M C Thomas

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

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Publications (44)171.81 Total impact

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    ABSTRACT: Congestive Heart Failure (CHF) is an ambulatory care sensitive condition, associated with significant morbidity and mortality, rarely with cure. Outpatient based pharmacological management represents the main and most important aspect of care, and is usually lifelong. This narrative styled opinion review looks at the pharmacological agents recommended in the guidelines in context of the Northern Territory (NT) of Australia. We explore the concept of validity, a term used to describe the basis of standardising a particular trial or study and the population to which it is applicable. We aim to highlight the problems of the current guidelines based approach. We also present alternatives that could utilise the core principles from major trials, while incorporating regional considerations, which could benefit clients living in the NT and remote Australia.
    Heart, Lung and Circulation 12/2014; 24(6). DOI:10.1016/j.hlc.2014.12.007 · 1.44 Impact Factor
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    ABSTRACT: OBJECTIVE: Osteopontin (OPN) is a multifunctional protein suggested to be a player in the arterial disease of patients with type 2 diabetes. However, its role for complications in patients with type 1 diabetes (T1D) is unknown. We therefore investigated the associations between OPN and diabetic vascular complications and all-cause mortality in patients with T1D. RESEARCH DESIGN AND METHODS: Serum OPN was measured in 2,145 adults with T1D without end-stage renal disease (ESRD; dialysis or transplantation) as part of the Finnish Diabetic Nephropathy (FinnDiane) study. Data on renal status, cardiovascular disease (CVD), and all-cause mortality during follow-up were verified from medical files, hospital discharge registries, and the Finnish Death Registry, respectively. The median follow-up time was 10.5 (interquartile range 8.9-11.8) years.RESULTS: Serum OPN was higher at baseline in patients who developed incident microalbuminuria (16.0 ± 0.9 vs. 14.1 ± 0.2 µg/L; P = 0.04), progressed to ESRD (28.3 ± 1.7 vs. 15.4 ± 0.2 µg/L; P < 0.001), suffered an incident CVD event (20.2 ± 1.2 vs. 15.5 ± 0.2 µg/L; P < 0.001), or died (23.3 ± 1.4 vs. 15.8 ± 0.2 µg/L; P < 0.001) during follow-up. In multivariate Cox regression analysis, OPN was independently associated with the development of incident microalbuminuria, an incident CVD event, and death, after adjustments for associated risk factors. Even after calculating reclassification indexes, OPN was predictive of CVD and all-cause mortality beyond the Framingham risk score covariates and hs-CRP.CONCLUSIONS: Serum OPN is a strong predictor of incipient diabetic nephropathy, a first-ever CVD event, and all-cause mortality in patients with T1D. Serum OPN may be of clinical significance for the risk prediction of CVD events in patients with T1D.
    Diabetes Care 06/2014; 37(9). DOI:10.2337/dc14-0065 · 8.42 Impact Factor

  • 35th Annual Scientific Meeting of the; 06/2014
  • P Iyngkaran · N Anavekar · W Majoni · M.C. Thomas ·
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    ABSTRACT: Feedback activation of neurohormonal pathways in the setting of kidney or heart failure contributes to the development and progression of dysfunction in the other. Diabetes and its management independently activate these same pathogenic pathways, feeding into this vicious cycle and contributing to a poor prognosis. One of the most important of these neurohormonal pathways is the sympathetic nervous system (SNS). The activity of the SNS in increased in patients with chronic kidney disease, even in the absence of renal impairment or heart failure. There is a strong relationship between SNS overactivity and prognosis, and evidence that blockade of SNS reduces morbidity and mortality in patients with diabetes. However, modulation of SNS is underutilised as a strategy to protect both the diabetic kidney and the heart. This is partly because of the historically poor tolerability, adverse haemodynamic and metabolic effects, lack of selectivity of β-blockers and the lack of specificity of other interventions that might modify SNS activation. The advent of "vasodilating β-blockers" with better tolerability as well as more favourable effects on renal function and metabolic profiles opens the door for their more widespread utility in patients with diabetes. Radiofrequency renal sympathectomy and baroreflex activation technologies also offer exciting new ways to tackle the challenge of sympathetic overactivity.
