Acute Hyperglycemia Research Articles

1,5-Anhydroglucitol as a Marker of Acute Hyperglycemia in Cardiovascular Events.

1,5-anhydroglucitol (1,5-AG) is a biomarker of acute hyperglycemia in diabetology and also in cardiodiabetology. It is used to monitor fluctuating glucose levels. 1,5-AG is a monosaccharide that is biochemically similar to D-glucose and originates from the nutrition. The presence of 1,5-AG in blood and tissue is nearly constant due to reabsorption in the renal proximal tubule. In acute hyperglycemia, renal reabsorption is inhibited by glucose and 1,5- AG is excreted in the urine, while its serum level decreases rapidly. 1,5-AG reflects glucose excursions over 1-3 days to 2 weeks. In this regard, low levels of serum 1,5-AG can be a clinical marker of short- term glycemic derangements such as postprandial hyperglycemia, which is an important risk factor for the pathogenesis of coronary artery disease (CAD) as low levels of 1,5-AG reflect severe plaque calcification in CAD and correlate with high-density lipoprotein cholesterol (HDL-C) levels. For these reasons, 1,5-AG may also be a marker for atherosclerosis; in fact an even better marker than HbA1c or fructosamine which are normally used. 1,5-AG may also be a predictor of cardiovascular disease, left ventricular dysfunction after acute coronary syndrome (ACS), and mortality after ACS. This articles reviews the current knowledge on 1,5-AG related to its use as predictor for cardiovascular events.

Evaluation of peripheral blood polymorphonuclear cell functions after an oral carbohydrate overload in obese and insulin dysregulated horses

Obesity and insulin dysregulation (ID) are increasingly prevalent conditions in equid populations worldwide. Immune impairment is well described in humans with metabolic dysfunction and is reported but still incompletely understood in horses. This study evaluated the effect of acute induced transient hyperglycemia on apoptosis, phagocytosis and oxidative burst activity of peripheral blood polymorphonuclear cells (PMN) of lean and obese adult horses with or without insulin dysregulation. Seventeen adult horses were allocated into three groups based on their body condition score (BCS) and metabolic status: lean-insulin sensitive (lean-IS), obese-insulin sensitive (obese-IS) and obese-insulin dysregulated (obese-ID). ID was determined by insulin tolerance testing (ITT). Blood glucose elevation was induced through an infeed-oral glucose test (in-feed OGT), and all assessments of PMN functions (apoptosis, phagocytosis and oxidative burst) were done in vitro after isolation from peripheral blood before and 120 min after carbohydrate overload. Results were analyzed using a repeated measures linear mixed model with significance defined at P < 0.05. No differences in apoptosis were observed between experimental groups at any time point. Phagocytic capacity was significantly lower at baseline in the obese-ID group but increased in response to glucose administration when compared to the other two groups. Basal reactive oxygen species production in the obese-IS group differed significantly from the lean-IS and obese-ID groups and decreased significantly in response to glucose administration. Results from this study showed that both metabolic status itself, and oral glucose administration, seem to be factors that alter PMN functionality in horses, specifically phagocytosis and oxidative burst.

412-P: Acute Hyperglycemia-Induced Endoplasmic Reticulum and Oxidative Stress Increases Monocyte Cholesterol Content and Cytokine Secretion

Background: Cardiovascular disease (CVD) is an inflammatory disorder enhanced by diabetes. The mechanisms by which recurrent acute hyperglycemia promotes inflammation and CVD are unclear. We showed that acute hyperglycemia mediates increased monocyte cholesterol uptake and cytokine release, but the underlying signaling pathways are unknown. We hypothesized that acute hyperglycemia-induced oxidative and ER stress in circulating monocytes increases cholesterol uptake and a pro-inflammatory phenotype. Methods: Circulating monocytes from 35 healthy subjects were isolated and exposed to euglycemic (5mM) or hyperglycemic (16.7 mM) conditions with or without inhibitors of ER stress (4 phenyl butyric acid) or oxidative stress (N-Acetyl cysteine) for 2 or 6 hrs to assess changes in LDL or oxLDL uptake and cytokine (TNF-α, IL1-β) release. Results: We found that acute hyperglycemia-induced ER and oxidative stress increased total and free cholesterol content via enhanced LDL (18% and 26%, p&amp;lt;0.05) and oxLDL (56% and 30%, p&amp;lt;0.05) uptake as a result of enhanced CD36 and LDL receptor expression. Conversely, inhibiting monocyte oxidative stress or ER stress attenuated monocyte LDL and oxLDL uptake. Finally, blocking monocyte ER stress decreased acute hyperglycemia-induced monocyte TNF-α (87% and 40%, p&amp;lt;0.05) and IL1-β (41% and 44%, p&amp;lt;0.05) secretion after 2 and 6 hrs. Conclusion: Recurrent acute hyperglycemia promotes inflammation by increasing monocyte ER and oxidative stress, which accelerates cholesterol uptake, cholesterol deposition, and cytokine secretion. Future studies are needed to test if acute hyperglycemia-induced monocyte cholesterol deposition is a mechanism to contribute to increased CVD in diabetes. Disclosure R.Zhang: Research Support; American Heart Association. J.Oh: None. G.A.Kutz: None. M.Bambouskova: None. A.S.Dusso: None. C.Bernal-mizrachi: None.

