Volume 2, Number 1, February 2005

POPULAR
TOPICEDITORIALDiabetes mellitus and vascular risk: continuing the quest for the elusive keystone
Steven P Marso

Diabetes Vasc Dis Res 2005;2:7-8.

POPULAR
TOPICREVIEWImpaired glucose tolerance and impaired fasting glucose – a review of diagnosis, clinical implications and management
John L Petersen, Darren K Mcguire

The diagnostic categories of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) were established in an effort to identify populations at risk for developing type 2 diabetes mellitus (T2DM). Both IGT and IFG are associated with increased risk of developing T2DM, but recent analyses found that the thresholds of risk vary among different populations and an even lower diagnostic threshold of IFG may be appropriate. IGT has been linked with an increased risk of cardiovascular events and some analyses have demonstrated an increased mortality risk compared with patients with normal glucose tolerance. In contrast, a continuum of increased risk of microvascular manifestations of T2DM has been demonstrated with IFG but an association of IFG with cardiovascular events has not been well established.
Although both IGT and IFG are associated with resistance to insulin and increased insulin secretion, they do not identify the identical patient populations and are not equivalent in predicting development of T2DM or cardiovascular events. IFG and IGT have been associated with other features of insulin resistance, including dyslipidaemia, hypertension, abdominal obesity, microalbuminuria, endothelial dysfunction, and markers of inflammation and hypercoagulability, traits collectively referred to as the metabolic syndrome. Analyses of combinations of these components have also been associated with progression to T2DM, cardiovascular disease and increased mortality.
The foundation of treatment for IGT, IFG, and the metabolic syndrome is lifestyle modification, including both dietary change and routine exercise. To date, several clinical trials have found that lifestyle modification is the most efficacious strategy to prevent progression to T2DM. Alternative treatments include pharmacotherapy with metformin or acarbose, both of which have been demonstrated to decrease the development of T2DM. Ongoing clinical trials are evaluating newer pharmaco-therapies, including angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, metglitinides and thiazolidinediones, to prevent both T2DM and cardiovascular events. In combination with lifestyle modification, these therapies offer hope for effective prevention of T2DM and its consequences in high-risk patients.

Diabetes Vasc Dis Res 2005;2:9-15.

POPULAR
TOPICREVIEWPathobiology and cell interactions of platelets in diabetes
Bernd Stratmann, Diethelm Tschoepe

Diabetes is a well-recognised risk factor for atherosclerotic cardiovascular disease and in fact most diabetic patients die from vascular complications. The Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS) indicate a consistent relationship between hyperglycaemia and the incidence of chronic vascular complications in patients with diabetes.1,2 Platelets are essential for haemostasis, and abnormalities of platelet function may cause vascular disease in diabetes. Diabetic patients have hyperreactive platelets with exaggerated adhesion, aggregation and thrombin generation. In summary, the entire coagulation cascade is dysfunctional in diabetes.
This review provides a comprehensive overview of the physiological role of platelets in maintaining haemostasis and of the pathophysiological processes that contribute to platelet dysfunction in diabetes and associated cardiovascular diseases, with special emphasis on proteomic approaches and leukocyte-platelet cross-talk.

Diabetes Vasc Dis Res 2005;2:16-23.

ORIGINAL PAPERTissue Doppler imaging for the detection and quantitation of myocardial dysfunction in patients with type 2 diabetes mellitus
Helene von Bibra, Inga S Thrainsdottir, Alexander Hansen, Vasilios Dounis, Klas Malmberg, Lars Rydén

The prevalence of type 2 diabetes mellitus is rapidly increasing. Myocardial dysfunction may be a consequence of diabetic cardiomyopathy and it contributes to the poor prognosis of diabetic patients.
Aims: This study was designed to test whether tissue Doppler imaging might be a suitable tool for early detection of myocardial dysfunction in diabetic patients.
Methods: Forty-three diabetic patients and 33 non-diabetic controls, including age-matched subgroups without evidence of coronary artery disease (n=12), were recruited if they had normal LV-function by standard 2-D echocardiography and no clinical signs of heart failure. They were investigated with tissue Doppler imaging at rest and during pharmacological stress with dipyridamole and/or dobutamine. Myocardial function was calculated as the mean value from six basal myocardial segments for peak velocity at systole (Vs), early diastole (Ve) and atrial contraction (Va).
Results: Compared to controls, diabetic patients had compromised Ve at rest (8.5+1.7 vs. 9.6+1.9 cm/sec, p<0.02), as did the subgroups without coronary artery disease (9.3+1.7 vs. 10.7±1.5 cm/sec, p<0.05). Dobutamine stress resulted in lower Vs (10.7+2.7 vs. 13.6+3.4 cm/sec, p<0.05) and Ve (10.0+2.1 vs. 13.1+3.8 cm/sec, p<0.05) in the diabetic patients, demonstrating an impaired increase of Vs, Vd and Va (p<0.05, p<0.0003 and p<0.03, respectively). An inverse correlation was observed between Ve and age in both control and diabetic individuals. Thus, abnormal values were defined in relation to age.
Conclusions: Diastolic and systolic myocardial dysfunction in patients with type 2 diabetes may be identified by quantitative tissue Doppler imaging before the onset of clinical signs of heart failure and before the appearance of traditional echocardiographic indices of systolic myocardial dysfunction.

