Impact of admission glucose and diabetes on recanalization and outcome after intra-arterial thrombolysis for ischaemic stroke

BACKGROUND: Stroke patients with diabetes and admission hyperglycaemia have worse outcomes than non-diabetics, with or without intravenous thrombolysis. Poor vessel recanalization was reported in diabetics treated with intravenous thrombolysis. AIMS: This study aimed to determine the impact of admission glucose and diabetes on recanalization and outcome after intra-arterial thrombolysis. METHODS: We analysed 389 patients (213 men, 176 women) treated with intra-arterial thrombolysis. The association of diabetes and admission glucose value with recanalization, outcome, mortality, and symptomatic intracranial haemorrhage was determined. Recanalization was classified according to thrombolysis in myocardial infarction grades. Outcome was measured using the modified Rankin Scale at three-months and categorized as favourable (modified Rankin Scale 0-2) or poor (modified Rankin Scale 3-6). RESULTS: The rate of partial or complete recanalization (thrombolysis in myocardial infarction 2-3) did not differ between patients with and without diabetes (67% vs. 66%; P = 1·000). Mean admission glucose values were similar in patients with poor recanalization (thrombolysis in myocardial infarction 0-1) and patients with partial or complete recanalization (thrombolysis in myocardial infarction 2-3; 7·3 vs. 7·3 mmol/l; P = 0·746). Follow-up at three-months was obtained in 388 of 389 patients. Clinical outcome was favourable (modified Rankin Scale 0-2) in 189 patients (49%) and poor (modified Rankin Scale 3-6) in 199 patients (51%). Mortality at three-months was 20%. Diabetics were more likely to have poor outcome (72% vs. 48%; P = 0·001) and to be dead (30% vs. 19%; P = 0·044) at three-months. After multivariable analysis, there remained an independent relationship between diabetes and outcome (P = 0·003; odds ratio 3·033, 95% confidence interval 1·452-6·336), but not with mortality (P = 0·310; odds ratio 1·436; 95% confidence interval 0·714-2·888). Moreover, higher age (P = 0·001; odds ratio 1·039; 95% confidence interval 1·017-1·061), higher baseline National Institutes of Health Stroke Scale score (P < 0·0001; odds ratio 1·130; 95% confidence interval 1·079-1·182), location of vessel occlusion as categorical variable (P < 0·0001), poor collaterals (P = 0·02; odds ratio 1·587; 95% confidence interval 1·076-2·341), poor vessel recanalization (P < 0·0001; odds ratio 4·713; 95% confidence interval 2·627-8·454), and higher leucocyte count (P = 0·032; odds ratio 1·094; 95% confidence interval 1·008-1·188) were independent baseline predictors of poor outcome. Higher admission glucose was associated with poor outcome (P = 0·006) and mortality (P < 0·0001). After multivariate analyses, glucose remained independently associated with poor outcome (P = 0·019; odds ratio 1·150; 95% confidence interval 1·023-1-292) and mortality (P = 0·005; odds ratio 1·183; 95% confidence interval 1052-1·331). The rate of symptomatic intracranial haemorrhage was similar in diabetics and non-diabetics (6·7% vs. 4·6%; P = 0·512). Mean admission glucose was higher in patients with symptomatic intracranial haemorrhage than without (8·58 vs. 7·26 mmol/l; P = 0·010). Multivariable analysis confirmed an independent association between admission glucose and symptomatic intracranial haemorrhage (P = 0·027; odds ratio 1·187; 95% confidence interval 1·020-1·381). CONCLUSIONS: Diabetes and glucose value on admission did not influence recanalization after intra-arterial thrombolysis; nevertheless, they were independent predictors of poor outcome after intra-arterial thrombolysis and a higher admission glucose value was an independent predictor of symptomatic intracranial haemorrhage. This indicates that factors on the capillary, cellular, or metabolic level may account for the worse outcome in patients with elevated glucose value and diabetes.

Induced hypoglycemia for 48 hours indicates differential glucose and insulin effects on liver metabolism in dairy cows