Implication of SMIT1 in ROS-dependent alteration of endothelial function during an acute hyperglycemia

Previous investigations from our group and others revealed that hyperglycemia (HG) impairs vascular endothelial function particularly through an increased oxidative stress. For a long time, little was known about the glucose transport mechanisms responsible for these alterations in the cardiovascular system under HG conditions. However, recent work has shown the involvement of the sodium myo-inositol transporter 1 (SMIT1) of the sodium-glucose co-transporter (SGLT) family in HG-dependent ROS production. However, few studies have focused on the involvement of these transporters in the vascular effects of HG. In this context, we aimed to evaluate the implication of the different SGLT isoforms on the increased oxidative stress and the subsequent vascular dysfunction reported during HG. Firstly, Gene expression of the 7 isoforms of SGLT Transporters was evaluated in vascular tissues by PCR. Then, in order to study the involvement of SGLT/SMIT transporters in HG-related vascular alterations, we incubated (1 hour, 100 mM) aortic rings from Wistar rats with either of the following sugars which each stimulate either one or more isoforms of these transporters (Glucose: GLUTs/SGLTs/SMITs transporters; α-MG: SGLT 1 to 5; Galactose: SGLT 1/2; myo-inositol: SMIT 1/2; L-Fucose: SMIT1). Then, incubated vessels were either mounted in organ chambers to study vascular endothelial function or embedded in OCT in order to measure reactive oxygen species (ROS) production with DHE fluorescence. First, PCR analyses highlighted that SMIT1 appears to be the transporter of the SGLT family whose gene expression is predominant in vascular tissue. As expected from previous studies, vascular exposure to glucose was responsible for an endothelial dysfunction associated with a higher ROS production. Interestingly, endothelial impairments and increased ROS production were not observed when SGLTs were stimulated with either α-MG or galactose. The main result of this work was that myo-inositol exposure was responsible for similar endothelial alteration than glucose and that L-Fucose which transport is highly dependent of SMIT1 was responsible for an exacerbation of those impairments. These results highlight the implication of SMIT1 in the increased oxidative stress and endothelial dysfunctions observed during HG in vascular tissues.

Temsirolimus (T) in patients (pts) with solid tumors with mTOR mutation: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

3114 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of solid tumor pts with mTOR mutation (mut) treated with T are reported. Methods: Eligible pts had solid tumors, no standard treatment (tx) options, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts matched to T had various solid tumors with mTOR mut. After antihistamine pre-treatment, 25 mg T was infused over 30-60 minutes weekly until disease progression. Primary endpoint was disease control (DC), defined as complete (CR) or partial (PR) response, or stable disease at 16+ weeks (wks) (SD 16+) (RECIST v1.1). Low accruing histology-specific cohorts with the same genomic alteration and tx were collapsed into a single histology-pooled cohort for this analysis. For histology-pooled cohorts with sample size ≤28, the results are evaluated based on a one-sided exact binomial test with a null DC rate of 15% vs. 35% (α = 0.10 and power=0.86 for N = 26) and one-sided 90% confidence interval (CI). Other efficacy endpoint estimates are presented with two-sided 95% CIs. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: 29 pts with solid tumors (11 histologies) with mTOR mut were enrolled from June 2016 to June 2020. 3 pts were not evaluable (2 pts, no post-baseline tumor eval; 1 pt, no measurable disease) and excluded from efficacy analyses. The Table shows demographics and outcomes. 2 PR and 10 SD16+ were observed for a DC rate of 46% (one-sided 90% CI: 32% to 100%) and an objective response (OR) rate of 8% (95% CI: 1% to 25%); the null hypothesis of a 15% DC rate is rejected (p&lt;0.001). 5/10 pts with SD16+ had CRC or biliary cancer. Of the 2 pts with PR, one had uterine cancer and T1977R mut and the other had head and neck cancer and I1636V mut. The durations of PR were 12.3 and 23.9 wks, respectively, and median duration of SD was 34.5 wks (range: 18.7, 90.0) for pts with SD16+. 8 pts experienced grade 3 or grade 4 AEs or SAEs at least possibly related to T, including acute kidney injury, epistaxis, hyperglycemia, hypertension, hypertriglyceridemia, mucositis, leukopenia, thrombocytopenia, and pneumonitis. Conclusions: Monotherapy T showed evidence of anti-tumor activity in pts with advanced solid tumors with mTOR mut. Additional study is warranted to confirm the efficacy of T in pts with mTOR mut. Clinical trial information: NCT02693535. [Table: see text]