    Diabetes & Metabolism 07/2013; 39(4). DOI:10.1016/j.diabet.2013.05.002 · 3.27 Impact Factor

  • Nephrology 08/2012; 17:43-43. · 2.08 Impact Factor
  • D. Lee · S. A. Fraser · M. Katerelos · K. Gleich · M. C. Thomas · P. F. Mount · D. A. Power ·

    Nephrology 08/2012; 17:58-59. · 2.08 Impact Factor
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    Chris Tikellis · M C Thomas ·
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    ABSTRACT: Angiotensin-converting enzyme 2 (ACE2) shares some homology with angiotensin-converting enzyme (ACE) but is not inhibited by ACE inhibitors. The main role of ACE2 is the degradation of Ang II resulting in the formation of angiotensin 1-7 (Ang 1-7) which opposes the actions of Ang II. Increased Ang II levels are thought to upregulate ACE2 activity, and in ACE2 deficient mice Ang II levels are approximately double that of wild-type mice, whilst Ang 1-7 levels are almost undetectable. Thus, ACE2 plays a crucial role in the RAS because it opposes the actions of Ang II. Consequently, it has a beneficial role in many diseases such as hypertension, diabetes, and cardiovascular disease where its expression is decreased. Not surprisingly, current therapeutic strategies for ACE2 involve augmenting its expression using ACE2 adenoviruses, recombinant ACE2 or compounds in these diseases thereby affording some organ protection.
    International Journal of Peptides 03/2012; 2012(5):256294. DOI:10.1155/2012/256294
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    M C Thomas · K A Jandeleit-Dahm · C Tikellis ·
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    ABSTRACT: Pharmaceutical agonists of peroxisome proliferator-activated receptors (PPARs) are widely used in the management of type 2 diabetes, chiefly as lipid-lowering agents and oral hypoglycaemic agents. Although most of the focus has been placed on their cardiovascular effects, both positive and negative, these agents also have significant renoprotective actions in the diabetic kidney. Over and above action on metabolic control and effects on blood pressure, PPAR agonists also appear to have independent effects on a number of critical pathways that are implicated in the development and progression of diabetic kidney disease, including oxidative stress, inflammation, hypertrophy, and podocyte function. This review will examine these direct and indirect actions of PPAR agonists in the diabetic kidney and explore recent findings of clinical trials of PPAR agonists in patients with diabetes.
    PPAR Research 02/2012; 2012(2):456529. DOI:10.1155/2012/456529 · 1.64 Impact Factor
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    ABSTRACT: Hyperfiltration is widely regarded as a contributing factor to the development of microalbuminuria and progressive nephropathy in type 1 diabetes. However, recent studies have questioned this conclusion. To address this conflicting evidence, we examined the association between hyperfiltration and progression to microalbuminuria in 2,318 adults with type 1 diabetes. We also compared the estimated GFR in our diabetic patients with rates observed in 6,247 adults from the Finnish general population, using age- and sex-specific z scores. The distribution of estimated GFR in adults with type 1 diabetes and normoalbuminuria was not significantly different from that expected in the general population (p = 0.51, Mann-Whitney test). Type 1 diabetic patients with a higher estimated GFR were also no more likely to develop microalbuminuria over a median of 5.2 years of follow-up than those with normal estimated GFR. This was the case regardless of whether hyperfiltration was defined by an absolute threshold, deciles of estimated GFR or a z score, using creatinine- or cystatin-based clearance formulas in men or in women. Together with other studies, these data suggest that creatinine- or cystatin-based estimates of GFR do not predict the development of microalbuminuria in patients with type 1 diabetes. Moreover, in the absence of incipient or overt nephropathy, conventionally determined renal function in patients with type 1 diabetes appears no different from that in the general population. This is hardly surprising, given that these individuals, by all definitions, do not have kidney disease.
