetes in NOD mice. The question is whether any of these, if scientifically and ethically acceptable, are likely to be effective in humans. Knowledge of the immunopathogenesis of T1D over the last three decades has expanded to provide a rationale for the advent of controlled clinical trials to answer this question, but the answers have not yet been affirmative. Nevertheless, there are important lessons from the intervention/ prevention trials conducted to date, and many improvements and refinements in trial design and translation from mice to humans remain to be implemented. Without knowing the environmental trigger agents or being able to modify genetic susceptibility, the prospect of primary prevention before the onset of disease is uncertain. It should not be forgotten, though, that primary prevention has already succeeded to a small extent through vaccination to prevent congenital rubella (German measles), the first-described and so far only known definite viral cause-of T1D (see below). Currently, most attention is focused on secondary prevention, to avert either progression to diabetes in people with autoantibody markers of islet autoimmunity or loss of residual β-cell function in those with recently diagnosed diabetes, by strategies aimed at suppressing pathogenic immune responses or promoting resistance of β cells to these responses.
The concept of T1D prevention is not irrelevant to people with established diabetes. T1D will not be cured, whether by transplantation of normal or engineered insulin-secreting cells or by stimulation of β-cell neogenesis, without preventing recurrent autoimmune disease. Here we examine the precepts and prospects for preventing T1D, with an emphasis on factors likely to be critical for successful clinical outcomes.
Effectiveness and side effects of thiazolidinediones for type 2 diabetes: real-life experience from a tertiary hospital
Hussein Z, Wentworth JM, Nankervis AJ, Proietto J, Colman PG
Med J Aust 181:536-539 (2004)
OBJECTIVE: To assess effectiveness and side effects of thiazolidinediones (TZDs) as adjunctive therapy in suboptimally controlled patients with type 2 diabetes. DESIGN AND SETTING: Review of a prospectively recorded database at the Royal Melbourne Hospital diabetes clinic. PARTICIPANTS: 203 patients with type 2 diabetes who received pioglitazone or rosiglitazone between 1 May 2000 and 31 October 2002. OUTCOME MEASURES: Response in glycohaemoglobin (HbA(1c)) level, lipid profile changes and side effects, including hypoglycaemia, weight gain, oedema and precipitation of cardiac failure. RESULTS: Both pioglitazone and rosiglitazone improved glycaemic control, with a reduction in the HbA(1c) level of 1.02% (range, 0.85%-1.19%) and 0.96% (range, 0.81%-1.11%), respectively, in the first 6 months of therapy. Rosiglitazone was associated with a 0.45 mmol (range, 0.31-0.59 mmol) increase in cholesterol level and 0.99 mmol (range, 0.60-1.38 mmol) increase in triglyceride level, while pioglitazone was associated with insignificant declines in cholesterol and triglyceride levels. There was reduced requirement for insulin, but not for oral hypoglycaemic agent (OHA), in most patients who used these agents. Pioglitazone and rosiglitazone were associated with increased rates of hypoglycaemia (17% and 11% of patients, respectively), significant weight gain (48% and 58%) and oedema (33% and 21%). There were four cases of acute left ventricular failure and two cases of reversible liver dysfunction in patients treated with TZDs. CONCLUSIONS: Adding pioglitazone or rosiglitazone therapy to OHA or insulin in patients with type 2 diabetes significantly improved glycaemic control. However, the use of these drugs in routine clinical practice was associated with more frequent adverse events than previously reported in clinical trials.
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Assessment and management of inpatients with acute diabetes-related foot complications: room for improvement
Lawrence SM, Wraight PR, Campbell DA, Colman PG
Intern Med J 34:229-233 (2004)
BACKGROUND: Australian data are currently lacking regarding management guidance, resource usage and outcomes of patients with diabetes requiring hospitalization for management of acute foot complications. AIMS: The aims of the present study were to review hospital admissions for diabetes-related foot complications and current assessment and management of these complications, and to formulate recommendations for future models of care. METHODS: A retrospective review of patient records from 1 July 1999 to 30 June 2000 was carried out. Recorded assessment, investigations, management, amputation rates, referral rates and length of hospital stay were reviewed. RESULTS: There were 69 admission episodes in 12 months (total patients n = 50). The mean age was 64 years, with 44 male patients (64%) and 25 female patients (36%). The mean diabetes duration was 11 years (range <1-47 years). The majority of patients had type 2 diabetes. Assessment for known risk factors for ulceration and amputation was variable with history of previous ulcer/amputation recorded for 24 (35%) admissions, results of neurological assessment recorded for 11 (16%) and assessment of pedal pulses documented for 51 (74%). Glycated haemoglobin was performed during 35 (51%) admissions. Patients were admitted under one of 11 different inpatient units and the average interdepartmental referral rate was one referral per patient per admission. The average length of stay was 17 days, with total bed days occupied 1163 days. Minor amputation was performed in 25 (36%) cases and major amputation in 8 (11%). CONCLUSIONS: Clinical assessment, investigation and management of this population are highly variable. This has a significant impact on the final clinical outcome, and changes to current processes are required to overcome the substantial burden of diabetic foot disease.
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CD4+ T cell proliferation in response to GAD and proinsulin in healthy, pre-diabetic, and diabetic donors
Mannering SI, Morris JS, Stone NL, Jensen KP, VAN Endert PM, Harrison LC
Ann N Y Acad Sci 1037:16-21 (2004)
The ability to measure proliferation of autoantigen-specific T cells is critical for the evaluation of cellular immune function. Using a novel, sensitive, CFSE-based assay, we were able to directly quantitate autoantigen-specific CD4(+) T cell proliferation. However, peripheral blood cells from healthy, pre-diabetic and diabetic donors exhibited overlap in responses to glutamic acid decarboxylase (GAD65) and proinsulin (PI). This indicates that autoantigen-induced CD4(+) T cell proliferation in a functionally complex cell population may not discriminate disease in the general population. Clear discrimination was found between diabetic and healthy sibs, suggesting the need to standardize the genetic and environmental background. In addition, the ability of the CFSE assay to allow analysis of the phenotype and function of autoantigen-responsive T cells may improve discrimination.
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