Effect of hyperglycaemia in combination with moxifloxacin on cardiac repolarization in male and female patients with type I diabetes

BackgroundPatients with Type 1 diabetes mellitus have been shown to be at a two to ten-fold higher risk of sudden cardiac death (SCD) (Svane et al., Curr Cardiol 2020; 22:112) than the general population, but the underlying mechanism is unclear. Hyperglycaemia is a recognised cause of QTc prolongation; a state patients with type 1 diabetes are more prone to, potentially increasing their risk of ventricular arrhythmia. Understanding the QTc prolongation effect of both hyperglycaemia and the concomitant additive risk of commonly prescribed QTc-prolonging drugs such as Moxifloxacin may help to elucidate the mechanism of sudden cardiac death in this cohort. This single-blinded, placebo-controlled study investigated the extent to which hyperglycaemia prolongs the QTc in controlled conditions, and the potential additive risk of QTc-prolonging medications.Methods21 patients with type 1 diabetes mellitus were enrolled to a placebo-controlled crossover study at a single clinical trials unit. Patients underwent thorough QTc assessment throughout the study. A ‘hyperglycaemic clamp’ of oral and intravenous glucose was administered with a target blood glucose of > 25 mM and maintained for 2 h on day 1 and day 3, alongside placebo on day 1 and moxifloxacin on day 3. Day 2 served as a control day between the two active treatment days.Thorough QTc assessment was conducted at matched time points over 3 days, and regular blood sampling was undertaken at matched time intervals for glucose levels and moxifloxacin exposure.ResultsConcentration-effect modelling showed that acute hyperglycaemia prolonged the QTc interval in female and male volunteers with type 1 diabetes by a peak mean increase of 13 ms at 2 h. Peak mean QTc intervals after the administration of intravenous Moxifloxacin during the hyperglycaemic state were increased by a further 9 ms at 2 h, to 22 ms across the entire study population. Regression analysis suggested this additional increase was additive, not exponential.Hyperglycaemia was associated with a significantly greater mean QTc-prolonging effect in females, but the mean peak increase with the addition of moxifloxacin was the same for males and females. This apparent sex difference was likely due to the exclusive use of basal insulin in the male patients, which provided a low level of exogenous insulin during the study assessments thereby mitigating the effects of hyperglycaemia on QTc. This effect was partially overcome by Moxifloxacin administration, suggesting both hyperglycaemia and moxifloxacin prolong QTc by different mechanisms, based on subinterval analysis.ConclusionsHyperglycaemia was found to be a significant cause of QTc prolongation and the additional effect of a QTc-prolonging positive control (moxifloxacin) was found to be additive. Given the high risk of sudden cardiac death in type 1 diabetes mellitus, extra caution should be exercised when prescribing any medication in this cohort for QTc effects, and further research needs to be undertaken to elucidate the exact mechanism underlying this finding and explore the potential prescribing risk in diabetes.Trial RegistrationNCT number: NCT01984827.Graphical abstract

Fasting or the short-term consumption of a ketogenic diet protects against antipsychotic-induced hyperglycaemia in mice.

Antipsychotic (AP) medications, such as olanzapine (OLZ), are used in the treatment of schizophrenia and a growing number of 'off-label' conditions. A single dose of OLZ causes robust increases in blood glucose within minutes of treatment. The purpose of the current study was to investigate whether interventions that increase circulating ketone bodies (fasting, β-hydroxybutyrate (βHB), ketone esters or a ketogenic diet (KD)) would be sufficient to protect against the acute metabolic side effects of OLZ. We demonstrate that fasting or the short-term consumption of a KD protects against OLZ-induced hyperglycaemia, independent of alterations in whole-body insulin action, and in parallel with a blunted rise in serum glucagon. Interestingly, the effects of fasting and KDs were not recapitulated by acutely increasing circulating concentrations of ketone bodies through treatment with βHB or oral ketone esters, approaches which increase ketone bodies to physiological or supra-physiological levels, respectively. Collectively, our findings demonstrate that fasting and the short-term consumption of a KD can protect against acute AP-induced perturbations in glucose homeostasis, whereas manipulations which acutely increase circulating ketone bodies do not elicit the same beneficial effects. KEY POINTS: Antipsychotic medications cause rapid and robust increases in blood glucose. Co-treatment approaches to offset these harmful metabolic side effects have not been identified. We demonstrate that fasting or the consumption of a short-term ketogenic diet, but not treatment with β-hydroxybutyrate or oral ketone esters, protects against acute antipsychotic-induced hyperglycaemia. The protective effects of fasting and ketogenic diets were paralleled by reductions in serum glucagon, but not improvements in whole-body insulin action.

