Publications by authors named "Josephine M Forbes"

122 Publications

Antigen-encoding bone marrow terminates islet-directed memory CD8+ T-cell responses to alleviate islet transplant rejection.

Diabetes 2016 05 9;65(5):1328-1340. Epub 2016 Mar 9.

The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, AUSTRALIA.

Islet-specific memory T cells arise early in type 1 diabetes (T1D), persist for long periods, perpetuate disease and are rapidly reactivated by islet transplantation. As memory T cells are poorly controlled by 'conventional' therapies, memory T-cell mediated attack is a substantial challenge in islet transplantation and this will extend to application of personalized approaches using stem-cell derived replacement β cells. New approaches are required to limit memory autoimmune attack of transplanted islets or replacement β cells. Here we show that transfer of bone marrow encoding cognate antigen directed to dendritic cells, under mild, immune-preserving conditions inactivates established memory CD8 T-cell populations and generates a long-lived, antigen-specific tolerogenic environment. Consequently, CD8 memory T cell-mediated targeting of islet-expressed antigens is prevented and islet graft rejection alleviated. The immunological mechanisms of protection are mediated through deletion and induction of unresponsiveness in targeted memory T-cell populations. The data demonstrate that hematopoietic stem cell-mediated gene therapy effectively terminates antigen-specific memory T-cell responses and this can alleviate destruction of antigen-expressing islets. This addresses a key challenge facing islet transplantation and importantly, the clinical application of personalized β-cell replacement therapies using patient-derived stem cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db15-1418DOI Listing
May 2016

Mapping time-course mitochondrial adaptations in the kidney in experimental diabetes.

Clin Sci (Lond) 2016 May 1;130(9):711-20. Epub 2016 Feb 1.

Glycation, Nutrition & Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria 8008, Australia Glycation and Diabetes, Mater Research Institute-The University of Queensland, TRI, South Brisbane, QLD 4102, Australia School of Medicine, Mater Clinical School, The University of Queensland, St Lucia, QLD 4067, Australia.

Oxidative phosphorylation (OXPHOS) drives ATP production by mitochondria, which are dynamic organelles, constantly fusing and dividing to maintain kidney homoeostasis. In diabetic kidney disease (DKD), mitochondria appear dysfunctional, but the temporal development of diabetes-induced adaptations in mitochondrial structure and bioenergetics have not been previously documented. In the present study, we map the changes in mitochondrial dynamics and function in rat kidney mitochondria at 4, 8, 16 and 32 weeks of diabetes. Our data reveal that changes in mitochondrial bioenergetics and dynamics precede the development of albuminuria and renal histological changes. Specifically, in early diabetes (4 weeks), a decrease in ATP content and mitochondrial fragmentation within proximal tubule epithelial cells (PTECs) of diabetic kidneys were clearly apparent, but no changes in urinary albumin excretion or glomerular morphology were evident at this time. By 8 weeks of diabetes, there was increased capacity for mitochondrial permeability transition (mPT) by pore opening, which persisted over time and correlated with mitochondrial hydrogen peroxide (H2O2) generation and glomerular damage. Late in diabetes, by week 16, tubular damage was evident with increased urinary kidney injury molecule-1 (KIM-1) excretion, where an increase in the Complex I-linked oxygen consumption rate (OCR), in the context of a decrease in kidney ATP, indicated mitochondrial uncoupling. Taken together, these data show that changes in mitochondrial bioenergetics and dynamics may precede the development of the renal lesion in diabetes, and this supports the hypothesis that mitochondrial dysfunction is a primary cause of DKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/CS20150838DOI Listing
May 2016

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis.

Diabetes 2016 04 28;65(4):1085-98. Epub 2016 Jan 28.

Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Glycation and Diabetes Group, Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, South Brisbane, Queensland, Australia School of Medicine, Mater Clinical School, The University of Queensland, St. Lucia, Queensland, Australia.

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein with dual roles in redox signaling and programmed cell death. Deficiency in AIF is known to result in defective oxidative phosphorylation (OXPHOS), via loss of complex I activity and assembly in other tissues. Because the kidney relies on OXPHOS for metabolic homeostasis, we hypothesized that a decrease in AIF would result in chronic kidney disease (CKD). Here, we report that partial knockdown of Aif in mice recapitulates many features of CKD, in association with a compensatory increase in the mitochondrial ATP pool via a shift toward mitochondrial fusion, excess mitochondrial reactive oxygen species production, and Nox4 upregulation. However, despite a 50% lower AIF protein content in the kidney cortex, there was no loss of complex I activity or assembly. When diabetes was superimposed onto Aif knockdown, there were extensive changes in mitochondrial function and networking, which augmented the renal lesion. Studies in patients with diabetic nephropathy showed a decrease in AIF within the renal tubular compartment and lower AIFM1 renal cortical gene expression, which correlated with declining glomerular filtration rate. Lentiviral overexpression of Aif1m rescued glucose-induced disruption of mitochondrial respiration in human primary proximal tubule cells. These studies demonstrate that AIF deficiency is a risk factor for the development of diabetic kidney disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db15-0864DOI Listing
April 2016

Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY): A Randomized Trial.

Clin J Am Soc Nephrol 2016 Feb 15;11(2):223-31. Epub 2016 Jan 15.

School of Medicine, Translational Research Institute, Brisbane, Queensland, Australia; Nephrology Department, Princess Alexandra Hospital, Brisbane, Queensland, Australia;

Background And Objectives: The generation of key uremic nephrovascular toxins, indoxyl sulfate (IS), and p-cresyl sulfate (PCS), is attributed to the dysbiotic gut microbiota in CKD. The aim of our study was to evaluate whether synbiotic (pre- and probiotic) therapy alters the gut microbiota and reduces serum concentrations of microbiome-generated uremic toxins, IS and PCS, in patients with CKD.

Design, Setting, Participants, & Measurements: Predialysis adult participants with CKD (eGFR=10-30 ml/min per 1.73 m(2)) were recruited between January 5, 2013 and November 12, 2013 to a randomized, double-blind, placebo-controlled, crossover trial of synbiotic therapy over 6 weeks (4-week washout). The primary outcome was serum IS. Secondary outcomes included serum PCS, stool microbiota profile, eGFR, proteinuria-albuminuria, urinary kidney injury molecule-1, serum inflammatory biomarkers (IL-1β, IL-6, IL-10, and TNF-α), serum oxidative stress biomarkers (F2-isoprostanes and glutathione peroxidase), serum LPS, patient-reported health, Gastrointestinal Symptom Score, and dietary intake. A prespecified subgroup analysis explored the effect of antibiotic use on treatment effect.

