Publications by authors named "Spiros Fourlanos"

38 Publications

Autoantibody-Negative Type 1 Diabetes: A Neglected Subtype.

Trends Endocrinol Metab 2021 May 9;32(5):295-305. Epub 2021 Mar 9.

Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, NSW, Australia; Department of Diabetes and Endocrinology, St. Vincent's Hospital, Sydney, NSW, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia. Electronic address:

Up to 15% of individuals with a clinical phenotype of type 1 diabetes (T1D) do not have evidence of seropositivity for pancreatic islet autoantibodies. On this basis, they are classified as nonimmune or idiopathic, and remain an understudied population, as they are excluded from T1D immunomodulatory trials. Our limited understanding of the disease aetiopathogenesis in autoantibody-negative T1D hinders our ability to improve diagnostic pathways and discover novel therapeutic agents; particularly as we progress towards an era of precision medicine. This review summarises the current understanding and challenges in studying autoantibody-negative T1D. We review the literature regarding T1D classification, and the role of autoimmunity and defects in the immunogenic pathway that may distinguish autoantibody-positive and -negative T1D.
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http://dx.doi.org/10.1016/j.tem.2021.02.001DOI Listing
May 2021

Comment on 'impact of routine Clinic Measurement of random Serum c-peptide in people with a Clinician Diagnosis of type 1 diabetes'.

Diabet Med 2021 Apr 27;38(4):e14513. Epub 2021 Jan 27.

Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, NSW, Australia.

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http://dx.doi.org/10.1111/dme.14513DOI Listing
April 2021

Increased Hyperglycemia and Hospital-Acquired Infections Following Withdrawal of the RAPIDS Early Intervention Model of Diabetes Care in Medical and Surgical Inpatients.

Diabetes Care 2021 Feb 16;44(2):e25-e26. Epub 2020 Dec 16.

Royal Melbourne Hospital, Parkville, Victoria, Australia

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http://dx.doi.org/10.2337/dc20-2469DOI Listing
February 2021

Letter: ACE2, IBD and COVID-19-why IBD patients may be at reduced risk of COVID-19.

Aliment Pharmacol Ther 2020 10;52(8):1422-1423

Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1111/apt.16063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537250PMC
October 2020

Clinical Prediction Tool To Identify Adults With Type 2 Diabetes at Risk for Persistent Adverse Glycemia in Hospital.

Can J Diabetes 2021 Mar 10;45(2):114-121.e3. Epub 2020 Jun 10.

Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville, Victoria, Australia; Department of Medicine, University of Melbourne and Royal Melbourne Hospital, Parkville, Victoria, Australia.

Objectives: Given the high incidence of hyperglycemia and hypoglycemia in hospital and the lack of prediction tools for this problem, we developed a clinical tool to assist early identification of individuals at risk for persistent adverse glycemia (AG) in hospital.

Methods: We analyzed a cohort of 594 consecutive adult inpatients with type 2 diabetes. We identified clinical factors available early in the admission course that were associated with persistent AG (defined as ≥2 days with capillary glucose <4 or >15 mmol/L during admission). A prediction model for persistent AG was constructed using logistic regression and internal validation was performed using a split-sample approach.

Results: Persistent AG occurred in 153 (26%) of inpatients, and was associated with admission dysglycemia (odds ratio [OR], 3.65), glycated hemoglobin ≥8.1% (OR, 5.08), glucose-lowering treatment regimen containing sulfonylurea (OR, 3.50) or insulin (OR, 4.22), glucocorticoid medication treatment (OR, 2.27), Charlson Comorbidity Index score and the number of observed days. An early-identification prediction tool, based on clinical factors reliably available at admission (admission dysglycemia, glycated hemoglobin, glucose-lowering regimen and glucocorticoid treatment), could accurately predict persistent AG (receiver-operating characteristic area under curve = 0.806), and, at the optimal cutoff, the sensitivity, specificity and positive predictive value were 84%, 66% and 53%, respectively.

Conclusions: A clinical prediction tool based on clinical risk factors available at admission to hospital identified patients at increased risk for persistent AG and could assist early targeted management by inpatient diabetes teams.
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http://dx.doi.org/10.1016/j.jcjd.2020.06.006DOI Listing
March 2021

A pilot study of the feasibility of empagliflozin in recent-onset type 1 diabetes.

Metabol Open 2020 Mar 3;5:100021. Epub 2020 Jan 3.

Royal Melbourne Hospital Department of Medicine, University of Melbourne, Australia.

Introduction: Sodium-glucose linked transporter (SGLT) inhibitors could improve glycaemia and simplify insulin regimens in recent-onset type 1 diabetes (T1D), provided they were well-tolerated and safe. This study aimed to determine the feasibility and safety of a SGLT inhibitor for the treatment of recent-onset T1D.

Method: An open label, prospective pilot study in adults with recent-onset T1D was performed. Empagliflozin, 25 mg orally daily, was given in combination with insulin and multidisciplinary care during a 24-week treatment phase, followed by wash-out visits at weeks 30 and 36.

Results: Fourteen participants (4 women; median age 26 years) began and 13 completed the study. No treatment-emergent serious adverse events were observed, with fatigue and genital infection the most common side-effects. Four participants stopped mealtime insulin for at least one month when taking empagliflozin. At week 24, median weight, HbA1c and insulin dose decreased by 4.4 kg, 1.5% (17 mmol/mol) and 0.03 units/kg/day, respectively. Meal-stimulated C-peptide was maintained during the treatment phase and then decreased at 36 weeks.

