%0 Journal Article
%~ PubMed
%A McLennan, Susan V
%A Abdollahi, Maryam
%A Twigg, Stephen M
%T Connective tissue growth factor, matrix regulation, and diabetic kidney disease.
%B Current Opinion in Nephrology & Hypertension
%D 2013
%C United States
%I Lippincott Williams & Wilkins
%V 22.
%N 1
%P 85-92
%@ 1062-4821
%X 
%Z FOR Codes: 110312


%0 Journal Article
%~ PubMed
%A Williams, K H
%A Shackel, N A
%A Gorrell, M D
%A McLennan, S V
%A Twigg, S M
%T Diabetes and Nonalcoholic Fatty Liver Disease: A Pathogenic Duo.
%B Endocrine Reviews
%D 2013
%C United States
%I The Endocrine Society
%V 34
%N 1
%P 84-129
%@ 1945-7189
%X 
%Z FOR Codes: 110306 60603 30405


%0 Journal Article
%~ PubMed
%A Min, Danqing
%A Brooks, Belinda
%A Wong, Jencia
%A Salomon, Robert
%A Bao, Wensheng
%A Harrisberg, Brian
%A Twigg, Stephen M
%A Yue, Dennis K
%A McLennan, Susan V
%T Alterations in Monocyte CD16 in Association with Diabetes Complications.
%B Mediators of Inflammation
%D 2012
%C United States
%I Hindawi Publishing Corporation
%V 2012
%N 
%P 649083
%@ 1466-1861
%X 
%Z FOR Codes: 110306 110201


%0 Journal Article
%~ PubMed
%A de Silva, Hasanthi C
%A Firth, Sue M
%A Twigg, Stephen M
%A Baxter, Robert C
%T Interaction Between IGF Binding Protein-3 and TGF?? in the Regulation of Adipocyte Differentiation.
%B Endocrinology
%D 2012
%C United States
%I The Endocrine Society
%V 153
%N 10
%P 4799-4807
%@ 0013-7227
%X The development of white adipose tissue involves both the hypertrophy of existing adipocytes and the proliferation and differentiation of preadipocytes. Adipogenic differentiation is inhibited by TGF?? signaling through Smad2/3, and IGF binding protein-3 (IGFBP-3) is also known to activate Smad2/3 signaling in some cell types. We previously reported that exogenous or overexpressed IGFBP-3 inhibits adipogenesis in 3T3-L1 cells, but the role of endogenous IGFBP-3 in this process, and its possible interaction with TGF??, is not known. During 10-d adipogenic differentiation initiated by insulin, dexamethasone, and 3-isobutyl-1-methylxanthine, 3T3-L1 cells expressed increasing levels of IGFBP-3 and TGF??1, secreting over 1000 pg/ml of both proteins. Exogenous recombinant human IGFBP-3 paralleled TGF??1 in stimulating Smad2 phosphorylation in 3T3-L1 preadipocytes, but no additive effect was observed for the two agents. In contrast, knockdown of endogenous IGFBP-3 by small interfering RNA (siRNA) significantly impaired Smad2 activation by 0.25 ng/ml TGF??1. Transient expression of human IGFBP-3 significantly inhibited the induction of adipogenic markers adiponectin and resistin, and the appearance of lipid droplets, but down-regulation of endogenous IGFBP-3 by siRNA had little effect on the expression of either marker during the 10-d differentiation, compared with nonsilencing control siRNA. However, down-regulation of endogenous IGFBP-3 using two different siRNA significantly reversed the inhibitory effect of TGF??1 on both adiponectin and resistin induction. We conclude that IGFBP-3 activates inhibitory Smad signaling in 3T3-L1 cells and that endogenous IGFBP-3 modulates their adipogenic differentiation by regulating cell sensitivity towards the inhibitory effect of TGF??.
%Z FOR Codes: 60103 110306


%0 Book Section
%A Twigg, Stephen
%A McLennan, Susan
%T Managing diabetes complications in the clinical arena
%B A Modern Epidemic
%D 2012
%C Australia
%I Sydney University Press
%V 
%N 
%P 353-371
%@ 9781920899851
%E Twigg, Stephen
%E Magnusson, Roger S
%E Baur, Louise
%X 
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Ly, Luong D
%A Twigg, Stephen M
%A Tran, Dung T
%A Nguyen, Khue T
%T Most type 1 diabetes presenting as diabetic ketoacidosis in Vietnamese people is negative for pancreatic islet cell autoantibodies.
%B Diabetes Research and Clinical Practice
%D 2012
%C Ireland, Belgium
%I Elsevier Ireland Ltd
%V 96
%N 3
%P e63-e65
%@ 0168-8227
%X Eighteen Vietnamese type 1 diabetic patients presented with ketoacidosis were serially recruited from three tertiary cares. They had mean age (±SD) 23.5±4.1years, median of blood glucose [interquartile range] 28.2 [24.3-31.3]mmol/L, pH 7.255 [7.232-7.285], C-peptide 0.265 [0.098-0.472]nmol/L. 61% were negative for both anti-GAD and ICA tests.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Jiwa, M
%A Meng, X
%A Sriram, D
%A Hughes, J
%A Colagiuri, S
%A Twigg, S M
%A Skinner, T
%A Shaw, T
%T The management of Type 2 diabetes: A survey of Australian general practitioners.
%B Diabetes Research and Clinical Practice
%D 2012
%C Ireland, Belgium
%I Elsevier Ireland Ltd
%V 95
%N 3
%P 326-332
%@ 0168-8227
%X To explore how clinical and demographic variables impact on the management of diabetes mellitus in general practice.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A d'Emden, Michael C
%A Shaw, Jonathan E
%A Colman, Peter G
%A Colagiuri, Stephen
%A Twigg, Stephen M
%A Jones, Graham R D
%A Goodall, Ian
%A Schneider, Hans G
%A Cheung, N Wah
%A , Australian Diabetes Society
%A , Royal College of Pathologists of Australasia
%A , Australasian Association of Clinical Biochemists
%T The role of HbA1c in the diagnosis of diabetes mellitus in Australia.
%B Medical Journal of Australia
%D 2012
%C Australia
%I Australasian Medical Publishing Company Pty. Ltd.
%V 197
%N 4
%P 220-221
%@ 1326-5377
%X 
%Z FOR Codes: 110306


%0 Journal Article
%A Zimmet, Paul
%A Campbell, Lesley
%A Toomath, Robyn
%A Twigg, Stephen
%A Wittert, Gary
%A Proietto, Joe
%T Bariatric surgery to treat severely obese patients with type 2 diabetes: A consensus statement
%B Obesity Research & Clinical Practice
%D 2011
%C Netherlands
%I Elsevier BV
%V 5
%N 1
%P e71-e78
%@ 1878-0318
%X 
%Z FOR Codes: 110306 111717


%0 Journal Article
%~ PubMed
%A Wang, Xiaoyu
%A McLennan, Susan V
%A Twigg, Stephen M
%T CCN-2 is up-regulated by and mediates effects of matrix bound advanced glycated end-products in human renal mesangial cells.
%B Journal of cell communication and signaling
%D 2011
%C Netherlands
%I Springer Netherlands
%V 5
%N 3
%P 193-200
%@ 1873-961X
%X CCN-2, also known as connective tissue growth factor (CCN-2/CTGF) is a cysteine rich, extracellular matrix protein that acts as a pro-fibrotic cytokine in tissues in many diseases, including in diabetic nephropathy. We have published that soluble advanced glycation end products (AGEs), that are present in increased amounts in diabetes, induce CCN-2. However in vivo AGEs are known to be heavily tissue bound and whether matrix bound AGEs regulate CCN-2 has not been investigated. In this study we determined in human renal mesangial cells if CCN-2 is induced by matrix associated AGEs and if CCN-2 may then secondarily mediate effects of matrix AGEs on extracellular matrix expansion. Data generated show that CCN-2 mRNA and protein expression are induced by matrix bound AGEs, and in contrast, this was not the case for TGF-??1 mRNA regulation. Using CCN-2 adenoviral anti-sense it was found that CCN-2 mediated the up-regulation of fibronectin and the tissue inhibitor of matrix metalloproteinase, TIMP-1, that was caused by matrix bound AGEs. In conclusion, CCN-2 is induced by non-enzymatically glycated matrix and it mediates downstream fibronectin and TIMP-1 increases, thus through this mechanism potentially contributing to ECM accumulation in the renal glomerulus in diabetes.
%Z FOR Codes: 60104


%0 Journal Article
%~ PubMed
%A Jones, Graham R D
%A Barker, George
%A Goodall, Ian
%A Schneider, Hans-Gerhard
%A Shephard, Mark D S
%A Twigg, Stephen M
%T Change of HbA1c reporting to the new SI units.
%B The Medical Journal of Australia
%D 2011
%C Australia
%I Australasian Medical Publishing Company Pty. Ltd
%V 195
%N 1
%P 45-46
%@ 1326-5377
%X An international consensus statement recommends that dual reporting of haemoglobin A (HbA(1c)) levels - in the current units (percentage) and Syst??me International (SI) units (mmol/mol) - be used as an interim measure for a 2-year transition period before progressing towards the use of SI units only. This recommendation is supported by the Australasian Association of Clinical Biochemists, the Australian Diabetes Educators Association, the Australian Diabetes Society and the Royal College of Pathologists of Australasia. The SI units are a true measure of HbA(1c) and remove potential confusion between HbA(1c) values and blood glucose values.
%Z FOR Codes: 110202


%0 Journal Article
%~ PubMed
%A Jones, Graham R D
%A Barker, George
%A Goodall, Ian
%A Schneider, Hans-Gerhard
%A Shephard, Mark D S
%A Twigg, Stephen M
%T Change of glycated haemoglobin (HbA1c) reporting to the new SI units.
%B Medical Journal of Australia
%D 2011
%C Australia
%I Australasian Medical Publishing Company Pty. Ltd
%V 195
%N 9
%P 524
%@ 1326-5377
%X 
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Lo, Lisa
%A McLennan, Susan V
%A F Williams, Paul
%A Bonner, James
%A Chowdhury, Sumaiya
%A McCaughan, Geoffrey W
%A Gorrell, Mark D
%A Yue, Dennis K
%A Twigg, Stephen M
%T Diabetes is a progression factor for hepatic fibrosis in a high fat fed mouse obesity model of non-alcoholic steatohepatitis.
%B Journal of hepatology
%D 2011
%C Netherlands, Denmark
%I Elsevier BV
%V 55
%N 2
%P 435-44
%@ 0168-8278
%X While type 2 diabetes is an independent risk factor for worsening of human non-alcoholic steatohepatitis (NASH) in clinical studies, it has not been systematically reported in any model whether diabetes exacerbates NASH. The study aim was to determine if diabetes causes NASH progression in a mouse model of diet induced obesity.
%Z FOR Codes: 110102 111103 60104


