Elevation of D-glucose impairs coronary artery autoregulation after slight reduction of coronary flow

Abstract. Diabetes mellitus is thought to increase the susceptibility of tissue to hypoxic injury through d-glucose-induced alterations of intracellular. metabolism. Therefore the effects of hyperglycaemia on coronary artery autoregulation under slight reduction of coronary flow were investigated in isolated perfused guinea-pig hearts. Under normal (10 mM) d-glucose concentrations coronary autoregulation was intact in response to a slight reduction of coronary flow (from 6 to 4.5 mL min^-1) when L-arginine as a precursor of the endothelium-derived relaxing factor (EDRF/NO) was available and formation of prosta-glandines was intact. Under high (44 mM) D-glucose concentrations on the other hand, a sustained vasodi-latation dependent on the availability of L-arginine was observed, when formation of prostaglandins was blocked. This effect was partially reduced in the presence of prostaglandin synthesis. Furthermore, the effect of L-arginine under both conditions could be antagonized by the L-arginine-analogue N A^G-nitro-L-arginine-methyl-ester (100 μm). Our results suggest that hyperglycaemia impairs coronary artery autoregulation by reducing the threshold for hypoxic vasodilatation in an EDRF/NO-dependent manner. Concomitantly a shift from the formation of vaso-dilatatory to vasoconstrictive prostaglandines was observed. These results might be of particular interest in patients with diabetes mellitus and ischaemic heart disease.     

The Modifying Effect of Spinal Anaesthesia on Intra- and Postoperative Adrenocortical and Hyperglycaemic Response to Surgery

Plasma cortisol and glucose were measured in 24 patients undergoing abdominal hysterectomy during spinal anaesthesia with 0.5% hyperbaric tetracaine or neurolept anaesthesia. The sensory level of analgesia to pinprick extended to at least T4 before skin incision in the spinal group. The mean sensory analgesic level regressed almost linearly, reaching the fourth lumbar segment 4 h after incision. Plasma cortisol and glucose measurements from before to 9 h after skin incision showed significant increases in both parameters during and after surgery. Plasma cortisol and glucose levels were significantly lower during and immediately after surgery in the spinal group, but later postoperatively the mean levels were similar in the two groups. The increase in plasma cortisol 1 h after skin incision in the spinal group correlated to the segmental level of analgesia at that time (r = 0.77, P less than 0.01) and a similar correlation was found with regard to plasma glucose changes (r = 0.60, P less than 0.05). The regression lines showed that maintenance of a sensory analgesic level about the fourth thoracic segment prevented the adrenocortical and hyperglycaemic response to surgery. These findings are in accordance with the anatomical assumption that the upper segmental level of visceral afferent input to the spinal cord is about the fourth thoracic segment. Our results further demonstrate that the inhibitory effect of spinal anaesthesia on the stress response to surgery is transient, and correlates to the regression of sensory analgesia.     

ECG COMPARED WITH MYOCARDIAL ULTRASTRUCTURE IN ANOXIC FOETUSES OF NORMAL AND HYPERGLYCAEMIC RABBITS

The heart function, as recorded by ECG, was correlated to the ultrastructural state of the myocardial cells. The material consisted of 4 rabbit mothers. Two were used as experimental animals, and were given 120 ml of 30% glucose solution intravenously on the 29th day of pregnancy. The other two served as controls. After the infusion, the rabbits were sacrificed, and their foetuses removed by laparotomy. One foetus was placed in a paraffin bath at 37°C for ECG recording, and the others were placed in physiological saline. The two parameters, i. e., ECG and ultrastructural state of the myocardial cells, were correlated at various times. Pathological changes in the ECG were found to be reflected in ultrastructural changes in the cells. These changes were similar in the experimental animals and in the controls, but occurred earlier in the latter animals than in the former.     

