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Hyperglycaemia
Kinds of Hyperglycaemia Selected AbstractsPRETREATMENT WITH INTRAVENOUS ASCORBIC ACID PRESERVES ENDOTHELIAL FUNCTION DURING ACUTE HYPERGLYCAEMIA (R1)CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2005Brian A Mullan SUMMARY 1.,Acute hyperglycaemia may impair endothelial function. Ascorbic acid (AA), administered intra-arterially, has been reported to improve endothelium-dependent vasodilatation during a forearm hyperglycaemic clamp. Using a randomized, double-blind, placebo-controlled, cross-over study, we investigated the potential for intravenous ascorbic acid to modify the endothelial response to acute systemic hyperglycaemia in humans. 2.,Nine healthy male volunteers were recruited from the hospital staff. Endothelial function was determined by measuring the forearm blood flow responses to intrabrachial infusions of endothelium-dependent (ED) and endothelium-independent (EID) vasodilators. The endothelial function index (EFI) was derived from the ratio of ED and EID vasodilatation. Haemodynamic and endothelial function measurements were performed at baseline and then repeated 2 h after a systemic hyperglycaemic clamp (14 mmol/L). The subjects, studied on two separate occasions, were randomized to placebo or 2 g intravenous ascorbic acid prior to the initiation of hyperglycaemia. 3.,After systemic hyperglycaemia with placebo pretreatment, the EFI fell from 1.08 ± 0.21 to 0.74 ± 0.13 (difference (95% confidence interval): 0.34 (0.20, 0.47); P < 0.001). When subjects were pretreated with ascorbic acid, the EFI was not affected by hyperglycaemia (1.11 ± 0.21 to 1.12 ± 0.17; P = 0.938). This difference between placebo and ascorbic acid was significant (P < 0.001). Plasma ascorbate concentrations decreased during hyperglycaemia and correlated directly with the reduction in the EFI (r = 0.798; P < 0.001). 4.,Pretreatment with an intravenous bolus of ascorbic acid can prevent endothelial dysfunction during acute systemic hyperglycaemia. Therefore, ascorbic acid may have potential therapeutic use in clinical situations where acute hyperglycaemia may be a complication. [source] Hyperglycaemia induced QT interval duration: a key to the increased risk of sudden death in diabetic patients?DIABETIC MEDICINE, Issue 8 2008G. Andrįssy No abstract is available for this article. [source] Hyperglycaemia and mortality of diabetic patients with candidaemiaDIABETIC MEDICINE, Issue 9 2005M. S. Bader Abstract Aims To determine whether the degree of hyperglycaemia has an impact on in-hospital mortality in diabetic patients with candidaemia. Methods A retrospective cohort study of 87 diabetic patients with candidaemia admitted between June 1995 and June 2003 was carried out at two medical centres. Patients were stratified into two groups: those with moderate hyperglycaemia (7 days post-candidaemia mean blood glucose < 13.9 mmol/l) and those with severe hyperglycaemia (7 days post-candidaemia mean blood glucose , 13.9 mmol/l). A stepwise logistic regression analysis was performed to determine whether the degree of hyperglycaemia was a significant predictor of mortality. Results During the follow-up period from admission till discharge, 34 (39.1%) patients had died. Nine (69.2%) of 13 patients with severe hyperglycaemia have died while 25 (33.8%) of 74 patients with moderate hyperglycaemia have died. Multivariate analysis identified three independent determinants of death; Apache II score , 23 [OR 8.1, 95% CI (2.6, 25.3), P = 0.0003], mean blood glucose levels 7 days post-candidaemia , 13.9 mmol/l [OR 6.8, 95% CI (1.2, 38.2), P = 0.03], and mechanical ventilation [OR 6.5, 95% CI (2.21), P = 0.03]. Conclusion Severe hyperglycaemia is an important marker of increased mortality among hospitalized diabetic patients with candidaemia. [source] Effects of acute hyperglycaemia on anorectal motor and sensory function in diabetes mellitusDIABETIC MEDICINE, Issue 2 2004A. Russo Abstract Aims To determine the effects of acute hyperglycaemia on anorectal motor and sensory function in patients with diabetes mellitus. Methods In eight patients with Type 1, and 10 patients with Type 2 diabetes anorectal motility and sensation were evaluated on separate days while the blood glucose concentration was stabilized at either 5 mmol/l or 12 mmol/l using a glucose clamp technique. Eight healthy subjects were studied under euglycaemic conditions. Anorectal motor and sensory function was evaluated using a sleeve/sidehole catheter, incorporating a barostat bag. Results In diabetic subjects hyperglycaemia was associated with reductions in maximal (P < 0.05) and plateau (P < 0.05) anal squeeze pressures and the rectal pressure/volume relationship (compliance) during barostat distension (P < 0.01). Hyperglycaemia had no effect on the perception of rectal distension. Apart from a reduction in rectal compliance (P < 0.01) and a trend (P = 0.06) for an increased number of spontaneous anal sphincter relaxations, there were no differences between the patients studied during euglycaemia when compared with healthy subjects. Conclusions In patients with diabetes, acute hyperglycaemia inhibits external anal sphincter function and decreases rectal compliance, potentially increasing the risk of faecal incontinence. Diabet. Med. 21, 176,182 (2004) [source] Application of surrogate indicators of insulin sensitivity to critically ill catsJOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 11-12 2005D. L. Chan Hyperglycaemia associated with critical illness is a common finding in non-diabetic human patients and has important implications for nutritional support. The aetiology of the hyperglycaemia is multi-factorial but believed to involve alterations in hormones regulating glucose metabolism and the development of insulin resistance. We have previously demonstrated that hyperglycaemia in critically cats similarly involves alterations in circulating concentrations of insulin, glucagon, and cortisol. Namely, with critical illness cats had hypoinsulinaemia, hyperglucagonaemia, and hypercortisolaemia. However, direct determinations of insulin sensitivity in