Comparison of Bayesian vs Frequentist Adaptive Trial Design in the Stroke Hyperglycemia Insulin Network Effort Trial

Bayesian adaptive trial design has the potential to create more efficient clinical trials. However, a barrier to the uptake of bayesian adaptive designs for confirmatory trials is limited experience with how they may perform compared with a frequentist design. To compare the performance of a bayesian and a frequentist adaptive clinical trial design. This prospective cohort study compared 2 trial designs for a completed multicenter acute stroke trial conducted within a National Institutes of Health neurologic emergencies clinical trials network, with individual patient-level data, including the timing and order of enrollments and outcome ascertainment, from 1151 patients with acute stroke and hyperglycemia randomized to receive intensive or standard insulin therapy. The implemented frequentist design had group sequential boundaries for efficacy and futility interim analyses at 90 days after randomization for 500, 700, 900, and 1100 patients. The bayesian alternative used predictive probability of trial success to govern early termination for efficacy and futility with a first interim analysis at 500 randomized patients and subsequent interims after every 100 randomizations. The main outcome was the sample size at end of study, which was defined as the sample size at which each of the studies stopped accrual of patients. Data were collected from 1151 patients. As conducted, the frequentist design passed the futility boundary after 936 participants were randomized. Using the same sequence and timing of randomization and outcome data, the bayesian alternative crossed the futility boundary approximately 3 months earlier after 800 participants were randomized. Both trial designs stopped for futility before reaching the planned maximum sample size. In both cases, the clinical community and patients would benefit from learning the answer to the trial's primary question earlier. The common feature across the 2 designs was frequent interim analyses to stop early for efficacy or for futility. Differences between how these analyses were implemented between the 2 trials resulted in the differences in early stopping.

Correlation between HbA1C and Infarct Volume in Acute Ischemic Stroke

BACKGROUND: Stroke is second leading cause of death worldwide. Chronic hyperglycemia can promote neuronal toxicity. The previous study shows that acute hyperglycemia is correlated with infarct volume of ischemic stroke. AIM: This study aims to investigate the correlation between hemoglobin A1C (HbA1C) and infarct volume on acute ischemic stroke. METHODS: This is a cross-sectional study in acute ischemic stroke patient in Dr. Moewardi General Hospital, Surakarta, Indonesia. Data of infarct volume were collected from head computed tomography (CT)-scan and calculated with A × B × C/2 formula. We also collected lipid and patients’ glycemic profile from patients’ blood laboratory result. Head CT-scan and laboratory data of participants analyzed with Pearson and Spearman’s rho test for parametric and non-parametric data, respectively. We also performed multivariate analysis to evaluate confounding covariates. p &lt; 0.05 was considered as statistically significant. RESULTS: A total of 38 participants were included in this study, with mean infarct volume was 0.46 ± 0.64cc and mean HbA1C was 6.96 ± 2.69%. Bivariate analysis shows strong positive correlation between infarct volume and HbA1C with r = 0.898 (p &lt; 0.001). Other variable that showed a significant correlation with infarct volume were diabetes mellitus history (r = 0.671; p &lt; 0.001), random blood su gar (r = 0.466; p = 0.003), fasting blood sugar (r = 0.636; p &lt; 0.001), 2-h postprandial glucose level (r = 0.646; p ≤ 0.001), high density lipoprotein (r = −0.354; p = 0.029), and triglyceride (r = 0.429; p = 0.007). Based on multivariate analysis, HbA1C regression coefficient on infarct volume was B = 0.222 (p &lt; 0.001), indicating that HbA1C as one of the variables contributing to volume of infarct. CONCLUSIONS: There is a strong positive correlation between infarct volume and HbA1C, and HbA1C is variable contribute to the volume of infarct.

