Volume 5, Number 3, September 2008

EDITORIALA Journal for our times
Peter J Grant

Diabetes Vasc Dis Res 2008;5:155.

POPULAR
TOPICEDITORIALMetformin: a multitasking medication
Cliff J Bailey

Diabetes Vasc Dis Res 2008;5:156.

POPULAR
TOPICREVIEWMetformin therapy and clinical uses
John HB Scarpello, Harry CS Howlett

Metformin is now established as a first-line antidiabetic therapy for the management of type 2 diabetes. Its early use in treatment algorithms is supported by lack of weight gain, low risk of hypoglycaemia and its mode of action to counter insulin resistance. The drug’s anti-atherosclerotic and cardioprotective effects have recently been confirmed in prospective and retrospective studies, and appear to reflect a collection of glucose-independent effects on the vascular endothelium, suppressant effects on glycation, oxidative stress and formation of adhesion molecules, stimulation of fibrinolysis and favourable effects on the lipid profile. Although avoidance of troublesome gastrointestinal tolerability issues requires careful dose titration, the risk of serious adverse events is considered low provided that contra-indications (especially with respect to renal function) are observed. As many of its actions go beyond glucose lowering, emerging evidence indicates potential benefits in other insulin-resistant states and possibly tumour suppression.

Diabetes Vasc Dis Res 2008;5:157-167.

POPULAR
TOPICREVIEWThe application of proteomics technology to thrombosis research: the identification of potential therapeutic targets in cardiovascular disease
Joanna-Marie Howes, Jeff N Keen, John BC Findlay, Angela M Carter

Thrombus formation underpins the development of cardiovascular diseases, including acute coronary syndromes and ischaemic stroke. A number of well-characterised cardiovascular risk factors which contribute to the development of the majority of cardiovascular events have been identified, including dyslipidaemia, hypertension and diabetes. Individuals with type 2 diabetes mellitus (T2DM) have a 3- to 5-fold increased risk for development of cardiovascular disease (CVD). They may have a cluster of haemostatic abnormalities, including elevated levels of plasminogen activator inhibitor-1 (PAI-1) and fibrinogen, which contribute to acute thrombotic events. It is clear that additional unidentified risk factors contribute to the pathogenesis of cardiovascular events, and so the search for novel biomarkers and effectors, particularly in individuals with T2DM, remains a major challenge of cardiovascular medicine. Plasma and cellular proteins which contribute to thrombus formation have the potential to confer a pro-thrombotic state and represent a link between genotype, environment and disease phenotype. The comprehensive analysis of these proteins is now increasingly facilitated through the continued development of proteomic technologies which provide multifaceted approaches to the identification of novel biomarkers and/or effectors of thrombus formation and on which future anticoagulant and thrombolytic therapies may be based.
This review provides an overview of current proteomic technologies. It focuses on the recent studies in which these technologies have been applied in the search for novel proteins that may confer increased risk of acute cardiovascular diseases and therefore that may influence disease progression and therapy.

Diabetes Vasc Dis Res 2008;5:205-212.

ORIGINAL PAPERImprovement of glycaemic and lipid profiles with muraglitazar plus metformin in patients with type 2 diabetes: an active-control trial with glimepiride
Cindy J Rubin, Jean-Marie Ledeine, Fred T Fiedorek

The efficacy and safety of muraglitazar versus glimepiride were evaluated in patients with type 2 diabetes. After open-label metformin monotherapy, 1,805 patients received randomised therapy with muraglitazar 2.5 mg or 5 mg or with glimepiride 1 mg in a double-blind 52-week study. The primary end point was change in glycosylated haemoglobin (HbA_1C); secondary end points were changes in fasting lipid levels and glycaemic indices. At week 52, the reduction in HbA_1C with muraglitazar 5 mg plus metformin was superior (p<0.0001) and with muraglitazar 2.5 mg it was non-inferior in comparison with glimepiride. At week 12, muraglitazar significantly decreased triglyceride levels (p<0.0001) and increased levels of high-density lipoprotein cholesterol (HDL-C) (p<0.0001). Oedema, weight gain and heart failure were more evident with muraglitazar. Muraglitazar 5 mg plus metformin significantly improved HbA_1C, triglyceride and HDL-C levels in patients with type 2 diabetes. Cardiovascular events were similar among groups (~2%), but there was an imbalance of total mortality in favour of glimepiride.