critically ill cats have remained untested due to the complexity of calculations and frequent blood sampling required. Such techniques have, therefore, been limited to experimental models. In the interest of studying insulin sensitivity in clinical cases, surrogate indicators of insulin sensitivity, e.g, Homeostasis Model Assessment (HOMA), and Quantitative Insulin Check Index (QUICKI), have been recently applied to cats and shown to correlate to more traditional insulin sensitivity testing. HOMA is calculated ([insulin]x[(glucose)/22.5]), while QUICKI is (1/ [log insulin + log glucose]). The goal of this study was to apply the HOMA and QUICKI indices to hyperglycaemic critically ill cats and compare them to those of euglycaemic critically ill cats and controls. Twenty-six critically ill, and 21 healthy control cats were evaluated. Groups were matched for age, weight, and body condition. Of the critically ill cats, 10 were euglycaemic, and 14 were hyperglycaemic (glucose > 180 mg/dL). As compared to euglycaemic critically ill cats, HOMA was found to be significantly greater in hyperglycaemic cats [median 5.30 (range 0.90 , 25.14) vs. [2.19 (0.69 , 7.33); p = 0.016], while QUICKI was significantly lower in hyperglycaemic cats [median 0.30 mg/dl (0.25 , 0.39 mg/dl) vs. [0.34 mg/dl (0.29 , 0.38 mg/dl); p = 0.039]. Higher HOMA and lower QUICKI indices are consistent with an insulin resistant state. However, HOMA and QUICKI were not significantly different between hyperglycaemic and control cats. While the application of these indices may prove useful in determining insulin sensitivity in critically ill cats, future studies are needed to resolve discrepancies demonstrate in the current study. [source] Hyperglycaemia and cardiovascular diseaseJOURNAL OF INTERNAL MEDICINE, Issue 2 2007M. Bartnik Abstract. Coronary artery disease and type 2 diabetes are chronic diseases of substantial and growing prevalence. Their coincidence is common, markedly enhancing mortality and morbidity. The risk for cardiovascular disease increases along a spectrum of blood glucose concentrations already apparent at levels regarded as normal. Accordingly, strategies for the early detection of glucometabolic disturbances are needed to find ways to prevent the occurrence of cardiovascular complications or to treat them already at an early stage. More specifically, abnormal glucose tolerance is almost twice as common amongst patients with a myocardial infarction as in population-based controls and a normal glucose regulation is indeed less common than abnormal glucose metabolism also amongst patients with stable coronary artery disease. Already an abnormal glucose tolerance is a strong risk factor for future cardiovascular events after an acute myocardial infarction. An oral glucose tolerance test should, therefore, be a part of the evaluation of total risk in all patients with coronary artery disease. As glucose disturbances are common and easy to detect, they may be suitable targets for novel secondary preventive efforts. [source] Survey of the management of neonatal hyperglycaemia in AustralasiaJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 9 2007Jane M Alsweiler Aim: Hyperglycaemia is a common problem in very low birthweight (VLBW) preterm neonates and has been associated with an increase in intraventricular haemorrhage and mortality. There are few data to guide clinicians on the best range of blood glucose levels to aim for when treating hyperglycaemic preterm babies with insulin. The aim of this study was to survey all Australasian tertiary neonatal intensive care units for their current practice in the definition and management of neonatal hyperglycaemia to aid in the design of a randomised controlled trial of the effect of tight glycaemic control on long-term outcome in VLBW babies. Methods: An online survey was sent to the 27 tertiary neonatal units in Australasia asking the respondents for details of their unit's definition and management of hyperglycaemia in VLBW infants. Results: Twenty-three tertiary neonatal units responded to the questionnaire. There were six different definitions of hyperglycaemia, with most units defining neonatal hyperglycaemia as a blood glucose level greater than 10 mM. There were large variations in the criteria for commencing insulin (blood glucose level 8,15 mM ± glycosuria) and target blood glucose ranges for babies on insulin (ranging from 2.5,8 mM to 8,15 mM). Conclusions: There is a wide variation in the management of neonatal hyperglycaemia between tertiary neonatal units in Australasia. This reflects the paucity of data available in this area. Further research on the management of neonatal hyperglycaemia is needed. [source] Diabetes and the enteric nervous systemNEUROGASTROENTEROLOGY & MOTILITY, Issue 12 2007B. Chandrasekharan Abstract, Diabetes is associated with several changes in gastrointestinal (GI) motility and associated symptoms such as nausea, bloating, abdominal pain, diarrhoea and constipation. The pathogenesis of altered GI functions in diabetes is multifactorial and the role of the enteric nervous system (ENS) in this respect has gained significant importance. In this review, we summarize the research carried out on diabetes-related changes in the ENS. Changes in the inhibitory and excitatory enteric neurons are described highlighting the role of loss of inhibitory neurons in early diabetic enteric neuropathy. The functional consequences of these neuronal changes result in altered gastric emptying, diarrhoea or constipation. Diabetes can also affect GI motility through changes in intestinal smooth muscle or alterations in extrinsic neuronal control. Hyperglycaemia and oxidative stress play an important role in the pathophysiology of these ENS changes. Antioxidants to prevent or treat diabetic GI motility problems have therapeutic potential. Recent research on the nerve,immune interactions demonstrates inflammation-associated neurodegeneration which can lead to motility related problems in diabetes. [source] Glutathione S-transferases and malondialdehyde in the liver of NOD mice on short-term treatment with plant mixture extract