FC024: Renal Proximal Tubules CB1 Receptor Modulates MTORC1 Signalling in Health and Disease

Abstract BACKGROUND AND AIMS Diabetic kidney disease (DKD), the renal manifestation of diabetes, contributes to increased morbidity and mortality of patients with diabetes. Activation of the cannabinoid-1 receptor (CB1R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of DKD. However, whether these two signalling molecules interact with each other to regulate kidney function during health and disease has not been described yet. METHOD By using a multidisciplinary approach that includes pharmacological and genetic manipulations of CB1R and mTORC1, we assessed the effect of CB1R activation/inhibition on mTORC1 activity under conditions of acute and chronic hyperglycaemia or normoglycaemia in RPTCs and mice. RESULTS We showed hyperglycaemia-induced endocannabinoid/CB1R stimulation. This stimulation increased mTORC1 activity and resulted in enhancing the expression of sterol regulatory element-binding protein 1c (SREBP1c) and its nuclear translocation, which in turn, induced the transcription of the facilitative glucose transporter 2 (GLUT2), thus leading to the development of DKD in mice. This effect was ameliorated by CB1R or mTORC1 nullification specifically in RPTCs. However, in non-diabetic conditions, CB1R maintained normal activation of mTORC1 by preventing the cellular excess of various amino acids via regulating their transporters, megalin, SLC6A19 and SLC7A5. CONCLUSION Our findings highlight two novel molecular mechanisms by which the activation of mTORC1 in RPTCs is tightly controlled by CB1R, either by enhancing the reabsorption of glucose and inducing renal dysfunction in diabetes or by preventing amino acid uptake and maintaining normal kidney function in healthy conditions. Moreover, this work highlights the therapeutic potential of targeting peripheral CB1Rs for the treatment of DKD, and on the other hand, avoiding its use in non-diabetic patients due to their possible effect on enhancing mTORC1 signalling.

Differential Expression of Microglial BDNF in Response to Acute Hyperglycemia and Hypoxia

Diabetes is one of the most common chronic disorders that affects the homeostasis of several systems including the central nervous system (CNS). Hyperglycemia, main feature of diabetes, is involved in pathogenesis of diabetic neuropathy. In addition, hyperglycemia increases mitochondrial oxygen consumption which leads to hypoxia and affects the neuronal survival, adversely. Brain‐derived neurotrophic (BDNF) is well known as neuroprotective factor which supports the survival of the neurons in the CNS. We hypothesize that microglial BDNF has a protective role against acute hyperglycemia and hypoxia. The objective of this study is to investigate the expression of BDNF in response to hyperglycemia and hypoxia. Murine microglial cell line BV‐2 cultured in Dulbecco's Modified Eagle Medium were used to investigate the effects of increased concentrations (30, 60, 90, 120 mM) at different durations (4, 8, 24 hours) on the viability of microglial cells. In addition, the effects of hypoxia on the survival rate of these cells was also assessed. Gene and protein expression of microglial BDNF was examined in response to increased concentrations of glucose and hypoxia as well as hypoxia inducible factor (HIF1‐alpha). Increased concentrations of glucose produced significant increase in gene expression of microglial BDNF and this response was concentration‐dependent (p &lt; 0.001). On the other hand, gene expression of microglial BDNF was significantly decreased in response to hypoxia (4, 8, 24 hours) and this response was associated with reduced expression of HIF‐1 alpha (p &lt; 0.05). In conclusion, the outcomes of this study demonstrated that expression of microglial BDNF was sensitive to increased concentration of glucose and decreased levels of oxygen. Further investigation will dissect the signaling pathways that are involved in this differential expression to gain a better understanding of the protective role of microglial BDNF against glucose and oxygen variability.

Acute onset movement disorders in diabetes mellitus: A clinical series of 59 patients

Background and purposeNo previous study has assessed the frequency and clinical–radiological characteristics of patients with diabetes mellitus (DM) and acute onset nonchoreic and nonballistic movements. We conducted a prospective study to investigate the spectrum of acute onset movement disorders in DM.MethodsWe recruited all the patients with acute onset movement disorders and hyperglycemia who attended the wards of three hospitals in West Bengal, India from August 2014 to July 2021.ResultsAmong the 59 patients (mean age = 55.4 ± 14.3 years, 52.5% men) who were included, 41 (69.5%) had choreic or ballistic movements, and 18 (30.5%) had nonchoreic and nonballistic movements. Ballism was the most common movement disorder (n = 18, 30.5%), followed by pure chorea (n = 15, 25.4%), choreoathetosis (n = 8, 13.6%), tremor (n = 5, 8.5%), hemifacial spasm (n = 3, 5.1%), parkinsonism (n = 3, 5.1%), myoclonus (n = 3, 5.1%), dystonia (n = 2, 3.4%), and restless leg syndrome (n = 2, 3.4%). The mean duration of DM was 9.8 ± 11.4 years (89.8% of the patients had type 2 DM). Nonketotic hyperglycemia was frequently (76.3%) detected. The majority (55.9%) had no magnetic resonance imaging (MRI) changes; the remaining showed striatal hyperintensity. Eight patients with MRI changes exhibited discordance with sidedness of movements. Most of the patients (76.3%) recovered completely.ConclusionsThis is the largest clinical series depicting the clinical–radiological spectrum of acute onset movement disorders in DM. Of note was that almost one third of patients had nonchoreic and nonballistic movements. Our findings highlight the importance of a capillary blood glucose measurement in patients with acute or subacute onset movement disorders, irrespective of their past glycemic status.