Results: Of 37 individuals randomized (age =69±10 years old; 57% men; eGFR=24±8 ml/min per 1.73 m(2)), 31 completed the study. Synbiotic therapy did not significantly reduce serum IS (-2 μmol/L; 95% confidence interval [95% CI], -5 to 1 μmol/L) but did significantly reduce serum PCS (-14 μmol/L; 95% CI, -27 to -2 μmol/L). Decreases in both PCS and IS concentrations were more pronounced in patients who did not receive antibiotics during the study (n=21; serum PCS, -25 μmol/L; 95% CI, -38 to -12 μmol/L; serum IS, -5 μmol/L; 95% CI, -8 to -1 μmol/L). Synbiotics also altered the stool microbiome, particularly with enrichment of Bifidobacterium and depletion of Ruminococcaceae. Except for an increase in albuminuria of 38 mg/24 h (P=0.03) in the synbiotic arm, no changes were observed in the other secondary outcomes.

Conclusion: In patients with CKD, synbiotics did not significantly reduce serum IS but did decrease serum PCS and favorably modified the stool microbiome. Large-scale clinical trials are justified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2215/CJN.05240515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741035PMC
February 2016

Tapping into Mitochondria to Find Novel Targets for Diabetes Complications.

Curr Drug Targets 2016 ;17(12):1341-9

Mater Research Institute, University of Queensland, Translational Research Institute, 37 Kent Street Woolloongabba, Queensland 4102, Australia.

Mitochondria produce the majority of cellular energy via the "slow burn" of substrates such as glucose, free fatty acids and ketones. In diabetes, altered mitochondrial energetics and substrate utilisation may explain, in part, an organ's susceptibility to complications. This is particularly evident at sites such as the kidney, heart, neurons and retina, which have high energy demands and oxygen consumption rates to meet functional requirements. Within this review we highlight the recent research implicating mitochondrial dysfunction, with particular focus on the contribution of mitochondrial reactive oxygen species, on the development and progression of diabetes complications. Finally, we discuss the current strategies which are being assessed to combat mitochondrial dysfunction in diabetes complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389450116666150727114410DOI Listing
August 2017

Impairment of Liver Glycogen Storage in the db/db Animal Model of Type 2 Diabetes: A Potential Target for Future Therapeutics?

Curr Drug Targets 2015 ;16(10):1088-93

The University of Queensland, Centre for Nutrition and Food Sciences, Queensland Alliance for Agriculture and Food Innovation, Brisbane, QLD 4072, Australia.

After the discovery of the db gene in 1966, it was determined that a blood-borne satiety factor was produced excessively, but was not responded to, in db/db mice. This model for type 2 diabetes is widely used since it phenocopies human disease and its co-morbidities including obesity, progressive deterioration in glucose tolerance, hypertension and hyperlipidaemia. Db/db mice, unlike their non-diabetic controls, have consistently elevated levels of liver glycogen, most likely due to hyperphagia. In transmission electron micrographs, liver glycogen usually shows a composite cauliflower-like morphology of large "α particles" (with a wide range of sizes) made up of smaller "β particles" bound together. New studies have explored the size distribution of liver glycogen molecules and found that α particles in db/db mice are more chemically fragile than those in healthy mice, and can readily break apart to smaller β particles. There is evidence that smaller glycogen particles have a higher association with glycogen phosphorylase, a key enzyme involved in glycogen degradation, as well as being degraded more rapidly in vitro; therefore the inability to form stable large glycogen α particles is predicted to result in a faster, less controlled degradation into glucose. The implications of this for glycaemic control remain to be fully elucidated. However, "rescuing" the more fragile diabetic glycogen to decrease hepatic glucose output in type 2 diabetes, may provide a potential therapeutic target which is the subject of this review.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389450116666150727123115DOI Listing
July 2016

Decrease in circulating concentrations of soluble receptors for advanced glycation end products at the time of seroconversion to autoantibody positivity in children with prediabetes.

Diabetes Care 2015 Apr 8;38(4):665-70. Epub 2015 Jan 8.

Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Department of Pediatrics, Tampere University Hospital, Tampere, Finland

Objective: Dietary advanced glycation end products (AGEs) and their interactions with the receptor for AGEs (RAGE) may play a role in the pathogenesis of type 1 diabetes. This study set out to assess whether there is any association of circulating concentrations of soluble RAGE (sRAGE), AGEs, and their ratio with the appearance of diabetes-associated autoantibodies in children progressing to clinical diabetes.

Research Design And Methods: Serum concentrations of sRAGE, N-ε(carboxymethyl)lysine (CML) adducts, and the sRAGE/CML ratio were analyzed in children who progressed to type 1 diabetes. The samples were taken at four time points: before seroconversion, at the time of the first autoantibody-positive sample, at the time of the first sample positive for multiple (>2) autoantibodies, and close to the disease diagnosis. Samples of autoantibody-negative controls matched for age, sex, and HLA-conferred diabetes risk were analyzed at corresponding time points.

Results: The prediabetic children had higher sRAGE concentrations before seroconversion (Pc = 0.03), at the appearance of multiple autoantibodies (Pc = 0.008), and close to diagnosis (Pc = 0.04). Close to diagnosis, the cases had lower CML concentrations than the controls (Pc = 0.004). Prediabetic children had a higher sRAGE/CML ratio than the controls before seroconversion (Pc = 0.008) and at diagnosis (Pc < 0.001).

Conclusions: Prediabetic children have higher concentrations of sRAGE and a higher sRAGE/CML ratio than healthy controls. Circulating sRAGE concentrations seem to decline with the appearance of diabetes-predictive autoantibodies in children progressing to type 1 diabetes. The higher sRAGE/CML ratio in prediabetic children may reflect a higher AGE scavenger capacity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc14-1186DOI Listing
April 2015

A rapid extraction method for glycogen from formalin-fixed liver.

Carbohydr Polym 2015 Mar 15;118:9-15. Epub 2014 Nov 15.

Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; The University of Queensland, Centre for Nutrition and Food Sciences, Queensland Alliance for Agriculture and Food Innovation, Brisbane, QLD 4072, Australia. Electronic address:

Liver glycogen, a highly branched polymer, acts as our blood-glucose buffer. While past structural studies have extracted glycogen from fresh or frozen tissue using a cold-water, sucrose-gradient centrifugation technique, a method for the extraction of glycogen from formalin-fixed liver would allow the analysis of glycogen from human tissues that are routinely collected in pathology laboratories. In this study, both sucrose-gradient and formalin-fixed extraction techniques were carried out on piglet livers, with the yields, purities and size distributions (using size exclusion chromatography) compared. The formalin extraction technique, when combined with a protease treatment, resulted in higher yields (but lower purities) of glycogen with size distributions similar to the sucrose-gradient centrifugation technique. This formalin extraction procedure was also significantly faster, allowing glycogen extraction throughput to increase by an order of magnitude. Both extraction techniques were compatible with mass spectrometry proteomics, with analysis showing the two techniques were highly complementary.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.carbpol.2014.11.005DOI Listing
March 2015

Nox-4 deletion reduces oxidative stress and injury by PKC-α-associated mechanisms in diabetic nephropathy.

Physiol Rep 2014 Nov 3;2(11). Epub 2014 Nov 3.

Diabetes Complications Division, Baker IDI Heart & Diabetes Institute, JDRF Danielle Alberti Memorial Centre for Diabetic Complications, Melbourne, Victoria, Australia Department of Medicine, Central Clinical School, Monash University, AMREP Precinct, Melbourne, Victoria, Australia.

Current treatments for diabetic nephropathy (DN) only result in slowing its progression, thus highlighting a need to identify novel targets. Increased production of reactive oxygen species (ROS) is considered a key downstream pathway of end-organ injury with increasing data implicating both mitochondrial and cytosolic sources of ROS. The enzyme, NADPH oxidase, generates ROS in the kidney and has been implicated in the activation of protein kinase C (PKC), in the pathogenesis of DN, but the link between PKC and Nox-derived ROS has not been evaluated in detail in vivo. In this study, global deletion of a NADPH-oxidase isoform, Nox4, was examined in mice with streptozotocin-induced diabetes (C57Bl6/J) in order to evaluate the effects of Nox4 deletion, not only on renal structure and function but also on the PKC pathway and downstream events. Nox4 deletion attenuated diabetes-associated increases in albuminuria, glomerulosclerosis, and extracellular matrix accumulation. Lack of Nox4 resulted in a decrease in diabetes-induced renal cortical ROS derived from the mitochondria and the cytosol, urinary isoprostanes, and PKC activity. Immunostaining of renal cortex revealed that major isoforms of PKC, PKC-α and PKC-β1, were increased with diabetes and normalized by Nox4 deletion. Downregulation of the PKC pathway was observed in tandem with reduced expression of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1 and restoration of the podocyte slit pore protein nephrin. This study suggests that deletion of Nox4 may alleviate renal injury via PKC-dependent mechanisms, further strengthening the view that Nox4 is a suitable target for renoprotection in diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14814/phy2.12192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255803PMC
November 2014

Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress.

Nat Med 2014 Dec 2;20(12):1417-26. Epub 2014 Nov 2.

1] Mucosal Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia. [2] School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia. [3] School of Medicine, University of Queensland, Brisbane, Queensland, Australia.

In type 2 diabetes, hyperglycemia is present when an increased demand for insulin, typically due to insulin resistance, is not met as a result of progressive pancreatic beta cell dysfunction. This defect in beta cell activity is typically characterized by impaired insulin biosynthesis and secretion, usually accompanied by oxidative and endoplasmic reticulum (ER) stress. We demonstrate that multiple inflammatory cytokines elevated in diabetic pancreatic islets induce beta cell oxidative and ER stress, with interleukin-23 (IL-23), IL-24 and IL-33 being the most potent. Conversely, we show that islet-endogenous and exogenous IL-22, by regulating oxidative stress pathways, suppresses oxidative and ER stress caused by cytokines or glucolipotoxicity in mouse and human beta cells. In obese mice, antibody neutralization of IL-23 or IL-24 partially reduced beta cell ER stress and improved glucose tolerance, whereas IL-22 administration modulated oxidative stress regulatory genes in islets, suppressed ER stress and inflammation, promoted secretion of high-quality efficacious insulin and fully restored glucose homeostasis followed by restitution of insulin sensitivity. Thus, therapeutic manipulation of immune regulators of beta cell stress reverses the hyperglycemia central to diabetes pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nm.3705DOI Listing
December 2014

Ramipril inhibits AGE-RAGE-induced matrix metalloproteinase-2 activation in experimental diabetic nephropathy.

Diabetol Metab Syndr 2014 13;6(1):86. Epub 2014 Aug 13.

Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia ; Department of Glycation and Diabetic Complications, Mater Medical Research Institute, Brisbane, Australia.

Background: Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angiotensin system (RAS) play a role in diabetic nephropathy (DN). Matrix metalloproteinase-2 (MMP-2) activation also contributes to DN. However, the pathological interaction among AGE-RAGE, RAS and MMP-2 in DN remains unknown. We examined here the involvement of AGE and RAS in MMP-2 activation in streptozotocin (STZ)-induced diabetic rats and in AGE-exposed rat renal proximal tubular cells (RPTCs).

Methods: Experimental diabetes was induced in 6-week-old male Sprague-Dawley (SD) rats by intravenous injection of STZ. Diabetic rats received ramipril (3 mg/kg body weight/day) or vehicle for 32 weeks. AGE-modified rat serum albumin (AGE-RSA) or RSA was intraperitoneally administrated to 6-week-old male SD rats for 16 weeks. RPTCs were stimulated with 100 μg/ml AGE-modified bovine serum albumin (AGE-BSA) or BSA in the presence or absence of 10(-7) M ramiprilat, an inhibitor of angiotensin-converting enzyme or 100 nM BAY11-7082, an IκB-α phosphorylation inhibitor.

Results: AGE and RAGE expression levels and MMP-2 activity in the tubules of diabetic rats was significantly increased in association with increased albuminuria, all of which were blocked by ramipril. AGE infusion induced tubular MMP-2 activation and RAGE gene expression in SD rats. Ramiprilat or BAY11-7082 inhibited the AGE-induced MMP-2 activation or reactive oxygen species generation in RPTCs. Angiotensin II increased MMP-2 gene expression in RPTCs, which was blocked by BAY11-7082.