%0 Journal Article
%~ PubMed
%A Hart, Susan
%A Abraham, Suzanne
%A Franklin, Richard C
%A Twigg, Stephen M
%A Russell, Janice
%T Hypoglycaemia following a mixed meal in eating disorder patients.
%B Postgraduate medical journal
%D 2011
%C United Kingdom
%I BMJ Group
%V 87
%N 1028
%P 405-9
%@ 1469-0756
%X OBJECTIVE To describe the incidence of hypoglycaemia, and variables associated with hypoglycaemia, in eating disorder patients following a mixed meal stimulus. METHODS Postprandial blood glucose values of patients admitted to a specialist eating disorder hospital for treatment of an eating disorder between 2000 and 2006 were reviewed and compared to body mass index (BMI), electrolytes, and weight losing behaviours. Analysis of variance (ANOVA) and stepwise logistic regression were undertaken. RESULTS 22% of patients had postprandial glucose values ???3.5 mmol/l (63 mg/dl). Only low BMI significantly predicted postprandial hypoglycaemia. CONCLUSION Clinicians should be aware that postprandial hypoglycaemia is a common finding in eating disorders patients receiving inpatient treatment. As hypoglycaemia is predicted by low BMI, weight restoration is a priority for treatment in patients experiencing hypoglycaemia. Future research should investigate the nutrient composition of refeeding regimens and whether altering the macronutrient composition attenuates the presence of hypoglycaemia. Investigation is warranted in a community sample of eating disorder patients to see if this finding is replicated in non-hospitalised patients.
%Z FOR Codes: 111199 111699


%0 Book
%A Craig, Maria
%A Twigg, Stephen
%A Donaghue, Kim
%A Cheung, Ngai
%A Cameron, FJ
%A Conn, J
%A Jenkins, AJ
%T National Evidence-Based
Clinical Care Guidelines for
Type 1 Diabetes in Children,
Adolescents and Adults
%B 
%D 2011
%C Australia
%I Australian Government Department of Health and Age
%V 
%N 
%P 
%@ 9780987220301
%X 
%Z FOR Codes: 111717


%0 Journal Article
%~ PubMed
%A Twigg, Stephen M
%A Irvine, Sandra
%A Leask, Andrew
%A Perbal, Bernard
%T Report on the 6th international workshop of the CCN family of genes.
%B Journal of Cell Communication and Signaling
%D 2011
%C Netherlands
%I Springer Netherlands
%V 5
%N 1
%P 1-3
%@ 1873-961X
%X 
%Z FOR Codes: 60103 60104


%0 Journal Article
%~ PubMed
%A Perera, Nimalie Jacintha
%A Molyneaux, Lynda
%A Constantino, Maria Ines
%A McGill, Marg
%A Yue, Dennis Koon-See
%A Twigg, Stephen Morris
%A Ross, Glynis Pauline
%T Suboptimal performance of blood glucose meters in an antenatal diabetes clinic.
%B Diabetes Care
%D 2011
%C United States
%I American Diabetes Association
%V 34
%N 2
%P 335-337
%@ 0149-5992
%X The objective of this study was to evaluate the performance of blood glucose meters in diabetes associated with pregnancy (DP).
%Z FOR Codes: 699


%0 Journal Article
%~ PubMed
%A Perera, N J
%A Stewart, P M
%A Williams, P F
%A Chua, E L
%A Yue, D K
%A Twigg, S M
%T The danger of using inappropriate point-of-care glucose meters in patients on icodextrin dialysis.
%B Diabetic medicine : a journal of the British Diabetic Association
%D 2011
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 28
%N 10
%P 1272-6
%@ 1464-5491
%X Icodextrin is a glucose polymer used to maintain an osmotic gradient in peritoneal dialysis. Metabolites of icodextrin are known to cause overestimation of blood glucose in glucose meters using glucose dehydrogenase/pyrroloquinolinequinone systems. The aim of this study is to determine the extent of icodextrin interference in glucose meters using the newer glucose dehydrogenase/NAD or glucose oxidase systems. This has not been established previously.
%Z FOR Codes: 1103


%0 Journal Article
%A Perera, NJ
%A HArding, AJ
%A Constantino, MI
%A Molyneaux, Lynda
%A McGill, Margaret
%A Chua, Elizabeth
%A Twigg, Stephen
%A Ross, GP
%A Yue, Dennis
%T Triple-B (basal-bolus-booster) subcutaneous insulin regimen: A pragmatic approach to managing hospital inpatient hyperglycaemia
%B Practical Diabetes International
%D 2011
%C United Kingdom
%I John Wiley & Sons Ltd.
%V 28
%N 6
%P 266-269
%@ 2047-2900
%X 
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Thomson, S E
%A McLennan, S V
%A Hennessy, A
%A Boughton, P
%A Bonner, J
%A Zoellner, H
%A Yue, D K
%A Twigg, S M
%T A novel primate model of delayed wound healing in diabetes: dysregulation of connective tissue growth factor.
%B Diabetologia
%D 2010
%C Germany
%I Springer
%V 53
%N 3
%P 572-83
%@ 0012-186X
%X Chronic non-healing wounds are a common complication of diabetes. Prolonged inflammation and decreased matrix accumulation may contribute. Connective tissue growth factor (CTGF) is induced during normal wound healing, but its regulation in diabetic wounds is unknown. We developed a primate model for the study of in vivo wound healing in baboons with long diabetes duration.
%Z FOR Codes: 699


%0 Journal Article
%A Chadban, Steven
%A Howell, M
%A Twigg, Stephen
%A Thomas, M
%A Cass, Alan
%A Campbell, Dianne
%A Tong, Alan
%A Mangos, G
%A Stack, A
%A MacIsaac, R
%A Girgis, Seham
%A Colagiuri, Ruth
%A Colagiuri, Stephen
%A Craig, Jonathan
%T Assessment of kidney function in type 2 diabetes
%B Nephrology
%D 2010
%C Australia
%I Wiley-Blackwell Publishing Asia
%V 15
%N Supp 1
%P S146-S161
%@ 1440-1797
%X 
%Z FOR Codes: 110312


%0 Journal Article
%~ PubMed
%A Wong, J
%A Molyneaux, L
%A Constantino, M
%A Twigg, S M
%A Yue, D K
%T Beyond ONTARGET: angiotensin-converting enzyme inhibition and angiotensin II receptor blockade in combination, a lesser evil in some?
%B Diabetes, Obesity & Metabolism
%D 2010
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 12
%N 12
%P 1072-1078
%@ 1463-1326
%X Aim: Following the recent Ongoing Telmistartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) finding of adverse renal outcomes, dual renin-angiotensin blockade has fallen out of favour, despite antihypertensive and antiproteinuric efficacy. However, in high-risk severe hypertension, not studied in ONTARGET, whether combination treatment should be withheld or withdrawn is not clear. We examine the renal effects of angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) monotherapy versus combination therapy in patients with type 2 diabetes and varying degrees of hypertension. Methods: Subjects attending a hospital diabetes centre were selected as case (combination therapy, n = 120) and control (monotherapy, n = 480). Subjects were matched for age, gender, ethnicity, estimated glomerular filtration rate (eGFR), blood pressure (BP) and study duration. Patients were stratified by BP, hypertension stage 1 (BP < 160/100, n = 506) and stage 2 (???160/100, n = 94), and by treatment group. Data were analysed for the primary renal outcome of eGFR decline ???20 ml/min, over a median of 3.7 years. Results: In keeping with the ONTARGET study, for stage 1 hypertension, combination treatment is significantly worse than monotherapy for the primary outcome of eGFR decline ???20 ml/min (20 vs. 10.7%, p = 0.01). In contrast, for stage 2 hypertension, this endpoint was reached less often for combination versus monotherapy (12.0 vs. 23.2%, p = 0.2). Combination treatment was also not detrimental in patients with proteinuria or eGFR < 60 ml/min and was associated with fewer macrovascular events. Conclusion: Given that hypertension control is paramount and in the spirit of primum non nocere, these data are reassuring should clinicians choose to use ACE-I and ARB combination therapy in the very hypertensive diabetic patient.
%Z FOR Codes: 30406 110299 110306


%0 Journal Article
%~ Isi
%A Wang, B.
%A Herman-Edelstein, M.
%A Koh, P.
%A Burns, W.
%A Jandeleit-Dahm, K.
%A Watson, A.
%A Saleem, M.
%A Goodall, G. J.
%A Twigg, S. M.
%A Cooper, M. E.
%A Kantharidis, P.
%T E-Cadherin Expression Is Regulated by miR-1921215 by a Mechanism That Is Independent of the Profibrotic Effects of Transforming Growth Factor-beta
%B Diabetes
%D 2010
%C United States
%I American Diabetes Association
%V 59
%N 7
%P 1794-1802
%@ 0012-1797
%X 
%Z FOR Codes: 110306


%0 Journal Article
%A Fulcher, Greg
%A Colagiuri, Stephen
%A Phillips, Patrick
%A Prins, Johannes
%A Sinha, Ashim
%A Twigg, Stephen
%A Dalton, Brad
%T Insulin Intensification for People with Type 2 Diabetes
%B Australasian Medical Journal
%D 2010
%C Australia
%I Australasian Medical Journal Pty. Ltd.
%V 3
%N 12
%P 808-813
%@ 1836-1935
%X 
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Bao, Wensheng
%A Min, Danqing
%A Twigg, Stephen M
%A Shackel, Nicholas
%A Warner, Fiona J
%A Yue, Dennis K
%A McLennan, Susan V
%T Monocyte CD147 is induced by Advanced Glycation Endproducts (AGEs) and High Glucose Concentration: Possible role in diabetic complications.
%B American journal of physiology. Cell physiology
%D 2010
%C United States
%I American Physiological Society
%V 299
%N 5
%P C1212-9
%@ 1522-1563
%X CD147 is a highly glycosylated transmembrane protein that is known to play a role in regulation of many protein families. It has the unique ability to maintain functional activity in both the membrane bound state and in the soluble form. CD147 is known to play a role in regulation of matrix metalloproteinase (MMP) expression, but whether its expression is affected by the diabetic milieu is not known, and its role in regulation of monocyte MMPs in this environment has not been investigated. Therefore, in this study we investigated the effect of advanced glycation end products (AGEs) and high glucose (HG; 25 mM), on monocyte CD147 expression. Culture of THP-1 monocytes in the presence of AGEs or HG significantly increased CD147 at the gene and protein level. THP-1 cell results were confirmed using freshly isolated monocytes from human volunteers. The effect of AGEs and HG on CD147 expression was also mimicked by addition of proinflammatory cytokines. Addition of AGEs or HG also increased expression of monocyte MMP-1 and MMP-9 but not MMP-2. This increase in MMPs was significantly attenuated by inhibition of CD147 using either a small interfering RNA or an anti-CD147 antibody. Inhibition of NF-??B or addition of antibodies to either TNF-?? or the receptor for AGE (RAGE) each significantly prevented in a dose-dependent manner the induction of CD147 gene and protein by AGE and also decreased MMP-1 and MMP-9. This novel result shows that AGEs can induce monocyte CD147 expression, an effect mediated by inflammatory pathways and RAGE. Because MMPs play a role in monocyte migration, inhibition of their regulator CD147 may assist in the prevention of diabetic complications, particularly those where monocyte infiltration is an early initiating event.
%Z FOR Codes: 1103


