Significant Hyperglycemia Research Articles

Euglycemic diabetic ketoacidosis in type 2 diabetes mellitus treated with sodium-glucose cotransporter 2 inhibitors. A report on two cases

Sodium-glucose cotransporter 2 inhibitors are a new second-line medication in the management of hyperglycemia in type 2 diabetes. These drugs can be associated with the development of diabetic ketoacidosis (DKA) with normal or moderately increased blood glucose levels. This is a life-threatening clinical condition termed euglycemic DKA (euDKA), of which the diagnosis can be delayed due to the relative euglycemia. We report on two patients with type 2 diabetes who presented to the Emergency Department with malaise, nausea and vomiting. Both patients had been taking dapagliflozin for at least six months. A risk factor for the development of ketoacidosis, namely heavy alcohol consumption, was found in one of the patients. Arterial blood gas analysis showed severe metabolic acidosis with increased anion gap, positive serum and urine ketones and normal arterial lactate. The patients were treated in Internal Medicine with intravenous fluids, insulin, sodium bicarbonate and potassium. Dapagliflozin was stopped. Both patients recovered uneventfully. Even in the absence of significant hyperglycemia, accurate interpretation of arterial blood gas analysis and serum ketones should lead to correct diagnosis of euDKA.

Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, 12-week randomised trial

SummaryBackgroundThe achievement of glycaemic control remains challenging for patients with type 1 diabetes. We assessed the effectiveness of day-and-night hybrid closed-loop insulin delivery compared with sensor-augmented pump therapy in people with suboptimally controlled type 1 diabetes aged 6 years and older.MethodsIn this open-label, multicentre, multinational, single-period, parallel randomised controlled trial, participants were recruited from diabetes outpatient clinics at four hospitals in the UK and two centres in the USA. We randomly assigned participants with type 1 diabetes aged 6 years and older treated with insulin pump and with suboptimal glycaemic control (glycated haemoglobin [HbA1c] 7·5–10·0%) to receive either hybrid closed-loop therapy or sensor-augmented pump therapy over 12 weeks of free living. Training on study insulin pump and continuous glucose monitoring took place over a 4-week run-in period. Eligible subjects were randomly assigned using central randomisation software. Allocation to the two study groups was unblinded, and randomisation was stratified within centre by low (<8·5%) or high (≥8·5%) HbA1c. The primary endpoint was the proportion of time that glucose concentration was within the target range of 3·9–10·0 mmol/L at 12 weeks post randomisation. Analyses of primary outcome and safety measures were done in all randomised patients. The trial is registered with ClinicalTrials.gov, number NCT02523131, and is closed to accrual.FindingsFrom May 12, 2016, to Nov 17, 2017, 114 individuals were screened, and 86 eligible patients were randomly assigned to receive hybrid closed-loop therapy (n=46) or sensor-augmented pump therapy (n=40; control group). The proportion of time that glucose concentration was within the target range was significantly higher in the closed-loop group (65%, SD 8) compared with the control group (54%, SD 9; mean difference in change 10·8 percentage points, 95% CI 8·2 to 13·5; p<0·0001). In the closed-loop group, HbA1c was reduced from a screening value of 8·3% (SD 0·6) to 8·0% (SD 0·6) after the 4-week run-in, and to 7·4% (SD 0·6) after the 12-week intervention period. In the control group, the HbA1c values were 8·2% (SD 0·5) at screening, 7·8% (SD 0·6) after run-in, and 7·7% (SD 0·5) after intervention; reductions in HbA1c percentages were significantly greater in the closed-loop group compared with the control group (mean difference in change 0·36%, 95% CI 0·19 to 0·53; p<0·0001). The time spent with glucose concentrations below 3·9 mmol/L (mean difference in change −0·83 percentage points, −1·40 to −0·16; p=0·0013) and above 10·0 mmol/L (mean difference in change −10·3 percentage points, −13·2 to −7·5; p<0·0001) was shorter in the closed-loop group than the control group. The coefficient of variation of sensor-measured glucose was not different between interventions (mean difference in change −0·4%, 95% CI −1·4% to 0·7%; p=0·50). Similarly, total daily insulin dose was not different (mean difference in change 0·031 U/kg per day, 95% CI −0·005 to 0·067; p=0·09) and bodyweight did not differ (mean difference in change 0·68 kg, 95% CI −0·34 to 1·69; p=0·19). No severe hypoglycaemia occurred. One diabetic ketoacidosis occurred in the closed-loop group due to infusion set failure. Two participants in each study group had significant hyperglycaemia, and there were 13 other adverse events in the closed-loop group and three in the control group.InterpretationHybrid closed-loop insulin delivery improves glucose control while reducing the risk of hypoglycaemia across a wide age range in patients with suboptimally controlled type 1 diabetes.FundingJDRF, NIHR, and Wellcome Trust.

Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care

BackgroundIn patients with diabetes, hospitalization can complicate the achievement of recommended glycemic targets. There is increasing evidence that a closed-loop delivery system (artificial pancreas) can improve glucose control in patients with type 1 diabetes. We wanted to investigate whether a closed-loop system could also improve glycemic control in patients with type 2 diabetes who were receiving noncritical care.MethodsIn this randomized, open-label trial conducted on general wards in two tertiary hospitals located in the United Kingdom and Switzerland, we assigned 136 adults with type 2 diabetes who required subcutaneous insulin therapy to receive either closed-loop insulin delivery (70 patients) or conventional subcutaneous insulin therapy, according to local clinical practice (66 patients). The primary end point was the percentage of time that the sensor glucose measurement was within the target range of 100 to 180 mg per deciliter (5.6 to 10.0 mmol per liter) for up to 15 days or until hospital discharge.ResultsThe mean (±SD) percentage of time that the sensor glucose measurement was in the target range was 65.8±16.8% in the closed-loop group and 41.5±16.9% in the control group, a difference of 24.3±2.9 percentage points (95% confidence interval [CI], 18.6 to 30.0; P<0.001); values above the target range were found in 23.6±16.6% and 49.5±22.8% of the patients, respectively, a difference of 25.9±3.4 percentage points (95% CI, 19.2 to 32.7; P<0.001). The mean glucose level was 154 mg per deciliter (8.5 mmol per liter) in the closed-loop group and 188 mg per deciliter (10.4 mmol per liter) in the control group (P<0.001). There was no significant between-group difference in the duration of hypoglycemia (as defined by a sensor glucose measurement of <54 mg per deciliter; P=0.80) or in the amount of insulin that was delivered (median dose, 44.4 U and 40.2 U, respectively; P=0.50). No episode of severe hypoglycemia or clinically significant hyperglycemia with ketonemia occurred in either trial group.ConclusionsAmong inpatients with type 2 diabetes receiving noncritical care, the use of an automated, closed-loop insulin-delivery system resulted in significantly better glycemic control than conventional subcutaneous insulin therapy, without a higher risk of hypoglycemia. (Funded by Diabetes UK and others; ClinicalTrials.gov number, NCT01774565.)

Continuous Glucose Monitoring and Insulin Informed Advisory System with Automated Titration and Dosing of Insulin Reduces Glucose Variability in Type 1 Diabetes Mellitus.

Glucose variability (GV) remains a key limiting factor in the success of diabetes management. While new technologies, for example, accurate continuous glucose monitoring (CGM) and connected insulin delivery devices, are now available, current treatment standards fail to leverage the wealth of information generated. Expert systems, from automated insulin delivery to advisory systems, are a key missing element to richer, more personalized, glucose management in diabetes. Twenty four subjects with type 1 diabetes mellitus (T1DM), 15 women, 37 ± 11 years of age, hemoglobin A1c 7.2% ± 1%, total daily insulin (TDI) 46.7 ± 22.3 U, using either an insulin pump or multiple daily injections with carbohydrate counting, completed two randomized crossover 48-h visits at the University of Virginia, wearing Dexcom G4 CGM, and using either usual care or the UVA decision support system (DSS). DSS consisted of a combination of automated insulin titration, bolus calculation, and CHO treatment advice. During each admission, participants were exposed to a variety of meal sizes and contents and two 45-min bouts of exercise. GV and glucose control were assessed using CGM. The use of DSS significantly reduced GV (coefficient of variation: 0.36 ± 08. vs. 0.33 ± 0.06, P = 0.045) while maintaining glycemic control (average CGM: 155.2 ± 27.1 mg/dL vs. 155.2 ± 23.2 mg/dL), by reducing hypoglycemia exposure (%<70 mg/dL: 3.8% ± 4.6% vs. 1.8% ± 2%, P = 0.018), with nonsignificant trends toward reduction of significant hyperglycemia overnight (%>250 mg/dL: 5.3% ± 9.5% vs. 1.9% ± 4.6%) and at mealtime (11.3% ± 14.8% vs. 5.8% ± 9.1%). A CGM/insulin informed advisory system proved to be safe and feasible in a cohort of 24 T1DM subjects. Use of the system may result in reduced GV and improved protection against hypoglycemia.

