Publications by authors named "Jenny E Gunton"

70 Publications

Beta-cell function and human islet transplantation: can we improve?

J Endocrinol 2021 Mar;248(3):R99-R112

The Westmead Institute for Medical Research, The University of Sydney Westmead Hospital, New South Wales, Australia.

Islet transplantation, a therapeutic option to treat type 1 diabetes, is not yet as successful as whole-pancreas transplantation as a treatment for diabetes. Mouse models are commonly used for islet research. However, it is clear disparities exist between islet transplantation outcomes in mice and humans. Given the shortage of transplant-grade islets, it is crucial that we further our understanding of factors that determine long-term islet survival and function post-transplantation. In turn, this may lead to new therapeutic targets and strategies that will improve transplant outcomes. Here, we summarise the current landscape in clinical transplantation, highlight underlying similarities and differences between mouse and human islets, and review interventions that are being considered to create a new pool of β-cells for clinical application.
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http://dx.doi.org/10.1530/JOE-20-0590DOI Listing
March 2021

Vitamin C Improves Healing of Foot Ulcers; A Randomised, Double-Blind, Placebo-Controlled Trial.

Br J Nutr 2020 Sep 28:1-21. Epub 2020 Sep 28.

Westmead Hospital, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, NSW. Australia.

Chronic foot ulcers are associated with a high risk of osteomyelitis, poor quality of life, amputations and disability. Few strategies improve their healing, and amputation rates in high-risk foot services are usually over 30%.We conducted a randomised, inactive-placebo controlled, double-blind trial of 500mg of slow-release vitamin C in 16 people with foot ulcers conducted in the foot-wound clinic at Westmead Hospital. Nine were randomised to control and 7 to vitamin C. When serum vitamin C results become available at 4 weeks, all people with deficiency were offered both vitamin C and glucosamine tablets for the next 4 weeks. Patients without baseline deficiency continued their original assigned treatment.The primary outcome was percent ulcer healing (reduction in ulcer size) at 8 weeks.Fifty percent of subjects had baseline vitamin C deficiency, half having undetectable levels. Healing at 8 weeks was significantly better in the vitamin C group (median 100% versus -14%, p=0.041). Healing without amputation occurred in all patients in the vitamin C group. In contrast, 44% of controls had not healed their ulcer at the end of the study period.Vitamin C improved healing of foot ulcers. Further studies are needed to determine whether there is a threshold effect for serum vitamin C above which therapy is ineffective and whether there are better or lesser responding subgroups. Because of its low cost and ease of access and administration we recommend offering vitamin C therapy to all people who have chronic foot ulcers and potentially suboptimal vitamin C intake.
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http://dx.doi.org/10.1017/S0007114520003815DOI Listing
September 2020

Hypoxia-inducible factors and diabetes.

Authors:
Jenny E Gunton

J Clin Invest 2020 10;130(10):5063-5073

Centre for Diabetes, Obesity and Endocrinology, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.

Hypoxia can be defined as a relative deficiency in the amount of oxygen reaching the tissues. Hypoxia-inducible factors (HIFs) are critical regulators of the mammalian response to hypoxia. In normal circumstances, HIF-1α protein turnover is rapid, and hyperglycemia further destabilizes the protein. In addition to their role in diabetes pathogenesis, HIFs are implicated in development of the microvascular and macrovascular complications of diabetes. Improving glucose control in people with diabetes increases HIF-1α protein and has wide-ranging benefits, some of which are at least partially mediated by HIF-1α. Nevertheless, most strategies to improve diabetes or its complications via regulation of HIF-1α have not currently proven to be clinically useful. The intersection of HIF biology with diabetes is a complex area in which many further questions remain, especially regarding the well-conducted studies clearly describing discrepant effects of different methods of increasing HIF-1α, even within the same tissues. This Review presents a brief overview of HIFs; discusses the range of evidence implicating HIFs in β cell dysfunction, diabetes pathogenesis, and diabetes complications; and examines the differing outcomes of HIF-targeting approaches in these conditions.
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http://dx.doi.org/10.1172/JCI137556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524477PMC
October 2020

A Pilot Study Examining Vitamin C Levels in Periodontal Patients.

Nutrients 2020 Jul 28;12(8). Epub 2020 Jul 28.

Westmead Hospital, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2145, Australia.

Background: Periodontal disease is the leading cause of tooth loss worldwide. Current periodontal treatment is limited by its dependency on patients learning and maintaining good dental habits, and repeated visits to oral health physicians. Vitamin C's role in collagen synthesis and immune function makes it important in wound healing and possibly periodontal healing. Therefore, if some patients are deficient, this may worsen patient outcomes.

Methods: Patients were invited to participate following assessment and treatment at the Westmead Centre of Oral Health Periodontic Clinic, regardless of current disease stage or treatment. Adults were eligible if they gave informed consent and had current periodontal disease. Study involvement consisted of periodontal assessment and care followed by an interview and measurement of serum vitamin C and C-reactive protein (CRP).

Results: A total of 6 out of 20 patients had vitamin C levels less than the institutional normal range, of whom 2 had levels <11.4 μmol/L and one <28 μmol/L. Low vitamin C was associated with higher periodontal disease stage ( = 0.03). Elevated CRP was found in 2/3 of people with low vitamin C and CRP was negatively correlated with vitamin C ( < 0.01). Vitamin C did not correlate with patient-reported fruit or vegetable consumption, but high processed meat intake was associated with lower vitamin C.

Conclusion: Although a small study, this rate of vitamin C deficiency in the periodontal clinic is clinically important and correlations with disease severity and CRP suggests biological importance. This warrants further studies to assess vitamin C and whether supplementation improves periodontal outcomes, particularly in deficient subjects.
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http://dx.doi.org/10.3390/nu12082255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469055PMC
July 2020

Cosmetic Fat Transplantation: A Review.

Curr Mol Med 2021 ;21(2):133-141

Centre for Diabetes, Obesity and Endocrinology (CDOE), The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia.