Hypoglycemia is a characteristic condition of early lactation dairy cows and is subsequently dependent on, and may affect, metabolism in the liver. The objective of the present study was to investigate the effects of induced hypoglycemia, maintained for 48 h, on metabolic parameters in plasma and liver of mid-lactation dairy cows. The experiment involved 3 treatments, including a hyperinsulinemic hypoglycemic clamp (HypoG, n=6) to obtain a glucose concentration of 2.5 mmol/L, a hyperinsulinemic euglycemic clamp (EuG, n=6) in which the effect of insulin was studied, and a control treatment with a 0.9% saline solution (NaCl, n=6). Blood samples for measurements of insulin, metabolites, and enzymes were taken at least once per hour. Milk yield was recorded and milk samples were collected before and after treatment. Liver biopsies were obtained before and after treatment to measure mRNA abundance by real-time, quantitative reverse transcription-PCR of 12 candidate genes involved in the main metabolic pathways. Milk yield decreased in HypoG and NaCl cows, whereas it remained unaffected in EuG cows. Energy-corrected milk yield (kg/d) was only decreased in HypoG cows. In plasma, concentration of beta-hydroxybutyrate decreased in response to treatment in EuG cows and was lower (0.41+/-0.04 mmol/L) on d 2 of the treatment compared with that in HypoG and NaCl cows (on average 0.61+/-0.03 mmol/L, respectively). Nonesterified fatty acids remained unaffected in all treatments. In the liver, differences between treatments for their effects were only observed in case of mitochondrial phosphoenolpyruvate carboxykinase (PEPCKm) and glucose-6-phosphatase (G6PC). In HypoG, mRNA abundance of PEPCKm was upregulated, whereas in EuG and NaCl cows, it was downregulated. The EuG treatment downregulated mRNA expression of G6PC, a marked effect compared with the unchanged transcript expression in NaCl. The mRNA abundance of the insulin receptor remained unaffected in all treatments, and no significant treatment differences were observed for genes related to lipid metabolism. In conclusion, low glucose concentrations in dairy cows affect liver metabolism at a molecular level through upregulation of PEPCKm mRNA abundance. Metabolic regulatory events in the liver are directed, apart from hormones, by the level of metabolites, either in excess (e.g., free fatty acids) or in shortage (e.g., glucose).

Exercise capacity in subjects with type 1 diabetes mellitus in eu- and hyperglycaemia

Circumstantial evidence suggests that an increase in plasma glucose availability improves exercise capacity in subjects with type 1 diabetes mellitus. The aim of this study was to assess exercise capacity in eu- and hyperglycaemic conditions in subjects with type 1 diabetes.

Endothelin A-receptor blockade in experimental diabetes improves glucose balance and gastrointestinal function

Secondary complications of diabetes mellitus often involve gastrointestinal dysfunction. In the experimental Goto Kakizaki rat, a model of Type II diabetes, hyperglycaemia and reduced glucose clearance is associated with elevated plasma endothelin (ET)-1 levels and selective decreases in nitric oxide synthase in circular muscle, longitudinal muscle and neuronal elements of the gastrointestinal tract. Functionally, this is accompanied by decreased nitrergic relaxatory responses of jejunal longitudinal muscle to tetrodotoxin-sensitive electrical field stimulation. Long-term treatment with a selective ET A-type receptor antagonist, markedly reduced hyperglycaemia and restored plasma glucose clearance rates towards normal. This was associated with a restoration of N(G)-nitro-L-arginine methyl ester-sensitive relaxatory responses of jejunal longitudinal muscle to electrical field stimulation. The results indicate that beneficial effects of ETA receptor blockade on gastrointestinal function may result from an improvement in insulin sensitivity with concomitant reduction of the severity of hyperglycaemia. ETA receptor blockade may represent a new therapeutic principle for improving glucose tolerance in Type II diabetes and could be beneficial in alleviating or preventing hyperglycaemia-related secondary complications in this condition.

Influence of oxygen therapy on glucose-lactate metabolism after diffuse brain injury

OBJECT: Severe traumatic brain injury (TBI) imposes a huge metabolic load on brain tissue, which can be summarized initially as a state of hypermetabolism and hyperglycolysis. In experiments O2 consumption has been shown to increase early after trauma, especially in the presence of high lactate levels and forced O2 availability. In recent clinical studies the effect of increasing O2 availability on brain metabolism has been analyzed. By their nature, however, clinical trauma models suffer from a heterogeneous injury distribution. The aim of this study was to analyze, in a standardized diffuse brain injury model, the effect of increasing the fraction of inspired O2 on brain glucose and lactate levels, and to compare this effect with the metabolism of the noninjured sham-operated brain. METHODS: A diffuse severe TBI model developed by Foda and Maramarou, et al., in which a 420-g weight is dropped from a height of 2 m was used in this study. Forty-one male Wistar rats each weighing approximately 300 g were included. Anesthesized rats were monitored by placing a femoral arterial line for blood pressure and blood was drawn for a blood gas analysis. Two time periods were defined: Period A was defined as preinjury and Period B as postinjury. During Period B two levels of fraction of inspired oxygen (FiO2) were studied: air (FiO2 0.21) and oxygen (FiO2 1). Four groups were studied including sham-operated animals: air-air-sham (AAS); air-O2-sham (AOS); air-air-trauma (AAT); and air-O2-trauma (AOT). In six rats the effect of increasing the FiO2 on serum glucose and lactate was analyzed. During Period B lactate values in the brain determined using microdialysis were significantly lower (p < 0.05) in the AOT group than in the AAT group and glucose values in the brain determined using microdialysis were significantly higher (p < 0.04). No differences were demonstrated in the other groups. Increasing the FiO2 had no significant effect on the serum levels of glucose and lactate. CONCLUSIONS: Increasing the FiO2 influences dialysate glucose and lactate levels in injured brain tissue. Using an FiO2 of 1 influences brain metabolism in such a way that lactate is significantly reduced and glucose significantly increased. No changes in dialysate glucose and lactate values were found in the noninjured brain.