Abstract 3933: Circadian timing regimen for alpelisib (NVP-BYL719), a selective inhibitor of the class Ia PI3K isoform alpha to maximize therapeutic index

Abstract The gene encoding for the catalytic subunit of the phosphatidylinositol-3-kinase (PI3K), p110a (PIK3CA) is the most frequently mutated kinase in cancer. This discovery triggered the development of small molecule anti-PI3K inhibitors, such as NVP-BYL719. However, the PI3K / Akt signaling pathway plays not only an important role in promoting cell growth, proliferation and survival but also in regulating glucose homeostasis by directly mediating insulin-stimulated glucose uptake into insulin sensitive tissues (adipocytes and muscles). NVP-BYL719 (a selective inhibitor of the class Ia PI3K isoform alpha) given in the morning is facing on-target tolerability challenge (hyperglycemia) in clinical trials limiting the dose being administered to patient (1). As glucose metabolism is highly impacted by circadian rhythms in patients and rodents, we have decided to adopt an integrative circadian-timing approach in our pre-clinical models to interrogate the benefit of morning vs evening dosing for BYL719. By using a newly developed radio-telemetry technology (2), we were able to record in real time and 'around-the-clock' blood glucose levels in stress-free, freely moving rats dosed with NVP-BYL719 at different regimens. The dynamic profile of hyperglycemia observed after active or inactive period dosing of NVP-BYL719 (50 mg/kg qd p.o.) were similar. Dosing before the inactive phase (10 a.m.) allowed blood glucose to normalize in between 2 doses, which could not be achieved when dosing before the active phase (5 p.m.). After treatment discontinuation a significant hyperglycemia remained for a period up to 12h in the group dosed before the active phase (5 p.m.). Circadian “evening” NVP-BYL719 dosing is associated with a better control of glycaemia. Clinically this could potentially translate to better compliance and longer time on treatment hence better efficacy for patient. Based on these findings we could recommend optimized treatment schedules for future combination experiments in the clinic with NVP-BYL719. 1) Juric et al, “Phase I study of the PI3Kα Inhibitor BYL719, as a Single Agent in Patients with Advanced Solid Tumors (AST)”, Annals of Oncology (2014), 25 (Supp. 4) 2) Brockway et al, “Fully Implantable Arterial Blood Glucose Device for Metabolic Research Applications in Rats for Two Months”, J Diabetes Sci Technol (2015), 9(4):771-81 Citation Format: Christian R. Schnell, Thomas Ferrat, Daniel Wyss, Walter Tinetto, Sonja Tobler, Christine Fritsch, Michael Jensen. Circadian timing regimen for alpelisib (NVP-BYL719), a selective inhibitor of the class Ia PI3K isoform alpha to maximize therapeutic index [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3933.

PBI-4547 Prevents Progression of Prediabetic Condition to Type 1 Diabetes in NOD Mice