Hyperglycaemia is associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease

BACKGROUND: Hyperglycaemia is associated with poor outcomes from pneumonia, myocardial infarction and stroke, but the effect of blood glucose on outcomes from acute exacerbations of chronic obstructive pulmonary disease (AECOPD) has not been established. Recent UK guidelines do not comment on measurement or control of blood glucose in AECOPD. A study was therefore undertaken to determine the relationship between blood glucose concentrations, length of stay in hospital, and mortality in patients admitted with AECOPD. METHODS: Data were retrieved from electronic records for patients admitted with AECOPD with lower respiratory tract infection in 2001-2. The patients were grouped according to blood glucose quartile (group 1, <6 mmol/l (n = 69); group 2, 6.0-6.9 mmol/l (n = 69); group 3, 7.0-8.9 mmol/l (n = 75); and group 4, >9.0 mmol/l (n = 71)). RESULTS: The relative risk (RR) of death or long inpatient stay was significantly increased in group 3 (RR 1.46, 95% CI 1.05 to 2.02, p = 0.02) and group 4 (RR 1.97, 95% CI 1.33 to 2.92, p < 0.0001) compared with group 1. For each 1 mmol/l increase in blood glucose the absolute risk of adverse outcomes increased by 15% (95% CI 4 to 27), p = 0.006. The risk of adverse outcomes increased with increasing hyperglycaemia independent of age, sex, a previous diagnosis of diabetes, and COPD severity. Isolation of multiple pathogens and Staphylococcus aureus from sputum also increased with increasing blood glucose. CONCLUSION: Increasing blood glucose concentrations are associated with adverse clinical outcomes in patients with AECOPD. Tight control of blood glucose reduces mortality in patients in intensive care or following myocardial infarction. A prospective study is now required to determine whether control of blood glucose can also improve outcomes from AECOPD.     

Plasma vasopressin during insulin withdrawal in insulin-dependent diabetes

Summary Plasma vasopressin was measured in seven insulin-treated diabetics during 24 h of insulin withdrawal to determine: 1) if abnormalities of the neurohypophysial-renal axis contribute to the dehydration of uncontrolled diabetes mellitus; and 2) the factors causing elevated levels of vasopressin in diabetic ketoacidosis. During the 24 h period of insulin withdrawal, blood glucose rose from 6.7±1.0 to 20.7±2.4 mmol/l, whereas plasma vasopressin was 3.6±0.5 pg/ml initially and in four patients showed little change. Markedly elevated levels of plasma vasopressin (17.8, 19.8 and 26.6 pg/ml) were observed in three patients following the onset of hypovolaemia, nausea and/or vomiting which are known to stimulate vasopressin release. Free water clearance was negative throughout the study in all patients. Thirst was not noted despite marked hyperglycaemia (16.9±2.5 mmol/l) until a significant fall in body weight of 0.9±0.2 kg had occurred (p<0.005). We conclude that marked elevation of vasopressin results from non-osmotic stimulation and that the mechanisms of body water conservation are overridden by the glycosuric diuresis.     

Effects of S21403 (mitiglinide) on postprandial generation of oxidative stress and inflammation in type 2 diabetic patients

Aim/hypothesis Evidence suggests that postprandial hyperglycaemia may be a cardiovascular risk factor in diabetes. Oxidative stress and inflammation are involved in the pathogenesis of diabetic complications and previous studies have shown increased oxidative stress and inflammation in the postprandial phase in diabetic patients. The aim of the present study was to evaluate whether controlling postprandial hyperglycaemia with S21403 (mitiglinide) is accompanied by a reduced generation of oxidative stress and inflammation.Subjects and methods Forty type 2 diabetic patients participated in the study. Two different breakfast-tests were performed in each patient, with placebo or S21403. Plasma nitrotyrosine, plasma malondialdehyde (MDA), oxidised LDL (oxLDL), plasma total radical-trapping antioxidant parameter (TRAP), IL-6, IL-18, TNF-, plasma glucose and insulin were measured.Results After the administration of S21403, 40 mg, a rapid stimulation of insulin secretion was observed, accompanied by a reduction of postprandial hyperglycaemia. With S21403, a significant decrease of either nitrotyrosine, MDA and oxLDL levels, and a preservation of plasma TRAP compared with placebo was found. Significant decreases of IL-6, IL-18 and TNF- were also observed with S21403 compared with placebo.Conclusions/interpretation This study shows that controlling postprandial hyperglycaemia with S21403 significantly improves the cluster of oxidative stress and inflammation markers that are increased in the postprandial state in diabetic patients.     