Conclusions: Treatment of adults with empagliflozin within 100 days of T1D diagnosis appeared safe and was associated with improved clinical outcomes. These findings justify a definitive trial to determine if SGLT inhibitors simplify treatment regimens and improve clinical outcomes in recent-onset T1D.

Registration: ACTRN12617000016336.
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http://dx.doi.org/10.1016/j.metop.2020.100021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424822PMC
March 2020

Routine glucose assessment in the emergency department for detecting unrecognised diabetes: a cluster randomised trial.

Med J Aust 2020 07 13;213(2):95-95.e1. Epub 2020 Mar 13.

Royal Melbourne Hospital, Melbourne, VIC.

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http://dx.doi.org/10.5694/mja2.50550DOI Listing
July 2020

Factors that predict glycaemic response to sodium-glucose linked transporter (SGLT) inhibitors.

Intern Med J 2020 Feb 24. Epub 2020 Feb 24.

Department of Diabetes and Endocrinology, Royal Melbourne Hospital, United States.

Aim: This study aimed to determine the clinical and biochemical variables associated with change in HbA1c in patients with type 2 diabetes who start sodium-glucose linked transporter (SGLT) inhibitor therapy.

Methods: We performed a prospective cohort study (ACTRN12616000833460) of 48 adults with type 2 diabetes (18 female, 38 male) who attended a tertiary hospital diabetes clinic. Fasting serum and urine samples, collected during clinic visits prior to and at 1, 12 and 24 weeks after commencing SGLT inhibitor treatment, were analysed for HbA1c, electrolytes, urea, creatinine and glucose.

Results: After 12 weeks, SGLT inhibitor therapy was associated with respective median (97% CI) decreases in weight, blood pressure, HbA1c and urine albumin/creatinine ratio of 3.0 (1.7 to 3.4) kg, 8 (2 to 16)/4 (3 to 9) mmHg, 6 (3 to 14) mmol/mol and 0.69 (0.18 to 1.8) mg/mmol. These effects persisted to 24 weeks. Urinary frequency and genitourinary infection were common adverse effects. Baseline HbA1c and eGFR independently predicted ΔHbA1c at 12 weeks whereas only baseline HbA1c independently predicted ΔHbA1c at 24 weeks. Urinary fractional glucose excretion and change in fasting glucose one week after starting SGLT inhibitor did not contribute to prediction of glycaemic response.

Conclusions: SGLT inhibitor therapy in a hospital clinic setting was associated with clinical improvements comparable to those observed in clinical trials but with higher incidence of genitourinary side effects. Baseline HbA1c and eGFR, but not urine fractional glucose excretion, predicted glycaemic response. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.14805DOI Listing
February 2020

Beware Ketoacidosis with SGLT2 Inhibitors in Latent Autoimmune Diabetes of the Adult.

Am J Med 2020 08 8;133(8):e422-e424. Epub 2020 Jan 8.

Department of Endocrinology, Northern Hospital, Epping, Victoria, Australia; Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia; Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are increasingly used for the treatment of type 2 diabetes, but have been associated with ketoacidosis.

Methods/results: We report a case series of three patients with latent autoimmune diabetes of the adult who presented with ketoacidosis, including one case with normal blood glucose levels, in the context of SGLT2 inhibitor use.

Conclusions: Sodium-glucose co-transporter-2 inhibitors should be used with caution and close clinical monitoring in patients with latent autoimmune diabetes of the adult. A clinical risk score permits targeted autoantibody testing and should be undertaken prior to commencement of SGLT2 inhibitors or cessation of insulin.
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http://dx.doi.org/10.1016/j.amjmed.2019.12.006DOI Listing
August 2020

Glucometric benchmarking in an Australian hospital enabled by networked glucose meter technology.

Med J Aust 2019 08 23;211(4):175-180. Epub 2019 Jun 23.

Royal Melbourne Hospital, Melbourne, VIC.

Objective: To assess glucometric outcomes and to estimate the incidence of hypo- and hyperglycaemia among non-critical care inpatients in a major Australian hospital.

Design, Setting And Participants: A prospective 10-week observational study (7 March - 22 May 2016) of consecutive inpatients with diabetes or newly detected hyperglycaemia admitted to eight medical and surgical wards at the Royal Melbourne Hospital. Point-of-care blood glucose (BG) data were collected with networked glucose meters.

Main Outcome Measures: Glycaemic control, as assessed with three glucometric models (by population, by patient, by patient-day); incidence of adverse glycaemic days (AGDs; patient-days with BG levels below 4 mmol/L or above 15 mmol/L).

Results: During the study period, there were 465 consecutive admissions of 441 patients with diabetes or newly detected hyperglycaemia, and 9817 BG measurements over 2953 patient-days. The mean patient-day BG level was 9.5 mmol/L (SD, 3.3 mmol/L). The incidence of hyperglycaemia was higher than for a United States hospital benchmark (patient-days with mean BG level above 10 mmol/L, 37% v 32), and that of hypoglycaemia lower (proportion of patient-days with mean BG level below 3.9 mmol/L, 4.1% v 6.1%). There were 260 (95% CI, 245-277) AGDs per 1000 patient-days; the incidence was higher in medical than surgical ward patients (290 [CI, 270-310] v 206 [CI, 181-230] per 1000 patient-days). 604 AGDs (79%) were linked with 116 patients (25%). Episodes of hyperglycaemia (BG above 15 mmol/L) were more frequent before lunch, dinner, and bedtime; 94 of 187 episodes of hypoglycaemia (BG below 4 mmol/L) occurred between 11 pm and 8 am.