Introduction: PBI-4547 is a novel orally active compound that is being developed for potential clinical use in patients suffering from metabolic and inflammatory/fibrosis-related diseases. This study examined the effect of PBI-4547 in NOD mice, a model of type 1 diabetes. Our objective was to demonstrate the efficacy of PBI-4547 to stop the progression of diabetes in mice exhibiting prediabetic glucose escalation. Methods: NOD/ShiLtJ female mice (8 weeks of age) were followed up to the appearance of the first sign of hyperglycemia (three consecutive weeks of glucose increase (over 7 mmol/l). Once identified as prediabetic, mice were randomly allocated to control (receiving vehicle (water)) or PBI-4547 (25 mg/kg/day) groups for treatment by daily gastric gavage for 8 to 12 weeks. Results: Mice treated with vehicle (n=9) evolved to a moderate to severe diabetic condition (glucose levels 11.7-37 mmol/l). Most of these vehicle-treated mice (6/9) survived only a few weeks after the onset of the prediabetic condition. At the opposite, NOD mice treated with PBI-4547 all showed a reversal of their hyperglycemia and none of the observed animals (n=12) evolved to a chronic hyperglycemia (over 11 mmol/l). Survival was also significantly improved in the group treated with PBI-4547 with 8 of 12 mice surviving more than 10 weeks after the onset of treatment. Analysis of insulinemia showed a significant difference between both groups. Immunohistological analysis of pancreas recovered at euthanasia revealed a significant reduction in islet inflammatory cell infiltration. Moreover, NOD mice treated with PBI-4547 maintained normoglycemia despite a reduced number of islets. In fact, PBI-4547 reduced by 30% the number of severely damaged islets. Conclusions: These data suggest that PBI-4547 could preclude the evolution of diabetes in a type 1 model. Disclosure F.A. Leblond: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. K. Hince: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. F. Sarra-Bournet: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. W. Gagnon: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Tremblay: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Cloutier: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. S. Létourneau: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. J. Simard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Leduc: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. B. Grouix: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. P. Laurin: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc.. Board Member; Self; Prometic Life Sciences Inc. L. Gagnon: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc..

Disrupted sphingolipid metabolism following acute clozapine and olanzapine administration

BackgroundSecond generation antipsychotics (SGAs) induce glucometabolic side-effects, such as hyperglycemia and insulin resistance, which pose a therapeutic challenge for mental illness. Sphingolipids play a role in glycaemic balance and insulin resistance. Endoplasmic reticulum (ER) stress contributes to impaired insulin signalling and whole-body glucose intolerance. Diabetogenic SGA effects on ER stress and sphingolipids, such as ceramide and sphingomyelin, in peripheral metabolic tissues are unknown. This study aimed to investigate the acute effects of clozapine and olanzapine on ceramide and sphingomyelin levels, and protein expression of key enzymes involved in lipid and glucose metabolism, in the liver and skeletal muscle.MethodsFemale rats were administered olanzapine (1 mg/kg), clozapine (12 mg/kg), or vehicle (control) and euthanized 1-h later. Ceramide and sphingomyelin levels were examined using electrospray ionization (ESI) mass spectrometry. Expression of lipid enzymes (ceramide synthase 2 (CerS2), elongation of very long-chain fatty acid 1 (ELOVL1), fatty acid synthase (FAS) and acetyl CoA carboxylase 1 (ACC1)), ER stress markers (inositol-requiring enzyme 1 (IRE1) and eukaryotic initiation factor (eIF2α) were also examined.ResultsClozapine caused robust reductions in hepatic ceramide and sphingolipid levels (p < 0.0001), upregulated CerS2 (p < 0.05) and ELOVL1 (+ 37%) and induced significant hyperglycemia (vs controls). In contrast, olanzapine increased hepatic sphingomyelin levels (p < 0.05 vs controls). SGAs did not alter sphingolipid levels in the muscle. Clozapine increased (+ 52.5%) hepatic eIF2α phosphorylation, demonstrating evidence of activation of the PERK/eIF2α ER stress axis. Hepatic IRE1, FAS and ACC1 were unaltered.ConclusionsThis study provides the first evidence that diabetogenic SGAs disrupt hepatic sphingolipid homeostasis within 1-h of administration. Sphingolipids may be key candidates in the mechanisms underlying the diabetes side-effects of SGAs; however, further research is required.

Ameliorating effect of berbamine on hepatic key enzymes of carbohydrate metabolism in high-fat diet and streptozotocin induced type 2 diabetic rats