P-9801091PHYTOTHERAPY RESEARCH, Issue 4 2003R. Petlevski Abstract Changes in the concentration of glutathione S-transferases (GSTs) and malondialdehyde (MDA) were assessed in the liver of normal and diabetic NOD mice with and without treatment with the plant extract P-9801091. The plant extract P-9801091 is an antihyperglycaemic preparation containing Myrtilli folium (Vaccinium myrtillus L.), Taraxaci radix (Taraxacum of,cinale Web.), Cichorii radix (Cichorium intybus L.), Juniperi fructus (Juniperus communis L.) , Centaurii herba (Centaurium umbellatum Gilib.), Phaseoli pericarpium (Phaseolus vulgaris L.), Millefolii herba (Achillea millefolium L.), Mori folium (Morus nigra L.), Valerianae radix (Valeriana of,cinalis L.) and Urticae herba et radix (Urtica dioica L). Hyperglycaemia in diabetes mellitus is responsible for the development of oxidative stress (via glucose auto-oxidation and protein glycation), which is characterized by increased lipid peroxide production (MDA is a lipid peroxidation end product) and/or decreased antioxidative defence (GST in the liver is predominantly an , enzyme, which has antioxidative activity). The catalytic concentration of GSTs in the liver was signi,cantly reduced in diabetic NOD mice compared with normal NOD mice (p < 0.01), while the concentration of MDA showed a rising tendency (not signi,cant). The results showed that statistically signi,cant changes in antioxidative defence occurred in the experimental model of short-term diabetes mellitus. A 7-day treatment with P-9801091 plant extract at a dose of 20 mg/kg body mass led to a signi,cant increase in the catalytic concentration of GSTs in the liver of diabetic NOD mice (p < 0.01) and a decrease in MDA concentration (not signi,cant), which could be explained by its antihyperglycaemic effect. Copyright © 2003 John Wiley & Sons, Ltd. [source] Intensive insulin treatment in coronary and intensive carePRACTICAL DIABETES INTERNATIONAL (INCORPORATING CARDIABETES), Issue 1 2007Dr C Jones MRCP, MB ChB Specialist Registrar Abstract Hyperglycaemia in the setting of acute illness carries a poor prognosis. The first Diabetes and Insulin-Glucose infusion in Acute Myocardial Infarction (DIGAMI) study demonstrated a reduction in total mortality with intravenous insulin to reduce hyperglycaemia followed by multi-dose subcutaneous insulin in diabetic patients following myocardial infarction. Unfortunately, there were several problems with the follow-up DIGAMI-2 study, so that it is not clear if maximum benefit was obtained by intravenous insulin, subcutaneous insulin, or a combination of both. In the surgical intensive care unit (ICU) setting, intensive insulin to restore normoglycaemia reduced total mortality in patients admitted to a surgical ICU who developed hyperglycaemia. In a follow-up study in medical ICU patients the results were disappointing, and there was no overall reduction in mortality. There is a need for a study which would combine these two complementary approaches, examining the possible benefits of using very intensive insulin treatment to achieve normoglycaemia following myocardial infarction in patients with diabetes. Copyright © 2007 John Wiley & Sons. [source] Improving the early management of blood glucose in emergency admissions with chest painPRACTICAL DIABETES INTERNATIONAL (INCORPORATING CARDIABETES), Issue 3 2001Martin K Rutter MRCP (UK) Locum Consultant Physician Abstract Hyperglycaemia is associated with a worse prognosis after myocardial infarction and good blood glucose control in the peri-infarct period has been shown to improve outcome. Our primary study was undertaken with the aims of assessing the prevalence and management of hyperglycaemia in patients admitted with acute chest pain. Ninety-three patients admitted to either Coronary Care (CCU) or Emergency Medical Admission Units (EMAU) with chest pain were studied and of these 14 (15%) had severe hyperglycaemia (>11.0,mmol/L). Blood glucose was not measured in seven (8%) patients and in only 1/14 (7%) patient were established guidelines for the management of hyperglycaemia applied. A revision of management protocol was undertaken and after 18 months we repeated the review of management of hyperglycaemia. Of 114 patients 22 (21%) had severe hyperglycaemia, blood glucose was not measured in ten (9%) and management guidelines were followed in 13 (65%). A major improvement in management of blood glucose in emergency admissions with chest pain has been demonstrated. Further staff education, discussion and review of protocol are indicated to improve and maintain performance on CCU and EMAU. Copyright © 2001 John Wiley & Sons, Ltd. [source] Influence of Hyperglycaemia on Chemical-Induced Toxicity: Study with Cyclophosphamide in RatBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2009Kalavatala Saandeep Hyperglycaemia perturbs the critical balance between oxidative stress and anti-oxidant defence mechanisms in the body and thereby alters the response of biological system towards various toxic chemicals. Cyclophosphamide (CP) is a widely prescribed anticancer drug, well-known genotoxic agent as well as used in the development of immunocompromised animal models. The present study investigated the modulating effect of diabetes on the cyclophosphamide-induced cytotoxicity and genotoxicity. The study was performed on male Sprague-Dawley rats (200 ± 10 g). Cyclophosphamide (10 mg/kg) was administered five consecutive days in a week for 3 weeks to both control and diabetic rats. Thiobarbituric acid reactive substances (TBARS) levels were measured in the plasma, liver, kidney and lung tissues. DNA damaging potential of cyclophosphamide under diabetic condition was evaluated using comet and halo assay as an endpoint. To further ascertain the mode of cell death, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay and immunohistochemical evaluation of p53 was performed. Significant increase in DNA damage was revealed by the comet assay parameters, halo assay indicated the level of cytotoxicity and the oxidative stress was measured using the TBARS assay in the diabetic rats receiving cyclophosphamide treatment. The toxic