Diabetes Vasc Dis Res 2008;5:168-176.

POPULAR
TOPICORIGINAL PAPERThe safety and tolerability of atorvastatin 10 mg in the Collaborative Atorvastatin Diabetes Study (CARDS)
Connie B Newman, Michael Szarek, Helen M Colhoun, D John Betteridge, Paul N Durrington, Graham A Hitman, H Andrew W Neil, David A Demicco, Sheila Auster, John H Fuller, On Behalf Of The Cards Investigators

The objective of this study was to evaluate the safety and tolerability of atorvastatin 10 mg compared with placebo in 2,838 patients with type 2 diabetes and no history of coronary heart disease who were enrolled in the Collaborative Atorvastatin Diabetes Study (CARDS) and followed for 3.9 years.
The percentages of patients experiencing treatment-associated adverse events (AEs), serious AEs and discontinuations due to AEs in the atorvastatin (n=1,428) and placebo (n=1,410) groups were 23.0% vs. 25.4%, 1.1% vs. 1.1% and 2.9% vs. 3.4%, respectively. The most common treatment-associated AEs in the atorvastatin and placebo groups were digestive system-related (8.9% vs. 10.0%). All-cause and treatment-associated myalgia were reported in 4.0% and 1.0% of atorvastatin-treated patients, and 4.8% and 1.2% of placebo-treated patients. An analysis of selected AEs by tertiles of baseline low-density lipoprotein (LDL) cholesterol showed no relationship between LDL cholesterol levels and the incidence of myalgia, cancer or nervous system AEs in either treatment group.
Overall, these data demonstrate that atorvastatin 10 mg was well tolerated in patients with type 2 diabetes during long-term treatment.

Diabetes Vasc Dis Res 2008;5:177-183.

ORIGINAL PAPERAssociation of glycosylated haemoglobin level and diabetes mellitus duration with the severity of coronary artery disease
Tahir Saleem, Kazim Hameedullah Mohammad, Moataz M Abdel-Fattah, Abdul Hafeez Abbasi

Diabetes mellitus (DM) is known to cause microvascular and possibly macrovascular complications. This study was performed to find the association between glycosylated haemoglobin (HbA_1C) level and the severity of coronary artery disease. One hundred and ten consecutive patients admitted to hospital with acute myocardial infarction were studied. Seventy-eight patients (70.9%) had DM, 73 (93.58%) had HbA_1C > 7%, 52 (47.3%) were hypertensive, 19 (17.3%) had a history of smoking and 37 (33.6%) had raised cholesterol. Coronary angiography was carried out in 87 (79.1%) patients and the severity of disease was assessed using the Gensini score. The mean Gensini score was 53.36+36.94 and the mean HbA_1C was 8.4+2.39%. There was a significant association between Gensini score and DM (p=0.003) and between Gensini score and hypertension (p=0.018). HbA_1C (r=0.427, p=0.001) and duration of DM (r=0.362, p=0.004) had a positive linear correlation with the Gensini score. Multiple regression analysis showed HbA_1C to be an independent factor that influenced the Gensini score (p=0.021).

Diabetes Vasc Dis Res 2008;5:184-189.

ORIGINAL PAPEREndogenous secretory RAGE but not soluble RAGE is associated with carotid atherosclerosis in type 1 diabetes patients
Naoto Katakami, Munehide Matsuhisa, Hideaki Kaneto, Taka-Aki Matsuoka, Ken’ya Sakamoto, Tetsuyuki Yasuda, Yoshimitsu Yamasaki

Advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE) system play an important role in the development of diabetic complications. The soluble form of RAGE (sRAGE) that potentially counteracts AGEs consists of several forms, including endogenous secretory RAGE (esRAGE; a splice variant of RAGE) and cleaved-type soluble RAGE derived from cell-surface RAGE. The aim of this study was to compare sRAGE and esRAGE directly in patients with type 1 diabetes.
The associations of both total sRAGE and esRAGE with markers of glycaemic control and with carotid intima-media thickness (IMT) as a marker of atherosclerosis were examined in 130 type 1 diabetes patients (aged 23.6+4.9 years) and 22 age-matched non-diabetic subjects.
IMT was inversely correlated with esRAGE (r=-0.254, p=0.0015) but neither with sRAGE nor subtracted soluble RAGE values (that is, circulating total sRAGE values – circulating esRAGE values). Furthermore, a stepwise multivariate regression analysis revealed that esRAGE (F=7.3), but not sRAGE, was a variable that interacted independently of IMT.
It is likely that circulating sRAGE and esRAGE are distinct markers and that circulating esRAGE levels, but not sRAGE levels, are associated with the status of early-stage atherosclerosis.

Diabetes Vasc Dis Res 2008;5:190-197.

ORIGINAL PAPERDominance of cytokine- over FasL-induced impairment of the mitochondrial transmembrane potential (Δψm) in the pancreatic β-cell line NIT-1
Petra Augstein, Peter Heinke, Eckhard Salzsieder, Rita Grimm, Jürgen Giebel, Christel Salzsieder, Leonard C Harrison

Mitochondria of pancreatic β-cells are potential targets of intrinsic and extrinsic apoptotic pathways in the autoimmune pathogenesis of type 1 diabetes. We aimed to investigate whether cytokine- and FasLigand (FasL)-induced apoptosis is associated with impaired mitochondrial transmembrane potential (Δψm) in the pancreatic β-cell line NIT-1. NIT-1 cells were exposed to the interleukin-1β/interferon-γ (IL-1β/IFN-γ) cytokine combination to induce apoptosis in vitro. Low concentrations of cytokines resulted in Δψm impairment, and increasing concentrations had only a minor additional effect. Treatment with the inducible nitric oxide synthase (iNOS) inhibitor Nw-nitro-L-arginine methyl ester hydrochloride (L-NAME) prevented cytokine-mediated Δψm impairment, implying that cytokines affect Δψm via nitric oxide. The broad-spectrum caspase inhibitor Z-VAD(Ome)-FMK (ZVAD) revealed dichotomic actions. In the presence of ZVAD, cytokine-induced nitrite generation was increased but cell death and Δψm impairment were reduced. Δψm impairment was also reduced by inhibitors of caspases 1, 6 and 8. Induction of Fas by IL-1β/IFN-γ coupled with activation by Super-FasL augmented cytokine-induced cell death. We observed a clear dominance of cytokine- over FasL-induced effects on Δψm.
Our findings show that IL-1β/IFN-γ cytokines have a strong effect to impair Δym and prime β-cells for apoptosis via the intrinsic pathway mediated by iNOS and caspases. Furthermore, at least in NIT-1 cells, the extrinsic FasL/Fas pathway has only a minor additive effect on cytokine-induced Δψm impairment.

Diabetes Vasc Dis Res 2008;5:198-204.

COMMENTFour decades of uncertainty: landmark trials in glycaemic control and cardiovascular outcome in type 2 diabetes
David R Matthews, Apostolos Tsapas

Diabetes Vasc Dis Res 2008;5:216-218.

LETTERApoptosis, vascular leakage and increased risk of severe dengue in a type 2 diabetes mellitus patient
Daniel Limonta, Griselda Torres, Virginia Capó, María G Guzmán

Diabetes Vasc Dis Res 2008;5:213-214.

POPULAR
TOPICLETTERThiamine deficiency in diabetes – is diet relevant?
Sally A Vindedzis, Kim G Stanton, Jill L Sherriff, Satvinder S Dhaliwal

Diabetes Vasc Dis Res 2008;5:215.