BackgroundAberrations in the activities of key enzymes of carbohydrate metabolism is well documented in diabetes mellitus. Previous studies have shown that active ingredients in the extracts of Berberis aristata exhibits diverse pharmacological activities in animal models. ObjectiveThe present study was undertaken to investigate whether berbamine (BBM), an alkaloid from the roots of Berberis aristata can ameliorate the altered activities of carbohydrate metabolic enzymes in high fat diet (HFD)/streptozotocin (STZ) induced diabetic rats. ResultsSupplementation of HFD for 4 weeks followed by intraperitonial administration of single low dose of STZ (40 mg/kg b.w.) to Sprague Dawley rats resulted in significant hyperglycemia with a decline in plasma insulin levels. The rats also exhibited decreased hemoglobin with an increase in glycated hemoglobin levels. The activities of hexokinase, glucose-6-phosphate dehydrogenase were decreased whereas increases in the activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase were observed in the hepatic tissues of diabetic control rats. Glycogen content in the hepatic and skeletal muscle tissues were found to be decreased in diabetic rats. Oral administration of BBM for 56 days, dose dependently (50, 100, 200 mg/kg b.w.) improved insulin secretion in diabetic treated rats. Immunohistochemical studies on pancreas revealed a strong immunoreactivity to insulin in BBM treated rats. At the effective dose of 100 mg/kg b.w., BBM restored the altered activities of carbohydrate metabolic enzymes and also improved glycogen content in insulin dependent tissues. ConclusionFrom the biochemical and histochemical data obtained in this study we conclude that BBM ameliorated the activities of metabolic enzymes and maintained glucose homeostasis in HFD/STZ induced diabetic rats and it can be used as a potential phytomedicine for the management of diabetes mellitus.

Pharmacologic Glycemic Management of Type 2 Diabetes in Adults.

Pharmacologic Glycemic Management of Type 2 Diabetes in Adults.

Use of biomarkers to evaluate the ecological risk of xenobiotics associated with agriculture

This research aimed to evaluate the ecological risk of xenobiotics associated with agricultural activities by determining metal contents and biomarker responses using tucunaré (Cichla sp.) as a bioindicator. The work was conducted in the southwest region of the state of Tocantins, in the cities of Lagoa da Confusão and Pium. Water samples and specimens of Cichla sp. were collected in the Javaés and Formoso Rivers at three collection points (A, B and C). The concentrations of Cd, Pb, Cu, Cr, Mn, Ni and Zn in water and fish were analyzed. In fish, genotoxic, biochemical (glucose serum levels, AST (aspartate aminotransferase) and ALT (alanine aminotransferase) and histological (gills and liver) biomarkers were assessed. In the water, the Cr and Mn concentrations at the three collection points exceeded the values for Class 1 rivers. In the muscle, Cr was above the maximum limit allowed for human consumption at the three collection points, although the values at Points B and C were not significantly different from that at Point A (p > 0.05). At the three collection points, the micronucleus test revealed a low frequency of micronuclei. Significant hyperglycemia and a decrease in the AST activity of the fish collected at Point C was observed. In the gills, the most frequent alterations were at Stages I and II, which indicated mild to moderate damage, and epithelial detachment was the most frequent variation. In the liver tissue, the most frequently observed histological changes were at Stages I and II and included cytoplasmic vacuolization, nuclear hypertrophy, dilated sinusoids and bile stagnation. The integrated evaluation of these biomarkers indicated that fish collected from areas with intense agricultural activities presented adaptive responses that were likely caused by the availability and bioaccumulation of certain xenobiotics in the environment.

The Hepatoprotective Effect of Olive Leaf Extract on Diabetic Pregnant Mice and Their Fetuses

Gestational diabetes mellitus (GDM) defined as is a disease with hyperglycemia, insulin resistance and fetal abnormality development. This study was designed to evaluate the hypoglycemic effect and hepatoprotective properties of olive leaves extract.The experimental mice divided into, the control group GI (not diabetic group), and the diabetic pregnant mice groups were divided into: the diabetic pregnant group (GII) single intraperitoneal injected by streptozotocine (STZ, 240mg/Kg b.wt.). The pregnant mice were given a daily oral dose of olive leaf extract (OLE) only (100 mg/kg) from day 1 to 18 of gestation group (GIII). The diabetic pregnant mice were given daily oral dose of olive leaf extract from day 1 to day 18 of gestation, group (GIV). The STZ-induced diabetic group(GII) exhibited a significant (p&lt;0.05) hyperglycemia, accompanied with a significant increase in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), enzyme activitieswhen compared with control group. This result is confirmed with extreme histopathological changes in liver tissues and decreased in glutathione peroxidase (GPx) expression. A significant improvement in glucose level, serum AST and ALT enzyme activities showed in (GIV). Also, OLE succeeded to minimize the severe changes in liver tissues of diabetic pregnant mice and their fetuses. Furthermore, level of (GPx) was returned to near normal level. The findings suggest that OLE have a hepatoprotective effect on pregnant diabetic mice and their fetus.