%0 Journal Article
%~ PubMed
%A Tu, Emily
%A Bagnall, Richard D
%A Duflou, Johan
%A Lynch, Matthew
%A Twigg, Stephen M
%A Semsarian, Christopher
%T Post-mortem pathologic and genetic studies in "dead in bed syndrome" cases in type 1 diabetes mellitus.
%B Human pathology
%D 2010
%C United States
%I WB Saunders Co.
%V 41
%N 3
%P 392-400
%@ 1532-8392
%X Dead in bed syndrome is a poorly understood cause of sudden death in young people with type 1 diabetes. The underlying cause remains unknown. One possible explanation may involve prolongation of the QT interval followed by a terminal malignant arrhythmia. Risk factors associated with QT interval prolongation include hypoglycemia and cardiac autonomic neuropathy. We sought to identify myocardial cellular changes and genetic influences that may contribute to the pathogenesis of dead in bed syndrome. Post-mortem reports between 1994 and 2006 from the 2 largest Departments of Forensic Medicine in Australia were reviewed for dead in bed syndrome cases. Post-mortem heart sections were immunohistochemically stained for collagen types I and III and connective tissue growth factor (CTGF). Genomic DNA was prepared from post-mortem samples, and genetic analysis was performed in the SCN5A, G6PC, PHOX2B, and CTGF genes. Twenty-two dead in bed syndrome cases were identified and staining of heart sections for collagen I and III, and CTGF showed no differences between dead in bed syndrome cases and controls. Genetic screening of SCN5A revealed 3 silent polymorphisms A29A, E1061E, and D1819D and 1 protein-changing variant H558R. No genetic variants were found in G6PC, PHOX2B, and CTGF, and dead in bed syndrome cases were not associated with the G-945C CTGF promoter polymorphism. In conclusion, this study is the first to investigate potential pathogenic mechanisms underlying the dead in bed syndrome in type 1 diabetes with the results substantially adding to knowledge of this condition. Understanding the causes and triggers of dead in bed syndrome will be critical in facilitating the identification of patients with type 1 diabetes at highest risk of developing sudden death.
%Z FOR Codes: 110201


%0 Journal Article
%~ PubMed
%A Wang, Xiaoyu
%A McLennan, Susan V
%A Allen, Terri J
%A Twigg, Stephen M
%T Regulation of pro-inflammatory and pro-fibrotic factors by CCN2/CTGF in H9c2 cardiomyocytes.
%B Journal of Cell Communication and Signaling
%D 2010
%C Netherlands
%I Springer Netherlands
%V 4
%N 1
%P 15-23
%@ 1873-961X
%X Connective tissue growth factor (CTGF), also known as CCN2, is implicated in fibrosis through both extracellular matrix (ECM) induction and inhibition of ECM degradation. The role of CTGF in inflammation in cardiomyocytes is unknown. In some mesenchymal cell systems, CTGF mediates effects through TGF-beta or tyrosine kinase cell surface receptor, TrkA, signalling. In this study, cellular mechanisms by which CTGF regulates pathways involved in fibrosis and inflammation were explored. Murine H9c2 cardiomyocytes were treated with recombinant human (rh)CTGF and ECM formation gene expression: fibronectin, collagen type -I and -III and ECM degradation genes: TIMP-1, TIMP-2 and PAI-1 were found to be induced. CTGF treatment also increased pro-inflammatory cytokines TNF-alpha, IL-6, MCP-1 and IL-8. CTGF upregulated TGF-beta1 mRNA and rapidly induced phosphorylation of TrkA. The CTGF-induced pro-fibrotic and pro-inflammatory effects were blocked by anti-TGF-beta neutralizing antibody and Alk 5 inhibitor (SB431542). A specific blocker of TrkA activation, k252a, also abrogated CTGF-induced effects on fibrosis and gene expresison of MCP-1 and IL-8, but not TNF-alpha or IL-6. Collectively, this data implicates CTGF in effects on pro-fibrotic genes and pro-inflammatory genes via TGF-beta pathway signalling and partly through TrkA.
%Z FOR Codes: 601


%0 Journal Article
%~ PubMed
%A Ban, C R
%A Twigg, S M
%A Franjic, B
%A Brooks, B A
%A Celermajer, D
%A Yue, D K
%A McLennan, S V
%T Serum MMP-7 is increased in diabetic renal disease and diabetic diastolic dysfunction.
%B Diabetes Research and Clinical Practice
%D 2010
%C Ireland, Belgium
%I Elsevier Ireland Ltd
%V 87
%N 3
%P 335-341
%@ 0168-8227
%X Circulating matrix metalloproteinase (MMP) levels may correlate with diabetic complications. Whether they are changed in early diabetic cardiomyopathy is not known and was examined in this study. TIMP-1 and collagen degradation products were also measured. Results from subjects with and without diastolic dysfunction were compared with those obtained for patients with varying stages of diabetic renal disease. Patients with type 2 diabetes with or without diastolic dysfunction with varying degrees of renal disease were recruited for this study. Age-matched non-diabetic subjects served as controls. MMPs (-1, -3 and -7) and TIMP-1 were measured by ELISA, MMP-2 and -9 by zymography and collagen degradation products by radioimmunoassay. Differences in the pattern of MMPs/TIMPs and collagen degradation products were observed. The most consistent change was in totalMMP-7, which was increased in those with diastolic dysfunction and those with macroalbuminuria. MMP-7 correlated with cardiac function (p<0.05 vs control, in those with diastolic dysfunction), and renal filtration function (p<0.05 vs control). In summary, we have identified novel relationships between serum MMP-7 and diabetic complications specifically in renal disease and in diastolic dysfunction. How increased circulating MMP-7 is associated with these diabetic microvascular complications and the significance of these findings will require prospective studies.
%Z FOR Codes: 1102 1103 601


%0 Journal Article
%~ PubMed
%A Tu, Emily
%A Twigg, Stephen M
%A Semsarian, Christopher
%T Sudden death in type 1 diabetes: The mystery of the 'dead in bed' syndrome.
%B International journal of cardiology
%D 2010
%C Ireland
%I Elsevier Ireland
%V 138
%N 1
%P 91-3
%@ 0167-5273
%X Sudden cardiac death is an unpredictable and devastating event, particularly in the young. A significant proportion of sudden deaths in the young are unexplained-no cause is identified either during life or at post-mortem. This is seen in a subgroup of young patients with type 1 diabetes who have dead in bed syndrome, where these victims are in good health, retire to bed, only to be found dead the following morning in a bed which is undisturbed, suggesting no terminal struggle or seizure. The underlying cause of dead in bed syndrome remains unknown, but is likely to be due to a terminal malignant arrhythmia. A plausible hypothesis is that it may be secondary to QT interval prolongation (followed by a degenerate ventricular tachycardia), caused by a number of factors including acute hypoglycaemia, on a background of cardiac autonomic neuropathy, and possible genetic influences. It is envisaged that understanding the causes and triggers of dead in bed syndrome will allow appropriate therapeutic interventions to be initiated in high-risk patients with type 1 diabetes, with the ultimate goal to prevent sudden death.
%Z FOR Codes: 110201


%0 Journal Article
%~ PubMed
%A Chadban, S
%A Howell, M
%A Twigg, S
%A Thomas, M
%A Jerums, G
%A Cass, A
%A Campbell, D
%A Nicholls, K
%A Tong, A
%A Mangos, G
%A Stack, A
%A MacIsaac, R J
%A Girgis, S
%A Colagiuri, R
%A Colagiuri, S
%A Craig, J
%A , CARI
%T The CARI guidelines. Cost-effectiveness and socioeconomic implications of prevention and management of chronic kidney disease in type 2 diabetes.
%B Nephrology
%D 2010
%C Australia
%I Wiley-Blackwell Publishing Asia
%V 15
%N Suppl 1
%P S195-S203
%@ 1440-1797
%X 
%Z FOR Codes: 1103


%0 Journal Article
%~ PubMed
%A Chadban, S
%A Howell, M
%A Twigg, S
%A Thomas, M
%A Jerums, G
%A Cass, A
%A Campbell, D
%A Nicholls, K
%A Tong, A
%A Mangos, G
%A Stack, A
%A MacIsaac, R J
%A Girgis, S
%A Colagiuri, R
%A Colagiuri, S
%A Craig, J
%A , CARI
%T The CARI guidelines. Prevention and management of chronic kidney disease in type 2 diabetes.
%B Nephrology
%D 2010
%C Australia
%I Wiley-Blackwell Publishing Asia
%V 15
%N Suppl 1
%P S162-S194
%@ 1440-1797
%X 
%Z FOR Codes: 1103


%0 Journal Article
%~ PubMed
%A Baxter, Robert C
%A Twigg, Stephen M
%T Actions of IGF binding proteins and related proteins in adipose tissue.
%B Trends in endocrinology and metabolism: TEM
%D 2009
%C United Kingdom
%I Elsevier Ltd.
%V 20
%N 10
%P 499-505
%@ 1879-3061
%X The insulin-like growth factors (IGFs), their binding proteins (IGFBPs) and structurally related proteins have been identified in adipose tissue but their roles in adipose tissue are poorly understood. IGF-I and IGFBP-3 expression increase during human preadipocyte differentiation. However, whereas IGF-I stimulates this process, IGFBP-3 is inhibitory both to preadipocyte differentiation and to differentiated adipocyte function. The direct interaction of IGFBP-3 with peroxisome proliferator-activated receptor-gamma is believed to contribute to its inhibitory effect on differentiation. Connective tissue growth factor (CTGF/CCN2) shares weak structural homology and functional similarities with IGFBP-3, including inhibition of preadipocyte differentiation. This review examines the current knowledge of IGFBP regulation and actions in adipocytes and proposes a common regulatory pathway involving IGFBP-3 and CTGF/CCN2.
%Z FOR Codes: 60103 110306


%0 Journal Article
%~ PubMed
%A Wang, Xiao-Yu
%A McLennan, Susan V
%A Allen, Terri
%A Tsoutsman, Tatiana
%A Semsarian, Christopher
%A Twigg, Stephen M
%T Adverse effects of high glucose and free fatty acid on cardiomyocytes are mediated by connective tissue growth factor.
%B American journal of physiology. Cell physiology
%D 2009
%C United States
%I American Physiological Society
%V 297
%N 6
%P C1490-500
%@ 0363-6143
%X Diabetic cardiomyopathy is characterized by interstitial fibrosis and cardiomyocyte hypertrophy and apoptosis. Also known as CCN2, connective tissue growth factor (CTGF) is implicated in the fibrosis; however, whether it contributes to cardiomyocytes changes and adverse effects of high glucose and lipids on these cells remains unknown. Hearts from streptozotocin-induced diabetic rats had elevated CTGF and changes of pathological myocardial hypertrophy, fibrosis, and cardiomyocyte apoptosis. Rat H9c2 cardiomyocytes were then treated with recombinant human (rh)CTGF, high glucose, or the saturated free fatty acid palmitate. Each reagent induced cell hypertrophy, as indicated by the ratio of total protein to cell number, cell size, and gene expression of cardiac hypertrophy marker genes atrial natriuretic peptide (ANP), and alpha-skeletal actin. Each treatment also caused apoptosis measured by increased caspase3/7 activity, apoptotic cells by transferase-mediated dUTP nick end labeling (TUNEL) assay, and lower viable cell number. Further studies showed CTGF mRNA was rapidly induced by high glucose and palmitate in H9c2 cells and in mouse neonatal cardiomyocyte primary cultures. small interfering RNA against CTGF blocked the high glucose and palmitate induction of hypertrophy and apoptosis. In addition, these CTGF effects were through the tyrosine kinase A (TrkA) receptor with tyrosine kinase activity, which has previously been implicated in CTGF signaling: TrkA was phosphorylated by CTGF, and a specific TrkA blocker abrogated CTGF-induced effects on hypertrophy and apoptosis. For the first time in any system, fatty acid is newly identified as a regulator of CTGF, and this work implicates autocrine CTGF as a mediator of adverse effects of high glucose and fatty acids in cardiomyocytes.
%Z FOR Codes: 110201 60111