Discussion: Glucometric analysis supported by networked glucose meter technology provides detailed inpatient data that could enable local benchmarking for promoting safe diabetes care in Australian hospitals.
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http://dx.doi.org/10.5694/mja2.50247DOI Listing
August 2019

Early Intervention for Diabetes in Medical and Surgical Inpatients Decreases Hyperglycemia and Hospital-Acquired Infections: A Cluster Randomized Trial.

Diabetes Care 2019 05 28;42(5):832-840. Epub 2019 Mar 28.

Royal Melbourne Hospital, Parkville, Victoria, Australia

Objective: To investigate if early electronic identification and bedside management of inpatients with diabetes improves glycemic control in noncritical care.

Research Design And Methods: We investigated a proactive or early intervention model of care (whereby an inpatient diabetes team electronically identified individuals with diabetes and aimed to provide bedside management within 24 h of admission) compared with usual care (a referral-based consultation service). We conducted a cluster randomized trial on eight wards, consisting of a 10-week baseline period (all clusters received usual care) followed by a 12-week active period (clusters randomized to early intervention or usual care). Outcomes were adverse glycemic days (AGDs) (patient-days with glucose <4 or >15 mmol/L [<72 or >270 mg/dL]) and adverse patient outcomes.

Results: We included 1,002 consecutive adult inpatients with diabetes or new hyperglycemia. More patients received specialist diabetes management (92% vs. 15%, < 0.001) and new insulin treatment (57% vs. 34%, = 0.001) with early intervention. At the cluster level, incidence of AGDs decreased by 24% from 243 to 186 per 1,000 patient-days in the intervention arm ( < 0.001), with no change in the control arm. At the individual level, adjusted number of AGDs per person decreased from a mean 1.4 (SD 1.6) to 1.0 (0.9) days (-28% change [95% CI -45 to -11], = 0.001) in the intervention arm but did not change in the control arm (1.8 [2.0] to 1.5 [1.8], -9% change [-25 to 6], = 0.23). Early intervention reduced overt hyperglycemia (55% decrease in patient-days with mean glucose >15 mmol/L, < 0.001) and hospital-acquired infections (odds ratio 0.20 [95% CI 0.07-0.58], = 0.003).

Conclusions: Early identification and management of inpatients with diabetes decreased hyperglycemia and hospital-acquired infections.
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http://dx.doi.org/10.2337/dc18-2342DOI Listing
May 2019

SGLT2 Inhibitors Increase the Risk of Diabetic Ketoacidosis Developing in the Community and During Hospital Admission.

J Clin Endocrinol Metab 2019 08;104(8):3077-3087

Department of Endocrinology and Diabetes, Alfred Health, Melbourne, Victoria, Australia.

Context: Diabetic ketoacidosis (DKA) has been associated with the use of sodium glucose cotransporter 2 inhibitors (SGLT2is).

Objective: To determine the incidence, characteristics, and outcomes of DKA in SGLT2i users vs nonusers with type 2 diabetes.

Design: Retrospective, multicenter, controlled cohort study.

Setting: All public hospitals in Melbourne and Geelong (combined population of 5 million), Australia, from 1 September 2015 to 31 October 2017.

Patients: Consecutive cases of DKA that developed in the community, or during the course of hospital admission, in patients with type 2 diabetes.

Main Outcome Measures: In SGLT2i users vs nonusers: (i) OR of DKA developing during hospital admission, and (ii) incidence of DKA.

Results: There were 162 cases of DKA (37 SGLT2i users and 125 non-SGLT2i users) with a physician-adjudicated diagnosis of type 2 diabetes. Of these, DKA developed during the course of inpatient admission in 14 (38%) SGLT2i users vs 2 (2%) non-SGLT2i users (OR, 37.4; 95% CI, 8.0 to 175.9; P < 0.0001). The incidence of DKA was 1.02 per 1000 (95% CI, 0.74 to 1.41 per 1000) in SGLT2i users vs 0.69 per 1000 (95% CI, 0.58 to 0.82 per 1000) in non-SGLT2i users (OR, 1.48; 95% CI, 1.02 to 2.15; P = 0.037). Fifteen SGLT2i users (41%) had peak blood glucose <250 mg/dL (14 mmol/L) compared with one (0.8%) non-SGLT2i user (P < 0.001).

Conclusions: SGLT2i users were more likely to develop DKA as an inpatient compared with non-SGLT2i users. SGLT2i use was associated with a small but significant increased risk of DKA.
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http://dx.doi.org/10.1210/jc.2019-00139DOI Listing
August 2019

International Consensus on Risk Management of Diabetic Ketoacidosis in Patients With Type 1 Diabetes Treated With Sodium-Glucose Cotransporter (SGLT) Inhibitors.

Diabetes Care 2019 Jun 6;42(6):1147-1154. Epub 2019 Feb 6.

Jesse Z and Sara Lea Shafer Institute of Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.

Sodium-glucose cotransporter (SGLT) inhibitors are new oral antidiabetes medications shown to effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure, and body weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes. However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with near-normal blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of DKA and potentially delaying treatment. Several SGLT inhibitors are currently under review by the U.S. Food and Drug Administration and European regulatory agencies as adjuncts to insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to the medical community to mitigate the associated DKA risk. This Consensus Report reviews current data regarding SGLT inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with type 1 diabetes.
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http://dx.doi.org/10.2337/dc18-2316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973545PMC
June 2019

A Group Lifestyle Intervention Program Is Associated with Reduced Emergency Department Presentations for People with Metabolic Syndrome: A Retrospective Case-Control Study.