effects were more prominent in diabetic animals as compared to non-diabetic rats. Cyclophosphamide treatment and diabetic condition per se led to increase in the p53 + and TUNEL + cells in the liver and kidney of rats. Under diabetic condition, further increase in the p53 + and TUNEL + cells was observed in response to cyclophosphamide. In the present study, we report that hyperglycaemic condition exaggerates the cyclophosphamide-induced toxicity and the response was found to be tissue specific. [source] High glucose levels enhance platelet activation: involvement of multiple mechanismsBRITISH JOURNAL OF HAEMATOLOGY, Issue 3 2006Dzana Sudic Summary Diabetes mellitus (DM) and hyperglycaemia are associated with platelet activation. The present study was designed to investigate how high glucose levels influence platelet function. Fasting human blood was incubated with different concentrations of d -glucose (5, 15 and 30 mmol/l) and other sugars without or with in vitro stimuli. Platelet activation was monitored by whole blood flow cytometry. High glucose levels enhanced adenosine diphosphate (ADP)- and thrombin receptor-activating peptide (TRAP)-induced platelet P-selectin expression, and TRAP-induced platelet fibrinogen binding. Similar effects were seen with 30 mmol/l l -glucose, sucrose and galactose. Hyperglycaemia also increased TRAP-induced platelet-leucocyte aggregation. Protein kinase C (PKC) blockade did not counteract the enhancement of platelet P-selectin expression, but abolished the enhancement of TRAP-induced platelet fibrinogen binding by hyperglycaemia. Superoxide anion scavenging by superoxide dismutase (SOD) attenuated the hyperglycaemic enhancement of platelet P-selectin expression, but did not counteract the enhancement of TRAP-induced platelet fibrinogen binding. Hyperglycaemia did not alter platelet intracellular calcium responses to agonist stimulation. Blockade of cyclo-oxygenase (COX), phosphotidylinositol-3 (PI3) kinase, or nitric oxide synthase, or the addition of insulin did not influence the effect of hyperglycaemia. In conclusion, high glucose levels enhanced platelet reactivity to agonist stimulation through elevated osmolality. This occurred via superoxide anion production, which enhanced platelet P-selectin expression (secretion), and PKC signalling, which enhanced TRAP-induced fibrinogen binding (aggregablity). [source] Haemoglobin A1c as a predictor of postoperative hyperglycaemia and complications after major colorectal surgery,BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 11 2009U. O. Gustafsson Background: Hyperglycaemia following major surgery increases morbidity, but may be improved by use of enhanced-recovery protocols. It is not known whether preoperative haemoglobin (Hb) A1c could predict hyperglycaemia and/or adverse outcome after colorectal surgery. Methods: Some 120 patients without known diabetes underwent major colorectal surgery within an enhanced-recovery protocol. HbA1c was measured at admission and 4 weeks after surgery. All patients received an oral diet beginning 4 h after operation. Plasma glucose was monitored five times daily. Patients were stratified according to preoperative levels of HbA1c (within normal range of 4·5,6·0 per cent, or higher). Results: Thirty-one patients (25·8 per cent) had a preoperative HbA1c level over 6·0 per cent. These had higher mean(s.d.) postoperative glucose (9·3(1·5) versus 8·0(1·5) mmol/l; P < 0·001) and C-reactive protein (137(65) versus 101(52) mg/l; P = 0·008) levels than patients with a normal HbA1c level. Postoperative complications were more common in patients with a high HbA1c level (odds ratio 2·9 (95 per cent confidence interval 1·1 to 7·9)). Conclusion: Postoperative hyperglycaemia is common among patients with no history of diabetes, even within an enhanced-recovery protocol. Preoperative measurement of HbA1c may identify patients at higher risk of poor glycaemic control and postoperative complications. Copyright © 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] Multiple Mechanisms Of Early Hyperglycaemic Injury Of The Rat Intestinal MicrocirculationCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2002H Glenn Bohlen SUMMARY 1. Hyperglycaemia in the vast majority of humans with diabetes mellitus is the end result of profound insulin resistance secondary to obesity. For patients in treatment, hyperglycaemia is usually not sustained but, rather, occurs intermittently. In in vivo studies of the rat intestinal microcirculation, endothelial impairment occurs within 30 min at D -glucose concentrations , 300 mg/dL. Endothelial-dependent dilation to acetylcholine and constriction to noradrenaline is impaired. Vasodilation to exogenous nitric oxide (NO) remains normal. 2. When initiated before hyperglycaemia, suppression of oxygen radicals by both scavenging and pretreatment with cyclo-oxygenase blockade to prevent oxygen radical formation minimized endothelial impairments during hyperglycaemia. Neither treatment was effective in restoring endothelial function once it was damaged by hyperglycaemia. 3. A mechanism that may initiate the arachidonic acid, oxygen radical process is activation of specific isoforms of protein kinase C (PKC). De novo formation of diacylglycerol during hyperglycaemia activates PKC. Blockade of the ,II PKC isoform with LY-333531 prior to hyperglycaemia protected NO formation within the arteriolar wall, as judged with NO-sensitive microelectrodes. Furthermore, once suppression of endothelial dilation was present in untreated animals, PKC blockade could substantially restore endothelial-dependent dilation. 