The Hepatoprotective Effect of Olive Leaf Extract on Diabetic Pregnant Mice and Their Fetuses

Gestational diabetes mellitus (GDM) is a disease with hyperglycemia, insulin resistance and fetal abnormality development. This study was designed to evaluate the hypoglycemic effect and hepatoprotective properties of olive leaves extract.The experimental mice divided into not diabetic group, the control group (GI), and the diabetic pregnant mice were divided into: the diabetic pregnant group (GII) single intraperitoneal injected by streptozotocine (STZ, 240mg/Kg b.wt.). The pregnant mice were given a daily oral dose of olive leaf extract (OLE) only (100 mg/kg) from day 1 to 18 of gestation group (GIII). The diabetic pregnant mice were given daily oral dose of olive leaf extract from day 1 to day 18 of gestation, group (GIV). The STZ-induced diabetic group(GII) exhibited a significant (p&lt;0.05) hyperglycemia, accompanied with a significant increase in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), enzyme activitieswhen compared with control group. This result is confirmed with extreme histopathological changes in liver tissues and decreased in glutathione peroxidase (GPx) expression. A significant improvement in glucose level, serum AST and ALT enzyme activities showed in (GIV). Also, OLE succeeded to minimize the severe changes in liver tissues of diabetic pregnant mice and their fetuses. Furthermore, level of (GPx) was returned to near normal level. The findings suggest that OLE have a hepatoprotective effect on pregnant diabetic mice and their fetus.

Proinflammatory cytokine MIF plays a role in the pathogenesis of type-2 diabetes mellitus, but does not affect hepatic mitochondrial function

BackgroundMacrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays an important role in the pathogenesis of type 2 diabetes mellitus (T2DM). Although the effect of high glucose on liver function has been described, the role of MIF in hepatic mitochondrial function during T2DM has not been studied. ObjectiveWe examine the influence of MIF to hepatic mitochondrial function in T2DM mouse model. MethodsWT and Mif−/− BALB/c mice were treated with a single dose of streptozotocin (STZ). After an 8-week follow-up, serum glucose, proinflammatory cytokines, C-reactive protein (CRP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzyme quantification, and liver histological analyses were performed. Liver mitochondria were extracted, and mitochondrial function was evaluated by oximetry, swelling and peroxide production. ResultsFollowing treatment with STZ, WT mice (WT/STZ) developed significant hyperglycemia and high serum levels of MIF, tumor necrosis factor (TNF)-α, interleukin-β (IL-β), and CRP. Liver damage enzymes ALT and AST were found at high levels. In contrast, Mif−/−STZ lacked serum MIF levels and showed smaller increases in blood glucose, less TNF-α, IL-1β, CPR, ALT and AST, and failure to develop clinical signs of disease compared to the WT/STZ group. Mitochondria extracted from the Mif−/−STZ liver showed similar respiratory control (RC) to WT/STZ or healthy mice with glutamate/malate or succinate as substrates. The four respiratory chain complexes also had comparable activities. WT/STZ-isolated mitochondria showed low swelling with calcium compared to mitochondria from Mif−/−STZ or healthy mice. Peroxide production was comparable in all groups. ConclusionThese results show although high systemic levels of MIF contribute to the development of T2DM pathology, the liver mitochondria remain unaltered. Importantly, the absence of MIF reduced the pathology of T2DM, also without altering liver mitochondrial function. These support MIF as a therapeutic target for the treatment of this disease in humans.