Conclusions: Our present study suggests the involvement of AGE-RAGE-induced, RAS-mediated MMP-2 activation in experimental DN. Blockade of AGE-RAGE axis by ramipril may protect against DN partly via suppression of MMP-2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1758-5996-6-86DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138378PMC
August 2014

Type 2 diabetes, skin autofluorescence, and brain atrophy.

Diabetes 2015 Jan 22;64(1):279-83. Epub 2014 Jul 22.

Stroke and Ageing Research Group, Department of Medicine, Southern Clinical School, Monash University, Melbourne, Victoria, Australia Neurosciences, Monash Medical Centre, Monash Health, Melbourne, Australia Menzies Research Institute Tasmania, Hobart, Tasmania, Australia

Type 2 diabetes mellitus (T2DM) is associated with brain atrophy, but the mechanisms underlying this link are unknown. Advanced glycation end products (AGEs) accumulate in T2DM, resulting in inflammation, oxidative stress, and protein cross-linking, which are known contributors to neurodegeneration. We aimed to study whether tissue AGE accumulation is associated with T2DM-related brain atrophy. We performed brain magnetic resonance imaging, cognitive tests, and noninvasive skin autofluorescence (SAF; a measure of tissue AGE levels) on people aged >55 years with and without T2DM. Multivariable linear regression was used to study the relationships among T2DM, SAF, and gray matter volume (GMV). There were 486 people included in the study. T2DM was associated with greater SAF. Greater SAF, T2DM, and cognitive impairment were each associated with lower GMV independently of age, sex, and total intracranial volume. SAF partially mediated the association between T2DM and GMV. Longitudinal studies may help confirm whether tissue AGE accumulation is associated with brain atrophy in T2DM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db14-0506DOI Listing
January 2015

SYNbiotics Easing Renal failure by improving Gut microbiologY (SYNERGY): a protocol of placebo-controlled randomised cross-over trial.

BMC Nephrol 2014 Jul 4;15:106. Epub 2014 Jul 4.

School of Medicine, University of Queensland, Brisbane, Australia.

Background: Emerging evidence suggests modulating the microbiota in the large bowel of patients with chronic kidney disease (CKD) through pre- and/probiotic supplementation may inhibit the development of key nephrovascular toxins. To date, quality intervention trials investigating this novel treatment in CKD are lacking. The aim of SYNERGY is to assess the effectiveness of synbiotics (co-administration of pre- and probiotics) as a potential treatment targeting the synthesis of uremic toxins, specifically, indoxyl sulphate (IS) and p-cresyl sulphate (PCS).

Methods/design: Thirty-seven patients with moderate to severe CKD (Stage IV and V, pre-dialysis) will be recruited to a double-blind, placebo-controlled, randomised cross-over trial. Patients will be provided with synbiotic therapy or placebo for 6 weeks, with a 4 week washout before cross-over. The primary outcome is serum IS, total and free (unbound) concentrations, measured using ultra-performance liquid chromatography. Secondary outcomes include serum PCS, total and free (unbound) concentrations; cardiovascular risk, measured by serum lipopolysaccharides, serum trimethylamine-N-oxide (TMAO) and inflammation and oxidative stress markers; kidney damage, measured by 24 hour proteinuria and albuminuria, estimated glomerular filtration rate and renal tubule damage (urinary kidney injury molecule-1); patients' self assessed quality of life; and gastrointestinal symptoms. In addition, the effects on the community structure of the stool microbiota will be explored in a subset of patients to validate the mechanistic rationale underpinning the synbiotic therapy.

Discussion: IS and PCS are two novel uremic toxins implicated in both cardiovascular disease (CVD) and progression of CKD. Preliminary studies indicate that synbiotic therapy maybe a promising strategy when considering a targeted, tolerable and cost-efficient therapy for lowering serum IS and PCS concentrations. This trial will provide high quality 'proof-of-concept' data to elucidate both the efficacy of synbiotic therapy for lowering the toxins and whether reductions in serum IS and PCS translate into clinical benefits. Considering the potential of pre- and probiotics to not only shift toxin levels, but to also impede CVD and CKD progression, SYNERGY will provide vital insight into the effectiveness of this innocuous nutritional therapy.

Trial Registration: Universal Trial Number: U1111-1142-4363. Australian New Zealand Clinical Trials Registry Number: ACTRN12613000493741, date registered: 2nd May 2013.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2369-15-106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094543PMC
July 2014

Stress in the kidney is the road to pERdition: is endoplasmic reticulum stress a pathogenic mediator of diabetic nephropathy?

J Endocrinol 2014 Sep 30;222(3):R97-111. Epub 2014 Jun 30.

Glycation and Diabetes GroupMater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, South Brisbane, Queensland, AustraliaMater Clinical SchoolThe University of Queensland, South Brisbane, Queensland, AustraliaGlycation and Diabetes GroupMater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, South Brisbane, Queensland, AustraliaMater Clinical SchoolThe University of Queensland, South Brisbane, Queensland, Australia

The endoplasmic reticulum (ER) is an organelle that primarily functions to synthesise new proteins and degrade old proteins. Owing to the continual and variable nature of protein turnover, protein synthesis is inherently an error-prone process and is therefore tightly regulated. Fortunately, if this balance between synthesis and degradation is perturbed, an intrinsic response, the unfolded protein response (UPR) is activated to restore ER homoeostasis through the action of inositol-requiring protein 1, activating transcription factor 6 and PKR-like ER kinase transmembrane sensors. However, if the UPR is oversaturated and misfolded proteins accumulate, the ER can shift into a cytotoxic response, a physiological phenomenon known as ER stress. The mechanistic pathways of the UPR have been extensively explored; however, the role of this process in such a synthetic organ as the kidney requires further clarification. This review will focus on these aspects and will discuss the role of ER stress in specific resident kidney cells and how this may be integral in the pathogenesis and progression of diabetic nephropathy (DN). Given that diabetes is a perturbed state of protein turnover in most tissues, it is important to understand if ER stress is a secondary or tertiary response to other changes within the diabetic milieu or if it is an independent accelerator of kidney disease. Modulators of ER stress could provide a valuable tool for the treatment of DN and are under active investigation in other contexts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/JOE-13-0517DOI Listing
September 2014

Deletion of bone-marrow-derived receptor for AGEs (RAGE) improves renal function in an experimental mouse model of diabetes.