Aim: To review current techniques used in fat grafting to optimise graft persistence and achieve optimal cosmetic outcomes.

Background: Fat transplantation has been used extensively in the reconstruction and cosmetic industry for many years. However, there is significant adipocyte loss and reabsorption rates, leading to the loss of external cosmetic volume and the need for repeat procedures. Adipocyte loss can occur at all four stages of transplantation and this review discusses each of these methods with the aim being to optimise graft outcome.

Results: Several new techniques have been discussed including liposuction techniques, fat processing, and assisted fat grafting which show an improvement in adipocyte survival, revasculisation and graft outcomes.

Conclusion: There have been many improvements in fat grafting and the implementation of these will optimise surgical outcomes but there are still strategies to improve further. However, there is still a lack of standardised techniques and training. More research is needed in the areas of fat processing and the use of additives to the fat graft. More clinical research is needed in the fat placement technique, which has very little published evidence and current techniques are mostly anecdotal by cosmetic surgeons.
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http://dx.doi.org/10.2174/1566524020666200703194355DOI Listing
January 2021

A fluorescent timer reporter enables sorting of insulin secretory granules by age.

J Biol Chem 2020 07 27;295(27):8901-8911. Epub 2020 Apr 27.

Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia; School of Life and Environmental Sciences, Faculty of Science, University of Sydney, Sydney, New South Wales, Australia. Electronic address:

Within the pancreatic β-cells, insulin secretory granules (SGs) exist in functionally distinct pools, displaying variations in motility as well as docking and fusion capability. Current therapies that increase insulin secretion do not consider the existence of these distinct SG pools. Accordingly, these approaches are effective only for a short period, with a worsening of glycemia associated with continued decline in β-cell function. Insulin granule age is underappreciated as a determinant for why an insulin granule is selected for secretion and may explain why newly synthesized insulin is preferentially secreted from β-cells. Here, using a novel fluorescent timer protein, we aimed to investigate the preferential secretion model of insulin secretion and identify how granule aging is affected by variation in the β-cell environment, such as hyperglycemia. We demonstrate the use of a fluorescent timer construct, syncollin-dsRedE5TIMER, which changes its fluorescence from green to red over 18 h, in both microscopy and fluorescence-assisted organelle-sorting techniques. We confirm that the SG-targeting construct localizes to insulin granules in β-cells and does not interfere with normal insulin SG behavior. We visualize insulin SG aging behavior in MIN6 and INS1 β-cell lines and in primary C57BL/6J mouse and nondiabetic human islet cells. Finally, we separated young and old insulin SGs, revealing that preferential secretion of younger granules occurs in glucose-stimulated insulin secretion. We also show that SG population age is modulated by the β-cell environment in the mouse islets and in C57BL/6J islets exposed to different glucose environments.
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http://dx.doi.org/10.1074/jbc.RA120.012432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335792PMC
July 2020

Beta-Cell-Specific Expression of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 5 Aggravates High-Fat Diet-Induced Impairment of Islet Insulin Secretion in Mice.

Antioxid Redox Signal 2020 03;32(9):618-635

Department of Internal Medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.

Nicotinamide adenine dinucleotide phosphate oxidases (NOX-es) produce reactive oxygen species and modulate β-cell insulin secretion. Islets of type 2 diabetic subjects present elevated expression of NOX5. Here, we sought to characterize regulation of NOX5 expression in human islets and to uncover the relevance of NOX5 in islet function using a novel mouse model expressing NOX5 in doxycycline-inducible, β-cell-specific manner (RIP/rtTA/NOX5 mice). hybridization and immunohistochemistry employed on pancreatic sections demonstrated NOX5 messenger ribonucleic acid (mRNA) and protein expressions in human islets. In cultures of dispersed islets, NOX5 protein was observed in somatostatin-positive (δ) cells in basal (2.8 m glucose) conditions. Small interfering ribonucleic acid (siRNA)-mediated knockdown of NOX5 in human islets cultured in basal glucose concentrations resulted in diminished glucose-induced insulin secretion (GIIS) . However, when islets were preincubated in high (16.7 m) glucose media for 12 h, NOX5 appeared also in insulin-positive (β) cells. , mice with β-cell NOX5 expression developed aggravated impairment of GIIS compared with control mice when challenged with 14 weeks of high-fat diet. Similarly, palmitate preincubation resulted in more severe reduction of insulin release in islets of RIP/rtTA/NOX5 mice compared with their control littermates. Decreased insulin secretion was most distinct in response to theophylline stimulation, suggesting impaired cyclic adenosine monophosphate (cAMP)-mediated signaling due to increased phosphodiesterase activation. Our data provide the first insight into the complex regulation and function of NOX5 in islets implying an important role for NOX5 in δ-cell-mediated intraislet crosstalk in physiological circumstances but also identifying it as an aggravating factor in β-cell failure in diabetic conditions.
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http://dx.doi.org/10.1089/ars.2018.7579DOI Listing
March 2020

Myeloid cell deletion of Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) induces non-alcoholic steatohepatitis.

PLoS One 2019 4;14(12):e0225332. Epub 2019 Dec 4.

Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia.

Background And Aim: Non-alcoholic steatohepatitis (NASH) is predicted to become the most common cause of cirrhosis and liver failure. Risk factors include obesity, insulin resistance and diabetes. Macrophages and other myeloid cells play crucial roles in initiating and driving inflammation. Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) is a transcription factor which binds to a range of partners to mediate responses to environmental signals, including the diet. In people with diabetes it is decreased in liver. We hypothesised that myeloid cell ARNT activity may contribute to the development of liver pathology.

Methods: Floxed-ARNT mice were bred with LysM-Cre mice to generate mice with reduced ARNT in myeloid cells. Animals were fed a high fat diet (HFD) and liver pathology was assessed. Histology, mRNA, fat accumulation and metabolism were studied.