%0 Journal Article
%~ PubMed
%A Loy, Clement T
%A Twigg, Stephen M
%T Growth factors, AGEing, and the diabetes link in Alzheimer's disease.
%B Journal of Alzheimer's disease : JAD
%D 2009
%C Netherlands
%I IOS Press
%V 16
%N 4
%P 823-31
%@ 1387-2877
%X Diabetes mellitus and Alzheimer''s disease (AD) each become increasingly common with age. Diabetes causes many chronic end-organ complications and among them is dementia, which may be due to an underlying vascular cause, as well as being related to AD. The pathogenic mechanisms that lead to diabetes complications include advanced glycation end products (AGEs) and growth factor dysregulation. This review explores the evidence for epidemiological links between diabetes and AD, as well as potential pathogenic mechanisms whereby AGEs, their cellular receptors, and key growth factors may contribute to AD development and progression in diabetes. Directions for future research are also discussed.
%Z FOR Codes: 1111


%0 Journal Article
%~ PubMed
%A Liu, Yu
%A Min, Danqing
%A Bolton, Thyra
%A Nubé, Vanessa
%A Twigg, Stephen M
%A Yue, Dennis K
%A McLennan, Susan V
%T Increased Matrix Metalloproteinase-9 Predicts Poor Wound Healing in Diabetic Foot Ulcers.
%B Diabetes care
%D 2009
%C United States
%I American Diabetes Association
%V 32
%N 1
%P 117-9
%@ 0149-5992
%X We studied the relationships of diabetic ulcer wound fluid matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and transforming growth factor-beta1 (TGF-beta1) with wound healing rate.
%Z FOR Codes: 1103


%0 Journal Article
%~ PubMed
%A Chan, Sophie S Y
%A Schedlich, Lynette J
%A Twigg, Stephen M
%A Baxter, Robert C
%T Inhibition of adipocyte differentiation by insulin-like growth factor-binding protein-3.
%B American Journal of Physiology: Endocrinology and Metabolism
%D 2009
%C United States
%I American Physiological Society
%V 296
%N 4
%P E654-E663
%@ 0193-1849
%X Insulin-like growth factor-binding protein-3 (IGFBP-3) interacts with the type II nuclear receptors retinoid X receptor (RXR)alpha and retinoic acid receptor-alpha and modulates their transcriptional activity. Peroxisome proliferator-activated receptor (PPAR)gamma, a related nuclear receptor that dimerizes with RXRalpha, plays an important role in adipocyte differentiation. IGFBP-3 is regulated during adipocyte differentiation, but its role in this process is unknown. We demonstrate that IGFBP-3 interferes with the PPARgamma-dependent processes of adipocyte differentiation and maintenance of the gene expression characteristic of mature adipocytes. Treatment of adipocytes with exogenous IGFBP-3, but not an IGFBP-3 mutant that does not bind RXRalpha or PPARgamma, decreased markers of adipocyte differentiation, PPARgamma, and resistin but increased the preadipocyte marker plasminogen activator inhibitor-1. Furthermore, expression of human IGFBP-3, but not the IGFBP-3 mutant, by preadipocytes inhibited preadipocyte differentiation as determined by gene markers and lipid accumulation. IGFBP-3 interacted with PPARgamma in vitro and in 3T3-L1 adipocyte lysates and inhibited PPARgamma heterodimerization with RXRalpha in vitro. Wild-type IGFBP-3, but not mutant IGFBP-3, blocked ligand-induced transactivation of PPAR response element in 3T3-L1 cells. The observation that IGFBP-3 inhibits adipocyte differentiation and impacts on the PPARgamma system suggests a role for IGFBP-3 in the pathogenesis of obesity and insulin resistance.
%Z FOR Codes: 60103 110306


%0 Journal Article
%~ PubMed
%A Min, Danqing
%A Lyons, J Guy
%A Bonner, James
%A Twigg, Stephen M
%A Yue, Dennis K
%A McLennan, Susan V
%T Mesangial cell-derived factors alter monocyte activation and function through inflammatory pathways: possible pathogenic role in diabetic nephropathy.
%B American Journal of Physiology: Renal Physiology
%D 2009
%C United States
%I American Physiological Society
%V 297
%N 5
%P F1229-F1237
%@ 1522-1466
%X Infiltration of macrophages to the kidney is a feature of early diabetic nephropathy. For this to happen monocytes must become activated, migrate from the circulation, and infiltrate the mesangium. This process involves degradation of extracellular matrix, a process mediated by matrix metalloproteinases (MMPs). In the present study we investigate the expression of proinflammatory cytokines TNF-alpha, IL-6, and MMP-9 in glomeruli of control and diabetic rodents and use an in vitro coculture system to examine whether factors secreted by mesangial cells in response to a diabetic milieu can induce monocyte MMP-9 expression and infiltration. After 8 wk of diabetes, the glomerular level of TNF-alpha, IL-6, and macrophage number and colocalization of MMP-9 with macrophage were increased (P < 0.01). Coculture of THP1 monocytes and glomerular mesangial cells in 5 or 25 mM glucose increased MMP-9 (5 mM: 65% and 25 mM: 112%; P < 0.05) and conditioned media degradative activity (5 mM: 30.0% and 25 mM: 33.5%: P < 0.05). These effects were reproduced by addition of mesangial cell conditioned medium to THP1 cells. High glucose (25 mM) increased TNF-alpha, IL-6, and monocyte chemoattractant protein-1 in mesangial cell conditioned medium. These cytokines all increased adhesion and differentiation of THP1 cells (P < 0.05), but only TNF-alpha and IL-6 increased MMP-9 expression (50- and 60-fold, respectively; P < 0.05). Our results show that mesangial cell-secreted factors increase monocyte adhesion, differentiation, MMP expression, and degradative capacity. High glucose could augment these effects by increasing mesangial cell proinflammatory cytokine secretion. This mesangial cell-monocyte interaction may be important in activating monocytes to migrate from the circulation to the kidney in the early stages of diabetic nephropathy.
%Z FOR Codes: 1103


%0 Journal Article
%~ PubMed
%A Wong, J
%A McLennan, S
%A Molyneaux, L
%A Min, D
%A Twigg, S
%A Yue, D
%T Mitochondrial DNA content in peripheral blood monocytes: relationship with age of diabetes onsetand diabetic complications.
%B Diabetologia
%D 2009
%C Germany
%I Springer
%V 52
%N 9
%P 1953-61
%@ 0012-186X
%X We examined whether age of type 2 diabetes onset is related to mitochondrial DNA content in peripheral blood monocytes (PBMCs).
%Z FOR Codes: 1103


%0 Book
%A Chadban, Steven
%A Howell, Martin
%A Twigg, Stephen
%A Thomas, Mark
%A Jerums, George
%A Cass, Alan
%A Campbell, Dianne
%A Nicholls, Kathy
%A Tong, Allison
%A Mangos, George
%A Stack, Annabelle
%A McIsaac, Richard
%A Girgis, Seham
%A Colagiuri, Ruth
%A Craig, Jonathan
%T National Evidence Based Guideline
for Diagnosis, Prevention and Management of Chronic Kidney Disease
in Type 2 Diabetes
%B 
%D 2009
%C Australia
%I Diabetes Australia and the NHMRC
%V 
%N 
%P 
%@ 9780980699739
%X 
%Z FOR Codes: 110306 110312