Association Between Insulin Resistance, Oxidative Stress, Sympathetic Activity and Coronary Microvascular Function in Patients With Early Stage Impaired Glucose Metabolism.

Although acute hyperglycemia and insulin resistance (IR) are risk factors for atherosclerosis development through oxidative stress and sympathetic activation in diabetes mellitus, the association of these factors with coronary microvascular function in the early diabetic stage remains controversial.Methods and Results: Using transthoracic echocardiography, coronary flow velocity (CFV) and its reserve (CFVR) as parameters of coronary microvascular function were measured before and 1 h after an oral glucose tolerance test (OGTT) in 40 patients (aged 59±12 years) without diagnosed diabetes mellitus or coronary artery disease. Plasma glucose, insulin and thiobarbituric acid reactive substance (TBARS; an oxidative stress marker) were measured during the OGTT. IR was evaluated as homeostasis model assessment of IR (HOMA-R). Sympathetic activity was evaluated by using plasma catecholamines after OGTT. CFVR decreased after an OGTT (P<0.0001) mainly because of an increased baseline CFV (P<0.0001). Although the change in CFVR was not associated with the change in TBARS and catecholamines, it was independently associated with HOMA-R on the multivariate regression analysis (β=-0.40, P=0.01). Another multivariate regression analysis revealed that change in baseline CFV was independently associated with HOMA-R (β=0.35, P=0.03). IR, rather than oxidative stress and sympathetic activity, was associated with an increase in baseline CFV and a decline in CFVR during acute hyperglycemia. IR might play an important role in increased myocardial oxygen demand and coronary microvascular dysfunction.

Inhibition of p38 MAPK decreases hyperglycemia-induced nephrin endocytosis and attenuates albuminuria

Chronic hyperglycemia, as in diabetes mellitus, may cause glomerular damage with microalbuminuria as an early sign. Noteworthy, even acute hyperglycemia can increase glomerular permeability before structural damage of the glomerular filter can be detected. Despite intensive research, specific antiproteinuric therapy is not available so far. Thus, a deeper understanding of the molecular mechanisms of albuminuria is desirable. P38 MAPK signaling is involved in the development of hyperglycemia-induced albuminuria. However, the mechanism of increased p38 MAPK activity leading to increased permeability and albuminuria remained unclear. Recently, we demonstrated that acute hyperglycemia triggers endocytosis of nephrin, the key molecule of the slit diaphragm, and induces albuminuria. Here, we identify p38 MAPK as a pivotal regulator of hyperglycemia-induced nephrin endocytosis. Activated p38 MAPK phosphorylates the nephrin c-terminus at serine 1146, facilitating the interaction of PKCα with nephrin. PKCα phosphorylates nephrin at threonine residues 1120 and 1125, mediating the binding of β-arrestin2 to nephrin. β-arrestin2 triggers endocytosis of nephrin by coupling it to the endocytic machinery, leading to increased glomerular permeability. Pharmacological inhibition of p38 MAPK preserves nephrin surface expression and significantly attenuates albuminuria.Key messagesAcute hyperglycemia triggers endocytosis of nephrin.Activated p38 MAPK phosphorylates the nephrin c-terminus at serine 1146, facilitating the interaction of PKCα with nephrin.PKCα phosphorylates nephrin at threonine residues 1120 and 1125, mediating the binding of β-arrestin2 to nephrin.β-arrestin2 triggers endocytosis of nephrin by coupling it to the endocytic machinery, leading to a leaky glomerular filter.Pharmacological inhibition of p38 MAPK preserves nephrin surface expression and significantly attenuates albuminuria under hyperglycemic conditions.

Glucocorticoid-induced hyperglycaemia and diabetes: Call for action.

Glucocorticoid-induced hyperglycaemia and diabetes: Call for action.

