Volume 2, Number 2, May 2005

EDITORIALWhence and whither the fixed-dose combination?
Clifford J Bailey

Diabetes Vasc Dis Res 2005;2:51-53.

POPULAR
TOPICREVIEWThe application of proteomics to diabetes
Eleanor M Scott, Angela M Carter, John BC Findlay

Proteomics is the investigation of all the proteins and their various modifications making up a system, be that a cell, tissue or organism. The techniques involved in proteomics allow the global screening of complex samples of proteins and provide qualitative and quantitative evidence of altered protein expression. This lends itself to the investigation of the molecular mechanisms underpinning disease processes and the effects of treatment. This review describes the main techniques of proteomics and how they have begun to be applied to diabetes research.

Diabetes Vasc Dis Res 2005;2:54-60.

POPULAR
TOPICREVIEWThiazolidinediones, peripheral oedema and congestive heart failure: what is the evidence?
Chetan Patel, Kathleen L Wyne, Darren K McGuire

Cardiovascular disease is the most common complication of type 2 diabetes mellitus (type 2 DM), accounting for approximately 80% of deaths. While atherosclerotic vascular disease accounts for much of the cardiovascular morbidity and mortality among diabetic patients, congestive heart failure (CHF) is another key complication associated with diabetes, with an incidence three to five times greater in diabetic patients than in those without diabetes.
One of the most promising developments in the treatment of type 2 DM has been the introduction of the thiazolidinedione (TZD) class of drugs, which appear to have pleiotropic effects beyond glycaemic control. Enthusiasm has been tempered, however, by concerns for safety in patients with CHF, given reports of worsening heart failure symptoms and peripheral oedema. With the growing epidemic of type 2 DM and the increasing use of TZDs, such concern has important therapeutic implications for a population of patients with a high prevalence of often subclinical systolic and diastolic dysfunction.
This review provides an overview of the currently available data regarding the effects of TZDs on fluid retention and cardiac function. Particular emphasis is placed on the mechanisms of development of peripheral oedema and its significance in patients with impaired left ventricular function. TZDs are well known to cause an expansion in plasma volume; there has also been concern that TZDs may have direct toxic effects on the myocardium, leading to impaired cardiac function. Studies to date do not support this hypothesis and in fact there is growing evidence from animal models and human trials that treatment with TZDs actually improves cardiac function. There are also preclinical data to suggest TZDs may protect the myocardium in the setting of ischaemic insult or the toxic effects of myocardial lipid deposition. Ongoing clinical trials examining the use of these agents in patients at risk for heart failure will probably provide further insight into the aggregate cardiovascular effects of this promising class of medications.

Diabetes Vasc Dis Res 2005;2:61-66.

POPULAR
TOPICORIGINAL PAPERCross-sectional evaluation of the Finnish Diabetes Risk Score: a tool to identify undetected type 2 diabetes, abnormal glucose tolerance and metabolic syndrome
Timo Saaristo, Markku Peltonen, Jaana Lindström, Liisa Saarikoski, Jouko Sundvall, Johan Gunnar Eriksson, Jaakko Tuomilehto

The aim of this study was to assess the performance of the Finnish Diabetes Risk Score as a screening tool for undetected type 2 diabetes (T2D), abnormal glucose tolerance (AGT) and metabolic syndrome in the general population.
In a cross-sectional, population-based survey, a total of 4,622 subjects aged 45–74 years were invited to a health examination that included an oral glucose tolerance test. Full data with risk score estimate and glucose tolerance status were available for 2,966 subjects without a prior history of diabetes.
The risk score was associated with the presence of previously undiagnosed T2D, AGT, metabolic syndrome and cardiovascular risk factors. The area under the receiver operating curve for the prevalence of undiagnosed diabetes was 0.72 in men and 0.73 in women. The sensitivity using a cutoff risk score of 11 to identify undiagnosed diabetes was 66% in men and 70% in women; the corresponding false-positive rates were 31% and 39%, respectively. The area under the receiver operating curve for detecting the metabolic syndrome was 0.72 in men and 0.75 in women.
The Finnish Diabetes Risk Score can be used as a self-administered test to screen subjects at high risk for T2D. It can also be used in the general population and clinical practice to identify undetected T2D, AGT and the metabolic syndrome.

Diabetes Vasc Dis Res 2005;2:67-72.

ORIGINAL PAPERContrasting clinical and cardiovascular risk status between early and later onset type 2 diabetes
Mensud Hatunic, Nicole Burns, Francis Finucane, Cynthia Mannion, John J Nolan

The prevalence of type 2 diabetes (T2DM) is increasing rapidly and the age of presentation is falling. These changes are likely to be linked to the current obesity epidemic. Our objective was to compare the characteristics of younger patients with T2DM (diagnosed at age < 40 years) with those of older patients (diagnosed at age 50–70 years).
We identified 149 younger patients with T2DM, from our diabetes clinic database, and compared them with 217 older T2DM patients randomly identified from the same database.
Younger patients with T2DM were more obese, more hypertriglyceridaemic, with lower high-density lipoprotein (HDL) cholesterol, higher total cholesterol/HDL ratio and worse initial and ongoing glycaemic control than older patients from the same clinic. Additional cardiovascular risk factors are associated with T2DM in the young. Treatment should be aimed at early modification of lifestyle and other forms of therapy to avoid long-term complications.

Diabetes Vasc Dis Res 2005;2:73-75.

POPULAR
TOPICORIGINAL PAPERCells expressing the stem cell factor receptor, c-kit, contribute to neoangiogenesis in diabetes
Darren J Kelly, Yuan Zhang, Renae M Gow, Silviu Itescu, Richard E Gilbert

While neoangiogenesis in diabetes is of greatest clinical significance in the retina, the pathological formation of new blood vessels also develops in other vascular beds in diabetes, including the mesentery of the streptozotocin-induced diabetic rat. However, the contribution of bone marrow-derived cells to this process of vasculogenesis is unknown. In this study, male Sprague-Dawley rats were randomised to receive either streptozotocin or vehicle, and their mesenteric vasculature was examined after three weeks. Origins from bone marrow and endothelial cell differentiation were identified by immunolabelling for the stem cell factor receptor, c-kit and von Willebrand factor (vWF), respectively. Expression for the angiogenic chemokine, stromal derived factor-1 (SDF-1) was assessed by quantitative real-time polymerase chain reaction (PCR).
At three weeks, rats with diabetes had a dramatic (190-fold) increase in lectin-labelled blood vessel profiles in the mesenteric bed (p<0.0001) in association with a five-fold increase in SDF-1 mRNA (p<0.01). Immunohistochemical studies identified abundant large, ovoid, lumen-forming, c-kit+ cells in the mesentery of diabetic, but not control, rats. Many of these c-kit+ cells also showed positive immunolabelling for vWF, consistent with endothelial differentiation.
In conclusion, cells of bone marrow origin contribute to new vessel formation in the diabetic mesentery. This phenomenon may also apply to the neovascularisation that develops at clinically important sites such as in the retina.

Diabetes Vasc Dis Res 2005;2:76-80.

ORIGINAL PAPERElevated release of sCD40L from platelets of diabetic patients by thrombin, glucose and advanced glycation end products
Nerea Varo, Peter Libby, Rebecca Nuzzo, Joseph Italiano, Alessandro Doria, Uwe Schönbeck

The pro-inflammatory CD40/CD40L dyad participates in atherogenesis. Plasma levels of the soluble ligand (sCD40L) predict cardiovascular events and are elevated in diabetic patients. This study compared CD40/CD40L surface expression on platelets and T lymphocytes of diabetic and control subjects, and tested whether glucose and advanced glycation end products (AGEs) stimulate sCD40L release.
Constitutive and inducible surface expression of CD40/CD40L on platelets or T lymphocytes did not differ between diabetic patients (n=9) and controls (n=13). Platelets from diabetic patients contained higher intracellular CD40L than controls (p<0.05) and thrombin stimulated greater platelet sCD40L release in diabetic patients (15.11+16.77 ng/ml) compared to controls (3.64+2.03 ng/ml; p<0.05). Glucose and AGEs induced platelet sCD40L release and CD40L expression in mouse megakaryocytes.
This study demonstrates elevated CD40L content and inducible release from platelets of diabetic patients, and identifies glucose and AGEs as potential triggers of expression and release accounting for the elevated sCD40L plasma levels in these patients.

Diabetes Vasc Dis Res 2005;2:81-87.

ORIGINAL PAPERPlatelet nitrate responsiveness in fasting and postprandial type 2 diabetes
Richard A Anderson, Gethin R Ellis, L Marc Evans, Keith Morris, Yuri Y Chirkov, John D Horowitz, Simon K Jackson, Alan Rees, Malcolm J Lewis, Michael P Frenneaux

Vascular responsiveness to exogenous nitrates in type 2 diabetes (T2DM) is attenuated in brachial and coronary vessels. We determined platelet responsiveness to nitric oxide (NO) in T2DM and control subjects. We examined whether the postprandial (PP) state affected platelet sensitivity to NO donors in T2DM patients and the extent of correlation between this and measures of oxidative stress, compared to changes in endothelial function.
Twelve T2DM subjects were studied fasting and four hours after a test meal and compared with 15 healthy controls. We assessed the inhibitory effects of NO donors on adenosine 5’-diphosphate (ADP)-induced platelet aggregation. Oxidative stress was assessed by lipid-derived free radicals, ex vivo by electron paramagnetic resonance spectroscopy and markers of lipid peroxidation. Endothelial function was assessed by flow-mediated vasodilatation (FMD) of the brachial artery.
Results are expressed as (mean+SEM). Fasting platelet aggregation was increased in diabetics versus controls (14.86+1.1 Ohms vs. 10.76+1.1 Ohms, p<0.05). Sodium nitroprusside (SNP) and glyceryl trinitrate (GTN) inhibited ADP-induced aggregation by 73.1+5.9% and 50.3+7.7% in healthy controls compared to 15.4+7% and 19.5+8.2% in T2DM (p<0.05). Fasting and postprandial inhibition of platelet aggregation with NO donors in T2DM was similar. T2DM patients had higher levels of oxidative stress in the fasting state and postprandially. There were no PP correlations with platelet NO resistance.
In conclusion, there is platelet hyporesponsiveness to NO donors (SNP/GTN) in T2DM compared to controls, with increased ADP-induced platelet aggregation. Platelet abnormalities were associated with increased oxidative stress.

Diabetes Vasc Dis Res 2005;2:88-93.

LETTERLetter to the Editors
Michael Hannemann, David Mawson, Angela Shore

Diabetes Vasc Dis Res 2005;2:94-95.