Fuel metabolism during exercise in euglycaemia and hyperglycaemia in patients with type 1 diabetes mellitus--a prospective single-blinded randomised crossover trial

We assessed systemic and local muscle fuel metabolism during aerobic exercise in patients with type 1 diabetes at euglycaemia and hyperglycaemia with identical insulin levels.

Reduced beta-cell mass and altered glucose sensing impair insulin-secretory function in betaIRKO mice

Pancreatic beta-cell-restricted knockout of the insulin receptor results in hyperglycemia due to impaired insulin secretion, suggesting that this cell is an important target of insulin action. The present studies were undertaken in beta-cell insulin receptor knockout (betaIRKO) mice to define the mechanisms underlying the defect in insulin secretion. On the basis of responses to intraperitoneal glucose, approximately 7-mo-old betaIRKO mice were either diabetic (25%) or normally glucose tolerant (75%). Total insulin content was profoundly reduced in pancreata of mutant mice compared with controls. Both groups also exhibited reduced beta-cell mass and islet number. However, insulin mRNA and protein were similar in islets of diabetic and normoglycemic betaIRKO mice compared with controls. Insulin secretion in response to insulin secretagogues from the isolated perfused pancreas was markedly reduced in the diabetic betaIRKOs and to a lesser degree in the nondiabetic betaIRKO group. Pancreatic islets of nondiabetic betaIRKO animals also exhibited defects in glyceraldehyde- and KCl-stimulated insulin release that were milder than in the diabetic animals. Gene expression analysis of islets revealed a modest reduction of GLUT2 and glucokinase gene expression in both the nondiabetic and diabetic mutants. Taken together, these data indicate that loss of functional receptors for insulin in beta-cells leads primarily to profound defects in postnatal beta-cell growth. In addition, altered glucose sensing may also contribute to defective insulin secretion in mutant animals that develop diabetes.

Self-monitoring of blood glucose in non-insulin treated patients with type 2 diabetes: a systematic review and meta-analysis

To assess the effect of self-monitoring of blood glucose (SMBG) on glycaemic control in non-insulin treated patients with type 2 diabetes by means of a systematic review and meta-analysis.

Differential influence of arterial blood glucose on cerebral metabolism following severe traumatic brain injury

INTRODUCTION: Maintaining arterial blood glucose within tight limits is beneficial in critically ill patients. Upper and lower limits of detrimental blood glucose levels must be determined. METHODS: In 69 patients with severe traumatic brain injury (TBI), cerebral metabolism was monitored by assessing changes in arterial and jugular venous blood at normocarbia (partial arterial pressure of carbon dioxide (paCO2) 4.4 to 5.6 kPa), normoxia (partial arterial pressure of oxygen (paO2) 9 to 20 kPa), stable haematocrit (27 to 36%), brain temperature 35 to 38 degrees C, and cerebral perfusion pressure (CPP) 70 to 90 mmHg. This resulted in a total of 43,896 values for glucose uptake, lactate release, oxygen extraction ratio (OER), carbon dioxide (CO2) and bicarbonate (HCO3) production, jugular venous oxygen saturation (SjvO2), oxygen-glucose index (OGI), lactate-glucose index (LGI) and lactate-oxygen index (LOI). Arterial blood glucose concentration-dependent influence was determined retrospectively by assessing changes in these parameters within pre-defined blood glucose clusters, ranging from less than 4 to more than 9 mmol/l. RESULTS: Arterial blood glucose significantly influenced signs of cerebral metabolism reflected by increased cerebral glucose uptake, decreased cerebral lactate production, reduced oxygen consumption, negative LGI and decreased cerebral CO2/HCO3 production at arterial blood glucose levels above 6 to 7 mmol/l compared with lower arterial blood glucose concentrations. At blood glucose levels more than 8 mmol/l signs of increased anaerobic glycolysis (OGI less than 6) supervened. CONCLUSIONS: Maintaining arterial blood glucose levels between 6 and 8 mmol/l appears superior compared with lower and higher blood glucose concentrations in terms of stabilised cerebral metabolism. It appears that arterial blood glucose values below 6 and above 8 mmol/l should be avoided. Prospective analysis is required to determine the optimal arterial blood glucose target in patients suffering from severe TBI.

A reduction in severe hypoglycaemia in type 1 diabetes in a randomized crossover study of continuous intraperitoneal compared with subcutaneous insulin infusion

Continuous intraperitoneal insulin infusion (CIPII) with the DiaPort system using regular insulin was compared to continuous subcutaneous insulin infusion (CSII) using insulin Lispro, to investigate the frequency of hypoglycemia, blood glucose control, quality of life, and safety.

Effect of IGF-I therapy on VLDL apolipoprotein B100 metabolism in type 1 diabetes mellitus

Abnormal lipid metabolism may be related to the increased cardiovascular risk in type 1 diabetes. Secretion and clearance rates of very low density lipoprotein (VLDL) apolipoprotein B100 (apoB) determine plasma lipid concentrations. Type 1 diabetes is characterized by increased growth hormone (GH) secretion and decreased insulin-like growth factor (IGF) I concentrations. High-dose IGF-I therapy improves the lipid profile in type 1 diabetes. This study examined the effect of low-dose (40 microg.kg(-1).day(-1)) IGF-I therapy on VLDL apoB metabolism, VLDL composition, and the GH-IGF-I axis during euglycemia in type 1 diabetes. Using a stable isotope technique, VLDL apoB kinetics were estimated before and after 1 wk of IGF-I therapy in 12 patients with type 1 diabetes in a double-blind, placebo-controlled trial. Fasting plasma triglyceride (P < 0.03), VLDL-triglyceride concentrations (P < 0.05), and the VLDL-triglyceride-to-VLDL apoB ratio (P < 0.002) significantly decreased after IGF-I therapy, whereas VLDL apoB kinetics were not significantly affected by IGF-I therapy. IGF-I therapy resulted in a significant increase in IGF-I and a significant reduction in GH concentrations. The mean overnight insulin concentrations during euglycemia decreased by 25% after IGF-I therapy. These results indicate that low-dose IGF-I therapy restores the GH-IGF-I axis in type 1 diabetes. IGF-I therapy changes fasting triglyceride concentrations and VLDL composition probably because of an increase in insulin sensitivity.

Normal VLDL metabolism despite altered lipoprotein composition in type 1 diabetes mellitus

Patients with type 1 diabetes are at increased risk of cardiovascular disease, which may be related to abnormal lipid metabolism. Secretion and clearance of VLDL apolipoprotein B100 (apoB) are important determinants of plasma lipid concentrations and are known to be influenced by hormones, including insulin and growth hormone.

Role of diuretics, blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study

OBJECTIVE To examine the degree to which use of β blockers, statins, and diuretics in patients with impaired glucose tolerance and other cardiovascular risk factors is associated with new onset diabetes. DESIGN Reanalysis of data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. SETTING NAVIGATOR trial. PARTICIPANTS Patients who at baseline (enrolment) were treatment naïve to β blockers (n=5640), diuretics (n=6346), statins (n=6146), and calcium channel blockers (n=6294). Use of calcium channel blocker was used as a metabolically neutral control. MAIN OUTCOME MEASURES Development of new onset diabetes diagnosed by standard plasma glucose level in all participants and confirmed with glucose tolerance testing within 12 weeks after the increased glucose value was recorded. The relation between each treatment and new onset diabetes was evaluated using marginal structural models for causal inference, to account for time dependent confounding in treatment assignment. RESULTS During the median five years of follow-up, β blockers were started in 915 (16.2%) patients, diuretics in 1316 (20.7%), statins in 1353 (22.0%), and calcium channel blockers in 1171 (18.6%). After adjusting for baseline characteristics and time varying confounders, diuretics and statins were both associated with an increased risk of new onset diabetes (hazard ratio 1.23, 95% confidence interval 1.06 to 1.44, and 1.32, 1.14 to 1.48, respectively), whereas β blockers and calcium channel blockers were not associated with new onset diabetes (1.10, 0.92 to 1.31, and 0.95, 0.79 to 1.13, respectively). CONCLUSIONS Among people with impaired glucose tolerance and other cardiovascular risk factors and with serial glucose measurements, diuretics and statins were associated with an increased risk of new onset diabetes, whereas the effect of β blockers was non-significant.