%0 Journal Article
%~ PubMed
%A Cheung, N Wah
%A Conn, Jennifer J
%A d'Emden, Michael C
%A Gunton, Jenny E
%A Jenkins, Alicia J
%A Ross, Glynis P
%A Sinha, Ashim K
%A Andrikopoulos, Sofianos
%A Colagiuri, Stephen
%A Twigg, Stephen M
%A , Australian Diabetes Society
%T Position statement of the Australian Diabetes Society: individualisation of glycated haemoglobin targets for adults with diabetes mellitus.
%B The Medical Journal of Australia
%D 2009
%C Australia
%I Australasian Medical Publishing Company Pty. Ltd.
%V 191
%N 6
%P 339-344
%@ 0025-729X
%X Tight glycaemic control reduces the risk of development and progression of organ complications in people with type 1 or type 2 diabetes. In this position statement, the Australian Diabetes Society recommends a general target glycated haemoglobin (HbA(1c)) level of </= 7.0% for most patients. This position statement also provides guidelines for the individualisation of glycaemic targets to a tighter or lesser degree, with a recommended target HbA(1c) level of </= 6.0% in some people, or up to </= 8.0% in others. Individualisation of the HbA(1c) target is based on patient-specific factors, such as the type of diabetes and its duration, pregnancy, diabetes medication being taken, presence of cardiovascular disease, risk of and problems from hypoglycaemia, and comorbidities. Management of diabetes also includes: adequate control of other cardiovascular risk factors, including weight, blood pressure and lipid serum levels; antiplatelet therapy; and smoking cessation.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Tu, Emily
%A Twigg, Stephen M
%A Duflou, Johan
%A Semsarian, Christopher
%T Causes of death in young Australians with type 1 diabetes: a review of coronial postmortem examinations.
%B The Medical Journal of Australia
%D 2008
%C Australia
%I Australasian Medical Publishing Company Pty. Ltd.
%V 188
%N 12
%P 699-702
%@ 1326-5377
%X OBJECTIVE: To determine the causes of death in Australians with type 1 diabetes mellitus who died aged 40 years or younger. DESIGN AND SETTING: Retrospective review of autopsy reports at the Department of Forensic Medicine, Sydney, New South Wales, 1 January 1994 - 31 December 2006. MAIN OUTCOME MEASURE: Causes of mortality in people with type 1 diabetes aged < 40 years. RESULTS: Of the 26 682 autopsy reports, 1914 were for individuals with diabetes (type 1, 400; type 2, 1514). Cardiovascular disease accounted for 51% of deaths (169/333) in people with type 1 diabetes aged > 40 years, versus 13% among those aged </= 40 years (9/67; P = 0.001). Acute complications of diabetes (27%; 18/67), unnatural deaths (28%; 19/67), and sudden unexpected deaths (22%; 15/67) were the predominant causes of death in young individuals with diabetes. Sudden unexpected death was more common in those with type 1 diabetes compared with a sex-matched control population in the same age range (22% v 5%; Xi(2) P < 0.001). Of the sudden unexpected deaths, 10 people were found dead in an undisturbed bed with no cause of death found at autopsy ("dead-in-bed" syndrome; mean age [SD], 30.2 [9.4] years; males : females = 4 :1). CONCLUSIONS: In deceased young people with type 1 diabetes examined by the Coroner, acute diabetic complications, unnatural causes, and sudden unexpected deaths were the predominant causes of death. The relatively high frequency of sudden unexpected deaths, such as dead-in-bed syndrome, requires further investigation.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Tan, Joanne T M
%A McLennan, Susan V
%A Song, William W
%A Lo, Lisa W Y
%A Bonner, James G
%A Williams, Paul F
%A Twigg, Stephen M
%T Connective tissue growth factor inhibits adipocyte differentiation.
%B American journal of physiology. Cell physiology
%D 2008
%C United States
%I American Physiological Society
%V 295
%N 3
%P C740-51
%@ 0363-6143
%X Adipocyte differentiation is a key process implicated in the pathogenesis of obesity and insulin resistance. Its regulation is triggered by a cascade of transcription factors, including the CCAAT/enhancer binding proteins (C/EBPs) and peroxisome proliferator-activated receptor-gamma (PPARgamma). Growth factors such as transforming growth factor-beta1 (TGF-beta1) are known to inhibit adipocyte differentiation in vitro, via the C/EBP pathway, and in vivo, but whether a downstream mediator of TGF-beta1, connective tissue growth factor (CTGF), also known as CCN2, has a similar role is unknown. Mouse 3T3-L1 cells were differentiated into adipocytes by using standard methods, and effects and regulation of CTGF were studied. Intervention with recombinant human CTGF during differing stages of differentiation caused an inhibition in the development of the adipocyte phenotype, according to the gene expression of the differentiation markers adiponectin and PPARgamma, as well as suppression of lipid accumulation and expression of the lipogenic enzyme glycerol-3-phosphate dehydrogenase. Whereas CTGF gene expression promptly fell by 90% as 3T3-L1 preadipocytes differentiated into mature adipocytes, CTGF mRNA expression was induced by added TGF-beta1. CTGF applied to cells early in the course of differentiation inhibited total cell protein levels and nuclear localization of the beta-isoform of C/EBP (C/EBP-beta) and, subsequently, total cell C/EBP-alpha levels. CTGF also inhibited the adipocyte differentiation program in primary cultures of mouse preadipocytes. Expression of CTGF mRNA was twofold higher in the central fat depots of mice compared with subcutaneous fat, suggesting a potential role for CTGF in vivo. In summary, these data show that CTGF inhibits the adipocyte differentiation program.
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Brooks, Belinda A
%A McLennan, Susan V
%A Twigg, Stephen M
%A Yue, Dennis K
%T Detection and characterisation of microcirculatory abnormalities in the skin of diabetic patients with microvascular complications.
%B Diabetes & Vascular Disease Research
%D 2008
%C United Kingdom
%I MediNews (Diabetes) Ltd
%V 5
%N 1
%P 30-35
%@ 1479-1641
%X The aim of this study was to characterise microvascular blood flow in the skin and to compare it with biomarkers of endothelial dysfunction and tissue inflammation in patients with type 2 diabetes with (n=20) or without (n=20) microvascular complications and 20 control subjects. Microvascular function was measured by laser Doppler velocimetry in combination with iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). Blood was collected for measurement of biomarkers including plasminogen activator inhibitor-1 (PAI-1), soluble intercellular adhesion molecule (sICAM), soluble vascular cell adhesion molecule (sVCAM) and high-sensitivity C-reactive protein (hsCRP). Both ACh and SNP responses fall progressively with the development of diabetes and microvascular complications. For the total cohort, there was a significant overall correlation between ACh and SNP response (r=0.7, p<0.0001), and this relationship was particularly strong in those with microvascular complications. There was a trend towards higher hsCRP levels across the three groups, but no difference in other biomarkers. Abnormalities of microvascular blood flow are evident in diabetes and become more marked with the development of microvascular complications. This relationship was similar to that shown by the marker of inflammation (hsCRP), but stronger than that pertaining to biomarkers of endothelial function. As both ACh and SNP responses are attenuated, the disturbance is not characteristic of endothelial dysfunction alone.
%Z FOR Codes: 110304 110299


%0 Journal Article
%~ PubMed
%A Wong, Jencia
%A Molyneaux, Lynda
%A Zhao, Deming
%A Constantino, Maria
%A Gray, Robert S
%A Twigg, Stephen M
%A Xu, Zhang Rong
%A Yue, Dennis K
%T Different accelerators to early-onset Type 2 diabetes: a comparison of Anglo-Celtic and Chinese patients.
%B Journal of diabetes and its complications
%D 2008
%C United States
%I Elsevier
%V 22
%N 6
%P 389-94
%@ 1056-8727
%X The "accelerator hypothesis" postulates that metabolic syndrome (MS) factors-overweight and insulin resistance-increase functional demand on islets, accelerating diabetes onset to a younger age in both Type 1 and Type 2 diabetes (T2DM). Previous research has focused only on the former. We examine to what extent the MS and individual components are accelerators to the earlier onset of T2DM in Anglo-Celtic and Chinese populations.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Ban, Camelia R
%A Twigg, Stephen M
%T Fibrosis in diabetes complications: Pathogenic mechanisms and circulating and urinary markers.
%B Vascular health and risk management
%D 2008
%C New Zealand
%I Dove Medical Press Ltd.
%V 4
%N 3
%P 575-596
%@ 1176-6344
%X Diabetes mellitus is characterized by a lack of insulin causing elevated blood glucose, often with associated insulin resistance. Over time, especially in genetically susceptible individuals, such chronic hyperglycemia can cause tissue injury. One pathological response to tissue injury is the development of fibrosis, which involves predominant extracellular matrix (ECM) accumulation. The main factors that regulate ECM in diabetes are thought to be pro-sclerotic cytokines and protease/anti-protease systems. This review will examine the key markers and regulators of tissue fibrosis in diabetes and whether their levels in biological fluids may have clinical utility.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Thomson, Sally E
%A McLennan, Susan V
%A Kirwan, Paul D
%A Heffernan, Scott J
%A Hennessy, Annemarie
%A Yue, Dennis K
%A Twigg, Stephen M
%T Renal connective tissue growth factor correlates with glomerular basement membrane thickness and prospective albuminuria in a non-human primate model of diabetes: possible predictive marker for incipient diabetic nephropathy.
%B Journal of diabetes and its complications
%D 2008
%C United States
%I Elsevier Inc.
%V 22
%N 4
%P 284-94
%@ 1056-8727
%X Diabetic renal disease is characterized by accumulation of extracellular matrix, glomerulosclerosis, and tubulointerstitial fibrosis. Connective tissue growth factor (CTGF) is implicated in these changes, as it contributes to new matrix synthesis and is increased in the diabetic kidney. CTGF also inhibits mesangial matrix degradation through up-regulation of the tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). In a non-human primate model of diabetes, we determined whether the level of renal CTGF protein before development of albuminuria correlated with renal matrix and TIMP-1 changes and whether renal CTGF predicts progression to albuminuria.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A McLennan, Susan V
%A Bonner, James
%A Milne, Sgtephen
%A Lo, Lisa
%A Charlton, Ana
%A Kurup, Savita
%A Jia, Junhong
%A Yue, Dennis K
%A Twigg, Stephen M
%T The anti-inflammatory agent Propolis improves wound healing in a rodent model of experimental diabetes.
%B Wound Repair and Regeneration
%D 2008
%C United States
%I Wiley-Blackwell
%V 16
%N 5
%P 706-713
%@ 1524-475X
%X Foot ulcers and poor wound healing are problematic for patients with diabetes. The beehive protectant Propolis can improve wound healing but whether it can improve healing in diabetic wounds has not been investigated. In this study, the effect of a single application of Propolis on epithelial closure, wound morphology, cellular infiltrate, and blood vessel density were investigated. Diabetes was induced in rats using streptozocin. After 6 weeks, diabetic and control animals were wounded and the wounds were treated with Propolis or saline as control. At days 6 and 12 animals were sacrificed and wounds were excised. Compared with controls, diabetes decreased epithelial closure and reepithelialization but had no effect on wound contraction. These delays were prevented by Propolis. At day 12, the impaired macrophage infiltration (C:1.49+/-0.09 vs. D:0.25+/-0.14), persistent neutrophil infiltration (C:0.22+/-0.19 vs. D:1.33+/-0.81), and increased myeloperoxidase activity (fourfold) in diabetic wounds were prevented by Propolis. Diabetes had no effect on wound volume, vessel number, or branch points. These novel data indicate that Propolis can accelerate wound healing in diabetes. As neutrophil infiltration is normalized, its mechanism of action may be through anti-inflammatory pathways. This result and the established safety profile of Propolis provide a rationale for studying topical application of this agent in a clinical setting.
%Z FOR Codes: 1103