Diabetologia 2014 Sep 24;57(9):1977-85. Epub 2014 Jun 24.

Department of Nephrology, Monash Medical Centre, Monash Health, Clayton, Melbourne, VIC, Australia.

Aims/hypothesis: The AGEs and the receptor for AGEs (RAGE) are known contributors to diabetic complications. RAGE also has a physiological role in innate and adaptive immunity and is expressed on immune cells. The aim of this study was to determine whether deletion of RAGE from bone-marrow-derived cells influences the pathogenesis of experimental diabetic nephropathy.

Methods: Groups (n = 8/group) of lethally irradiated 8 week old wild-type (WT) mice were reconstituted with bone marrow from WT (WT → WT) or RAGE-deficient (RG) mice (RG → WT). Diabetes was induced using multiple low doses of streptozotocin after 8 weeks of bone marrow reconstitution and mice were followed for a further 24 weeks.

Results: Compared with diabetic WT mice reconstituted with WT bone marrow, diabetic WT mice reconstituted with RG bone marrow had lower urinary albumin excretion and podocyte loss, more normal creatinine clearance and less tubulo-interstitial injury and fibrosis. However, glomerular collagen IV deposition, glomerulosclerosis and cortical levels of TGF-β were not different among diabetic mouse groups. The renal tubulo-interstitium of diabetic RG → WT mice also contained fewer infiltrating CD68(+) macrophages that were activated. Diabetic RG → WT mice had lower renal cortical concentrations of CC chemokine ligand 2 (CCL2), macrophage inhibitory factor (MIF) and IL-6 than diabetic WT → WT mice. Renal cortical RAGE ligands S100 calgranulin (S100A)8/9 and AGEs, but not high mobility box protein B-1 (HMGB-1) were also decreased in diabetic RG → WT compared with diabetic WT → WT mice. In vitro, bone-marrow-derived macrophages from WT but not RG mice stimulated collagen IV production in cultured proximal tubule cells.

Conclusions/interpretation: These studies suggest that RAGE expression on haemopoietically derived immune cells contributes to the functional changes seen in diabetic nephropathy by promoting macrophage infiltration and renal tubulo-interstitial damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-014-3291-zDOI Listing
September 2014

Circulating concentrations of soluble receptor for AGE are associated with age and AGER gene polymorphisms in children with newly diagnosed type 1 diabetes.

Diabetes Care 2014 Jul 17;37(7):1975-81. Epub 2014 Apr 17.

Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, FinlandDiabetes and Obesity Research Program, University of Helsinki, Helsinki, FinlandFolkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, FinlandDepartment of Pediatrics, Tampere University Hospital, Tampere, Finland.

Objective: We analyzed the relationship among soluble receptor for advanced glycation end products (sRAGEs), the clinical phenotype, HLA genotype, and risk-associated single nucleotide polymorphisms (SNPs) in the AGER gene in a large population of Finnish children with newly diagnosed type 1 diabetes.

Research Design And Methods: Samples from 2,115 clinically phenotyped children <15 years of age in whom type 1 diabetes was diagnosed and 316 control subjects were analyzed for sRAGEs. Three SNPs of AGER, previously associated with HLA-DR/DQ haplotype independent diabetes risk (rs2070600, rs9469089, and rs17493811), were analyzed in 1,390 affected subjects.

Results: Children with type 1 diabetes and control subjects had similar sRAGE concentrations (1,171 vs. 1,153 pg/mL, P = 0.48). There was a correlation between age at diagnosis and serum sRAGE concentrations (r = 0.10, P < 0.001) among the patients but not among the control subjects. Children <2 years of age had the lowest concentrations in the diabetic population (1,027 vs. 1,181 pg/mL, P < 0.001) and the highest among the control subjects (1,329 vs. 1,140 pg/mL, P = 0.04). Ketoacidosis at diagnosis was associated with reduced concentrations (1,086 vs. 1,190 pg/mL, P < 0.001). HLA DR3/DR4 heterozygosity and the DR3 allele were associated with reduced sRAGE concentrations. The predisposing AA genotype of rs2070600 was associated with decreased sRAGE concentrations, while the protective CC genotype of rs9469089 was linked to increased concentrations.

Conclusions: Age and AGER polymorphisms are associated with the circulating sRAGE concentration among children with type 1 diabetes. The observations of reduced sRAGE concentrations in young children, in those with ketoacidosis, and in carriers of the high-risk HLA DR3/DR4 genotype suggest that decreased sRAGE concentration reflects a more aggressive disease phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc13-3049DOI Listing
July 2014

Dietary glycotoxins exacerbate progression of experimental fatty liver disease.

J Hepatol 2014 Apr 6;60(4):832-8. Epub 2013 Dec 6.

Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia; Department of Gastroenterology and Hepatology, Austin Health, Austin Hospital, Heidelberg, Melbourne, Victoria, Australia.

Background & Aims: Advanced glycation end-products (AGEs) levels are high in western diets and contribute to tissue injury via activation of RAGE (receptor for AGEs) and generation of reactive oxygen species (ROS). Here, we determined if high dietary AGE intake worsens progression of non-alcoholic fatty liver disease (NAFLD).

Methods: Male Sprague Dawley rats were fed a methionine choline deficient (MCD) diet for 6 weeks before 6 weeks of a high AGE MCD diet through baking. They were compared with animals on MCD diet or a methionine choline replete (MCR) diet alone for 12 weeks. Hepatic ROS, triglycerides, biochemistry, picro-sirius morphometry, hepatic mRNA expression and immunohistochemistry were determined. Primary hepatic stellate cells (HSCs) from both MCR and MCD animals were exposed to AGEs. ROS, proliferation and mRNA expression were determined.

Results: The high AGE MCD diet increased hepatic AGE content and elevated triglycerides, NADPH dependent superoxide production, HNE adducts, steatosis, steatohepatitis (CD43, IL-6, TNF-α) and fibrosis (α-SMA, CTGF, COL1A, picrosirius) compared to MCD alone. In HSCs, AGEs significantly increased ROS production, bromodeoxyuridine proliferation and MCP-1, IL-6, α-SMA, and RAGE expression in HSCs from MCD but not MCR animals. These effects were abrogated by RAGE or NADPH oxidase blockade.