Antioxidants attenuate hyperglycaemia-mediated brain endothelial cell dysfunction and blood–brain barrier hyperpermeability

Aims:  Hyperglycaemia (HG), in stroke patients, is associated with worse neurological outcome by compromising endothelial cell function and the blood–brain barrier (BBB) integrity. We have studied the contribution of HG-mediated generation of oxidative stress to these pathologies and examined whether antioxidants as well as normalization of glucose levels following hyperglycaemic insult reverse these phenomena.
Methods:  Human brain microvascular endothelial cell (HBMEC) and human astrocyte co-cultures were used to simulate the human BBB. The integrity of the BBB was measured by transendothelial electrical resistance using STX electrodes and an EVOM resistance meter, while enzyme activities were measured by specific spectrophotometric assays.
Results:  After 5 days of hyperglycaemic insult, there was a significant increase in BBB permeability that was reversed by glucose normalization. Co-treatment of cells with HG and a number of antioxidants including vitamin C, free radical scavengers and antioxidant enzymes including catalase and superoxide dismutase mimetics attenuated the detrimental effects of HG. Inhibition of p38 mitogen-activated protein kinase (p38MAPK) and protein kinase C but not phosphoinositide 3 kinase (PI3 kinase) also reversed HG-induced BBB hyperpermeability. In HBMEC, HG enhanced pro-oxidant (NAD(P)H oxidase) enzyme activity and expression that were normalized by reverting to normoglycaemia.
Conclusions:  HG impairs brain microvascular endothelial function through involvements of oxidative stress and several signal transduction pathways.     

Diabetes mellitus and stroke

The aim of this article was to describe (i) the epidemiology and outcomes of stroke relating to diabetes; (ii) the pathophysiology of diabetes as a risk factor for stroke; (iii) the management of acute stroke in patients with diabetes; (iv) the evidence of primary and secondary prevention of stroke in patients with diabetes; and (v) the risk of new-onset diabetes using older antihypertensive agents. The combination of diabetes and stroke disease is a major cause of morbidity and mortality worldwide. Evidence from large clinical trials performed in patients with diabetes supports the need for aggressive and early intervention to target patients' cardiovascular (CV) risks in order to prevent the onset, recurrence and progression of acute stroke. Identification of at-risk patients with diabetes and metabolic syndrome has also allowed the delivery of early and effective intervention to reduce stroke risks, while active treatment during the acute phase of stroke will reduce long-term neurological and functional deficits. While the ongoing debate on the risk benefits of different antihypertensive, lipid-lowering and antiplatelet agents should not detract clinicians from pursuing aggressive CV risk reduction, the application of evidence-based medicine specifically in patients with diabetes will facilitate the use of appropriate agents to improve clinical outcomes. The overall management of patients with diabetes and acute stroke or at risk of secondary stroke should also include multifactorial intervention that not only targets patient's CV risk but also includes behavioural, lifestyle and, where appropriate, surgical intervention.     

Addressing the burden of type 2 diabetes and cardiovascular disease through the management of postprandial hyperglycaemia: an Asian-Pacific perspective and expert recommendations

The world is facing an epidemic of cardiovascular disease (CVD) and type 2 diabetes, with populations in low- to middle-income countries, including many in the Asia Pacific (AP) region, being disproportionately affected. Emerging data identify postprandial hyperglycaemia (PPHG) as an important predictor of CVD, and several professional bodies, including the International Diabetes Federation, have issued guidelines on the management of PPHG in type 2 diabetes. Guidance on how international recommendations could be implemented in Asian populations is currently lacking. Therefore, a panel of experts from the AP region convened to consider the current status of PPHG and CVD in the region, and to develop recommendations for clinical practice. The group concluded that improved awareness of the impact of PPHG on CVD risk, among clinicians and the general public, and more widespread use of routine screening for PPHG, using oral glucose tolerance testing in those without recognised diabetes, are required. Additionally, frequent meal-based testing and effective PPHG management are essential to the management of IGT and type 2 diabetes.