Results: Animals with reduced myeloid ARNT developed steatohepatitis on a HFD, with additional alterations of metabolism and fat deposition. Steatohepatitis was accompanied by hepatic macrophage infiltration and expression of both M1 and M2 markers. Expression of mRNAs for Cxcl1, Mcp-1, Tnf-α and Tgf-β1 were increased. Human livers from controls and people with NASH were tested; ARNT mRNA was decreased by 80% (p = 0.0004).

Conclusions: Decreased myeloid ARNT may play a role in the conversion from non-alcoholic fatty liver to steatohepatitis. Increasing ARNT may be a therapeutic strategy to reduce NASH.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225332PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892561PMC
March 2020

The Changing Landscape of Pharmacotherapy for Diabetes Mellitus: A Review of Cardiovascular Outcomes.

Int J Mol Sci 2019 Nov 21;20(23). Epub 2019 Nov 21.

Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, The University of Sydney, NSW 2145, Australia.

The prevention of cardiovascular morbidity and mortality has always been a primary concern in patients with type 2 diabetes. Modern trials of glucose-lowering therapies now assess major adverse cardiac events as an endpoint in addition to the effects on glycaemic control. Whilst the data on the efficacy of intensive glucose lowering on reducing cardiovascular risk are limited, there are now increasing numbers of glucose-lowering therapies that have proven cardiovascular benefit independent of glucose lowering. This review will summarise the available literature on cardiovascular outcomes in relation to metformin, sulphonylureas, di-peptidyl peptidase-4 inhibitors, glucagon-like peptide receptor agonists, sodium-glucose co-transporter 2 inhibitors, thiazolidinediones, acarbose and insulin. In addition, new paradigms in diabetes management and the importance of treatment selection based on considerations including but not limited to glycaemic control will be discussed.
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http://dx.doi.org/10.3390/ijms20235853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928800PMC
November 2019

Inducible UCP1 silencing: A lentiviral RNA-interference approach to quantify the contribution of beige fat to energy homeostasis.

PLoS One 2019 21;14(11):e0223987. Epub 2019 Nov 21.

The Westmead Institute for Medical Research, Westmead, Sydney, Australia.

Energy consuming, heat-producing beige adipocytes, located in classic white adipose tissue (WAT), hold promise for the treatment of obesity. Few reports have quantitatively assessed the contribution of browned 'WAT' to energy expenditure. There is a need for methods to examine beige-fat thermogenesis, independently of classical brown fat. The aim of this study is to optimize an inducible lentiviral shRNA to conditionally knock-down Ucp1 and assess the effects on 'browned' WAT. Primary adipocytes from mouse inguinal WAT converted into thermogenic adipocytes when stimulated with β-adrenergic agonist and thiazolidinedione. There was increased UCP1 protein and importantly increases in various indicators of mitochondrial bioenergetics. Next, we determined optimal transfection conditions for the UCP1-shRNA lentiviral system and subsequently applied this to 'browned' WAT. UCP1 knockdown decreased the brown/beige-fat gene profile and decreased mitochondrial respiration. In summary, this study optimizes lentiviral UCP1-shRNA technology in vitro. This technique could be applied to inguinal fat depots in vivo. This would allow investigation of contribution of depots to whole-body metabolism to help elucidate the physiological relevance of beige fat.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223987PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872148PMC
March 2020

Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function.

J Cachexia Sarcopenia Muscle 2019 12 21;10(6):1228-1240. Epub 2019 Jun 21.

Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, New South Wales, Australia.

Background: It has long been recognized that vitamin D deficiency is associated with muscle weakness and falls. Vitamin D receptor (VDR) is present at very low levels in normal muscle. Whether vitamin D plays a direct role in muscle function is unknown and is a subject of hot debate. Myocyte-specific deletion of VDR would provide a strategy to answer this question.

Methods: Myocyte-specific vitamin D receptor (mVDR) null mice were generated by crossing human skeletal actin-Cre mice with floxed VDR mice. The effects of gene deletion on the muscle phenotype were studied in terms of body tissue composition, muscle tissue histology, and gene expression by real-time PCR.

Results: Unlike whole-body VDR knockout mice, mVDR mice showed a normal body size. The mVDR showed a distinct muscle phenotype featuring reduced proportional lean mass (70% vs. 78% of lean mass), reduced voluntary wheel-running distance (22% decrease, P = 0.009), reduced average running speed, and reduced grip strength (7-16% reduction depending on age at testing). With their decreased voluntary exercise, and decreased lean mass, mVDR have increased proportional fat mass at 20% compared with 13%. Surprisingly, their muscle fibres showed slightly increased diameter, as well as the presence of angular fibres and central nuclei suggesting ongoing remodelling. There were, however, no clear changes in fibre type and there was no increase in muscle fibrosis. VDR is a transcriptional regulator, and changes in the expression of candidate genes was examined in RNA extracted from skeletal muscle. Alterations were seen in myogenic gene expression, and there was decreased expression of cell cycle genes cyclin D1, D2, and D3 and cyclin-dependent kinases Cdk-2 and Cdk-4. Expression of calcium handling genes sarcoplasmic/endoplasmic reticulum calcium ATPases (SERCA) Serca2b and Serca3 was decreased and Calbindin mRNA was lower in mVDR muscle.

Conclusions: This study demonstrates that vitamin D signalling is needed for myocyte function. Despite the low level of VDR protein normally found muscle, deleting myocyte VDR had important effects on muscle size and strength. Maintenance of normal vitamin D signalling is a useful strategy to prevent loss of muscle function and size.
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http://dx.doi.org/10.1002/jcsm.12460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903451PMC
December 2019

β Cell Hypoxia-Inducible Factor-1α Is Required for the Prevention of Type 1 Diabetes.