Effect of amlodipine on blood glucose level in euglycemic and streptozotocin induced diabetic Albino rats and its pharmacodynamic interaction with glibenclamide

Background: Diabetes is one of the largest global health emergencies of the 21st century and its co-existence with hypertension is frequent. These conditions often require polypharmacy with possible risk of drug interaction. This study is conducted to investigate the effect of amlodipine on blood glucose level in euglycemic and diabetic rats and its pharmacodynamic interaction with glibenclamide.Methods: Rats were divided into six groups of 6 rats in each group. Group 1 and 3 were non-diabetic given 1% Gum acacia and amlodipine respectively. Group 2, 4, 5 and 6 were made diabetic by using nicotinamide and streptozotocin injection intra peritoneally and given 1% Gum acacia, glibenclamide, amlodipine and amlodipine + glibenclamide respectively for the period of 28 days. Fasting Blood Glucose (FBG) levels were measured before induction of diabetes, 72 hrs after the induction, on day 0, 7th, 14th, 21st and 28th day.Results: Amlodipine produced no significant effect on FBG level in non-diabetic rats but in diabetic rats statistically significant hyperglycemia were observed on day 21st and 28th of study with the ‘p’ value (&lt;0.05). Glibenclamide treated rats shows better controlled FBG level throughout study than concomitant administration of glibenclamide with amlodipine. Significant rise in blood FBG level with ‘P’ value (&lt;0.05) were observed in amlodipine + glibenclamide treated group on 21st and 28th day of study.Conclusions: This study suggest amlodipine produce no effect on the FBG level of normal rats but causes significant hyperglycemia in diabetic rats. Hypoglycemic effect of glibenclamide gets blunted when co-administered with amlodipine.

So Many Antihyperglycemics: How to Choose? A Practical Approach.

Guidelines from around the world have stressed the importance of glycemic control in the management of patients with type 2 diabetes (T2DM) to reduce the risk of developing complications. To achieve this goal, both lifestyle and pharmacologic therapies are available. There are 9 classes of antihyperglycemic therapies available in Canada and each class provides a different mechanism of action to address the pathophysiology of T2DM. Metformin remains the first choice for pharmacologic therapy. Thereafter, individualization is essential. If there is significant hyperglycemia at diagnosis, initial combination therapy should be considered. The choice of therapy after metformin depends on a number of factors with the first consideration being the presence or absence of cardiovascular disease. If present, an agent with proven cardiovascular benefit should be added. Otherwise, individualization should be based on desired glycemic lowering, risk of hypoglycemia, effect on weight, cardiovascular effects, other side effects and accessibility.

Aging-associated metabolic disorder induces Nox2 activation and oxidative damage of endothelial function

Oxidative stress attributable to the activation of a Nox2-containing NADPH oxidase is involved in the development of vascular diseases and in aging. However, the mechanism of Nox2 activation in normal aging remains unclear. In this study, we used age-matched wild-type (WT) and Nox2 knockout (KO) mice at 3–4 months (young); 11–12 months (middle-aged) and 21–22 months (aging) to investigate age-related metabolic disorders, Nox2 activation and endothelial dysfunction. Compared to young mice, middle-aged and aging WT mice had significant hyperglycaemia, hyperinsulinaemia, increased systemic oxidative stress and higher blood pressure. Endothelium-dependent vessel relaxation to acetylcholine was significantly impaired in WT aging aortas, and this was accompanied by increased Nox2 and ICAM-1 expressions, MAPK activation and decreased insulin receptor expression and signaling. However, these aging-associated disorders were significantly reduced or absent in Nox2KO aging mice. The effect of metabolic disorder on Nox2 activation and endothelial dysfunction was further confirmed using high-fat diet-induced obesity and insulin resistance in middle-aged WT mice treated with apocynin (a Nox2 inhibitor). In vitro experiments showed that in response to high glucose plus high insulin challenge, WT coronary microvascular endothelial cells increased significantly the levels of Nox2 expression, activation of stress signaling pathways and the cells were senescent, e.g. increased p53 and β–galactosidase activity. However, these changes were absent in Nox2KO cells. In conclusion, Nox2 activation in response to aging-associated hyperglycaemia and hyperinsulinaemia plays a key role in the oxidative damage of vascular function. Inhibition or knockout of Nox2 preserves endothelial function and improves global metabolism in old age.