4. These results indicate that acute hyperglycaemia is far from benign and, in the rat, causes rapid endothelial impairment. Both oxygen radical scavenging and cyclo-oxygenase blockade prior to bouts of hyperglycaemia minimize endothelial impairment with limited side effects. Blockade of specific PKC isozymes protects endothelial function both as a pre- or post-treatment during moderately severe hyperglycaemia. [source] Role of orexin in the regulation of glucose homeostasisACTA PHYSIOLOGICA, Issue 3 2010H. Tsuneki Abstract Orexin-A (hypocretin-1) and orexin-B (hypocretin-2) are hypothalamic neuropeptides that play key roles in the regulation of wakefulness, feeding, reward, autonomic functions and energy homeostasis. To control these functions indispensable for survival, orexin-expressing neurones integrate peripheral metabolic signals, interact with many types of neurones in the brain and modulate their activities via the activation of orexin-1 receptor or orexin-2 receptor. In addition, a new functional role of orexin is emerging in the regulation of insulin and leptin sensitivities responsible for whole-body glucose metabolism. Recent evidence indicates that orexin efficiently protects against the development of peripheral insulin resistance induced by ageing or high-fat feeding in mice. In particular, the orexin receptor-2 signalling appears to confer resistance to diet-induced obesity and insulin insensitivity by improving leptin sensitivity. In fact, the expression of orexin gene is known to be down-regulated by hyperglycaemia in the rodent model of diabetes, such as ob/ob and db/db mice. Moreover, the levels of orexin receptor-2 mRNA have been shown to decline in the brain of mice along with ageing. These suggest that hyperglycaemia due to insulin insensitivity during ageing or by habitual consumption of a high-fat diet leads to the reduction in orexin expression in the hypothalamus, thereby further exacerbating peripheral insulin resistance. Therefore, orexin receptor controlling hypothalamic insulin/leptin actions may be a new target for possible future treatment of hyperglycaemia in patients with type 2 diabetes. [source] Pregnancy and lactation have anti-obesity and anti-diabetic effects in Ay/a miceACTA PHYSIOLOGICA, Issue 2 2010E. N. Makarova Abstract Aim:, Dominant ,yellow' mutation at the mouse agouti locus (Ay) results in obesity. Pregnancy and lactation are characterized by large energy demand. The aim of this study was to investigate whether obesity would develop in pregnant and suckling Ay mice. Methods:, Body weight and food intake in pregnancy, lactation, and after weaning, plasma leptin, insulin, corticosterone and blood glucose concentrations on days 7, 13 and 18 of pregnancy, days 1, 10, 21 and 80 postpartum, glucose and insulin tolerance on pregnancy days 7 and 18 were measured in C57Bl/6J mice of a/a (normal metabolism) and Ay/a genotypes. The same parameters were also measured in age-matched virgin females. Results:, Virgin Ay/a females exhibited hyperphagia, enhanced body weight, glucose intolerance and normal blood parameters at the mating age. With age, they developed obesity, hyperleptinaemia, hyperinsulinaemia and hyperglycaemia. Obesity did not develop in mated Ay/a mice; during suckling, they had equal food intake and body weight as a/a mice. During pregnancy, glucose tolerance was enhanced in Ay/a mice and became equal in both genotypes. In both genotypes, concentrations of hormones increased, and glucose decreased from pregnancy day 7 to day 18 and returned to normal values after parturition. Ay/a mice did not differ from a/a in corticosterone, insulin and glucose levels during pregnancy and lactation, in leptin levels during suckling; however, Ay/a mice had two times higher leptin levels than a/a during pregnancy. After weaning, Ay/a mice began to eat and weigh more than a/a exhibiting normal metabolic parameters for 50 days. Conclusion:, Pregnancy and lactation retard obesity and diabetes development in Ay mice. [source] DHEA improves impaired activation of Akt and PKC ,/,-GLUT4 pathway in skeletal muscle and improves hyperglycaemia in streptozotocin-induced diabetes ratsACTA PHYSIOLOGICA, Issue 3 2009K. Sato Abstract Aim:, Addition of dehydroepiandrosterone (DHEA) to a cultured skeletal muscle locally synthesizes 5,-dihydrotestosterone (DHT). It induced activation of glucose metabolism-related signalling pathway via protein kinase B (Akt) and protein kinase C zeta/lambda (PKC ,/,)-glucose transporter-4 (GLUT4) proteins. However, such an effect of DHEA in vivo remains unclear. Methods:, Using streptozotocin (STZ)-induced rats with type 1 diabetes mellitus, we tested the hypothesis that a single bout of DHEA injection in the rats improves hyperglycaemia and muscle GLUT4-regulated signalling pathway. After 1 week of STZ injection (55 mg kg,1) with male Wistar rats, fasting glucose concentrations were determined in a blood sample taken from the tail vein. Blood glucose levels were then monitored for 180 min after DHEA or sesame oil (control) was injected (n = 10 for each group). Results:, Blood glucose levels decreased significantly for 30,150 min after 2 mg DHEA injection in the STZ rats. In the skeletal muscle, expression and translocation of GLUT4 protein, phosphorylation of Akt and PKC ,/,, and phosphofructokinase and hexokinase enzyme activities increased significantly by DHEA injection. However, DHEA-induced improvements in Akt and PKC ,/,-GLUT4 pathways were blocked by a DHT inhibitor. Conclusion:, These results suggest that a single bout of DHEA injection can improve hyperglycaemia and activate the glucose metabolism-related signalling pathway via Akt and PKC ,/,-GLUT4 proteins of skeletal muscles in rats. Moreover, these results show that a DHEA-induced increase in muscle glucose uptake and utilization might contribute to improvement in hyperglycaemia in type 1 diabetes mellitus. [source] Imidazoline-induced amplification of glucose- and carbachol-stimulated insulin release includes a marked suppression of islet nitric oxide generation in the mouseACTA PHYSIOLOGICA, Issue 3 2009S. Meidute-Abaraviciene Abstract Aim:, The role of islet nitric oxide (NO) production in insulin-releasing mechanisms is unclear. We examined whether the beneficial effects of the imidazoline derivative RX 871024 (RX) on ,-cell function might be related to perturbations of islet NO production. Methods:, Experiments were performed with isolated islets or intact mice challenged with glucose or carbachol with or without RX treatment. Insulin was determined with radioimmunoassay, NO generation with high-performance liquid chromatography and expression of inducible NO synthase (iNOS) with confocal microscopy. Results:, RX treatment, in doses lacking effects on basal insulin, greatly amplified insulin release stimulated by the NO-generating secretagogues glucose and carbachol both in vitro and in vivo. RX also improved the glucose tolerance curve. Islets incubated at high glucose levels (20 mmol L,1) displayed increased NO production derived from both neuronal constitutive NO synthase (ncNOS) and iNOS. RX abrogated this glucose-induced NO production concomitant with amplification of insulin release. Confocal microscopy revealed abundant iNOS expression in , cells after incubation of islets at high but not low glucose levels. This was abolished after RX treatment. Similarly, islets cultured for 24 h at high glucose levels showed intense iNOS expression in , cells. This was abrogated with RX and followed by an amplified glucose-induced insulin release. Conclusion:, RX effectively counteracts the negative impact of ,-cell NO generation on insulin release stimulated by glucose and carbachol suggesting imidazoline compounds by virtue of NOS inhibitory properties being of potential therapeutic value for treatment of ,-cell dysfunction in hyperglycaemia and type 2 diabetes. [source] Initial short-term intensive insulin therapy as a strategy for evaluating the preservation of beta-cell function with oral antidiabetic medications: a pilot study with sitagliptinDIABETES OBESITY & METABOLISM, Issue 10 2010R. Retnakaran Aim: Studies evaluating the effects of oral antidiabetic drugs (OADs) on beta-cell function in type 2 diabetes mellitus (T2DM) are confounded by an inability to establish the actual baseline degree of beta-cell dysfunction, independent of the deleterious effects of hyperglycaemia (glucotoxicity). Because intensive insulin therapy (IIT) can induce normoglycaemia, we reasoned that short-term IIT could enable evaluation of the beta-cell protective capacity of OADs, free from confounding hyperglycaemia. We applied this strategy to assess the effect of sitagliptin on beta-cell function. Methods: In this pilot study, 37 patients with T2DM of 6.0 + 6.4 years duration and A1c 7.0 + 0.8% on 0,2 OADs were switched to 4,8 weeks of IIT consisting of basal detemir and premeal insulin aspart. Subjects achieving fasting glucose <7.0 mmol/l 1 day after completing IIT (n = 21) were then randomized to metformin with either sitagliptin (n = 10) or placebo (n = 11). Subjects were followed for 48 weeks, with serial assessment of beta-cell function [ratio of AUCCpep to AUCgluc over Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) (AUCCpep/gluc/HOMA-IR)] on 4-h meal tests. Results: During the study, fasting glucagon-like-peptide-1 was higher (p = 0.003) and A1c lower in the sitagliptin arm (p = 0.016). Nevertheless, although beta-cell function improved during the IIT phase, it declined similarly in both arms over time (p = 0.61). By study end, AUCCpep/gluc/HOMA-IR was not significantly different between the placebo and sitagliptin arms (median 71.2 vs 80.4; p = 0.36). Conclusions: Pretreatment IIT can provide a useful strategy for evaluating the beta-cell protective capacity of diabetes interventions. In this pilot study, improved A1c with sitagliptin could not be attributed to a significant effect on preservation of beta-cell function. [source] Mid- and high-ratio premix insulin analogues: potential treatment options for patients with type 2 diabetes in need of greater postprandial blood glucose controlDIABETES OBESITY & METABOLISM, Issue 2 2010J. S. Christiansen Some patients with type 2 diabetes continue to have high postprandial blood glucose levels on twice-daily regimens of ,low-ratio' premix insulin formulations (up to 30% rapid-acting, with 70% protracted insulin). These patients require intensified insulin therapy, which can be provided by a twice- or thrice-daily regimen of mid-ratio (50% rapid-acting and 50% protaminated intermediate-acting insulin , human or analogue) or high-ratio (70% rapid-acting and 30% protaminated insulin , analogue only) premix insulin. Alternatively, a third daily injection of low-ratio premix insulin can be added to the regimen, with the option of incorporating one or more injections of mid- or high-ratio premix as required, and as an alternative to basal,bolus therapy. How these mid- and high-ratio formulations differ from the low-ratio premix insulins is reviewed here, with the aim of identifying the role of these formulations in diabetes management. Glucose clamp studies have shown that premix analogues give serum insulin levels proportional to their percentage of rapid-acting uncomplexed insulin: the higher the proportion, the greater the maximum level reached. Other pharmacokinetic parameters were not always significantly different between the mid- and high-ratio formulations. In clinical trials, postprandial plasma glucose and glycated haemoglobin A1c (HbA1c) levels were significantly reduced with thrice-daily mid- /high-ratio premix analogue when compared with twice-daily low-ratio biphasic human insulin (BHI) 30/70 or once-daily insulin glargine. Moreover, glycaemic control with mid-/high-ratio premix analogue was found to be similar to that with a basal,bolus therapy. Mid- and high-ratio premix regimens are generally well tolerated. The frequency of minor hypoglycaemia was reportedly higher with mid- /high-ratio premix analogues than with BHI 30, but nocturnal hypoglycaemia was less frequent. Although there is little evidence that clinical outcomes with mid-ratio premix analogues are different from those with high-ratio, they are useful additions to the low-ratio formulations for the management of diabetes, and addressing postprandial hyperglycaemia in particular. [source] Treatment of diabetic hypertensionDIABETES OBESITY & METABOLISM, Issue 5 2009David S. H. Bell Insulin resistance and hyperglycaemia combine to make hypertension more prevalent in the type 2 diabetic patient. Blood pressure goals below those for the non-diabetic subject have been shown to be more effective in lowering mortality and cardiovascular events in the diabetic patient. To achieve these goals in most cases, three to five antihypertensives