Intensive insulin therapy improves the survival probability of non-diabetic COVID-19 patients presenting with acute hyperglycemia

ABSTRACT Background Evaluation of the impact of at-admission hyperglycemia and its management on the outcome of non-diabetic COVID-19 patients concerning development of critical illness. Methods In total, 364 patients were categorized according to at-admission random blood glucose (RBG) as persistent hyperglycemic (PHG) if at-admission and 6-hr RBG was >140 mg/dl or as stress hyperglycemic (SHG) if at-admission RBG was >140 mg/dl but decreased 6 hr later. Only PHG patients received intensive insulin therapy (IIT) using dose titration schedule according to Leuven titration protocol. All patients were evaluated for critical illness risk using the COVID-GRAM Critical Illness Risk (CG-CIR) score. Study outcomes are the incidence of critical illness and mortality rate (MR) and its relation with the levels of at-admission RBG and inflammatory markers. Results One hundred and twenty-three patients had PHG and received IIT, and 241 had SHG. Unfortunately, 138 patients developed critical illness and 58 of them deceased with significantly lower incidences among patients who received IIT. Progress to critical disease and mortality were significantly correlated with high CG-CIS scores, RBG and serum levels of CRP and IL-6 but showed negative significant correlation with the application of IIT. The automatic linear modeling analysis defined high at-admission RBG as the most important predictor for progress to critical illness (57%) and mortality (60%), and the Mentel-Haenszel statistic defined IIT as a significant independent predictor for survival of critical COVID patients with at-admission hyperglycemia. Conclusion Admission hyperglycemia worsens the outcomes of non-diabetic COVID patients, and this effect is positively correlated with RBG. IIT is a safe and effective management and improves outcomes.

Predictive value of the stress hyperglycemia ratio in patients with acute ST-segment elevation myocardial infarction: insights from a multi-center observational study

BackgroundStress hyperglycemia is a strong predictor of adverse outcomes in patients with acute myocardial infarction (AMI). Recently, the stress hyperglycemia ratio (SHR) has been designed as an index to identify acute hyperglycemia with true risk; however, data regarding the impact of SHR on the prognosis of ST-segment elevation myocardial infarction (STEMI) remains limited. This study aimed to evaluate the predictive value of the SHR in patients with acute STEMI and to assess whether it can improve the predictive efficiency of the Thrombolysis in Myocardial Infarction (TIMI) risk score.MethodsThis study included 7476 consecutive patients diagnosed with acute STEMI across 274 emergency centers. After excluding 2052 patients due to incomplete data, 5417 patients were included in the final analysis. Patients were divided into three groups according to SHR tertiles (SHR1, SHR2, and SHR3) and were further categorized based on diabetes status. All patients were followed up for major cardiovascular adverse events (MACEs) and all-cause mortality.ResultsAfter 30 days of follow-up, 1547 MACEs (28.6%) and 789 all-cause deaths (14.6%) occurred. The incidence of MACEs was highest among patients in the SHR3 group with diabetes mellitus (DM) (42.6%). Kaplan–Meier curves demonstrated that patients with SHR3 and DM also had the highest risk for MACEs when compared with other groups (p < 0.001). Moreover, C-statistics improved significantly when SHR3 was added into the original model: the ΔC-statistics (95% confidence interval) were 0.008 (0.000–0.013) in the total population, 0.010 (0.003–0.017) in the DM group, and 0.007 (0.002–0.013) in the non-DM group (all p < 0.05). In the receiver operating characteristic analysis, the area under the curve (AUC) for the original TIMI risk score for all-cause death was 0.760. When an SHR3 value of 1 point was used to replace the history of DM, hypertension, or angina in the original TIMI risk score, the Delong test revealed significant improvements in the AUC value (∆AUC of 0.009, p < 0.05), especially in the DM group (∆AUC of 0.010, p < 0.05).ConclusionThe current results suggest that SHR is independently related to the risks of MACEs and mortality in patients with STEMI. Furthermore, SHR may aid in improving the predictive efficiency of the TIMI risk score in patients with STEMI, especially those with DM.

Impact of glycemia and insulin treatment in fatal outcome of severe fever with thrombocytopenia syndrome

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with a high fatality rate. How the glucose level might affect the clinical outcome remains obscure. MethodsA multicenter study was performed in 2 hospitals from 2011 to 2021. Patients with SFTS and acute hyperglycemia (admission fasting plasma glucose [FPG] ≥7 mmol/L), postadmission hyperglycemia (admission FPG <7 mmol/L but FPG ≥7 mmol/L after admission), and euglycemia (FPG <7 mmol/L throughout hospitalization) were compared for their clinical progress and outcomes. ResultsA total of 3225 patients were included in this study, 37.9% of whom developed acute hyperglycemia and 7.6% postadmission hyperglycemia. The presence of acute hyperglycemia, with or without known diabetes, was associated with increased risk of death (odds ratio [OR]: 1.63; 95% confidence interval [CI]: 1.29-2.05) compared with euglycemia. This effect, however, was only determined in female patients (OR: 2.15; 95% CI: 1.54-2.93). Insulin treatment of patients with SFTS and acute hyperglycemia without previous diabetes was associated with significantly increased mortality (OR: 1.58; 95% CI: 1.16-2.16). ConclusionAcute hyperglycemia can act as a strong predictor of SFTS-related death in female patients. Insulin treatment of hyperglycemia in patients with SFTS without pre-existing diabetes has adverse effects.