Cell Rep 2019 05;27(8):2370-2384.e6

Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia; Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW, Australia. Electronic address:

The development of autoimmune disease type 1 diabetes (T1D) is determined by both genetic background and environmental factors. Environmental triggers include RNA viruses, particularly coxsackievirus (CV), but how they induce T1D is not understood. Here, we demonstrate that deletion of the transcription factor hypoxia-inducible factor-1α (HIF-1α) from β cells increases the susceptibility of non-obese diabetic (NOD) mice to environmentally triggered T1D from coxsackieviruses and the β cell toxin streptozotocin. Similarly, knockdown of HIF-1α in human islets leads to a poorer response to coxsackievirus infection. Studies in coxsackievirus-infected islets demonstrate that lack of HIF-1α leads to impaired viral clearance, increased viral load, inflammation, pancreatitis, and loss of β cell mass. These findings show an important role for β cells and, specifically, lack of β cell HIF-1α in the development of T1D. These data suggest new strategies for the prevention of T1D.
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http://dx.doi.org/10.1016/j.celrep.2019.04.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661122PMC
May 2019

Differential associations of ferritin and 25-hydroxyvitamin D with fasting glucose and diabetes risk in community dwelling older men.

Diabetes Metab Res Rev 2019 10 10;35(7):e3172. Epub 2019 Jun 10.

Medical School, University of Western Australia, Perth, Australia.

Aims: We examined associations of ferritin and 25-hydroxyvitamin D with fasting glucose and prevalent diabetes in older men.

Methods: Cross-sectional analysis of 4153 community-dwelling men aged 70 to 89 years in Western Australia. Plasma ferritin, 25-hydroxyvitamin D, and glucose were assayed. Diabetes was ascertained from self-report, medications, and fasting glucose.

Results: There were 577 men with diabetes (13.9%). In the whole cohort, ferritin was associated with fasting glucose (0.051 mmol/L per 1 SD increase in ferritin, P = .006) and 25-hydroxyvitamin D was inversely associated (-0.085 mmol/L per 1 SD, P < .001). Ferritin was not associated with prevalent diabetes (highest vs. lowest quartile; >225 vs <66 μg/L: adjusted odds ratio [OR] 0.97, 95% confidence interval [CI], 0.74-1.27, P = .83). Higher vitamin D was associated with decreased odds of prevalent diabetes (highest vs lowest quartile; >82 nmol/L vs <53 nmol/L: OR = 0.57, 95% CI = 0.43-0.75, P < .001). There was no interaction between ferritin and vitamin D on diabetes risk.

Conclusions: In older men, ferritin is associated with fasting glucose but not prevalent diabetes. Higher 25-hydroxyvitamin D concentrations are independently associated with lower fasting glucose and reduced risk of diabetes. Clinical trials are required to determine whether interventions, which raise vitamin D concentrations, would reduce incidence of diabetes in this expanding demographic group.
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http://dx.doi.org/10.1002/dmrr.3172DOI Listing
October 2019

Iodine deficiency in women of childbearing age: not bread alone?

Asia Pac J Clin Nutr 2018;27(4):853-859

Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, Australia.

Background And Objectives: Iodine deficiency remains a public health concern, particularly in pregnant women and those planning pregnancy because of the risk of impaired fetal neurological development. Following implementation of strategies to improve iodine intake in Australia, there has been minimal investigation into current iodine status. We aimed to characterise iodine status in a population of women of childbearing-age in Australia.

Methods And Study Design: A cross-sectional study was performed in 97 women of childbearing-age attending outpatient clinics at a tertiary hospital in Sydney. Pregnant and postmenopausal women were excluded. Iodine intake was surveyed via questionnaire. Spot urinary iodine (UI) was concurrently measured. The relationships between UI, dietary intake and use of iodine-containing multivitamins/medications were examined.

Results: Median UI was 117 ug/L. Forty women (41%) were iodine deficient (UI <100 ug/L). The most commonly consumed source of dietary iodine was bread (29/97, 30% daily). Forty-three women took iodine-containing multivitamins but 18/43 (41.2%) remained deficient. There were no significant associations between UI and diet. There was a smaller proportion of deficient people than in our previous study (125/180 non-pregnant subjects, 69%, vs 41% in this study, p<0.001).

Conclusion: The overall population median is now sufficient, however, a significant proportion of this multicultural group are iodine deficient. There are similar proportions of deficiency in those using iodine supplements versus not. Contributors may include ethnicity-related dietary practices, limited awareness or poor adherence to iodine supplements. Despite public health strategies, a significant proportion of women of child-bearing age remained iodine deficient. Further research involving a larger population and contributors to iodine deficiency is warranted.
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http://dx.doi.org/10.6133/apjcn.102017.02DOI Listing
September 2019

Vitamin D and muscle.

Bone Rep 2018 Jun 18;8:163-167. Epub 2018 Apr 18.

Centre for Diabetes, Obesity and Endocrinology Research, The Westmead Institute of Medical Research, Westmead, Sydney, Australia.

Vitamin D is increasingly recognised to play an important role in normal muscle function. Low vitamin D status is associated with an increased risk of falls and proximal weakness. Since vitamin D deficiency is very common, and the signs are non-specific, it is important to maintain a high index of suspicion of vitamin D deficiency in patients with muscle pain and weakness, and it is simple to measure serum 25(OH) vitamin D. Therapy is cheap, safe and effective, but sometimes a larger dose may be needed, and, as shown in our case report, willingness of people to pay for an over the counter medication can be an issue. Following a striking case report that demonstrates muscle defects in severe vitamin D deficiency, we discuss clinical studies examining specific effects of vitamin D on physical performance, muscle strength and falls. Finally, we present an overview of molecular mechanisms that explain vitamin D's biological effects on muscle.
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http://dx.doi.org/10.1016/j.bonr.2018.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021354PMC
June 2018

Women with type 2 diabetes in pregnancy remain a high-risk group.

Minerva Endocrinol 2018 Jun;43(2):224-225

Department of Diabetes, Endocrinology and Metabolism, the Northern Clinical School, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, Australia.

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http://dx.doi.org/10.23736/S0391-1977.17.02653-0DOI Listing
June 2018

Vitamin D and the Liver-Correlation or Cause?