A study on HbA1c profile in children with asthma using inhaled corticosteroids

Background: Inhaled corticosteroids (ICS) are the mainstay of treatment for persistent bronchial asthma in children. Even though ICS is comparatively safe, few systemic toxicities have been reported. We have conducted a study on HbA1c profile of 170 asthmatic children who are on ICS for atleast 6 months. Glycosylated hemoglobin (HbA1c), fasting blood sugar (FBS), Postprandial blood sugar (PPBS) levels were measured before initiating ICS and after 6 months using venous blood samples. HbA1c measured using immunoassay. The objective of the study was to detect prevalence of significant hyperglycemia among children with asthma who are on inhaled corticosteroids. Study design used as a prospective follow up study, setting of the study was to Pediatric asthma clinic, Govt. TDMCH, Alappuzha, Study population used Children between 3 to 12 years attending pediatric asthma clinic.Methods: Cumulative doses of ICS and bronchodialators were measured by providing an asthma diary to mark the dose of medication. FBS, PPBS, and HbA1c levels were measured before initiating ICS and after 6 months. To elucidate the assosiations comparisons between different parameters Chi-square test was used as non-parametric test. Student’s T- test was used to compare mean values between 2 groups and different groups. Initial and follow up two groups of HbA1c and ICS administrations were compared using paired and unpaired T-test.Results: There is a significant increase in the mean HbA1c of the total study population before and after treatment with ICS.Conclusions: Long term use of ICS can affect glucose metabolism of asthmatic children.

Perioperative management of the patient with diabetes requiring emergency surgery

Perioperative management of the patient with diabetes requiring emergency surgery

Modulation of Postprandial Glucose Bioavailability in a Cohort of Healthy and Pre-Diabetics Subjects during Ramadan Fasting in C&amp;amp;ocirc;te d’Ivoire

Objective: After the Ramadan fasting period, there is an increasing prevalence of diabetes in Cote d’Ivoire, in diabetes care centers. The objective of this study was to assess the consumption of sugary foods during this period and to determine the risks of diabetes in Muslim populations. Methods: Information was collected on the type and amount of sugary foods consumed. Methods for the preparation of these foods have been determined. Intake frequencies and postprandial glycemic responses were studied. The usual statistical methods were used. Results: Between 70% and 85% of the “fasters” consume plenty of these sugary foods during this period, with an average added sugar level varying between 10% and 35% and a daily consumption of between 250 cl and 0.5 l. The added sugar leads to hyperglycemia in both healthy subjects and pre diabetics. Conclusion: Regular consumption of these sugary foods results in significant hyperglycaemia throughout the month of fasting with a significantly higher blood glucose level in pre diabetic subjects. This makes pre diabetics people more at risk of diabetes among Muslim populations during Ramadan fasting.

Impact of creatinine methodology on glomerular filtration rate estimation in diabetes.

AIMTo evaluate the influence of creatinine methodology on the performance of chronic kidney disease (CKD)-Epidemiology Collaboration Group-calculated estimated glomerular filtration rate (CKD-EPI-eGFR) for CKD diagnosis/staging in a large cohort of diabetic patients.METHODSFasting blood samples were taken from diabetic patients attending our clinic for their regular annual examination, including laboratory measurement of serum creatinine and eGFR.RESULTSOur results indicated an overall excellent agreement in CKD staging (kappa = 0.918) between the Jaffé serum creatinine- and enzymatic serum creatinine-based CKD-EPI-eGFR, with 9% of discordant cases. As compared to the enzymatic creatinine, the majority of discordances (8%) were positive, i.e., associated with the more advanced CKD stage re-classification, whereas only 1% of cases were negatively discordant if Jaffé creatinine was used for eGFR calculation. A minor proportion of the discordant cases (3.5%) were re-classified into clinically relevant CKD stage indicating mildly to moderately decreased kidney function (< 60 mL/min per 1.73 m2). Significant acute and chronic hyperglycaemia, assessed as plasma glucose and HbA1c levels far above the recommended glycaemic goals, was associated with positively discordant cases. Due to a very low frequency, positive discordance is not likely to present a great burden for the health-care providers, while intensified medical care may actually be beneficial for the small number of discordant patients. On the other hand, a very low proportion of negatively discordant cases (1%) at the 60 mL/min per 1.73 m2 eGFR level indicate a negligible possibility to miss the CKD diagnosis, which could be the most prominent clinical problem affecting patient care, considering high risk of CKD for adverse patient outcomes.CONCLUSIONThis study indicate that compensated Jaffé creatinine procedure, in spite of the glucose-dependent bias, is not inferior to enzymatic creatinine in CKD diagnosis/staging and therefore may provide a reliable and cost-effective tool for the renal function assessment in diabetic patients.