Treating dyslipidaemia in the setting of diabetes mellitus and cardiovascular disease: a less commonly perceived therapeutic perspective in clinical practice.

Diabetes mellitus and cardiovascular disease are being managed more belligerently in recent times, with multifactorial cardiovascular risk reduction being the focus of therapeutic interventions. We review some of the caveats to be exercised in the treatment of these patients that are pertinent to clinicians in daily clinical practice.

An assessment of the coverage of a district-wide diabetic retinopathy screening service.

AIMS: To assess the coverage of the diabetes retinopathy screening service (DRSS) in North Staffordshire, to identify patient characteristies associated with non-attendance and to assess the proportion of patients with diabetic retinopathy who achieved glycaemic and blood pressure (BP) control targets. METHODS: Data for all patients who underwent annual retinal screening between 1 May 2000 and 30 April 2001 were obtained from the North Staffordshire Diabetes Register. Age, gender, ethnicity, socio-economic status, type and duration of diabetes were compared between patients who underwent eye screening and those who did not. Frequencies of patients who achieved glycaemic and BP targets in these groups of patients were compared to the remaining patients. RESULTS: 5646 of the 11682 (48%) patients on the diabetes register underwent retinal screening during the year. Patients with Type 2 diabetes, older patients, patients belonging to ethnic minorities and those wholly managed in primary care were less likely to attend for eye screening (P < 0.05 for all groups) with ethnic minority or primary care management demonstrating independent influence (P < 0.001). The percentage of patients with retinopathy achieving HbA1c and systolic BP targets was significantly lower than in their unaffected counterparts (chi2 = 63, P < 0.001 and chi2 = 71, P < 0.001 respectively). CONCLUSIONS: The efficacy of the DRSS in North Staffordshire is low and might be improved by targeting specific patient groups. Glycaemic control and systolic BP control needs to be improved in patients with diabetic retinopathy.

A case of thoracic aortic dissection presenting as lateral pleuritic chest pain.

An unusual presentation of thoracic aortic dissection in a 73 year old man is described. He was admitted to hospital with severe left sided pleuritic chest pain. Examination on admission was normal apart from minor tenderness on palpation of the left lower chest wall. Chest x ray showed cardiomegaly with right lung shadowing, and ventilation/perfusion scan was negative. Spiral computed tomography done on the fourth day showed a false lumen on the ascending aorta. He underwent surgery but deteriorated postoperatively because of intrathoracic bleeding and developed cardiac tamponade from which resuscitation was not possible.

Evidence that protein kinase Cdelta is not required for palmitate-induced cytotoxicity in BRIN-BD11 beta-cells.

Chronic exposure of pancreatic beta-cells to saturated fatty acids leads to loss of viability, an effect that has been implicated in the process of beta-cell 'lipotoxicity' associated with the progression of type 2 diabetes. The mechanisms involved are unknown but recent evidence has implicated the delta isoform of protein kinase C (PKCdelta) in mediating fatty acid toxicity. We have investigated this proposition in the clonal insulin-secreting cell line, BRIN-BD11. BRIN-BD11 cells were found to undergo apoptosis when exposed to palmitate and this response was attenuated by the purportedly selective inhibitor of PKCdelta, rottlerin. However, activation of PKCdelta with the phorbol ester, phorbol-12-myristate-13-acetate (PMA), failed to promote cell death and down-regulation of PKCdelta did not prevent the cytotoxic effects of palmitate. Moreover, rottlerin remained effective as a blocker of the palmitate response in cells depleted of PKCdelta. Since rottlerin can inhibit various other kinases in addition to PKCdelta, a range of additional kinase inhibitors was also tested. Of these, only the putative Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) inhibitor, KN-62, was found to inhibit palmitate-induced cell death. However, this effect was not reproduced by a more selective pseudo-substrate inhibitor of CaM kinase II. Therefore, the present results reveal that palmitate induces cell death in BRIN-BD11 cells and suggest that this may involve the activation of a rottlerin (and KN-62)-sensitive kinase. However, it is clear that PKCdelta is not required for this response.

Improving survival with metformin: the evidence base today.

Establishing and maintaining control of glycaemia is a key step in the reduction of diabetic microvascular complications. By contrast, macrovascular disease which is the most important complication and shortens the lives of many people with type 2 diabetes is not reduced by glycaemic control alone. The landmark UK Prospective Diabetes Study (UKPDS) showed that intensive glycaemic management with metformin significantly reduced the risk of a range of debilitating and/or life-threatening macrovascular complications, compared with other oral agents, diet and insulin who achieved similar overall glycaemic control. The benefits observed included diabetes-related mortality (reduced by 42%, compared with diet treatment, p=0.017), all-cause mortality (reduced by 36%, p=0.011), myocardial infarction (reduced by 39%, p=0.01), and any diabetes-related endpoint (reduced by 32%, p=0.002). Other clinical and experimental studies have shown metformin to be associated with improved outcomes and support the conclusions from the UKPDS. In addition, a well-designed retrospective analysis has shown significantly lower mortality rates in patients receiving metformin compared with patients treated with sulphonylurea monotherapy. Metformin provides a greater degree of cardiovascular protection than would be expected from its antihyperglycaemic actions alone and is the first drug of choice for the treatment of type 2 diabetes unless there are contraindications in the individual patient.

Differential effects of genistein on apoptosis induced by fluoride and pertussis toxin in human and rat pancreatic islets and RINm5F cells.

Clonal pancreatic beta-cell lines have been used widely for the study of the factors involved in the regulation of apoptosis but it has not been firmly established that the response of normal islets mirrors that found in transformed beta-cells. In the present work, the role of pertussis toxin (Ptx)-sensitive G-proteins in the control of beta-cell apoptosis was studied in isolated rat and human islets of Langerhans and compared with the clonal beta-cell line, RINm5F. Annexin-V and deoxycarboxyfluoroscein diacetate staining was used to identify viable, apoptotic and necrotic cells directly, under fluorescence illumination. Treatment of human and rat islet cells with the G-protein activator fluoride (NaF; 5 mM) caused a marked increase in apoptosis that was further potentiated in islets pretreated with Ptx. The tyrosine kinase inhibitor genistein (100 microM) also increased islet cell apoptosis and the combination of 100 microM genistein and 5 mM NaF did not lead to any diminution of the apoptotic response. This latter effect was quite different from that seen in RINm5F cells where the combination of 100 microM genistein and 5 mM NaF resulted in much less apoptosis than was observed with either agent alone. In islets treated with a lower concentration of genistein (25 microM; that did not, itself, increase cell death), the drug attenuated NaF-induced apoptosis and also blocked the enhancement mediated by Ptx. These results revealed that human (and rat) islets are equipped with a Ptx-sensitive pathway that may be regulated by tyrosine phosphorylation and is anti-apoptotic. However, they also define conditions under which marked differences in response between RINm5F cells and normal islets were observed and they suggest that care should be taken when extrapolating data obtained with clonal cell lines to the situation in normal islet cells.