Intensive Versus Standard Treatment of Hyperglycemia in Acute Ischemic Stroke Patient: A Randomized Clinical Trial Subgroups Analysis.

Background:Benefit from blood glucose (BG) control during acute ischemic stroke may depend on glycemic parameters. We evaluated for associations between the SHINE (Stroke Hyperglycemia Insulin Network Effort) randomized treatment group and the SHINE predefined 90-day functional outcome, within-patient subgroups defined by various glycemic parameters.Methods:The SHINE Trial randomized 1151 patients within 12 hours with acute ischemic stroke and hyperglycemia to standard (target BG 80–179 mg/dL) or intensive (target BG 80–130 mg/dL) BG control for 72 hours. We predefined 6 glycemic parameters: acute BG level, absence versus presence of diagnosed and undiagnosed diabetes, hemoglobin A1c, glycemic gap (acute BG–average daily hemoglobin A1c based BG), stress hyperglycemia ratio (acute BG/average daily hemoglobin A1c based BG), and BG variability (SD). Favorable functional outcome was defined by the SHINE Trial and based on the modified Rankin Scale score at 90 days, adjusted for stroke severity. We computed relative risks adjusted for baseline stroke severity and thrombolysis use.Results:Likelihood for favorable outcome was lowest among patients with undiagnosed diabetes compared to patients with true nondiabetes (adjusted relative risk, 0.42 [99% CI, 0.19–0.94]). We did not find any relationship between the favorable outcome rate and baseline BG or any of the glycemic parameters. No differences between SHINE treatment groups were identified among any of these patient subgroups.Conclusions:In this exploratory subgroup analysis, intensive versus standard insulin treatment of hyperglycemia in acute ischemic stroke patient subgroups, did not influence the 90-day functional outcomes, nor did we identify associations between these glycemic parameters and 90-day functional outcomes.

Measuring of Advanced Glycation End Products in Acute Stroke Care: Skin Autofluorescence as a Predictor of Ischemic Stroke Outcome in Patients with Diabetes Mellitus.

Background: Patients with diabetes mellitus (DM) are known to show poor recovery after stroke. This specific burden might be due to acute and chronic hyperglycemic effects. Meanwhile, the underlying mechanisms are a cause of discussion, and the best measure to predict the outcome is unclear. Skin autofluorescence (SAF) reflects the in-patient load of so-called advanced glycation end products (AGEs) beyond HbA1c and represents a valid and quickly accessible marker of chronic hyperglycemia. We investigated the predictive potential of SAF in comparison to HbA1c and acute hyperglycemia on the functional outcome at 90 days after ischemic stroke in a cohort of patients with DM. Methods: We prospectively included 113 patients with DM type 2 hospitalized for acute ischemic stroke. SAF was measured on each patient’s forearm by a mobile AGE-Reader mu© in arbitrary units. HbA1c and the area under the curve (AUC) of the blood sugar profile after admission were assessed. Functional outcome was assessed via phone interview after 90 days. A poor outcome was defined as a deterioration to a modified Rankin Scale score ≥ 3. A good outcome was defined as a modified Rankin Scale score < 3 or as no deterioration from premorbid level. Results: Patients with a poor outcome presented with higher values of SAF (mean 3.38 (SD 0.55)) than patients with a good outcome (mean 3.13 (SD 0.61), p = 0.023), but did not differ in HbA1c and acute glycemia. In logistic regression analysis, age (p = 0.021, OR 1.24 [1.12–1.37]) and SAF (p = 0.021, OR 2.74 [1.16–6.46]) significantly predicted a poor outcome, whereas HbA1c and acute glycemia did not. Patients with a poor 90-day outcome and higher SAF experienced more infections (4.2% vs. 33.3% (p < 0.01)) and other various in-hospital complications (21.0% vs. 66.7% (p < 0.01)) than patients with a good outcome and lower SAF levels. Conclusions: SAF offers an insight into glycemic memory and appears to be a significant predictor of poor stroke outcomes in patients with DM exceeding HbA1c and acute glycemia. Measuring SAF could be useful to identify specifically vulnerable patients at high risk of complications and poor outcomes.