    Diabetologia 02/2012; 55(5):1505-13. DOI:10.1007/s00125-012-2485-5 · 6.67 Impact Factor
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    ABSTRACT: Aims/hypothesisActivation of the receptor for AGE (RAGE) is implicated in the development and progression of vascular complications of diabetes. In this study, we explore factors and mortality outcomes associated with soluble RAGE (sRAGE) in a multicentre nationwide cohort of Finnish adults with type 1 diabetes. MethodsBaseline sRAGE concentrations were estimated in 3,100 adults with type 1 diabetes. Clinical and biological variables independently associated with sRAGE were identified using multivariate regression analysis. Independent predictors of mortality were determined using Cox and Fine–Gray proportional-hazards models. ResultsThe main independent determinants of sRAGE concentrations were estimated glomerular filtration rate, albuminuria, body mass index, age, duration of diabetes, HbA1c and insulin dose (all p < 0.05). During a median of 9.1years of follow-up there were 202 deaths (7.4 per 1,000 patient years). sRAGE was independently associated with all-cause (Cox model: HR 1.03) and cardiovascular mortality (Fine–Gray competing risks model: HR 1.06) such that patients with the highest sRAGE concentrations had the greatest risk of mortality, after adjusting for age, sex, macrovascular disease, HDL-cholesterol, HbA1c, triacylglycerol, high-sensitivity C-reactive protein (hsCRP) and the presence and severity of chronic kidney disease. Although polymorphisms in the gene coding for RAGE were significantly associated with sRAGE concentrations, none were associated with mortality outcomes. Conclusions/interpretationIncreased concentrations of sRAGE are associated with increased all-cause and cardiovascular mortality in type 1 diabetes, potentially reflecting the activation and production of RAGE in the context of accelerated vascular disease. These novel findings highlight the importance of the RAGE activation in the prevention and management of diabetic complications. KeywordsAdvanced glycation end-products–AGE–Mortality–RAGE–Type 1 diabetes
    Diabetologia 10/2011; 54(10):2669-2677. DOI:10.1007/s00125-011-2186-5 · 6.67 Impact Factor
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    ABSTRACT: Adiponectin is widely regarded as an anti-atherogenic, antioxidant and anti-inflammatory molecule. However, adiponectin concentration is paradoxically increased in individuals with type 1 diabetes, in whom it is positively associated with adverse clinical outcomes. To explore the association between serum adiponectin concentration and mortality outcomes in adults with type 1 diabetes. Multicentre prospective cohort study. Primary and tertiary care. Finnish adults with type 1 diabetes (n= 2034). Main outcome measures.  All-cause and cardiovascular mortality. Independent predictors of mortality were determined using the Cox and the Fine and Gray competing risks proportional hazards models. During a median of 11 years of follow-up, there were 173 deaths (8.5%, 1.0 per hundred person-years). Adiponectin was linearly associated with all-cause mortality [Cox model: hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.01-1.03, P<0.001] and cardiovascular mortality (Fine and Gray model: HR 1.02, 95% CI 1.00-1.04, P=0.035); patients with the highest adiponectin concentrations had the shortest survival. The mortality risk associated with adiponectin was independent of glycaemic and lipid control, pre-existing cardiovascular disease, markers of inflammation and the presence and severity of kidney disease. Although adiponectin is generally considered to be a protective molecule, increased concentrations of adiponectin in type 1 diabetes are independently associated with all-cause and cardiovascular mortality. Moreover, the fact that this association was observed for the first time in patients with normal urinary albumin levels, who have few comorbidities, suggests that adiponectin is specifically linked with vascular damage in type 1 diabetes.
    Journal of Internal Medicine 05/2011; 270(4):346-55. DOI:10.1111/j.1365-2796.2011.02406.x · 6.06 Impact Factor
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    ABSTRACT: Deficiency of the intrinsic lysosomal protein human scavenger receptor class B, member 2 (SCARB2; Limp-2 in mice) causes collapsing focal and segmental glomerular sclerosis (FSGS) and myoclonic epilepsy in humans, but patients with no apparent kidney damage have recently been described. We now demonstrate that these patients can develop tubular proteinuria. To determine the mechanism, mice deficient in Limp-2, the murine homolog of SCARB2, were studied. Most low-molecular-weight proteins filtered by the glomerulus are removed in the proximal convoluted tubule (PCT) by megalin/cubilin-dependent receptor-mediated endocytosis. Expression of megalin and cubilin was unchanged in Limp-2(-/-) mice, however, and the initial uptake of injected Alexa Fluor 555-conjugated bovine serum albumin (Alexa-BSA) was similar to wild-type mice, indicating that megalin/cubilin-dependent, receptor-mediated endocytosis was unaffected. There was a defect in proteolysis of reabsorbed proteins in the Limp-2(-/-) mice, demonstrated by the persistence of Alexa-BSA in the PCT compared with controls. This was associated with the failure of the lysosomal protease cathepsin B to colocalize with Alexa-BSA and endogenous retinol-binding protein in kidneys from Limp-2(-/-) mice. The data suggest that tubular proteinuria in Limp-2(-/-) mice is due to failure of endosomes containing reabsorbed proteins to fuse with lysosomes in the proximal tubule of the kidney. Failure of proteolysis is a novel mechanism for tubular proteinuria.