Conclusions: In the MCD model of NAFLD, high dietary AGEs increases hepatic AGE content and exacerbates liver injury, inflammation, and liver fibrosis via oxidative stress and RAGE dependent profibrotic effects of AGEs on activated HSCs. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2013.11.033DOI Listing
April 2014

Targeting advanced glycation endproducts and mitochondrial dysfunction in cardiovascular disease.

Curr Opin Pharmacol 2013 Aug 16;13(4):654-61. Epub 2013 Jul 16.

Department of Glycation and Diabetic Complications, Mater Research, Brisbane, Queensland 4102, Australia.

Cardiovascular disease (CVD) is a leading cause of mortality in the Western World. The development and onset of disease can be attributed to many risk factors including genetic susceptibility, diabetes, obesity and atherosclerosis. Numerous studies highlight the production of advanced glycation endproducts (AGEs) and interaction with their receptor (RAGE) as playing a key pathogenic role. The AGEs-RAGE axis is thought to contribute to a proinflammatory environment inducing cellular dysfunction which cascades towards pathology. Mitochondrial dysfunction concurrently plays a role in these proinflammatory responses presenting excess reactive oxygen species (ROS) production under pathological conditions. This ROS release can exacerbate the production of AGEs fuelling the fire somewhat. However, the AGEs-RAGE axis may influence mitochondrial function independently of inflammation. Therefore instigation of the AGEs-RAGE axis may facilitate spiralling towards pathology on many fronts including CVD development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.coph.2013.06.009DOI Listing
August 2013

Advanced glycation end products (AGEs) are cross-sectionally associated with insulin secretion in healthy subjects.

Amino Acids 2014 Feb 6;46(2):321-6. Epub 2013 Jul 6.

Baker IDI Heart and Diabetes Institute, Melbourne, Australia,

It has been postulated that chronic exposure to high levels of advanced glycation end products (AGEs), in particular from dietary sources, can impair insulin secretion. In the present study, we investigated the cross-sectional relationship between AGEs and acute insulin secretion during an intravenous glucose tolerance test (IVGTT) and following a 75 g oral glucose tolerance test (OGTT) in healthy humans. We report the cross-sectional association between circulating AGE concentrations and insulin secretory function in healthy humans (17 F: 27 M, aged 30 ± 10 years) with a wide range of BMI (24.6-31.0 kg/m(2)). Higher circulating concentrations of AGEs were related to increased first phase insulin secretion during IVGTT (r = 0.43; p < 0.05) and lower 2-h glucose concentrations during OGTT (r = -0.31; p < 0.05). In addition, fasting (r = -0.36; p < 0.05) and 2-h glucose concentrations were negatively related to circulating levels of soluble receptor for AGE (RAGE) isoforms (r = -0.39; p < 0.01). In conclusion, in healthy humans, we show a cross-sectional association between advanced glycation end products and acute insulin secretion during glucose tolerance testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00726-013-1542-9DOI Listing
February 2014

Report on ISN Forefronts, Melbourne, Australia, 4-7 October 2012: tubulointerstitial disease in diabetic nephropathy.

Kidney Int 2013 Oct 22;84(4):653-6. Epub 2013 May 22.

1] Mater Medical Research Institute, South Brisbane, Queensland, Australia [2] Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.

The mechanisms involved in expansion of the tubulointerstitial compartment of the kidney in individuals with diabetes are not well understood. Given that tubulointerstitial damage is an important predictor of progression to end-stage kidney disease in most forms of chronic kidney disease it is imperative to gain a greater understanding of the processes involved. With this in mind, a very clear objective for the scientific content of this meeting was to spend more than half the program outside the comfort zone of nephrology, gaining insights from sources such as neurodegenerative and mitochondrial diseases, stem cells, cancer and high-level computing to reconstruct organ systems. The meeting also aimed to place the new concepts presented in the context of current knowledge in diabetic kidney disease and the milestones achieved to date in this area. The presenters were all extremely generous, giving not only their time, but also showing a large proportion of unpublished data to stimulate discussions, questions and innovation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ki.2013.89DOI Listing
October 2013

Effects of high-density lipoprotein elevation with cholesteryl ester transfer protein inhibition on insulin secretion.

Circ Res 2013 Jul 15;113(2):167-75. Epub 2013 May 15.

Baker IDI Heart and Diabetes Institute, Melbourne, Australia.

Rationale: High-density lipoprotein cholesterol elevation via cholesteryl ester transfer protein (CETP) inhibition represents a novel therapy for atherosclerosis, which also may have relevance for type 2 diabetes mellitus.

Objective: The current study assessed the effects of a CETP inhibitor on postprandial insulin, ex vivo insulin secretion, and cholesterol efflux from pancreatic β-cells.

Methods And Results: Healthy participants received a daily dose of CETP inhibitor (n=10) or placebo (n=15) for 14 days in a randomized double-blind study. Insulin secretion and cholesterol efflux from MIN6N8 β-cells were determined after incubation with treated plasma. CETP inhibition increased plasma high-density lipoprotein cholesterol, apolipoprotein AI, and postprandial insulin. MIN6N8 β-cells incubated with plasma from CETP inhibitor-treated individuals (compared with placebo) exhibited an increase in both glucose-stimulated insulin secretion and cholesterol efflux over the 14-day treatment period.

Conclusions: CETP inhibition increased postprandial insulin and promoted ex vivo β-cell glucose-stimulated insulin secretion, potentially via enhanced β-cell cholesterol efflux.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.113.300689DOI Listing
July 2013

Plasma advanced glycation end products (AGEs) and NF-κB activity are independent determinants of diastolic and pulse pressure.

Clin Chem Lab Med 2014 Jan;52(1):129-38

Background: High levels of circulating advanced glycation end products (AGEs) can initiate chronic low-grade activation of the immune system (CLAIS) with each of these factors independently associated with cardiovascular (CV) morbidity and mortality. Therefore, our objective was to characterize the relationship between serum AGEs, CLAIS and other risk factors for CV disease in normotensive non-diabetic individuals.

Methods: We measured body mass index (BMI), waist-to-hip ratio (WHR), blood pressure, lipid and glucose profile in 44 non-diabetic volunteers (17 female, 27 males). Carboxymethyl-lysine (CML) was measured by ELISA as a marker for circulating AGEs and NF-κB p65 activity as an inflammatory marker by DNA-binding in peripheral blood mononuclear cells lysates (PBMC).

Results: Plasma CML concentrations were related to diastolic blood pressure (r=-0.51, p<0.01) independently of age, sex, BMI and WHR (p<0.05). Diastolic blood pressure was also related to NF-κB activity in PBMC (r=0.47, p<0.01) before and after adjustment for age, sex, BMI and WHR (p<0.05). Plasma CML concentrations were related to the pulse pressure before (r=0.42; p<0.05) and after adjustment for age, sex, BMI and waist (p<0.05). Neither CML nor NF-κB activity were related to systolic blood pressure (both p=ns). Plasma CML concentrations were not associated with plasma lipid or glucose concentrations (all p=ns).

Conclusions: Plasma AGE levels and NF-κB activity in PBMC were independent determinants of diastolic and pulse pressure in healthy normotensive individuals. This association suggests a role for AGEs in the etiology of hypertension, possibly via the initiation of CLAIS and aortic stiffening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/cclm-2012-0850DOI Listing
January 2014

Deficiency in mitochondrial complex I activity due to Ndufs6 gene trap insertion induces renal disease.

Antioxid Redox Signal 2013 Aug 1;19(4):331-43. Epub 2013 Mar 1.

Glycation, Nutrition and Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Australia.

Aims: Defects in the activity of enzyme complexes of the mitochondrial respiratory chain are thought to be responsible for several disorders, including renal impairment. Gene mutations that result in complex I deficiency are the most common oxidative phosphorylation disorders in humans. To determine whether an abnormality in mitochondrial complex I per se is associated with development of renal disease, mice with a knockdown of the complex I gene, Ndufs6 were studied.

Results: Ndufs6 mice had a partial renal cortical complex I deficiency; Ndufs6gt/gt, 32% activity and Ndufs6gt/+, 83% activity compared with wild-type mice. Both Ndufs6gt/+ and Ndufs6gt/gt mice exhibited hallmarks of renal disease, including albuminuria, urinary excretion of kidney injury molecule-1 (Kim-1), renal fibrosis, and changes in glomerular volume, with decreased capacity to generate mitochondrial ATP and superoxide from substrates oxidized via complex I. However, more advanced renal defects in Ndufs6gt/gt mice were observed in the context of a disruption in the inner mitochondrial electrochemical potential, 3-nitrotyrosine-modified mitochondrial proteins, increased urinary excretion of 15-isoprostane F2t, and up-regulation of antioxidant defence. Juvenile Ndufs6gt/gt mice also exhibited signs of early renal impairment with increased urinary Kim-1 excretion and elevated circulating cystatin C.

Innovation: We have identified renal impairment in a mouse model of partial complex I deficiency, suggesting that even modest deficits in mitochondrial respiratory chain function may act as risk factors for chronic kidney disease.

Conclusion: These studies identify for the first time that complex I deficiency as the result of interruption of Ndufs6 is an independent cause of renal impairment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ars.2012.4719DOI Listing
August 2013

Glucose homeostasis can be differentially modulated by varying individual components of a western diet.

J Nutr Biochem 2013 Jul 11;24(7):1251-7. Epub 2013 Jan 11.

Diabetes Complications, Baker IDI Heart and Diabetes Research Institute, Melbourne, Victoria, Australia.

Chronic overconsumption of a Western diet has been identified as a major risk factor for diabetes, yet precisely how each individual component contributes to defects in glucose homeostasis independent of consumption of other macronutrients remains unclear. Eight-week-old male Sprague Dawley rats were randomized to feeding with one of six semi-pure diets: control, processed (high advanced glycation end products/AGE), high protein, high dextrose (glucose polymer), high in saturated fat (plant origin), or high in saturated fat (animal origin). After chronic feeding for 24 weeks, body composition was determined by bioelectrical impedance spectroscopy and glucose homeostasis was assessed. When compared to the control and high AGE diets, excess consumption of the diet high in saturated fat (animal source) increased body weight and adiposity, and decreased insulin sensitivity, as defined by HOMA IR, impaired skeletal muscle insulin signaling and insulin hypersecretion in the context of increased circulating glucagon-like peptide (GLP-1). Compared to the control diet, chronic consumption of the high AGE, protein or dextrose diet increased fasting plasma glucose, decreased fasting plasma insulin and insulin secretion. These diets also reduced circulating GLP-1 concentrations. These data suggest that individual components of a western diet have differential effects in modulating glucose homeostasis and adiposity. These data provide clear evidence of a link between over-consumption of a western diet and the development of diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jnutbio.2012.09.009DOI Listing
July 2013

Mechanisms of diabetic complications.

Physiol Rev 2013 Jan;93(1):137-88

Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.

It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/physrev.00045.2011DOI Listing
January 2013

Coming full circle in diabetes mellitus: from complications to initiation.

Nat Rev Endocrinol 2013 Feb 8;9(2):113-23. Epub 2013 Jan 8.

Glycation and Diabetes Complications, Mater Medical Research Institute, Raymond Terrace, South Brisbane, QLD, Australia.

Glycaemic control, reduction of blood pressure using agents that block the renin-angiotensin system and control of dyslipidaemia are the major strategies used in the clinical management of patients with diabetes mellitus. Each of these approaches interrupts a number of pathological pathways, which directly contributes to the vascular complications of diabetes mellitus, including renal disease, blindness, neuropathy and cardiovascular disease. However, research published over the past few years has indicated that many of the pathological pathways important in the development of the vascular complications of diabetes mellitus are equally relevant to the initiation of diabetes mellitus itself. These pathways include insulin signalling, generation of cellular energy, post-translational modifications and redox imbalances. This Review will examine how the development of diabetes mellitus has come full circle from initiation to complications and suggests that the development of diabetes mellitus and the progression to chronic complications both require the same mechanistic triggers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nrendo.2012.236DOI Listing
February 2013

Insulin infusion reduces hepatocyte growth factor in lean humans.

Metabolism 2013 May 26;62(5):647-50. Epub 2012 Nov 26.

Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.

Objective: Plasma Hepatocyte Growth Factor (HGF) is significantly elevated in obesity and may contribute to vascular disease, metabolic syndrome or cancer in obese individuals. The current studies were done to determine if hyperinsulinemia increases plasma HGF.

Materials/methods: Twenty-two participants (10 women/12 men, BMI 20.6-34.5 kg/m(2), age 18-49 years) underwent a hyperinsulinemic euglycemic clamp with measurement of HGF at baseline and steady state. Relationships between baseline HGF, anthropometrics, triglycerides, liver enzymes, c-reactive protein and adiponectin were also evaluated.

Results: Fasting HGF was positively correlated (P<0.050) with weight (r=0.63), BMI (r=0.55), waist circumference (r=0.68), WHR (r=0.48), triglycerides (r=0.44), alanine aminotransferase (r=0.74) and γ-glutamyl transpeptidase (r=0.56), but not c-reactive protein or adiponectin. In stepwise regression, alanine aminotransferase and insulin sensitivity accounted for significant variation in fasting HGF. A significant effect of insulin to suppress HGF during the clamp (P=0.029) was found after adjustment for BMI. HGF was reduced 7% at steady state in the lean subjects only (437.1 ±57.8 vs 405.4±72.0 pg/ml; P=0.030).

Conclusions: The positive correlation of HGF with hepatic enzymes suggests liver may be a significant source of circulating HGF in lean subjects. The strong correlation of plasma HGF with adiposity and the lack of an effect of insulin to increase HGF during the clamp in obese subjects suggest that adiposity, rather than elevated insulin levels, may be the major contributor to plasma HGF in obese subjects. Thus, a reduction in plasma HGF through weight loss is likely the best way to decrease comorbidities mediated by this angiogenic and mitogenic factor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.metabol.2012.10.013DOI Listing
May 2013

Targeting the AGE-RAGE axis improves renal function in the context of a healthy diet low in advanced glycation end-product content.

Nephrology (Carlton) 2013 Jan;18(1):47-56

Diabetes Complications Division, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia.

Aim: Mouse chow is commonly high in advanced glycation end-products, known contributors to diabetic nephropathy. The aim of this study was to evaluate if targeting of the AGE-RAGE axis was still effective in the context of a diet low in AGE content, which is more comparable to diets consumed by individuals with type 1 diabetes.

Methods: C57BL/6J wild-type and mice deficient in the receptor for AGEs (RAGE-KO) consumed a diet low in AGE content. Groups of mice were given (i) vehicle; (ii) streptozotocin; or (iii) streptozotocin + AGE lowering therapy (alagebrium chloride) and followed for 24 weeks.

Results: Diabetic mice had high urinary albumin excretion rates, hyperfiltration and release of urinary Kim-1, not seen in diabetic RAGE-KO mice. Diabetic mice also had renal fibrosis, measured by glomerulosclerosis, tubulointerstitial expansion, TGF-β1 and glomerular collagen-IV deposition which almost all improved by RAGE-KO or alagebium. Diabetic mice had a greater renal burden of AGEs and increased expression of renal specific PKC-α phosphorylation, which was improved in RAGE-KO mice, or those treated with alagebrium.

Conclusion: Diabetic mice given a low-AGE diet still developed renal disease, which could be attenuated by targeting of the AGE-RAGE axis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1440-1797.2012.01665.xDOI Listing
January 2013

Advanced glycation end products as environmental risk factors for the development of type 1 diabetes.

Curr Drug Targets 2012 Apr;13(4):526-40

BakerIDI Diabetes and Heart Institute, Melbourne, Victoria, Australia.

The globally rising incidence of Type 1 diabetes (T1D) is no longer restricted to individuals with higher risk genotypes, but is now significantly increasing in a population with lower risk genotypes, likely as the result of environmental factors. In this review, we discuss the potential of advanced glycation end products (AGEs) as environmental contributors to the development of T1D. AGEs are nonenzymatically formed protein modifications found in the body, as well as, consumed in our daily diets. To date, many studies have provided evidence of AGE involvement in β cell dysfunction, whether by AGE modification itself or via interaction with AGE receptors. The receptor for AGE (RAGE) and AGE-receptor-1 (AGE-R1) are of particular interest, given that studies have demonstrated the deleterious effects of RAGE modulation and the protection afforded by AGE-R1 in the context of diabetes. More interestingly, we have recently found that two RAGE polymorphism are predictive of T1D in humans while the third is protective. Moreover, soluble RAGE (sRAGE) levels (a circulating competitive inhibitor of RAGE) were greatly reduced at seroconversion to autoantibodies in both children on high risk of T1D background and in an animal model of autoiummune diabetes. Taken together with the fact that AGEs have also shown to be involved in immunomodulation, it is tempting to postulate that dietary AGEs, RAGE and even AGE-R1 could be working synergistically or independently to breach the tightly regulated immune system, providing a missing link in the development of T1D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/138945012799499758DOI Listing
April 2012

Ubiquinone (coenzyme Q10) prevents renal mitochondrial dysfunction in an experimental model of type 2 diabetes.

Free Radic Biol Med 2012 Feb 21;52(3):716-723. Epub 2011 Nov 21.

Glycation and Diabetes Complications, Baker IDI Heart Research Institute, Melbourne, VIC 3004, Australia; Department of Immunology and Department of Medicine, Monash University, Alfred Medical Research Education Precinct, Melbourne, Australia; Mater Medical Research Institute, South Brisbane, QLD, Australia.

Cardiovascular benefits of ubiquinone have been previously demonstrated, and we administered it as a novel therapy in an experimental model of type 2 diabetic nephropathy. db/db and dbH mice were followed for 10 weeks, after randomization to receive either vehicle or ubiquinone (CoQ10; 10mg/kg/day) orally. db/db mice had elevated urinary albumin excretion rates and albumin:creatinine ratio, not seen in db/db CoQ10-treated mice. Renal cortices from db/db mice had lower total and oxidized CoQ10 content, compared with dbH mice. Mitochondria from db/db mice also contained less oxidized CoQ10(ubiquinone) compared with dbH mice. Diabetes-induced increases in total renal collagen but not glomerulosclerosis were significantly decreased with CoQ10 therapy. Mitochondrial superoxide and ATP production via complex II in the renal cortex were increased in db/db mice, with ATP normalized by CoQ10. However, excess renal mitochondrial hydrogen peroxide production and increased mitochondrial membrane potential seen in db/db mice were attenuated with CoQ10. Renal superoxide dismutase activity was also lower in db/db mice compared with dbH mice. Our results suggest that a deficiency in mitochondrial oxidized CoQ10 (ubiquinone) may be a likely precipitating factor for diabetic nephropathy. Therefore CoQ10 supplementation may be renoprotective in type 2 diabetes, via preservation of mitochondrial function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.freeradbiomed.2011.11.017DOI Listing
February 2012