from different therapeutic groups need to be utilized. Suppression of the renin,angiotensin system (RAS) with angiotensin-converting enzyme inhibitors, angiotensin 2 receptor blockers or a renin inhibitor should be the primary therapy. A second goal should be suppression of the sympathetic nervous system utilizing a beta-blocker that does not increase insulin resistance. The addition of a diuretic, calcium channel blocker or a vasodilator to suppressors of the RAS and sympathetic nervous system aid in achieving hypertensive goals in the diabetic patient. Achieving hypertensive goals with suppression of the RAS and sympathetic nervous system should result in a decrease in mortality and cardiovascular events in the diabetic hypertensive patient. In this review article, the benefits and disadvantages of the different antihypertensive therapies in the diabetic patient are discussed. [source] Novel pathways for glycaemic control in type 2 diabetes: focus on bile acid modulationDIABETES OBESITY & METABOLISM, Issue 11 2008Eliot A. Brinton Type 2 diabetes is a common disorder with high risk of macrovascular and microvascular complications. These complications are largely driven by hyperglycaemia, dyslipidaemia and hypertension, for which aggressive treatment is thus warranted. Achieving and maintaining control of all three risk factors is especially difficult, however, and new therapeutic approaches could be useful. Bile acids have a well-established and important role in cholesterol homeostasis. Normally, their levels are maintained primarily by ileal reabsorption and enterohepatic recycling. Bile acid sequestrants bind bile acids in the intestine, reduce this recycling and deplete the bile acid pool, thereby stimulating use of hepatic cholesterol for bile acid synthesis, which leads to accelerated removal of LDL from the plasma and a decrease in LDL-cholesterol levels. Interestingly, recent evidence suggests that bile acid sequestrants can lower glucose levels to a clinically meaningful degree. This review presents this evidence and the possible mechanisms by which these glucose-lowering effects occur and discusses the apparently unique ability of bile acid sequestrants among lipid-lowering agents to significantly improve two cardiovascular risk factors, hyperglycaemia and dyslipidaemia. There is renewed interest in the use of bile acid sequestrants in individuals with type 2 diabetes, most of whom would benefit from additional reductions in both LDL-cholesterol and glycaemia. [source] Hepatic dysfunction and insulin insensitivity in type 2 diabetes mellitus: a critical target for insulin-sensitizing agentsDIABETES OBESITY & METABOLISM, Issue 9 2008P. D. Home The liver plays an essential role in maintaining glucose homeostasis, which includes insulin-mediated processes such as hepatic glucose output (HGO) and uptake, as well as in clearance of insulin itself. In type 2 diabetes, the onset of hyperglycaemia [itself a potent inhibitor of hepatic glucose output (HGO)], alongside hyperinsulinaemia, indicates the presence of hepatic insulin insensitivity. Increased HGO is central to the onset of hyperglycaemia and highlights the need to target hepatic insulin insensitivity as a central component of glucose-lowering therapy. The mechanisms underlying the development of hepatic insulin insensitivity are not well understood, but may be influenced by factors such as fatty acid oversupply and altered adipocytokine release from dysfunctional adipose tissue and increased liver fat content. Furthermore, although the impact of insulin insensitivity as a marker of cardiovascular disease is well known, the specific role of hepatic insulin insensitivity is less clear. The pharmacological tools available to improve insulin sensitivity include the biguanides (metformin) and thiazolidinediones (rosiglitazone and pioglitazone). Data from a number of sources indicate that thiazolidinediones, in particular, can improve multiple aspects of hepatic dysfunction, including reducing HGO, insulin insensitivity and liver fat content, as well as improving other markers of liver function and the levels of mediators with potential involvement in hepatic function, including fatty acids and adipocytokines. The current review addresses this topic from the perspective of the role of the liver in maintaining glucose homeostasis, its key involvement in the pathogenesis of type 2 diabetes and the tools currently available to reduce hepatic insulin insensitivity. [source] Suppression of post-prandial hyperglycaemia by pioglitazone improved islet fibrosis and macrophage migration in the Goto,Kakizaki ratDIABETES OBESITY & METABOLISM, Issue 9 2008H. Mizukami First page of article [source] Tagatose, a new antidiabetic and obesity control drugDIABETES OBESITY & METABOLISM, Issue 2 2008Y. Lu A potentially important new drug for treating type 2 diabetes, tagatose, is now in phase 3 clinical trial. The history, development, additional health benefits, mechanisms of action and the potential for the drug are presented in context with a review of the rapidly growing epidemic of type 2 diabetes and treatments for it. An epimer of fructose, the natural hexose tagatose was originally developed by Spherix Incorporated (formerly Biospherics Inc.) as a low-calorie sugar substitute. Only 20% of orally ingested tagatose is fully metabolized, principally in the liver, following a metabolic pathway identical to that of fructose. Following a decade of studies, tagatose became generally recognized as safe for use in foods and beverages under US FDA regulation. The simple sugar is commercially produced by isomerization of galactose, which is prepared from lactose. Early human studies suggested tagatose as a potential antidiabetic drug through its beneficial effects on postprandial hyperglycaemia and hyperinsulinaemia. A subsequent 14-month trial confirmed its potential for treating type 2 diabetes, and tagatose showed promise for inducing weight loss and raising high-density lipoprotein cholesterol, both important to the control of diabetes and constituting benefits independent of the disease. Furthermore, tagatose was shown