    AJP Renal Physiology 03/2011; 300(6):F1437-47. DOI:10.1152/ajprenal.00015.2011 · 3.25 Impact Factor
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    ABSTRACT: Formation of AGEs is increased in the diabetic milieu, which contributes to accelerated atherogenesis. We studied whether delayed treatment with AGE-inhibiting compounds, alagebrium chloride and pyridoxamine dihydrochloride, affected established atherosclerosis in experimental diabetes in comparison with the angiotensin-converting enzyme inhibitor, quinapril. Streptozotocin-induced diabetic male Apoe (-/-) mice (n = 24 per group) received, by oral gavage, from week 10 to 20 of diabetes: no treatment; alagebrium (1 mg kg(-1) day(-1)); pyridoxamine (1 g/l in drinking water); or quinapril (30 mg kg(-1) day(-1)). Atherosclerotic lesion area (en face analysis) was evaluated for all groups. Delayed intervention with alagebrium decreased plaque area in the diabetic Apoe (-/-) mice compared with untreated mice (total plaque area: alagebrium 10.6 ± 1.6%, untreated, 15.1 ± 1.5%, p < 0.05). This anti-atherosclerotic effect was comparable with that achieved with quinapril (quinapril 8.4 ± 1.4%, vs untreated, p < 0.05). Pyridoxamine also attenuated plaque development in diabetic mice (5.7 ± 1.2% vs untreated 11.9 ± 1.1%, p < 0.05). The anti-atherosclerotic effect conferred by alagebrium and quinapril was associated with a significant reduction in vascular oxidative stress and circulating AGEs and methylglyoxal, although preformed AGEs were not removed from the vascular wall with either delayed intervention. Inhibition of AGE accumulation, using a delayed intervention with alagebrium or pyridoxamine, significantly attenuated the progression of established diabetes-associated atherosclerosis, similar to results obtained with quinapril. These findings provide further evidence that blockade of AGE-mediated pathways may present a novel therapy for the prevention of atherosclerosis in diabetes.
    Diabetologia 03/2011; 54(3):681-9. DOI:10.1007/s00125-010-2000-9 · 6.67 Impact Factor
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    ABSTRACT: The receptor for AGEs (RAGE) contributes to the development and progression of diabetic nephropathy. In this study, we examined whether the protective effects of RAGE blockade are exerted via modulation of the renal angiotensin II type 2 (AT2) receptor. Control and streptozotocin diabetic mice, wild-type or deficient in the AT2 receptor (At2 knockout [KO]) or RAGE (Rage KO), were studied for 24 weeks. Adenoviral overexpression of full-length Rage in primary rat mesangial cells was also used to determine the effects on AT2 production. With diabetes, Rage-deficient mice had less albuminuria, and an attenuation of hyperfiltration and glomerulosclerosis as compared with diabetic wild-type and At2 KO mice. Renal gene and protein expression of RAGE was elevated with diabetes. Diabetic Rage KO mice had a greater increase in renal AT2 receptor protein than was seen in diabetic wild-type mice. Diabetes-induced increases in renal cytosolic and mitochondrial superoxide generation were prevented in diabetic Rage KO mice, but enhanced in all At2 KO mice. Adenoviral overexpression of RAGE or AGE treatment decreased cell surface AT2 expression, in association with increasing superoxide generation; both were reversed using antioxidants N-acetylcysteine and apocynin, and soluble RAGE in primary mesangial cells. RAGE appears to be a common and key modulator of AT2 receptor expression, a finding that would implicate a newly defined RAGE-AT2 axis in the development and progression of diabetic nephropathy.
    Diabetologia 11/2010; 53(11):2442-51. DOI:10.1007/s00125-010-1837-2 · 6.67 Impact Factor
  • Wendy C. Burns · M.C. Thomas ·
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    ABSTRACT: Activation of the intra-renal renin-angiotensin system (RAS) and the subsequent generation of angiotensin II (Ang II) are important mediators of haemodynamic changes in both health and disease. However, the effects of locally produced Ang II are not limited to haemodynamic actions. Ang II is also an important stimulus for tubular hypertrophy with the induction of growth factors, including transforming growth factor (TGF)-β(1) and connective tissue growth factor. In this article, we explore the direct pro-fibrotic effects of Ang II and its role in inducing tubular epithelial to mesenchymal transition (EMT, also known as type 2 EMT), a known mediator of renal fibrogenesis. There is accumulating evidence that Ang II is able to induce EMT by both TGF-dependent and TGF-independent actions, both in vitro and in vivo. Moreover, blockade of the RAS has synergistic renoprotective effects across a number of causally different forms of renal disease. There is hope that targeted combinations to offset angiotensin-converting enzyme escape in the setting of RAS blockade will eventually achieve the long-term efficacy that has been expected for so long.
    Cells Tissues Organs 11/2010; 193(1-2):74-84. DOI:10.1159/000320359 · 2.14 Impact Factor

  • Obesity Research & Clinical Practice 10/2010; 4. DOI:10.1016/j.orcp.2010.09.015 · 1.18 Impact Factor
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    W C Burns · E Velkoska · R Dean · L M Burrell · M C Thomas ·
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    ABSTRACT: Epithelial-to-mesenchymal transformation (EMT) of tubular cells into a myofibroblastic phenotype is an important mediator of renal scarring in chronic nephropathy. This study examines the role of the renin-angiotensin system (RAS) in this process. NRK-52E cells were exposed to angiotensin (ANG) II and ANG 1-7 in the presence or absence of inhibitors and agonists of RAS signaling. EMT was assessed at 3 days by expression of alpha-smooth muscle actin (alpha-SMA) and E-cadherin and the induction of a myofibroblastic phenotype. Expression of fibrogenic growth factors and matrix proteins was assessed by RT-PCR and immunofluorescence microscopy. To confirm findings in vivo, rats were also infused with ANG 1-7 (24 microg*kg(-1)*h(-1)) or saline via an osmotic minipump for 10 days, and renal fibrogenesis was then assessed. Treatment of NRK-52E cells with ANG II induced characteristic changes of EMT. Selective blockade of the AT(1) receptor or the AT(2) receptor failed to inhibit ANG II-induced EMT. However, blockade of the ANG 1-7 receptor, Mas-1, was able to prevent ANG II-dependent EMT. To confirm these findings, both ANG 1-7 and the selective Mas receptor agonist, AVE-0991, were able to induce NRK-52E cells in a dose-dependent manner. Exposing cells to recombinant ACE2 was also able to induce EMT. In addition, an infusion of ANG 1-7 induced the tubular expression of alpha-SMA and the expression of matrix proteins in the kidney. ANG II is a potent stimulus for EMT, but not through conventional pathways. This study points to the possible limitations of conventional RAS blockade, which not only fails to antagonize this pathway, but also may enhance it via augmenting the synthesis of ANG 1-7.
    AJP Renal Physiology 09/2010; 299(3):F585-93. DOI:10.1152/ajprenal.00538.2009 · 3.25 Impact Factor
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    ABSTRACT: There is convincing evidence that the endothelin system contributes to diabetic nephropathy and cardiovascular disease. This study aimed to assess the effects of the non-peptidergic endothelin receptor A (ETA) antagonist avosentan in a mouse model of accelerated diabetic nephropathy and atherosclerosis in comparison with the ACE inhibitor, quinapril. Apolipoprotein E (Apoe) knockout (KO) mice (n = 20 per group, five groups) were randomised to the following groups: non-diabetic controls and streptozotocin-induced diabetic animals gavaged daily for 20 weeks with placebo, avosentan (high dose: 30 mg/kg, or low dose: 10 mg/kg) or quinapril (given in drinking water, 30 mg/kg). BP was unchanged by avosentan treatment but decreased with quinapril treatment. Diabetes-associated albuminuria was significantly attenuated by high-dose avosentan after 10 and 20 weeks of treatment. Diabetic animals showed a decreased creatinine clearance, which was normalised by avosentan treatment. In diabetic mice, high-dose avosentan treatment significantly attenuated the glomerulosclerosis index, mesangial matrix accumulation, glomerular accumulation of the matrix proteins collagen IV, and renal expression of genes encoding connective tissue growth factor, vascular endothelial growth factor, transforming growth factor beta and nuclear factor kappaB (p65 subunit). Furthermore, high-dose avosentan treatment was also associated with reduced expression of the genes for ETA, ETB and angiotensin receptor 1. The renoprotective effects of avosentan were comparable or superior to those observed with quinapril. High-dose avosentan also significantly attenuated diabetes-associated aortic atherosclerosis in Apoe KO mice and reduced macrophage infiltration and aortic nitrotyrosine expression. This study demonstrates that ETA blockade with avosentan may provide an alternate therapeutic strategy for the treatment of diabetic micro- and macrovascular complications.