Diabetes Vasc Dis Res 2005;2:24-30.

ORIGINAL PAPERMetabolic syndrome-mediated inflammation following elective percutaneous coronary intervention
Steven P Marso, Joseph W Murphy, John A House, David M Safley, William S Harris

There are few data concerning the relationship between diabetes mellitus, the metabolic syndrome and inflammation following elective percutaneous coronary intervention (PCI). The purpose of this study was to assess basal and peak levels of candidate cytokines in 40 patients undergoing elective PCI. Patients were categorised as having diabetes mellitus, the metabolic syndrome, or neither.
Patients with the metabolic syndrome exhibited significantly greater levels of tumour necrosis factor-a over the study period, although this was unrelated to PCI. There was a trend for increased levels of interleukin-6 following PCI, primarily among patients with metabolic syndrome. Basal levels of monocyte chemoattractant protein-1 (MCP-1) were not different among study groups; however, the metabolic syndrome cohort had a trend towards increased circulating levels of MCP-1 after PCI. In this patient population, the metabolic syndrome correlates with a heightened inflammatory response following elective PCI.

Diabetes Vasc Dis Res 2005;2:31-36.

POPULAR
TOPICORIGINAL PAPEREffect of rosiglitazone treatment on circulating vascular and inflammatory markers in insulin-resistant subjects
James W Chu, Fahim Abbasi, Cynthia Lamendola, Tracey Mclaughlin, Gerald M Reaven, Philip S Tsao

Thiazolidinedione (TZD) compounds enhance insulin sensitivity and attenuate inflammation. The effect of the TZD compound, rosiglitazone (RSG) on both actions was evaluated in two groups of insulin-resistant subjects with minimal elevations of fasting plasma glucose (PG) concentration: group A (n=15, PG < 7.0 mmol/L) and group B (n=14, PG 7.0–8.3 mmol/L). Insulin action, quantified by the insulin suppression test, improved after three months of treatment in both groups, and concentrations of C-reactive protein, plasminogen activator inhibitor-1 and E-selectin all fell. Significant decreases in L-selectin and P-selectin were confined to group B, and concentrations of interleukin-6, intercellular adhesion molecule-1 and vascular cellular adhesion molecule-1 did not fall in either group.
Significant relationships were not discerned between enhanced insulin sensitivity and related variables and decreases in inflammatory/vascular markers, suggesting that RSG-induced changes in the latter variables in insulin-resistant individuals might be at least partly independent of the effects of the drug on insulin action.

Diabetes Vasc Dis Res 2005;2:37-41.

ORIGINAL PAPERRAGE polymorphisms and the heritability of insulin resistance: the Leeds Family Study
Clair M Sullivan, T Simon Futers, Jennifer H Barrett, Barry I Hudson, Mark S Freeman, Peter J Grant

Activation of the receptor for advanced glycation end-products (RAGE) leads to a cascade of pro-inflammatory and pro-coagulant responses which are important in the pathogenesis of the vascular complications of diabetes mellitus. It is known that pro-inflammatory mechanisms underpin the development of type 2 diabetes. Our hypothesis is that RAGE may be involved in the evolution of insulin resistance in addition to mediating glucotoxic complications of diabetes mellitus.
Methods: To investigate the relationship between RAGE allelic variation and insulin resistance, the Gly82Ser variant and three promoter variants (–429, –374, 63 bp deletion) were studied in 480 subjects of known relationship from 89 families characterised for insulin resistance (using homeostasis model assessment [HOMA]) and for atherothrombotic risk. Carriage of the –429 C allele was weakly associated with increased insulin resistance (p=0.02) when pedigree analysis was performed using SOLAR software.
Results: Insulin resistance was estimated to have a heritability of 25.8% before the addition of covariates. Analysis of the relationship between RAGE and insulin resistance indicated that the –429 polymorphism reduced the unexplained heritability of insulin resistance after adjusting for covariates (age, sex, body mass index) from 17.5% of the total variance to 15.6% of the total variance.
Conclusions: These preliminary results indicate that the RAGE gene may affect the development of insulin resistance or be in linkage disequilibrium with a locus involved in this process.

Diabetes Vasc Dis Res 2005;2:42-44.