Nutrients 2018 Apr 16;10(4). Epub 2018 Apr 16.

Centre for Diabetes, Obesity & Endocrinology, The Westmead Institute for Medical Research (WIMR), Westmead, Sydney, NSW 2145, Australia.

Vitamin D is becoming increasingly accepted as an important physiological regulator outside of its classical role in skeletal homeostasis. A growing body of evidence connects vitamin D with hepatic disease. This review summarises the role of vitamin D in liver homeostasis and disease and discusses the therapeutic potential of vitamin D-based treatments to protect against hepatic disease progression and to improve response to treatment. While pre-clinical experimental data is promising, clinical trials around liver diseases have mostly been under-powered, and further studies will be required to clarify whether vitamin D or vitamin D analogues have beneficial effects on liver disease.
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http://dx.doi.org/10.3390/nu10040496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946281PMC
April 2018

Vitamin D Improves Cardiac Function After Myocardial Infarction Through Modulation of Resident Cardiac Progenitor Cells.

Heart Lung Circ 2018 Aug 3;27(8):967-975. Epub 2018 Feb 3.

Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia; Department of Cardiology, Westmead Hospital, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; Victor Chang Cardiac Research Institute, Sydney, NSW, Australia. Electronic address:

Background: Vitamin D has been implicated in the prevention of heart failure. However the underlying mechanism remains unclear. We hypothesised that these effects may be partially mediated by cardiac stem/progenitor cells (CPCs). Therefore, we examined the effects of 1,25-dihydroxyvitamin D3 (1,25D) on cell cycle activity and differentiation of a previously described CPC population called cardiac colony-forming unit fibroblasts (cCFU-Fs).

Methods: cCFU-Fs were isolated from adult male C57Bl/6 mouse hearts using fluorescence-activated cell sorting. The effect of 1,25D on cell proliferation and differentiation were was assessed by colony-forming and fibroblast differentiation assays. Cell cycle was analysed by flow cytometry. Mice with induced myocardial infarction (MI) were treated with 1,25D or vehicle controls and cardiac function assessed by echocardiography.

Results: 1,25D dose-dependently increased expression of vitamin D receptor (Vdr) and reduced large colony formation. Addition of 1,25D to cCFU-Fs slowed cell proliferation, promoted cell cycle arrest and decreased expression of pro-fibrotic factors during TGF-β-induced fibroblast differentiation of cCFU-Fs. After MI, 1,25D-treated mice had less left ventricular wall thinning and significant improvement in left ventricular systolic function compared to vehicle-treated controls. Although no significant changes in myocardial fibrotic area and cardiomyocyte size were noted, treatment with 1,25D significantly inhibited cardiac interstitial cell proliferation after MI.

Conclusions: Vitamin D signalling promotes cardioprotection after myocardial infarction. This may be through modulation of cCFU-F cell cycle. The role of 1,25D and VDR in regulating cardiac stem/progenitor cell function therefore warrants further investigation.
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http://dx.doi.org/10.1016/j.hlc.2018.01.006DOI Listing
August 2018

The Geometric Framework for Nutrition as a tool in precision medicine.

Nutr Healthy Aging 2017 Dec 7;4(3):217-226. Epub 2017 Dec 7.

Charles Perkins Centre, The University of Sydney, NSW, Australia.

Fundamental questions in nutrition include, "What constitutes a nutritionally balanced diet?", "What are the consequences of failing to achieve diet balance?", and "How does diet balance change across the lifecourse and with individual circumstances?". Answering these questions requires coming to grips with the multidimensionality and dynamic nature of nutritional requirements, foods and diets, and the complex relationships between nutrition and health, while at the same time avoiding becoming overwhelmed by complexity. Here we illustrate the use of an integrating framework for taming the complexity of nutrition, the Geometric Framework for Nutrition (GFN), and show how this might be used to untap the full potential for nutrition to provide targeted primary interventions and treatments for the chronic diseases of aging. We first briefly introduce the concepts behind GFN, then provide an example of how GFN has been used to relate nutrition to various behavioural, physiological and health outcomes in a large mouse experiment, and end by suggesting a translational pathway to human health.
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http://dx.doi.org/10.3233/NHA-170027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734128PMC
December 2017

Hepatic Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) regulates metabolism in mice.

PLoS One 2017 30;12(11):e0186543. Epub 2017 Nov 30.

The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW. Australia.

Background & Aims: Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) and its partners hypoxia-inducible factors (HIF)-1α and HIF-2α are candidate factors for the well-known link between the liver, metabolic dysfunction and elevation in circulating lipids and glucose. Methods: Hepatocyte-specific ARNT-null (LARNT), HIF-1α-null (LHIF1α) and HIF-2α-null (LHIF2α) mice were created.

Results: LARNT mice had increased fasting glucose, impaired glucose tolerance, increased glucose production, raised post-prandial serum triglycerides (TG) and markedly lower hepatic ATP versus littermate controls. There was increased expression of G6Pase, Chrebp, Fas and Scd-1 mRNAs in LARNT animals. Surprisingly, LHIF1α and LHIF2α mice exhibited no alterations in any metabolic parameter assessed.

Conclusions: These results provide convincing evidence that reduced hepatic ARNT can contribute to inappropriate hepatic glucose production and post-prandial dyslipidaemia. Hepatic ARNT may be a novel therapeutic target for improving post-prandial hypertriglyceridemia and glucose homeostasis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186543PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708799PMC
December 2017

Transplantation sites for human and murine islets.

Diabetologia 2017 10 22;60(10):1961-1971. Epub 2017 Jul 22.

Centre for Diabetes, Obesity & Endocrinology, The Westmead Institute for Medical Research (WIMR), Room 2040, Level 2, Darcy Rd, Westmead Hospital, The University of Sydney, Sydney, NSW, 2145, Australia.

Aims/hypothesis: Beta cell replacement is a potential cure for type 1 diabetes. In humans, islet transplants are currently infused into the liver via the portal vein, although this site has disadvantages. Here, we investigated alternative transplantation sites for human and murine islets in recipient mice, comparing the portal vein with quadriceps muscle and kidney, liver and spleen capsules.

Methods: Murine islets were isolated from C57BL6/J mice and transplanted into syngeneic recipients. Human islets were isolated and transplanted into either severe combined immunodeficiency (SCID) or recombination-activating gene 1 (RAG-1) immunodeficient recipient mice. All recipient mice were 8-12 weeks of age and had been rendered diabetic (defined as blood glucose concentrations ≥20 mmol/l on two consecutive days before transplantation) by alloxan tetrahydrate treatment. Islets were transplanted into five different sites (portal vein, quadriceps muscle, kidney, liver and spleen capsules). Blood glucose concentrations were monitored twice weekly until mice were killed. Dose-response studies were also performed to determine the minimum number of islets required to cure diabetes ('cure' is defined for this study as random fed blood glucose of <15 mmol/l).

Results: For transplantation of murine islets into the different sites, the kidney yielded 100% success, followed by muscle (70%), portal vein (60%), spleen capsule (29%) and liver capsule (0%). For human islets, transplantation into the kidney cured diabetes in 75-80% of recipient mice. Transplantation into muscle and portal vein had intermediate success (both 29% at 2000 islet equivalents), while transplantation into liver and spleen capsule failed (0%). With increased islet mass, success rates for muscle grafts improved to 52-56%.

Conclusions/interpretation: For both human and murine islets, equivalent or superior glucose lowering results were obtained for transplantation into skeletal muscle, compared with the portal vein. Unfortunately, kidney grafts are not feasible in human recipients. Skeletal muscle offers easier access and greater potential for protocol biopsies. This study suggests that human trials of muscle as a transplant site may be warranted.
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http://dx.doi.org/10.1007/s00125-017-4362-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448863PMC
October 2017

Transplantation sites for porcine islets.

Diabetologia 2017 10 21;60(10):1972-1976. Epub 2017 Jul 21.

National Pancreas and Islet Transplant Unit, University of Sydney, Westmead Hospital, Sydney, NSW, Australia.

Aims/hypothesis: Xenotransplantation has great potential to provide beta cell replacement and thereby provide a cure for large numbers of people with type 1 diabetes. Crucial to the success of xenotransplantation is establishment of the most viable sites for transplantation.

Methods: We compared porcine islet tissue transplanted into kidney, liver and spleen in pig recipients as assessed by blood glucose levels and IVGTT.

Results: Kidney was the superior site for porcine islet tissue transplantation, followed by liver then spleen. This was demonstrated by IVGTTs showing significant difference between the peak glucose levels: 22.8 ± 2.9 mmol/l for kidney compared with 26.8 ± 1.3 mmol/l for spleen and 24.7 ± 1.7 mmol/l for liver.

Conclusions/interpretation: Kidney grafts are not as feasible in humans and liver results were relatively poorer than spleen. For islet transplantation to be viable and successful in the longer term, there remains a need for future investigation of alternative sites.
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http://dx.doi.org/10.1007/s00125-017-4363-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448811PMC
October 2017

GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation.

Sci Rep 2017 06 1;7(1):2661. Epub 2017 Jun 1.

School of Biomedical Sciences, Curtin Health Innovation Research Institute, Perth, WA, Australia.

Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic β-cells in a glucose dependent manner. Several pathways mediate this action by rapid, kinase phosphorylation-dependent, but gene expression-independent mechanisms. Since GLP-1-induced insulin secretion requires glucose metabolism, we aimed to address the hypothesis that GLP-1 receptor (GLP-1R) signalling can modulate glucose uptake and utilization in β-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 β-cells and rodent islets to the GLP-1R agonist Exendin-4 (50 nM). Here we report for the first time that prolonged stimulation of the GLP-1R for 18 hours promotes metabolic reprogramming of β-cells. This is evidenced by up-regulation of glycolytic enzyme expression, increased rates of glucose uptake and consumption, as well as augmented ATP content, insulin secretion and glycolytic flux after removal of Exendin-4. In our model, depletion of Hypoxia-Inducible Factor 1 alpha (HIF-1α) impaired the effects of Exendin-4 on glucose metabolism, while pharmacological inhibition of Phosphoinositide 3-kinase (PI3K) or mTOR completely abolished such effects. Considering the central role of glucose catabolism for stimulus-secretion coupling in β-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated β-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression.
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http://dx.doi.org/10.1038/s41598-017-02838-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454020PMC
June 2017

Diabetes Medications and Cardiovascular Outcomes in Type 2 Diabetes.

Heart Lung Circ 2017 Nov 10;26(11):1133-1141. Epub 2017 Apr 10.

Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW, Australia; The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. Electronic address:

Introduction: Patients with type 2 diabetes have an increased risk of developing adverse cardiovascular (CV) outcomes. The evidence relating to the effects of glucose-lowering medications on CV outcomes is of variable quality and there are numerous trials ongoing.

Results: In this review, we summarise the available literature on CV outcomes of the following diabetes treatments: metformin, the sulfonylureas, acarbose, glucagon-like peptide 1 (GLP1) receptor agonists, dipeptidyl peptidase-4 inhibitors (DPP4i), sodium-glucose co-transporter 2 inhibitors (SGLT2i), thiazolidinediones (TZDs) and insulin.

Conclusions: Insulin is required if glucose levels are very high. Otherwise, metformin, acarbose, some GLP1 receptor agonists and one SGLT2i appear beneficial for CV outcomes.
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http://dx.doi.org/10.1016/j.hlc.2017.02.030DOI Listing
November 2017

Vitamin D in liver disease: Current evidence and potential directions.

Biochim Biophys Acta Mol Basis Dis 2017 04 4;1863(4):907-916. Epub 2017 Jan 4.

The Garvan Institute of Medical Research, The University of New South Wales (UNSW), Sydney, NSW, Australia; The Westmead Institute of Medical Research, The University of Sydney, NSW, Australia. Electronic address:

Consistent with its multifaceted nature, growing evidence links vitamin D with hepatic disease. In this review, we summarise the roles of vitamin D in different liver pathologies and explore the clinical utility of vitamin D-based treatments in hepatology. We find that the small number of clinical trials coupled with the profound heterogeneity of study protocols limits the strength of evidence needed to ascribe definite clinical value to the hormone in liver disease. Nevertheless, the experimental data is promising and further bench and bedside studies will likely define a clearer role in hepatic therapeutics.
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http://dx.doi.org/10.1016/j.bbadis.2017.01.001DOI Listing
April 2017

Islet Transplantation Provides Superior Glycemic Control With Less Hypoglycemia Compared With Continuous Subcutaneous Insulin Infusion or Multiple Daily Insulin Injections.

Transplantation 2017 06;101(6):1268-1275

1 Department of Endocrinology, University of Sydney at Westmead Hospital, NSW, Australia. 2 Centre for Diabetes, Obesity and Endocrinology Research, The Westmead Institute, University of Sydney at Westmead Hospital, Sydney, Australia. 3 Department of Diabetes and Endocrinology, Westmead Hospital Westmead, NSW, Australia. 4 National Pancreas Transplant Unit, University of Sydney at Westmead Hospital, Westmead Hospital, Westmead, NSW, Australia. 5 Centre for Renal and Transplant Research, Westmead Millennium Institute, University of Sydney at Westmead, NSW, Australia. 6 Department of Renal Medicine, Westmead Hospital, NSW, Australia. 7 Department of Paediatrics, Murdoch Children's Research Institute and University of Melbourne, Victoria, Australia. 8 St Vincent's Institute, University of Melbourne, Victoria, Australia. 9 Departments of Endocrinology and Clinical Biochemistry, St Vincent's Hospital, Melbourne, Victoria, Australia. 10 Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.

Background: The aim was to compare efficacy of multiple daily injections (MDI), continuous subcutaneous insulin infusion (CSII) and islet transplantation to reduce hypoglycemia and glycemic variability in type 1 diabetes subjects with severe hypoglycemia.

Methods: This was a within-subject, paired comparison of MDI and CSII and CSII with 12 months postislet transplantation in 10 type 1 diabetes subjects referred with severe hypoglycemia, suitable for islet transplantation. Individuals were assessed with HbA1c, Edmonton Hypoglycemia Score (HYPOscore), continuous glucose monitoring (CGM) and in 8 subjects measurements of glucose variability using standard deviation of glucose (SD glucose) from CGM and continuous overlapping net glycemic action using a 4 hour interval (CONGA4).

Results: After changing from MDI to CSII before transplantation, 10 subjects reduced median HYPOscore from 2028 to 1085 (P < 0.05) and hypoglycemia events from 24 to 8 per patient-year (P < 0.05). While HbA1c, mean glucose and median percent time hypoglycemic on CGM were unchanged with CSII, SD glucose and CONGA4 reduced significantly (P < 0.05). At 12 months posttransplant 9 of 10 were C-peptide positive, (5 insulin independent). Twelve months postislet transplantation, there were significant reductions in all baseline parameters versus CSII, respectively, HbA1c (6.4% cf 8.2%), median HYPOscore (0 cf 1085), mean glucose (7.1 cf 8.6 mmol L), SD glucose (1.7 cf 3.2 mmol/L), and CONGA4 (1.6 cf 3.0).

Conclusions: In subjects with severe hypoglycemia suitable for islet transplantation, CSII decreased hypoglycemia frequency and glycemic variability compared with MDI whereas islet transplantation resolved hypoglycemia and further improved glycemic variability regardless of insulin independence.
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http://dx.doi.org/10.1097/TP.0000000000001381DOI Listing
June 2017

Bone Mineral Density in Postmenopausal Women Heterozygous for the C282Y HFE Mutation.

J Osteoporos 2016 31;2016:5638273. Epub 2016 Mar 31.

Department of Endocrinology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; Northern Clinical School, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.

Mutations in the HFE gene may be associated with increased tissue iron stores reflected in an elevated serum ferritin. With homozygous mutation C282Y, the increase in serum ferritin may be associated with tissue damage in the liver, pancreas, and pituitary and with a reduced bone mineral density. With heterozygous mutation C282Y, the degree of iron retention is less but information relating to how a heterozygous C282Y mutation might impact bone mineral density is uncertain. The present study was undertaken to study the relationships between bone mineral density measured by dual energy X-ray absorptiometry and the serum ferritin and serum iron in postmenopausal women heterozygous for the C282Y mutation. The spinal bone mineral density, L2-4, was significantly less than age matched community controls (P = 0.016). There was no significant change in the femoral neck bone mineral density compared to age matched community controls. The correlation between the spinal bone mineral density, L2-4, the femoral neck bone mineral density, and the serum ferritin was not significant. The serum iron correlated significantly inversely with the femoral neck bone mineral density (P = 0.048). The heterozygous C282Y mutation may be associated with impairment of bone cell function in postmenopausal women when only small increases in the serum iron or serum ferritin have occurred.
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http://dx.doi.org/10.1155/2016/5638273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830734PMC
April 2016

Changes in beta cell function occur in prediabetes and early disease in the Lepr (db) mouse model of diabetes.

Diabetologia 2016 06 5;59(6):1222-30. Epub 2016 Apr 5.

School of Biomedical Sciences, University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.

Aims/hypothesis: Type 2 diabetes is a progressive disease that increases morbidity and the risk of premature death. Glucose dysregulation, such as elevated fasting blood glucose, is observed prior to diabetes onset. A decline in beta cell insulin secretion contributes to the later stages of diabetes, but it is not known what, if any, functional beta cell changes occur in prediabetes and early disease.

Methods: The Lepr (db) mouse (age 13-18 weeks) was used as a model of type 2 diabetes and a two-photon granule fusion assay was used to characterise the secretory response of pancreatic beta cells.

Results: We identified a prediabetic state in db/db mice where the animals responded normally to a glucose challenge but have elevated fasting blood glucose. Isolated islets from prediabetic animals secreted more and were bigger. Insulin secretion, normalised to insulin content, was similar to wild type but basal insulin secretion was elevated. There was increased glucose-induced granule fusion with a high prevalence of granule-granule fusion. The glucose-induced calcium response was not changed but there was altered expression of the exocytic machinery. db/db animals at the next stage of disease had overt glucose intolerance. Isolated islets from these animals had reduced insulin secretion, reduced glucose-induced granule fusion events and decreased calcium responses to glucose.

Conclusions/interpretation: Beta cell function is altered in prediabetes and there are further changes in the progression to early disease.
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http://dx.doi.org/10.1007/s00125-016-3942-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869737PMC
June 2016

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells.

Diabetologia 2016 07 4;59(7):1492-1502. Epub 2016 Apr 4.

Garvan Institute of Medical Research, St Vincent's Hospital, UNSW Australia, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia.

Aims/hypothesis: Hypoxia may contribute to beta cell failure in type 2 diabetes and islet transplantation. The adaptive unfolded protein response (UPR) is required for endoplasmic reticulum (ER) homeostasis. Here we investigated whether or not hypoxia regulates the UPR in beta cells and the role the adaptive UPR plays during hypoxic stress.

Methods: Mouse islets and MIN6 cells were exposed to various oxygen (O2) tensions. DNA-damage inducible transcript 3 (DDIT3), hypoxia-inducible transcription factor (HIF)1α and HSPA5 were knocked down using small interfering (si)RNA; Hspa5 was also overexpressed. db/db mice were used.

Results: Hypoxia-response genes were upregulated in vivo in the islets of diabetic, but not prediabetic, db/db mice. In isolated mouse islets and MIN6 cells, O2 deprivation (1-5% vs 20%; 4-24 h) markedly reduced the expression of adaptive UPR genes, including Hspa5, Hsp90b1, Fkbp11 and spliced Xbp1. Coatomer protein complex genes (Copa, Cope, Copg [also known as Copg1], Copz1 and Copz2) and ER-to-Golgi protein trafficking were also reduced, whereas apoptotic genes (Ddit3, Atf3 and Trb3 [also known as Trib3]), c-Jun N-terminal kinase (JNK) phosphorylation and cell death were increased. Inhibition of JNK, but not HIF1α, restored adaptive UPR gene expression and ER-to-Golgi protein trafficking while protecting against apoptotic genes and cell death following hypoxia. DDIT3 knockdown delayed the loss of the adaptive UPR and partially protected against hypoxia-induced cell death. The latter response was prevented by HSPA5 knockdown. Finally, Hspa5 overexpression significantly protected against hypoxia-induced cell death.

Conclusions/interpretation: Hypoxia inhibits the adaptive UPR in beta cells via JNK and DDIT3 activation, but independently of HIF1α. Downregulation of the adaptive UPR contributes to reduced ER-to-Golgi protein trafficking and increased beta cell death during hypoxic stress.
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http://dx.doi.org/10.1007/s00125-016-3947-yDOI Listing
July 2016

Fluconazole in the treatment of Cushing's disease.

Endocrinol Diabetes Metab Case Rep 2016 20;2016:150115. Epub 2016 Jan 20.

Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, 2145, Australia; Faculty of Medicine, Westmead Hospital, University of Sydney, Sydney, 2145, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, 2010, Australia; Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, 2010, Australia; Department of Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, The University of Sydney, Sydney, 2045, Australia.

Unlabelled: Ketoconazole was a first-line agent for suppressing steroidogenesis in Cushing's disease. It now has limited availability. Fluconazole, another azole antifungal, is an alternative, although its in vivo efficacy is unclear. A 61-year-old female presented with weight gain, abdominal striae and worsening depression. HbA1c increased to 76 mmol/mol despite increasing insulin. Investigations confirmed cortisol excess; afternoon serum cortisol was 552 nmol/l with an inappropriate ACTH of 9.3 pmol/l. In total, 24-h urinary free cortisol (UFC):creatinine ratio was 150 nmol/mmol with failure to suppress after 48 h of low-dose dexamethasone. Pituitary MRI revealed a 4-mm microadenoma. Inferior petrosal sinus sampling confirmed Cushing's disease. Transsphenoidal resection was performed and symptoms improved. However, disease recurred 6 months later with elevated 24-h UFC >2200 nmol/day. Metyrapone was commenced at 750 mg tds. Ketoconazole was later added at 400 mg daily, with dose reduction in metyrapone. When ketoconazole became unavailable, fluconazole 200 mg daily was substituted. Urine cortisol:creatinine ratio rose, and the dose was increased to 400 mg daily with normalisation of urine hormone levels. Serum cortisol and urine cortisol:creatinine ratios remain normal on this regimen at 6 months. In conclusion, to our knowledge, this is the first case demonstrating prolonged in vivo efficacy of fluconazole in combination with low-dose metyrapone for the treatment of Cushing's disease. Fluconazole has a more favourable toxicity profile, and we suggest that it is a potential alternative for medical management of Cushing's disease.

Learning Points: Surgery remains first line for the management of Cushing's disease with pharmacotherapy used where surgery is unsuccessful or there is persistence of cortisol excess.Ketoconazole has previously been used to treat cortisol excess through inhibition of CYP450 enzymes 11-β-hydroxylase and 17-α-hydroxylase, though its availability is limited in many countries.Fluconazole shares similar properties to ketoconazole, although it has less associated toxicity.Fluconazole represents a suitable alternative for the medical management of Cushing's disease and proved an effective addition to metyrapone in the management of this case.
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http://dx.doi.org/10.1530/EDM-15-0115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744941PMC
February 2016