    Diabetologia 10/2009; 53(1):192-203. DOI:10.1007/s00125-009-1540-3 · 6.67 Impact Factor
  • R J Macisaac · G Jerums · AJ Weekes · M C Thomas ·
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    ABSTRACT: Intensive glycaemic control delays the onset and progression of diabetes-related complications, especially microvascular complications. However, only limited information is available regarding glucose-lowering treatment practices in Australian primary care. The aim of the study was to describe patterns of glycaemic control in subjects participating in the National Evaluation of the Frequency of Renal Impairment co-existing with Non-Insulin Dependent Diabetes Mellitus study. Expressions of interest were invited from all registered general practitioners in Australia, from which 500 investigators were randomly selected and asked to provide data on 10-15 consecutive adults with type 2 diabetes presenting to their practice. Just less than half of the 3893 enrolled patients had a haemoglobin (Hb)A(1c) <7.0% (47.7%, 95% confidence interval (CI) 46.1-49.3%) and quarter had an HbA(1c)> or =8.0% (24.3%, 95%CI 22.9-25.9%. For patients using lifestyle alone, one or two oral glucose-lowering agents or insulin there was a progressive decline in the proportion achieving an HbA(1c) <7.0%, that is, 81, 55, 31 and 24%, respectively. There was a very good concordance between general practitioners' perception of optimal control (HbA(1c) <7.0%) and the actual glycaemic levels achieved in this study. Current targets for glycaemic control in type 2 diabetes have generally been followed in Australian general practice, but there is still a significant gap in the achievement of recommended glycaemic goals. A quarter of the patients clearly have poor glycaemic control. The immediate steps that can be taken to improve glycaemic control include the early use of combination oral glucose-lowering therapies and the increased use of insulin.
    Internal Medicine Journal 11/2008; 39(8):512-8. DOI:10.1111/j.1445-5994.2008.01821.x · 1.64 Impact Factor
  • A Koitka · M E Cooper · M C Thomas · C Tikellis ·
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    ABSTRACT: 1. Angiotensin converting enzyme 2 (ACE2) is an important homeostatic component of the renin angiotensin system (RAS). ACE2 both degrades the vasoconstrictor, angiotensin II and generates the potent vasodilator peptide, angiotensin 1-7. These actions counterbalance those of ACE. 2. ACE2 is highly expressed in the healthy kidney, particularly in the proximal tubules, where it colocalizes with ACE and angiotensin receptors. 3. Kidney disease and subtotal nephrectomy is associated with a reduction in renal ACE2 expression, possibly facilitating the damaging effects of angiotensin II in the failing kidney. Acquired or genetic ACE2 deficiency also appears to exacerbate renal damage and albuminuria in experimental models, supporting this hypothesis. 4. ACE2 also has an important role in blood pressure control. Many models of hypertension are associated with reduced ACE2 expression. Although ACE2 KO animals are normotensive, in states associated with activation of the RAS, ACE2 overexpression improves blood pressure control and reduces angiotensin responsiveness.
    Clinical and Experimental Pharmacology and Physiology 05/2008; 35(4):420-5. DOI:10.1111/j.1440-1681.2008.04889.x · 2.37 Impact Factor

Publication Stats

1k Citations
171.81 Total Impact Points


  • 2006-2013
    • Baker IDI Heart and Diabetes Institute
      • Diabetic Complications Division
      Melbourne, Victoria, Australia
  • 2011
    • University of Helsinki
      Helsinki, Uusimaa, Finland