to be an antioxidant and a prebiotic, both properties cited in the maintenance and promotion of health. No current therapies for type 2 diabetes provide these multiple health benefits. The predominant side effects of tagatose are gastrointestinal disturbances associated with excessive consumption, generally accommodated within 1- to 2-week period. The health and use potentials for tagatose (branded Naturlose® for this use) are given with respect to current type 2 diabetes drugs and markets. Under an FDA-affirmed protocol, Spherix is currently conducting a phase 3 trial to evaluate a placebo-subtracted treatment effect based on a decrease in HbA1c levels. Side effects, contraindications and possibly beneficial new findings will be carefully monitored. It is hoped that early results of the trial may become available by mid-2008. If a subsequent NDA is successful, tagatose may fill a major health need. [source] Pomegranate flower: a unique traditional antidiabetic medicine with dual PPAR-,/-, activator propertiesDIABETES OBESITY & METABOLISM, Issue 1 2008Yuhao Li PPARs are transcription factors belonging to the superfamily of nuclear receptors. PPAR-, is involved in the regulation of fatty acid (FA) uptake and oxidation, inflammation and vascular function, while PPAR-, participates in FA uptake and storage, glucose homeostasis and inflammation. The PPARs are thus major regulators of lipid and glucose metabolism. Synthetic PPAR-, or PPAR-, agonists have been widely used in the treatment of dyslipidaemia, hyperglycaemia and their complications. However, they are associated with an incidence of adverse events. Given the favourable metabolic effects of both PPAR-, and PPAR-, activators, as well as their potential to modulate vascular disease, combined PPAR-,/-, activation has recently emerged as a promising concept, leading to the development of mixed PPAR-,/-, activators. However, some major side effects associated with the synthetic dual activators have been reported. It is unclear whether this is a specific effect of the particular synthetic compounds or a class effect. To date, a medication that may combine the beneficial metabolic effects of PPAR-, and PPAR-, activation with fewer undesirable side effects has not been successfully developed. Pomegranate plant parts are used traditionally for the treatment of various disorders. However, only pomegranate flower has been prescribed in Unani and Ayurvedic medicines for the treatment of diabetes. This review provides a new understanding of the dual PPAR-,/-, activator properties of pomegranate flower in the potential treatment of diabetes and its associated complications. [source] Glucose homeostasis and the gastrointestinal tract: insights into the treatment of diabetesDIABETES OBESITY & METABOLISM, Issue 1 2008D. Maggs The gastrointestinal tract is increasingly viewed as a critical organ in glucose metabolism because of its role in delivering glucose to the circulation and in secreting multiple glucoregulatory hormones that, in concert with insulin and glucagon, regulate glucose homeostasis. Under normal conditions, a complex interplay of these hormones acts to maintain plasma glucose within a narrow range despite large variations in the availability of glucose, particularly during transition from the fasting to fed state. In the fed state, the rate at which nutrients are passed from the stomach to the duodenum, termed gastric emptying rate, is a key determinant of postprandial glucose flux. In patients with diabetes, the regulation of glucose metabolism is disrupted resulting in fasting and postprandial hyperglycaemia. Elucidation of the role of the gastrointestinal tract, gut-derived glucoregulatory peptides and gastric emptying rate offers a new perspective on glucose homeostasis and the respective importance of these factors in the diabetes state. This review will highlight the importance of the gastrointestinal tract in playing a key role in glucose homeostasis, particularly in the postprandial period, and the role of established or new therapies that either leverage or modify gastrointestinal function to improve glycaemic state. [source] Glycaemic status and cardiovascular disease in type 2 diabetes mellitus: re-visiting glycated haemoglobin targets for cardiovascular disease preventionDIABETES OBESITY & METABOLISM, Issue 6 2007Sherita H. Golden Cardiovascular disease (CVD) is the leading cause of death among people with type 2 diabetes. Recent attention has focused on chronic hyperglycaemia as an additional risk factor in people with diabetes since their excess CVD risk is not entirely explained by traditional cardiovascular risk factors. Clinical trials of intensive glucose control to reduce CVD events have been equivocal, but recent epidemiological studies have shown that HbAlc, a measure of chronic hyperglycaemia, predicts incident cardiovascular events. This review, which focuses on type 2 diabetes, summarizes (i) the epidemiological literature examining the relation between glycaemic status, as assessed by glycated haemoglobin (HbAlc) and CVD, (ii) the controversy regarding treatment goals for HbAlc in terms of preventing microvascular disease vs. macrovascular disease and (iii) on-going clinical trials of intensive glycaemic control for CVD prevention. [source] Atherosclerosis in diabetes and insulin resistanceDIABETES OBESITY & METABOLISM, Issue 4 2007Jane E.-B. Atherosclerosis and cardiovascular disease are the major causes of morbidity and mortality in patients with diabetes and those with insulin resistance and the metabolic syndrome. Both conditions profoundly accelerate the development of atherosclerosis and increase the morbidity and mortality of cardiovascular events. The question, therefore, is what are the molecular/biochemical mechanisms that underlie the potentiating influence of diabetes, the metabolic syndrome and/or insulin resistance on the development and progression of atherosclerosis? The following review will focus on the molecular mechanism whereby hyperglycaemia and/or hyperinsulinemia either directly or indirectly promote atherosclerosis. [source] | ||||||||||||||||||||||||||||||||||