Metab Syndr Relat Disord 2018 03 23;16(2):110-116. Epub 2018 Jan 23.

1 Department of Rehabilitation, Nutrition and Sport, School of Allied Health, Physiotherapy, La Trobe University , Melbourne, Australia .

Background: One quarter of the world's adults have metabolic syndrome. Lifestyle modification is the first line of intervention as improvements in diet and exercise can have positive effects on the individual components of metabolic syndrome. The primary aim of this research was to evaluate the effect of an 8-week lifestyle intervention program for people with metabolic syndrome on emergency department presentations, hospital admissions, and metabolic parameters.

Methods: A retrospective case-control study of adults (n = 58, mean age 60 ± 7 years) with metabolic syndrome referred to a group lifestyle self-management intervention program between 2013 and 2015. The intervention program consisted of 8 weekly sessions of group exercise and education delivered in a community healthcare setting. The intervention group (n = 29) was compared with a group of people who declined to attend the program (n = 29). Data were collected from the time a participant was referred to the program, and all participants were followed for a minimum of 100 days.

Results: Participants who attended the lifestyle intervention program had significantly fewer emergency department presentations [risk ratio (RR) 0.31, 95% confidence interval (CI) 0.11 to 0.83] and potentially avoidable emergency department presentations (RR 0.06, 95% CI 0.004 to 0.097) over the follow-up period (mean 495 ± 224 days per participant). There were no differences between the groups in hospital admissions and there were insufficient data to determine changes in metabolic parameters. Lifestyle group participants increased their exercise capacity [6-min walk test mean difference (MD) 41 m, 95% CI 20 to 62, P < 0.001] and had a mild decrease in weight (MD -0.8 kg, 95% CI -1.5 to -0.2, P = 0.018) and waist circumference (MD -1.3 cm, 95% CI -2.1 to -0.6, P = 0.002) after 8 weeks.

Conclusions: Implementation of a group lifestyle intervention program to improve activity and self-management skills may assist in decreasing emergency department presentations.
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http://dx.doi.org/10.1089/met.2017.0127DOI Listing
March 2018

Pooled genome wide association detects association upstream of FCRL3 with Graves' disease.

BMC Genomics 2016 11 18;17(1):939. Epub 2016 Nov 18.

Department of Ophthalmology, Flinders University of South Australia, Bedford Park, South Australia, Australia.

Background: Graves' disease is an autoimmune thyroid disease of complex inheritance. Multiple genetic susceptibility loci are thought to be involved in Graves' disease and it is therefore likely that these can be identified by genome wide association studies. This study aimed to determine if a genome wide association study, using a pooling methodology, could detect genomic loci associated with Graves' disease.

Results: Nineteen of the top ranking single nucleotide polymorphisms including HLA-DQA1 and C6orf10, were clustered within the Major Histo-compatibility Complex region on chromosome 6p21, with rs1613056 reaching genome wide significance (p = 5 × 10). Technical validation of top ranking non-Major Histo-compatablity complex single nucleotide polymorphisms with individual genotyping in the discovery cohort revealed four single nucleotide polymorphisms with p ≤ 10. Rs17676303 on chromosome 1q23.1, located upstream of FCRL3, showed evidence of association with Graves' disease across the discovery, replication and combined cohorts. A second single nucleotide polymorphism rs9644119 downstream of DPYSL2 showed some evidence of association supported by finding in the replication cohort that warrants further study.

Conclusions: Pooled genome wide association study identified a genetic variant upstream of FCRL3 as a susceptibility locus for Graves' disease in addition to those identified in the Major Histo-compatibility Complex. A second locus downstream of DPYSL2 is potentially a novel genetic variant in Graves' disease that requires further confirmation.
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http://dx.doi.org/10.1186/s12864-016-3276-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116198PMC
November 2016

Recent advances in type 1 diabetes.

Med J Aust 2015 Oct;203(7):290-3

Royal Melbourne Hospital, Melbourne, VIC.

Type 1 diabetes (T1D) is caused by an autoimmune attack on pancreatic beta cells that leads to insulin deficiency. The incidence of T1D in Australia has doubled over the past 20 years. T1D treatment focuses on physiological insulin replacement, aiming for near-normal blood glucose levels. Hypoglycaemia is a significant cause of morbidity and mortality in T1D. Optimal T1D management is complex, and is enhanced by empowering individuals in all aspects of managing diabetes. New technologies, including insulin pumps, continuous glucose monitors and sensor-augmented pumps, can assist people achieve better glycaemic control and reduce the risk of severe hypoglycaemia. Women with T1D can achieve significantly better outcomes during pregnancy and for their infants by planning for their pregnancy and by intensive glycaemic control. Several trials are underway that seek to identify the determinants of autoimmunity and to develop therapies that prevent T1D in at-risk individuals. Pancreatic and islet cell transplants are proven therapies, but are only offered to individuals with diabetes and renal failure (pancreas) or severe hypoglycaemia unawareness (islet cell transplants). Although T1D is still associated with considerable premature mortality, recent findings show that a significant improvement in life expectancy has occurred.
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http://dx.doi.org/10.5694/mja14.01691DOI Listing
October 2015

Lymphocytic hypophysitis in the elderly.

J Clin Neurosci 2015 Nov 18;22(11):1842-3. Epub 2015 Jun 18.

Department of Neurosurgery, Royal Melbourne Hospital, Grattan Street, Parkville, VIC 3050, Australia.

We report a 73-year-old woman with lymphocytic hypophysitis who presented with atypical clinical features and what appeared to be pituitary apoplexy on radiological analysis. Lymphocytic hypophysitis is a rare cause of pituitary dysfunction, and is thought to be an autoimmune disorder. It typically affects young peri-partum women, with clinical features that are related to pituitary hypofunction, and an uncertain natural history. It is difficult to radiologically differentiate lymphocytic hypophysitis from pituitary macroadenoma, therefore, the gold standard of diagnosis remains histological. It is rarely reported in the elderly (> 70 years old), however, given its unpredictable clinical course it remains an important differential diagnosis in patients of this age group who present with features suggestive of pituitary dysfunction.
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http://dx.doi.org/10.1016/j.jocn.2015.03.051DOI Listing
November 2015

Impact of Diabetes Status and Medication on Presentation, Treatment, and Outcome of Stage II Colon Cancer Patients.

J Cancer Epidemiol 2015 5;2015:189132. Epub 2015 May 5.

Royal Melbourne Hospital, Melbourne, VIC 3050, Australia ; Western Hospital, Footscray, VIC 3011, Australia ; BioGrid Australia, Melbourne, VIC 3050, Australia.

Diabetes is a risk factor for colorectal cancer and several reports suggest worse cancer-specific outcomes in diabetes patients. Recent studies in multiple tumour types indicate metformin may positively impact on cancer-specific and overall survival. A population-based series of stage II colorectal cancer patients treated and followed from 2000 to 2013 were analysed for baseline characteristics, treatment, and outcomes. 1116 patients with stage II colon cancer were identified, 55.5% were male and median age was 70.9 years (range 20.5-101.2). The diabetes patients (21.6%, n = 241) were older than nondiabetes patients (median 74.0 versus 69.6, p = 0.0001). There was no impact of diabetes on cancer presentation or pathology. Diabetes patients were less likely to receive adjuvant treatment (13.7 versus 24.8%, p = 0.002) but were equally likely to complete treatment (69.7 versus 67.7%, p = 1.00). Diabetes did not significantly impact cancer recurrence (HR = 1.07, 95% CI 0.71-1.63) or overall survival (HR = 1.23, 95% CI 0.88-1.72), adjusted for age. Diabetes medication did not impact cancer recurrence or survival. Cancer presentation and outcomes in diabetes patients are comparable to those of nondiabetes patients in those with stage II colon cancer. The effect of metformin merits further evaluation in patients with colon cancer.
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http://dx.doi.org/10.1155/2015/189132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4436511PMC
June 2015

A randomised controlled trial of high dose vitamin D in recent-onset type 2 diabetes.

Diabetes Res Clin Pract 2014 Dec 28;106(3):576-82. Epub 2014 Sep 28.

Burnet Clinical Research Unit, Royal Melbourne Hospital, Parkville 3050, VIC, Australia.

Aims: Vitamin D insufficiency has been associated with impaired pancreatic beta-cell function. We aimed to determine if high dose oral vitamin D3 (D) improves beta-cell function and glycaemia in type 2 diabetes.

Methods: Fifty adults with type 2 diabetes diagnosed less than 12 months, with normal baseline serum 25-OH D (25D), were randomised to 6000 IU D (n=26) or placebo (n=24) daily for 6 months. Beta-cell function was measured by glucagon-stimulated serum C-peptide (delta C-peptide [DCP], nmol/l). Secondary outcome measures were fasting plasma glucose (FPG), post-prandial blood glucose (PPG), HbA1c and insulin resistance (HOMA-IR).

Results: In the D group, median serum 25D (nmol/l) increased from 59 to 150 (3 months) and 128 (6 months) and median serum 1,25D (pmol/l) from 135 to 200 and 190. After 3 months, change in DCP from baseline in D (+0.04) and placebo (-0.08) was not different (P=0.112). However, change in FPG (mmol/l) was significantly lower in D (-0.40) compared to placebo (+0.1) (P=0.007), as was the change in PPG in D (-0.30) compared to placebo (+0.8) (P=0.005). Change in HbA1c (%) between D (-0.20) and placebo (-0.10) was not different (P=0.459). At 6 months, changes from baseline in DCP, FPG, PPG and HbA1c were not different between groups.

Conclusion: Oral D3 supplementation in type 2 diabetes was associated with transient improvement in glycaemia, but without a measurable change in beta-cell function this effect is unlikely to be biologically significant. High dose D3 therefore appears to offer little or no therapeutic benefit in type 2 diabetes.
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http://dx.doi.org/10.1016/j.diabres.2014.08.030DOI Listing
December 2014

Latent autoimmune diabetes in Stiff-Person Syndrome.

Diabetes Care 2014 Oct;37(10):e214-5

Department of Neurology, Royal Melbourne Hospital, Parkville, Victoria, Australia.

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http://dx.doi.org/10.2337/dc14-1444DOI Listing
October 2014

Obesity is associated with retinopathy and macrovascular disease in type 1 diabetes.

Obes Res Clin Pract 2014 Mar-Apr;8(2):e178-82

Walter and Eliza Hall Institute, 1G Royal Parade, Parkville 3050, Australia.

Excessive body weight is increasingly seen in type 1 diabetes but its impact is debated. To address this uncertainty, we aimed to determine the association between excess body weight and the macro- and microvascular complications of type 1 diabetes. We identified 501 adults with type 1 diabetes attending an Australian hospital clinic and extracted their clinical and biochemical data from our patient management database. In both men and women, obesity (BMI > 30 kg/m(2)) was the predominant risk factor for retinopathy and cardiovascular disease despite similar HbA1c and increased use of cardioprotective drugs compared to non-obese patients. Obesity was associated with albuminuria in women, but not renal impairment or neuropathy in either sex. We conclude that obesity in type 1 diabetes may promote retinopathy and macrovascular disease. Future trials to determine the effect of weight loss on type 1 diabetes in obese people are needed.
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http://dx.doi.org/10.1016/j.orcp.2013.03.007DOI Listing
January 2015

A practical limited sampling strategy to predict free prednisolone exposure and glycemia in kidney transplant recipients.

Ther Drug Monit 2014 Feb;36(1):18-23

*Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; †Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville, Victoria, Australia; ‡Department of Nephrology, University of Queensland at the Princess Alexandra Hospital, Brisbane, Queensland, Australia; §Department of Chemical Pathology, Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Departments of ¶Chemical Pathology, and ‖Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia; and #Department of Medicine, NorthWest Academic Centre, University of Melbourne, St Albans, Victoria, Australia.

Background: Despite significant interindividual variability in prednisolone pharmacokinetics and potentially serious consequences with inadequate or excessive exposure, monitoring of prednisolone levels is not employed to guide therapy. As ultrahigh-performance liquid chromatography-tandem mass spectrometry methods can now measure the active free fraction of prednisolone, this study aimed to evaluate the performance of 15 published limited sampling strategies (LSSs) for predicting free prednisolone exposure in adult kidney transplant recipients and to examine the relationship between free/total prednisolone exposure and plasma glucose.

Methods: The study was performed in 11 subjects without diabetes 3-4 weeks postkidney transplantation. Area under the concentration time curve profiles of total and free prednisolone from 0 to 12 hours postdose (AUC₀₋₁₂) were determined and compared with predicted AUC₀₋₁₂ values calculated from published LSSs. Venous glucose was measured concurrently with the 13 sampling time points.

Results: The mean (±SD) age of subjects was 52 ± 12 years, 5 were men and the median (interquartile range) daily prednisolone dose was 20.0 mg (20.0-22.5). Interindividual variation in dose-adjusted free and total prednisolone exposure was 1.9- and 3.2-fold, respectively. All 15 free prednisolone LSSs exhibited good correlation (r ≥ 0.83), with bias and imprecision less than 15%. An LSS incorporating 1.25- and 3-hour samples had the highest predictive power (r = 0.97, bias 1.2%, imprecision 5.6%). Free prednisolone AUC₀₋₁₂ correlated with peak glucose levels (r = 0.65, P = 0.037), as did predicted AUC₀₋₁₂ from 14/15 LSSs.

Conclusions: Biologically active free prednisolone exposure can be accurately predicted postkidney transplantation by LSSs incorporating 2-point concentration sampling. Peak plasma glucose concentration correlated well with prednisolone exposure.
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http://dx.doi.org/10.1097/FTD.0b013e31829daae4DOI Listing
February 2014

Divided dosing reduces prednisolone-induced hyperglycaemia and glycaemic variability: a randomized trial after kidney transplantation.

Nephrol Dial Transplant 2014 Mar 5;29(3):698-705. Epub 2013 Sep 5.

Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne, VIC, Australia.

Background: Prednisolone is a major risk factor for hyperglycaemia and new-onset diabetes after transplantation. Uncontrolled observational data suggest that divided dosing may reduce requirements for hypoglycaemic agents. This study aims to compare the glycaemic effects of divided twice daily (BD) and once daily (QD) prednisolone.

Methods: Twenty-two kidney transplant recipients without diabetes were randomized to BD or QD prednisolone. Three weeks post-transplant, a continuous glucose monitor (iPro2(®) Medtronic) was applied for 5 days with subjects continuing their initial prednisolone regimen (Days 1-2) before crossover to the alternative regimen. Mean glucose, peak glucose, nadir glucose, exposure to hyperglycaemia (glucose ≥7.8 mmol/L) and glycaemic variability were assessed.

Results: The mean ± standard deviation (SD) age of subjects was 50 ± 10 years and 77% were male. Median (interquartile range) daily prednisolone dose was 25 (20, 25) mg. BD prednisolone was associated with decreased mean glucose (mean 7.9 ± 1.7 versus 8.1 ± 2.3 mmol/L, P < 0.001), peak glucose [median 10.4 (9.5, 11.4) versus 11.4 (10.3, 13.4) mmol/L, P< 0.001] and exposure to hyperglycaemia [median 25.5 (14.6, 30.3) versus 40.4 (33.2, 51.2) mmol/L/h, P = 0.003]. Median glucose peaked between 14:55-15.05 h with BD and 15:25-15:30 h with QD. Median glycaemic variability scores were decreased with BD: SD (1.1 versus 1.9, P < 0.001), mean amplitude of glycaemic excursion (1.5 versus 2.2, P = 0.001), continuous overlapping net glycaemic action-1 (CONGA-1; 1.0 versus 1.2, P = 0.039), CONGA-2 (1.2 versus 1.4, P = 0.008) and J-index (25 versus 31, P = 0.003).

Conclusions: Split prednisolone dosing reduces glycaemic variability and hyperglycaemia early post-kidney transplant.
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http://dx.doi.org/10.1093/ndt/gft377DOI Listing
March 2014

Screening for new-onset diabetes after kidney transplantation: limitations of fasting glucose and advantages of afternoon glucose and glycated hemoglobin.

Transplantation 2013 Oct;96(8):726-31

1 Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia. 2 Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville, Victoria, Australia. 3 Department of Renal Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia. 4 Department of Medicine, NorthWest Academic Centre, University of Melbourne, St Albans, Victoria, Australia. 5 Address for correspondence: Dr. Christopher J. Yates, Department of Diabetes and Endocrinology, Royal Melbourne Hospital, University of Melbourne, Level 4 West, Grattan Street, Parkville, Victoria 3050, Australia.

Background: The sensitivity of fasting plasma glucose (FPG) in screening for new-onset diabetes after transplantation (NODAT) has been questioned, particularly in the presence of moderate-dose prednisolone, where peak plasma glucose occurs 7 to 8 hr after administration. Oral glucose tolerance testing (OGTT) has been mooted as an alternative but is inconvenient for patients.

Methods: We compared sensitivity of screening tests for NODAT at 6 weeks, 3 months, and 12 months after kidney transplantation in recipients receiving prednisolone, mycophenolate, and tacrolimus.

Results: At 6 weeks, NODAT (capillary blood glucose [CapBG] ≥11.1 mmol/L, FPG ≥7.0 mmol/L, 2-hr plasma glucose ≥11.1 mmol/L, or glycated hemoglobin [HbA1c] ≥6.5%) was detected in 46% with CapBG versus 12% with OGTT (P=0.013), 4% with HbA1c (P<0.001), and 0% with FPG (P<0.001; n=26). At 3 months, NODAT was present in 14% with HbA1c versus 20% with OGTT (P=0.600) and 2% with FPG (P=0.059; n=50), whereas, at 12 months, NODAT was found in 4% with HbA1c versus 6% with OGTT (P=1.00) and 2% with FPG (P=0.618; n=51). Combining 3- and 12-month data, OGTT recorded NODAT in 14% and impaired glucose tolerance in 28%, whereas HbA1c detected NODAT in 10% and impaired glucose tolerance (from ≥5.7 to <6.5%) in 51%. Employing HbA1c as a screening test and reserving OGTT for those with impaired glucose tolerance would detect NODAT with a sensitivity more than 94%, avoiding the need for OGTT in 49% of patients.

Conclusions: This study confirms the inadequacy of FPG screening for NODAT in the first 6 weeks after transplantation, at which time 4 p.m. CapBG also outperformed OGTT. From 3 months, HbA1c had similar sensitivity to OGTT and represents a convenient alternative.
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http://dx.doi.org/10.1097/TP.0b013e3182a012f3DOI Listing
October 2013

Lipid lowering agents, cognitive decline, and dementia: the three-city study.

J Alzheimers Dis 2012 ;30(3):629-37

Inserm, U1061, Montpellier, France.

The aim of this prospective cohort study was to evaluate the effects of lipid lowering agent (LLA) intake on cognitive function in 6,830 community-dwelling elderly persons. Cognitive performance (global cognitive functioning, visual memory, verbal fluency, psychomotor speed, and executive function), clinical diagnosis of dementia, and fibrate and statin use, were evaluated at baseline, and 2, 4, and 7 year follow-up. Multivariate Cox models were stratified by gender and adjusted for sociodemographic characteristics, mental and physical health including vascular risk factors, and genetic vulnerability (apolipoprotein E and cholesteryl ester transfer protein). For women but not men, fibrate use was specifically associated with an increased risk over 7 years of decline in visual memory only (HR = 1.29, 95% CI = 1.09-1.54, p = 0.004), and did not increase risk for incident dementia. This association was independent of genetic vulnerability related to apolipoprotein E and cholesteryl exchange transfer protein polymorphisms and occurred only in women with higher low density lipoprotein (LDL)-cholesterol levels and treated with fibrate (HR = 1.39, 95% CI = 1.08-1.79, p = 0.01) and not in those with lower LDL-cholesterol levels irrespective of fibrate treatment. For both genders, no significant associations were found between statins (irrespective of their lipophilicity) and either cognitive decline or dementia incidence. This prospective study, adjusting for multiple confounders, found no evidence that LLA given in late life reduced the risk of cognitive decline and dementia, but did raise the possibility that women with treatment-resistant high LDL-cholesterol may be at increased risk of decline in visual memory.
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http://dx.doi.org/10.3233/JAD-2012-120064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743740PMC
October 2012

Body mass index correlates with ischemic heart disease and albuminuria in long-standing type 2 diabetes.

Diabetes Res Clin Pract 2012 Jul 22;97(1):57-62. Epub 2012 Mar 22.

Royal Melbourne Hospital Department of Diabetes and Endocrinology, Melbourne, Victoria, Australia.

Aims: Comprehensive data describing the effect of obesity on type 2 diabetes outcomes is lacking. We sought to address this by analyzing a tertiary hospital clinical database.

Methods: We extracted clinical and biochemical data for patients who attended a tertiary hospital diabetes clinic between 1998 and 2011 and were aged less than 65 years. Body mass index (BMI) was correlated with the prevalence of vascular complications and with cardiovascular risk factors.

Results: The means of age and duration of diabetes for the 711 patients (392 men and 319 women) were 53 and 11 years respectively. BMI correlated with the prevalence of ischemic heart disease and, to a lesser degree, albuminuria, but not with the prevalence of cerebrovascular disease, neuropathy, retinopathy or renal function. BMI did not correlate with glycosylated hemoglobin, although obese patients used insulin both more frequently and at higher doses.

Conclusions: In people with long-standing type 2 diabetes who attend a tertiary hospital outpatient clinic, ischemic heart disease, in contrast to other vascular complications, correlates robustly with BMI. These findings indicate that clinical trials of weight loss in type 2 diabetes should use cardiac endpoints as their primary outcomes.
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http://dx.doi.org/10.1016/j.diabres.2012.02.012DOI Listing
July 2012

Glycemic outcome not predicted by baseline psychological measures in a diabetes management program.

Popul Health Manag 2012 Jun 21;15(3):163-7. Epub 2012 Feb 21.

Dept of Medicine, Northern Clinical Research Centre, Northern Health and The University of Melbourne, Melbourne, Australia.

The Northern Health Diabetes Hospital Admission Risk Program is a chronic disease management program that aims to improve the glycemic management of patients with diabetes. The aim of this project was to determine if there was any relationship between psychological characteristics and glycemic outcome in a diabetes management program. A prospective study of patients attending the diabetes management program investigated validated measures of cognition, stage of change, locus of control, self-efficacy, depression and anxiety, and quality of life. The study investigated 86 type 2 diabetes patients (mean age 59 years, 49% female). Glycemic control (HbA1c) was measured at baseline and after 12 months in the program. Glycemic control was poor on admission to the service with a mean HbA1c of 8.9%. The measures of cognition, self-efficacy, locus of control, mental health, and quality of life were not associated with improvements in HbA1c. Those participants with shorter duration of disease and more contacts with the service were significantly more likely to experience improvements in HbA1c. Psychometric data were not predictive of glycemic outcome. Rather, in this chronic disease management program, glycemia improved more in patients who were seen earlier in their disease course and managed more intensively, regardless of their psychometric status.
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http://dx.doi.org/10.1089/pop.2011.0043DOI Listing
June 2012

Advanced glycation end products are direct modulators of β-cell function.

Diabetes 2011 Oct 12;60(10):2523-32. Epub 2011 Sep 12.

Division of Diabetes Complications, Diabetes and Metabolism Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.

Objective: Excess accumulation of advanced glycation end products (AGEs) contributes to aging and chronic diseases. We aimed to obtain evidence that exposure to AGEs plays a role in the development of type 1 diabetes (T1D).

Research Design And Methods: The effect of AGEs was examined on insulin secretion by MIN6N8 cells and mouse islets and in vivo in three separate rodent models: AGE-injected or high AGE-fed Sprague-Dawley rats and nonobese diabetic (NODLt) mice. Rodents were also treated with the AGE-lowering agent alagebrium.

Results: β-Cells exposed to AGEs displayed acute glucose-stimulated insulin secretory defects, mitochondrial abnormalities including excess superoxide generation, a decline in ATP content, loss of MnSOD activity, reduced calcium flux, and increased glucose uptake, all of which were improved with alagebrium treatment or with MnSOD adenoviral overexpression. Isolated mouse islets exposed to AGEs had decreased glucose-stimulated insulin secretion, increased mitochondrial superoxide production, and depletion of ATP content, which were improved with alagebrium or with MnTBAP, an SOD mimetic. In rats, transient or chronic exposure to AGEs caused progressive insulin secretory defects, superoxide generation, and β-cell death, ameliorated with alagebrium. NODLt mice had increased circulating AGEs in association with an increase in islet mitochondrial superoxide generation, which was prevented by alagebrium, which also reduced the incidence of autoimmune diabetes. Finally, at-risk children who progressed to T1D had higher AGE concentrations than matched nonprogressors.

Conclusions: These findings demonstrate that AGEs directly cause insulin secretory defects, most likely by impairing mitochondrial function, which may contribute to the development of T1D.
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http://dx.doi.org/10.2337/db10-1033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178291PMC
October 2011

Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes.

Diabetes 2011 Apr 9;60(4):1237-45. Epub 2011 Feb 9.

Autoimmunity and Transplantation Division, Walter and Eliza Hall, Institute of Medical Research, Parkville, Victoria, Australia.

Objective: Insulin in pancreatic β-cells is a target of autoimmunity in type 1 diabetes. In the NOD mouse model of type 1 diabetes, oral or nasal administration of insulin induces immune tolerance to insulin and protects against autoimmune diabetes. Evidence for tolerance to mucosally administered insulin or other autoantigens is poorly documented in humans. Adults with recent-onset type 1 diabetes in whom the disease process is subacute afford an opportunity to determine whether mucosal insulin induces tolerance to insulin subsequently injected for treatment.

Research Design And Methods: We randomized 52 adults with recent-onset, noninsulin-requiring type 1 diabetes to nasal insulin or placebo for 12 months. Fasting blood glucose and serum C-peptide, glucagon-stimulated serum C-peptide, and serum antibodies to islet antigens were monitored three times monthly for 24 months. An enhanced ELISpot assay was used to measure the T-cell response to human proinsulin.

Results: β-Cell function declined by 35% overall, and 23 of 52 participants (44%) progressed to insulin treatment. Metabolic parameters remained similar between nasal insulin and placebo groups, but the insulin antibody response to injected insulin was significantly blunted in a sustained manner in those who had received nasal insulin. In a small cohort, the interferon-γ response of blood T-cells to proinsulin was suppressed after nasal insulin.

Conclusions: Although nasal insulin did not retard loss of residual β-cell function in adults with established type 1 diabetes, evidence that it induced immune tolerance to insulin provides a rationale for its application to prevent diabetes in at-risk individuals.
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http://dx.doi.org/10.2337/db10-1360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064097PMC
April 2011

Reappraising the stereotypes of diabetes in the modern diabetogenic environment.

Nat Rev Endocrinol 2009 Sep 28;5(9):483-9. Epub 2009 Jul 28.

Autoimmunity & Transplantation Division, The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

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.
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http://dx.doi.org/10.1038/nrendo.2009.149DOI Listing
September 2009