%0 Journal Article
%~ PubMed
%A Brooks, Belinda A
%A Heffernan, Scott
%A Thomson, Sally
%A McLennan, Susan V
%A Twigg, Stephen M
%A Yue, Dennis K
%T The effects of diabetes and aminoguanidine treatment on endothelial function in a primate model of type 1 diabetes.
%B American journal of primatology
%D 2008
%C United States
%I John Wiley & Sons, Inc.
%V 70
%N 8
%P 796-802
%@ 1098-2345
%X Abnormalities of endothelial function have been demonstrated in diabetes and are thought to play a role in the pathogenesis of diabetic complications. The aims of this study were to determine whether aminoguanidine, an inhibitor of glycation, can prevent endothelial and microcirculation abnormalities in a primate model of type 1 diabetes. Male baboons (Papio hamadryas) were assigned to one of the four groups: control, diabetes, control treated with aminoguanidine or diabetes treated with aminoguanidine. Diabetes was induced by streptozocin (60 mg/kg) and treated with once daily injection of insulin. Aminoguanidine was given subcutaneously (10 mg/kg), once a day. Diabetic animals had a mean duration of diabetes of 8.9 +/- 3.4 years and HbA1c of 8.9 +/- 1.1%. Microvascular function was measured by laser Doppler velocimetry, with examination of endothelium-dependent increase in skin blood flow (SkBF) following iontophoresis of acetylcholine (ACh) and endothelium-independent increase in SkBF in response to the nitric oxide (NO) donor sodium nitroprusside (SNP). Multiple regression analysis identified diabetes (P = 0.049) and aminioguanidine treatment (P = 0.026) as significant determinants of ACh response. The diabetic baboons treated with aminoguanidine had less Ach-mediated SkBF response compared with controls (1.39 +/- 0.32 vs. 2.26 +/- 0.61, F = 3.3, P = 0.04), but there was no difference between groups in SkBF response to SNP. We conclude that endothelial dysfunction can be demonstrated in this primate model of type 1 diabetes at a stage when overt diabetic complications are not present. This occurred in the absence of insulin resistance or significant hypercholesterolemia. Administration of aminoguanidine from the onset of diabetes was not able to prevent this abnormality and in fact aggravated the endothelial response. Effects of aminoguanidine on NO synthase may contribute to this phenomenon.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A McGill, Margaret
%A Molyneaux, Lynda
%A Twigg, Stephen M
%A Yue, Dennis K
%T The metabolic syndrome in type 1 diabetes: does it exist and does it matter?
%B Journal of Diabetes and its Complications
%D 2008
%C USA
%I Elsevier
%V 22
%N 1
%P 18-23
%@ 1056-8727
%X The significance of the metabolic syndrome in type 1 diabetes is not well understood. This study aimed to estimate its prevalence and attendant complications. Four hundred twenty-seven type 1 diabetic subjects were grouped according to the presence or absence of metabolic syndrome (WHO criteria). Macro- and microvascular complications were compared between the groups as individual and as composite endpoints. Data were analyzed for the total cohort and in subgroups according to duration of diabetes quartiles (<6.9, 7-12.9, 13-19.9, and >20 years) and year of presentation. Fifteen percent of individuals fulfilled the WHO criteria for metabolic syndrome, and of these, 26.9% were insulin resistant, as compared with 3.4% of those without metabolic syndrome [odds ratio (OR)=8.9, P=.001]. Both BMI and metabolic syndrome showed an increasing trend from 1992 to 2003. Those with metabolic syndrome required significantly higher insulin dosage [0.9 (0.7-1.2) vs. 0.6 (0.5-0.9) units/kg, P=.03], were older [35.0 (26.2-47.3) vs. 29.7 (23.4-36.4) years, P=.002], and had longer duration of diabetes [19.7 (10.7-25.6) vs. 12.1 (6.3-17.9) years, P=.0001]. They also had a significantly higher macrovascular composite endpoint (OR=3.3, P=.02) as well as higher macrovascular and microvascular composite endpoint (OR=3.1, P=.0001). The prevalence of stroke (OR=22.8, P=.008), peripheral vascular disease (OR=7.3, P=.05), and severe retinopathy (OR=3.7, P=.01) is higher in subjects with metabolic syndrome in the >or=20-year quartile group; in addition, these subjects have higher macrovascular composite endpoint (OR=3.9, P=.03) and macrovascular and microvascular composite endpoint (OR=2.9, P=.03). This remained so even when subjects with albuminuria were excluded. Some individuals with type 1 diabetes can also have metabolic syndrome. They are more prone to complications and require even more intensive glycemic control and reduction of macrovascular risk factors.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Wong, Jencia
%A Molyneaux, Lynda
%A Constantino, Maria
%A Twigg, Stephen M
%A Yue, Dennis K
%T Timing is Everything: Age of Onset Influences Long Term Retinopathy Risk in Type 2 Diabetes, Independent of Traditional Risk Factors.
%B Diabetes care
%D 2008
%C United States
%I American Diabetes Association
%V 31
%N 10
%P 1985-90
%@ 0149-5992
%X To test the hypothesis that age of type 2 diabetes onset influences inherent susceptibility to diabetic retinopathy, independent of disease duration and degree of hyperglycemia.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Jamieson, H
%A Cogger, V
%A Twigg, S
%A McLennan, S
%A Warren, A
%A Cheluvappa, R
%A Hilmer, S
%A Fraser, R
%A de Cabo, R
%A Le Couteur, D
%T Alterations in liver sinusoidal endothelium in a baboon model of type 1 diabetes.
%B Diabetologia
%D 2007
%C Germany
%I Springer-Verlag
%V 50
%N 9
%P 1969-76
%@ 0012-186X
%X Diabetes mellitus is associated with extensive vascular pathology, yet little is known about its long-term effects on liver sinusoidal endothelial cells (LSECs). Potential diabetic changes in LSECs are important because of the role played by fenestrations in the LSECs in hepatic disposition of lipoproteins.
%Z FOR Codes: 110307


%0 Journal Article
%~ PubMed
%A Xu, Ling
%A McLennan, Susan V
%A Lo, Lisa
%A Natfaji, Anas
%A Bolton, Thyra
%A Liu, Yu
%A Twigg, Stephen M
%A Yue, Dennis K
%T Bacterial load predicts healing rate in neuropathic diabetic foot ulcers.
%B Diabetes care
%D 2007
%C 1701 N BEAUREGARD ST
%I Amer Diabetes Assoc
%V 30
%N 2
%P 378-380
%@ 0149-5992
%X 
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Brooks, B A
%A Franjic, B
%A Ban, C R
%A Swaraj, K
%A Yue, D K
%A Celermajer, D S
%A Twigg, S M
%T Diastolic dysfunction and abnormalities of the microcirculation in type 2 diabetes.
%B Diabetes, obesity & metabolism
%D 2007
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 10
%N 0
%P 739-46
%@ 1462-8902
%X Diabetic cardiomyopathy is an increasingly recognized entity. The pathogenic factors that may contribute to its development, especially the earliest changes of diastolic dysfunction (DD), have not been clearly defined. Microvessel dysfunction and upregulation of profibrotic growth factors have been described as possible causes. The aim of this study was therefore to determine whether microvascular dysfunction and/or upregulation of the profibrotic connective tissue growth factor (CTGF) are associated with subclinical DD in subjects with type 2 diabetes.
%Z FOR Codes:


%0 Journal Article
%~ Isi
%A Zoellner, I
%A Twigg, SM
%A Yue, DK
%A Bonner, J
%A Hennessy, A
%A Thomson, SE
%A McLennan, SV
%T Dysregulated inflammation predicts reduced connective tissue growth factor expression in a baboon wound healing model of type 1 diabetes
%B Diabetologia
%D 2007
%C Germany
%I Springer-Verlag
%V 50
%N 
%P S490-S491
%@ 0012-186X
%X 
%Z FOR Codes:


%0 Journal Article
%A McLennan, Susan
%A McGill, Margaret
%A Twigg, Stephen
%A Yue, Dennis
%T Improving wound-healing outcomes in diabetic foot ulcers
%B Expert Review of Endocrinology and Metabolism
%D 2007
%C United Kingdom
%I Future Drugs
%V 2
%N 
%P 205-213
%@ 1744-6651
%X 
%Z FOR Codes: 110306 110306


%0 Journal Article
%~ PubMed
%A Xie, Lijuan
%A Galettis, Anoula
%A Morris, Jonathan
%A Jackson, Christopher
%A Twigg, Stephen M
%A Gallery, Eileen D M
%T Intercellular adhesion molecule-1 (ICAM-1) expression is necessary for monocyte adhesion to the placental bed endothelium and is increased in type 1 diabetic human pregnancy.
%B Diabetes/metabolism research and reviews
%D 2007
%C United Kingdom
%I John Wiley & Sons Ltd.
%V 24
%N 0
%P 294-300
%@ 1520-7552
%X That adhesion molecule expression is upregulated in endothelial cells of the placental bed in pregnancies complicated by type 1 diabetes mellitus, and that this is associated with increased adherence of peripheral blood monocytes, which can be reversed by reduction in activity or expression of relevant adhesion molecules. Specific aims were to compare the adherence of monocytes from normal pregnancies to decidual endothelial cells from both normal and diabetic pregnancies, and to examine the involvement of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in regulation of such adhesion.
%Z FOR Codes: 111404 111402 111401


%0 Journal Article
%~ PubMed
%A Twigg, Stephen M
%A Kamp, Maarten C
%A Davis, Timothy M
%A Neylon, Elizabeth K
%A Flack, Jeffrey R
%A , Australian Diabetes Society
%A , Australian Diabetes Educators Association
%T Prediabetes: a position statement from the Australian Diabetes Society and Australian Diabetes Educators Association.
%B The Medical journal of Australia
%D 2007
%C Australia
%I Australasian Medical Publishing Company Pty. Ltd.
%V 186
%N 9
%P 461-465
%@ 1326-5377
%X Prediabetes, the presence of impaired fasting glucose/glycaemia and/or impaired glucose tolerance, affects about 16.4% of Australian adults. People with prediabetes are at increased risk of developing diabetes, and cardiovascular and other macrovascular disease. Management includes reducing cardiovascular disease risk factors, specifically lipid and blood pressure abnormalities, and smoking-cessation counselling. To help prevent progression to diabetes, people with prediabetes who are overweight or obese require intensive lifestyle intervention. Medication to help prevent diabetes may also be used, but only after a minimum of 6 months of lifestyle intervention. In people with prediabetes, there is no role for routinely testing: capillary blood glucose; glycated haemoglobin (HbA(1c)) levels; serum insulin or pancreatic C-peptide levels; or testing for ischaemic heart disease or the microvascular complications of diabetes. Follow-up assessment of glycaemia in prediabetes requires a formal 75 g oral glucose tolerance test, initially performed annually, with subsequent individualised testing frequency.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Qi, Weier
%A Chen, Xinming
%A Twigg, Stephen
%A Zhang, Yuan
%A Gilbert, Richard E
%A Kelly, Darren J
%A Pollock, Carol A
%T The differential regulation of Smad7 in kidney tubule cells by connective tissue growth factor and transforming growth factor-beta1.
%B Nephrology (Carlton, Vic.)
%D 2007
%C Australia
%I Blackwell Publishing Asia
%V 12
%N 3
%P 267-274
%@ 1320-5358
%X AIMS: Smad7 is an inhibitory Smad that regulates transforming growth factor-beta (TGF-beta) signaling. Connective tissue growth factor (CTGF) is recognized as a potent downstream mediator of the fibrogenic effects of TGF-beta1. SMAD binding sites have been identified in both TGF-beta and CTGF promoters. The effect of CTGF on Smad7 expression and its role in the regulation of Smad7 induced by TGF-beta1 in renal tubular cells is unknown. METHODS: Human model of proximal tubular cells (HK-2 cells) was used and confirmed using a diabetic rat model. RT-PCR was performed to measure Smad7, TGF-beta1 and Smad2 and ELISA was performed to measure active TGF-beta1. CTGF or TGF-beta1 was silenced in HK-2 cells using siRNA methodology. RESULTS: TGF-beta1 induced Smad7 in a time-dependent manner, peaking at 30 min (P<0.0005) but sustained up to 24 hrs (p<0.005). Conversely, CTGF reduced Smad7, which was maximal at 24 hrs (p<0.05). This was supported by our in vivo data demonstrating that CTGF protein significantly increased while Smad7 mRNA level was reduced in a diabetic rat model. The basal expression level of Smad7 decreased in TGF-beta1 silenced cells compared to cells transfected with non-specific siRNA (p<0.0005). The basal expression level of Smad7 increased in CTGF silenced cells (p<0.05), which was increased by TGF-beta1 (p<0.005). Both mRNA and protein levels of TGF-beta1 decreased in CTGF silenced cells (p<0.05 and p<0.005 respectively) accompanied by reduction in Smad2 mRNA level in CTGF silenced cells. CONCLUSIONS: Smad7 is induced rapidly by TGF-beta1 limiting the response to TGF-beta1. CTGF likely plays a key role in promoting TGF-beta1 activity by decreasing the availability of Smad7 and increasing Smad2.
%Z FOR Codes:


%0 Journal Article
%~ Isi
%A Ferreira, S.
%A Ramachandran, A.
%A Aschner, P.
%A Chan, J.
%A Hancu, N.
%A Baik, S. H.
%A Ilkova, H.
%A Twigg, S.
%A Gagliardino, J. J.
%T Basic characteristics and treatment regimens in people with type 1 diabetes in the international diabetes management practices study (IDMPS).
%B Diabetologia
%D 2006
%C Germany
%I Springer-Verlag
%V 49
%N 
%P 557-557
%@ 0012-186X
%X 
%Z FOR Codes:


%0 Journal Article
%~ Isi
%A Hancu, N.
%A Baik, S. H.
%A Ferreira, S.
%A Gagliardino, J. J.
%A Chan, J.
%A Aschner, P.
%A Ramachandran, A.
%A Twigg, S.
%A Ilkova, H.
%T Basic characteristics and treatment regimens in people with type 2 diabetes in the international diabetes management practices study (IDMPS).
%B Diabetologia
%D 2006
%C Germany
%I Springer-Verlag
%V 49
%N 
%P 203-204
%@ 0012-186X
%X 
%Z FOR Codes:


%0 Journal Article
%~ Isi
%A Ramachandran, A.
%A Aschner, P.
%A Chan, J.
%A Hancu, N.
%A Baik, S. H.
%A Ferreira, S.
%A Ilkova, H.
%A Twigg, S.
%A Gagliardino, J. J.
%T Complications and cardiovascular risk factors in people with type 1 diabetes in the International Diabetes Management Practices Study (IDMPS).
%B Diabetologia
%D 2006
%C Germany
%I Springer-Verlag
%V 49
%N 
%P 626-627
%@ 0012-186X
%X 
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Burns, Wendy C
%A Twigg, Stephen M
%A Forbes, Josephine M
%A Pete, Josefa
%A Tikellis, Christos
%A Thallas-Bonke, Vicki
%A Thomas, Merlin C
%A Cooper, Mark E
%A Kantharidis, Phillip
%T Connective Tissue Growth Factor Plays an Important Role in Advanced Glycation End Product-Induced Tubular Epithelial-to-Mesenchymal Transition: Implications for Diabetic Renal Disease.
%B Journal of the American Society of Nephrology : JASN
%D 2006
%C United States
%I Lippincott Williams & Wilkins
%V 17
%N 9
%P 2484-94
%@ 1046-6673
%X Epithelial-to-mesenchymal transition (EMT) of tubular cells contributes to the renal accumulation of matrix protein that is associated with diabetic nephropathy. Both TGF-beta1 and advanced glycation end products (AGE) are able to induce EMT in cell culture. This study examined the role of the prosclerotic growth factor connective tissue growth factor (CTGF) as a downstream mediator of these processes. EMT was assessed by the expression of alpha-smooth muscle actin, vimentin, E-cadherin, and matrix proteins and the induction of a myofibroblastic phenotype. CTGF, delivered in an adenovirus or as recombinant human CTGF (250 ng/ml), was shown to induce a partial EMT. This was not blocked by neutralizing anti-TGF-beta1 antibodies, suggesting that this action was TGF-beta1 independent. NRK-52E cells that were exposed to AGE-modified BSA (AGE-BSA; 40 microM) or TGF-beta1 (10 ng/ml) also underwent EMT. This was associated with the induction of CTGF gene and protein expression. Transfection with siRNA to CTGF was able to attenuate EMT-associated phenotypic changes after treatment with AGE or TGF-beta1. These in vitro effects correlate with the in vivo finding of increased CTGF expression in the diabetic kidney, which co-localizes on the tubular epithelium with sites of EMT. In addition, inhibition of AGE accumulation was able to reduce CTGF expression and attenuate renal fibrosis in experimental diabetes. These findings suggest that CTGF represents an important independent mediator of tubular EMT, downstream of the actions of AGE or TGF-beta1. This interaction is likely to play an important role in progressive diabetic nephropathy and strengthens the rationale to consider CTGF as a potential target for the treatment of diabetic nephropathy.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Burgess, Janette K
%A Ge, Qi
%A Poniris, Maree H
%A Boustany, Sarah
%A Twigg, Stephen M
%A Black, Judith L
%A Johnson, Peter R A
%T Connective tissue growth factor and vascular endothelial growth factor from airway smooth muscle interact with the extracellular matrix.
%B American journal of physiology. Lung cellular and molecular physiology
%D 2006
%C USA
%I American Physiological Society
%V 290
%N 1
%P L153-61
%@ 1040-0605
%X Airway remodeling describes the structural changes that occur in the asthmatic airway that include airway smooth muscle hyperplasia, increases in vascularity due to angiogenesis, and thickening of the basement membrane. Our aim in this study was to examine the effect of transforming growth factor-beta on the release of connective tissue growth factor and vascular endothelial growth factor from human airway smooth muscle cells derived from asthmatic and nonasthmatic patients. In addition we studied the immunohistochemical localization of these cytokines in the extracellular matrix after stimulating bronchial rings with transforming growth factor-beta. Connective tissue growth factor and vascular endothelial growth factor were released from both cell types and colocalized in the surrounding extracellular matrix. Prostaglandin E2 inhibited the increase in connective tissue growth factor mRNA but augmented the release of vascular endothelial growth factor. Matrix metalloproteinase-2 decreased the amount of connective tissue growth factor and vascular endothelial growth factor, but not fibronectin deposited in the extracellular matrix. This report provides the first evidence that connective tissue growth factor may anchor vascular endothelial growth factor to the extracellular matrix and that this deposition is decreased by matrix metalloproteinase-2 and prostaglandin E2. This relationship has the potential to contribute to the changes that constitute airway remodeling, therefore providing a novel focus for therapeutic intervention in asthma.
%Z FOR Codes: 111505 111799


%0 Journal Article
%~ PubMed
%A Johnson, Peter R A
%A Burgess, Janette K
%A Ge, Qi
%A Poniris, Maree
%A Boustany, Sarah
%A Twigg, Stephen M
%A Black, Judith L
%T Connective tissue growth factor induces extracellular matrix in asthmatic airway smooth muscle.
%B American journal of respiratory and critical care medicine
%D 2006
%C USA
%I American Thoracic Society
%V 173
%N 1
%P 32-41
%@ 1073-449X
%X Transforming growth factor (TGF)-beta and connective tissue growth factor may be implicated in extracellular matrix protein deposition in asthma. We have recently reported that TGF-beta increased connective tissue growth factor expression in airway smooth muscle cells isolated from patients with asthma. In this study, we examined fibronectin and collagen production and signal transduction pathways after stimulation with TGF-beta and connective tissue growth factor. In both asthmatic and nonasthmatic airway smooth muscle cells, TGF-beta and connective tissue growth factor led to the production of fibronectin and collagen I. Fibronectin and collagen expression was extracellular regulated kinase-dependent in both cell types but phosphoinositide-3 kinase-dependent only in asthmatic airway smooth muscle cells. p38 was implicated in fibronectin but not collagen expression in both cell types. TGF-beta induction of fibronectin and collagen was in part mediated by an autocrine action of connective tissue growth factor. Phosphorylation of SMAD-2 may represent an additional pathway because this was increased in asthmatic cells. Our results suggest that these two cytokines may be important in the deposition of extracellular matrix proteins and that the signal transduction pathways may be different in asthmatic and nonasthmatic cells.
%Z FOR Codes: 111799


%0 Journal Article
%~ PubMed
%A Thomson, Sally E
%A McLennan, Susan V
%A Twigg, Stephen M
%T Growth factors in diabetic complications.
%B Expert review of clinical immunology
%D 2006
%C United Kingdom
%I Expert Reviews Ltd.
%V 2
%N 3
%P 403-18
%@ 1744-8409
%X Diabetes mellitus is characterized by a lack of insulin, causing elevated blood glucose, often with associated insulin resistance. Over time, especially in genetically susceptible individuals, such chronic hyperglycemia can cause tissue injury. Dysregulation of growth factors in diabetes occurs through biochemical and hemodynamic pathways. In some tissues affected by diabetes, growth factors are induced to an excess, while in other sites a relative deficit of growth factors occurs. There is evidence that these growth factor changes contribute to the tissue pathology in diabetes, whether it be fibrosis, persistent inflammation or a combination of the two. This review focuses on the role of growth factors in diabetic nephropathy and wound healing in diabetes. Growth factor therapy in diabetic foot ulcers is already a clinical reality. As methods to finely regulate growth factors in a tissue- and time-specific manner are further developed and tested, downregulation of growth factors in vivo may well become a therapy to prevent and treat diabetic nephropathy.
%Z FOR Codes: 110306


%0 Journal Article
%~ Isi
%A Gagliardino, J. J.
%A Aschner, P.
%A Baik, S. H.
%A Chan, J.
%A Ferreira, S.
%A Hancu, N.
%A Ilkova, H.
%A Twigg, S.
%A Ramachandran, A.
%T Hypoglycaemia and self-monitoring blood glucose are predictive factors for achieving glycaemic control in people with diabetes.
%B Diabetologia
%D 2006
%C Germany
%I Springer-Verlag
%V 49
%N 
%P 246-247
%@ 0012-186X
%X 
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Samaras, Katherine
%A McElduff, Aidan
%A Twigg, Stephen M
%A Proietto, Joseph
%A Prins, John B
%A Welborn, Timothy A
%A Zimmet, Paul
%A Chisholm, Donald J
%A Campbell, Lesley V
%T Insulin levels in insulin resistance: phantom of the metabolic opera?
%B The Medical journal of Australia
%D 2006
%C Australia
%I Australasian Medical Publishing Company Pty. Ltd.
%V 185
%N 3
%P 159-61
%@ 0025-729X
%X Insulin resistance is considered a core component in the pathophysiology of the metabolic syndrome. Some clinicians measure serum insulin concentrations in the mistaken belief that they can be used to diagnose insulin resistance. Serum insulin levels are poor measures of insulin resistance. Furthermore, there is no clinical benefit in measuring insulin resistance in clinical practice. Measurements of fasting serum insulin levels should be reserved for large population-based epidemiological studies, where they can provide valuable data on the relationship of insulin sensitivity to risk factors for diabetes and cardiovascular disease. Clinicians should shift from identifying "insulin resistance" to identifying risk factors, such as fasting glucose and lipid levels, hypertension and central obesity. These proven risk factors converge within the metabolic syndrome. Individuals "at risk" of diabetes and atherosclerotic cardiac disease can be identified simply and inexpensively, using classic clinical techniques, such as history-taking, physical examination, and very basic investigations.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Ong, Cynthia R
%A Molyneaux, Lynda M
%A Constantino, Maria I
%A Twigg, Stephen M
%A Yue, Dennis K
%T Long-term efficacy of metformin therapy in nonobese individuals with type 2 diabetes.
%B Diabetes care
%D 2006
%C USA
%I American Diabetes Association
%V 29
%N 11
%P 2361-4
%@ 0149-5992
%X OBJECTIVE: The U.K. Prospective Diabetes Study (UKPDS) has demonstrated that metformin is as effective as sulfonylureas in obese subjects and is associated with less weight gain, fewer hypoglycemic episodes, and better cardiovascular outcomes. It is hence the pharmacological therapy of choice in this subgroup. However, a gap in our present knowledge is the long-term response to metformin in nonobese individuals. In this study, we compared metformin therapy in normal, overweight, and obese individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: A database of patients treated at a referral center in Sydney, Australia, were analyzed. Patients with type 2 diabetes and complete HbA(1c) (A1C) data and treated with metformin or sulfonylurea monotherapy for at least three visits before receiving dual oral therapy were included (n = 644). Analysis by BMI and the type of oral agent was performed. Individuals were categorized as normal, overweight, or obese (BMI <25, 25-29.9, and >/=30 kg/m(2), respectively). RESULTS: There were no differences between the initial, follow-up, and last A1C between the three metformin-treated groups. The duration of successful glycemic control with metformin monotherapy in the normal and overweight individuals and their incidences of diabetes-related complications for the entire duration of follow-up were not inferior to those of the obese individuals. The nonobese patients performed better regardless of the type of oral hypoglycemic agent used. CONCLUSIONS: We conclude that metformin is at least as efficacious in normal and overweight individuals as it is in those who are obese. Our study provides evidence-based data to support metformin use in nonobese individuals with type 2 diabetes.
%Z FOR Codes:


%0 Journal Article
%~ Isi
%A McLennan, S. V.
%A Jia, J.
%A Milne, S.
%A Lo, L.
%A Bonner, J.
%A Yue, D. K.
%A Twigg, S. M.
%T Propolis, the anti-inflammatory bee hive protectant improves wound healing in experimental diabetes.
%B Diabetologia
%D 2006
%C Germany
%I Springer-Verlag
%V 49
%N 
%P 684-685
%@ 0012-186X
%X 
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Qi, Weier
%A Chen, Xinming
%A Polhill, Tania S
%A Sumual, Siska
%A Twigg, Stephen
%A Gilbert, Richard E
%A Pollock, Carol A
%T TGF-beta1 induces IL-8 and MCP-1 through a connective tissue growth factor-independent pathway.
%B American journal of physiology. Renal physiology
%D 2006
%C USA
%I American Physiological Society
%V 290
%N 3
%P F703-9
%@ 0363-6127
%X Transforming growth factor-beta(1) (TGF-beta(1)) functions as an important immunomodulatory cytokine in human kidney. Evidence suggests that connective tissue growth factor (CTGF) is an important downstream mediator of the profibrotic effects of TGF-beta(1). However, the role of CTGF in TGF-beta(1)-induced chemokine production remains unknown. This study was undertaken to determine whether CTGF is involved in mediating TGF-beta(1)-induced chemokine production in renal proximal tubular (HK-2) cells. Interleukin-8 (IL-8) and macrophage chemoattractant protein-1 (MCP-1) were measured. TGF-beta(1) induced an increase in IL-8 and MCP-1 (both P < 0.05) compared with control levels. CTGF was effectively silenced using small interference RNA (siRNA) in HK-2 cells. RT-PCR and real-time PCR confirmed a 94% reduction in CTGF mRNA. In the CTGF-silenced cells, TGF-beta(1)-stimulated IL-8 and MCP-1 secretion was not altered compared with control cells. Similarly, basal secretion of IL-8 and MCP-1 was not changed in CTGF-silenced cells. The direct effect of CTGF (20, 200, and 400 ng/ml) on IL-8 and MCP-1 was assessed at 24-, 48-, and 72-h time points and no stimulation was observed. Our studies further demonstrate that in the CTGF gene-silenced cells, CTGF partially mediates TGF-beta(1)-induced fibronectin and collagen IV secretion. These data suggest that TGF-beta(1) induced IL-8 and MCP-1 via CTGF-independent pathway. TGF-beta mediates both fibrosis and chemokine production in the proximal tubule of the kidney. However, CTGF plays a more specific role as a downstream mediator of TGF-beta(1)-induced fibrosis.
%Z FOR Codes: 111601 110312


%0 Journal Article
%~ PubMed
%A Wong, J
%A Molyneaux, L
%A Constantino, M I
%A Twigg, S M
%A Yue, D K
%T The metabolic syndrome in type 2 diabetes: When does it matter?
%B Diabetes, obesity & metabolism
%D 2006
%C UK
%I Blackwell Publishing Ltd.
%V 8
%N 6
%P 690-7
%@ 1462-8902
%X Aims: Young adults with type 2 diabetes (T2Dm) present the clinician with the problem of when to start therapies for the primary prevention of vascular disease and how to identify those at most vascular risk. We examine whether the metabolic syndrome (MetS) can be a useful clinical tool to stratify vascular risk in this context. Methods: Data were collected from 5928 subjects with T2Dm, and subjects were categorized as having MetS by World Health Organization criteria (body mass index criteria modified for Asians using >23 kg/m(2)). The prevalence of macrovascular disease was examined by MetS status and age. Results: The overall MetS prevalence was 72.3%. MetS was associated with an increased prevalence of ischaemic heart disease (IHD) (17.2% MetS vs. 11.6% no MetS, p < 0.0001), coronary artery bypass graft (7.6 vs. 4.7%, p < 0.0003), peripheral vascular disease (PVD) (4.7 vs. 3.7%, p = 0.08) and stroke (6 vs. 3.9%, p = 0.002) across all age groups. MetS subjects had an IHD prevalence equivalent to that seen in subjects who were one decade older without MetS. The most significant impact of MetS was for the age group of 40-49 years with much lesser impact seen with progressively increasing age [odds ratio (OR) = 2.1 for IHD in MetS compared with no MetS at age 40-50 years, p < 0.05; falling progressively to OR = 1.5 at age >70 years, p > 0.05]. Similar trends were seen for coronary artery by-pass graft (CABG) and PVD. There was a strong relationship between the number of MetS risk factors and IHD prevalence (r = 0.99, p = 0.0001). Conclusions: These data suggest that MetS is particularly useful in stratifying vascular risk in younger T2Dm patients and in those with a high number of MetS components. For patients with MetS, especially those with a full house of MetS risk factors, commencing risk-lowering interventions 10 years earlier than their MetS-free counterparts could be considered.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Qi, W
%A Chen, X
%A Twigg, S
%A Polhill, T S
%A Gilbert, R E
%A Pollock, C A
%T Tranilast attenuates connective tissue growth factor-induced extracellular matrix accumulation in renal cells.
%B Kidney international
%D 2006
%C United States
%I Blackwell Publishing, Inc.
%V 69
%N 6
%P 989-95
%@ 0085-2538
%X Tranilast (N-[3,4-dimethoxycinnamoyl]anthranilic acid) is a synthetic compound that we have recently reported to inhibit transforming growth factor-beta1 (TGF-beta1)-induced tubulointerstitial fibrosis in the kidney. Connective tissue growth factor (CTGF) is recognized as a potent downstream mediator of TGF-beta1. Both proximal tubule cells (PTCs) and cortical fibroblasts (CFs) are considered to be responsible for the production of tubulointerstitial extracellular matrix (ECM). These studies were undertaken to assess the profibrotic effects of CTGF in an in vitro model of the human PTCs and CFs, and to determine whether tranilast is effective in limiting the in vitro matrix responses induced by CTGF. Primary cultures of PTCs and CFs were exposed to CTGF (20 ng/ml)+/-tranilast (100 microM). Cell hypertrophy and the secretion of the ECM proteins fibronectin and collagen IV were determined. The effects of tranilast on TGF-beta1-induced CTGF mRNA expression and on phosphorylation of Smad2 were determined. CTGF significantly induced cell hypertrophy, increased fibronectin, and collagen IV secretion in PTCs and CFs. In all cases, the CTGF-induced increase in ECM protein was inhibited in the presence of tranilast. Tranilast reduced CTGF mRNA and phosphorylation of Smad2, which were induced by TGF-beta1 in PTCs and CFs. These results suggest that tranilast is a potential effective antifibrotic compound in the kidney, exerting its effects via inhibition of TGF-beta1-induced CTGF expression and downstream activation of the Smad2 pathway in both PTCs and CFs.
%Z FOR Codes: 111601 110312


%0 Journal Article
%~ PubMed
%A Qi, Weier
%A Chen, Xinming
%A Holian, John
%A Mreich, Ellein
%A Twigg, Stephen
%A Gilbert, Richard E
%A Pollock, Carol A
%T Transforming growth factor-beta1 differentially mediates fibronectin and inflammatory cytokine expression in kidney tubular cells.
%B American journal of physiology. Renal physiology
%D 2006
%C United States
%I American Physiological Society
%V 291
%N 
%P F1070-7
%@ 0363-6127
%X Transforming growth factor-beta(1) (TGF-beta(1)) is not only an important fibrogenic but also immunomodulatory cytokine in the human kidney. We have recently demonstrated that TGF-beta(1) induces interleukin-8 (IL-8), macrophage chemoattractant protein-1 (MCP-1), and fibronectin production in renal proximal tubular (HK-2) cells. However, the unique dependence of IL-8, MCP-1, and fibronectin on TGF-beta(1) expression is unknown. The TGF-beta(1) gene was effectively silenced in HK-2 cells using small-interference (si) RNA. Basal secretion of IL-8 and MCP-1 decreased (both P < 0.05) but, paradoxically, fibronectin increased (P < 0.05) in TGF-beta(1)-silenced cells compared with cells transfected with nonspecific siRNA. Significant increases were observed in mRNA for the TGF-beta(2) (P < 0.05), TGF-beta(3) (P < 0.05) isoforms and pSmad2 (P < 0.05), which were reflected in protein expression. Concurrent exposure to pan-specific TGF-beta antibody reversed the observed increase in fibronectin expression, suggesting that TGF-beta(2) and TGF-beta(3) isoforms mediate the increased fibronectin expression in TGF-beta(1)-silenced cells. An increase in the DNA binding activity of activator protein-1 (AP-1; P < 0.05) was also observed in TGF-beta(1)-silenced cells. In contrast, nuclear factor-kappaB (NF-kappaB) DNA binding activity was significantly decreased (P < 0.0005). These studies demonstrate that TGF-beta(1) is a key regulator of IL-8 and MCP-1, whereas fibronectin expression is regulated by a complex interaction between the TGF-beta isoforms in the HK-2 proximal tubular cell line. Decreased expression of TGF-beta(1) reduces chemokine production in association with reduced NF-kappaB DNA binding activity, suggesting that immunomodulatory pathways in the kidney are specifically dependent on TGF-beta(1). Conversely, decreased expression of TGF-beta(1) results in increased TGF-beta(2), TGF-beta(3), AP-1, and pSmad2 that potentially mediates the observed increase in fibronectin.
%Z FOR Codes: 110312 111601


%0 Journal Article
%~ Isi
%A Qi, W.
%A Chen, X. M.
%A Holian, J.
%A Twigg, S.
%A Gilbert, R.
%A Pollock, C.
%T Transforming growth factor-beta1 differentially mediates fibrosis and immunomodulation in kidney tubular cells.
%B Nephrology Dialysis Transplantation
%D 2006
%C United Kingdom
%I Oxford University Press
%V 21
%N 
%P 32-32
%@ 0931-0509
%X 
%Z FOR Codes: