Acute Hyperglycemia Research Articles

Acute-to-chronic glycemic ratio as an outcome predictor in ischemic stroke in patients with and without diabetes mellitus

ObjectiveElevated plasma glucose levels are common in patients suffering acute ischemic stroke (AIS), and acute hyperglycemia has been defined as an independent determinant of adverse outcomes. The impact of acute-to-chronic glycemic ratio (ACR) has been analyzed in other diseases, but its impact on AIS prognosis remains unclear. The main aim of this study was to assess whether the ACR was associated with a 3-month poor prognosis in patients with AIS.Research, design and methodsRetrospective analysis of patients admitted for AIS in Hospital del Mar, Barcelona. To estimate the chronic glucose levels (CGL) we used the formula eCGL= [28.7xHbA1c (%)]-46.7. The ACR (glycemic at admission / eCGL) was calculated for all subjects. Tertile 1 was defined as: 0.28–0.92, tertile 2: 0.92–1.13 and tertile 3: > 1.13. Poor prognosis at 3 months after stroke was defined as mRS score 3–6.Results2.774 subjects with AIS diagnosis were included. Age, presence of diabetes, previous disability (mRS), initial severity (NIHSS) and revascularization therapy were associated with poor prognosis (p values < 0.05). For each 0.1 increase in ACR, there was a 7% increase in the risk of presenting a poor outcome. The 3rd ACR tertile was independently associated with a poor prognosis and mortality. In the ROC curves, adding the ACR variable to the classical clinical model did not increase the prediction of AIS prognosis (0.786 vs. 0.781).ConclusionsACR was positively associated with a poor prognosis and mortality at 3-months follow-up after AIS. Subjects included in the 3rd ACR tertile presented a higher risk of poor prognosis and mortality. Baseline glucose or ACR did not add predictive value in comparison to only using classical clinical variables.

Phase II study of vemurafenib in children and young adults with tumors harboring BRAF V600 mutations: NCI-COG pediatric MATCH trial (APEC1621) Arm G.

This is a phase II subprotocol of the NCI-COG Pediatric MATCH study evaluating vemurafenib, a selective oral inhibitor of BRAF V600 mutated kinase, in patients with relapsed or refractory solid tumors harboring BRAF V600 mutations. Patients received vemurafenib at 550 mg/m2 (maximum 960 mg/dose) orally twice daily for 28-day cycles until progression or intolerable toxicity. The primary aim was to determine the objective response rate and secondary objectives included estimating progression-free survival and assessing the tolerability of vemurafenib. Twenty-two patients matched to the subprotocol and 4 patients (18%) enrolled. Primary reasons for non-enrollment were ineligibility due to exclusions of low-grade glioma (n = 7) and prior BRAF inhibitor therapy (n = 7). Enrolled diagnoses were one each of histiocytosis, ameloblastoma, Ewing sarcoma, and high-grade glioma, all with BRAF V600E mutations. Treatment was overall tolerable with mostly expected grade 1/2 adverse events (AE). Grade 3 or 4 AE on treatment were acute kidney injury, hyperglycemia, and maculopapular rash. One patient came off therapy due to AE. One patient (glioma) had an objective partial response and remained on protocol therapy for 15 cycles. There was a low accrual rate on this MATCH subprotocol, with only 18% of those who matched with BRAFV600 mutations enrolling, resulting in early termination, and limiting study results (ClinicalTrials.gov Identifier: NCT03220035).

1783-LB: Acute Hyperglycemia Induces Human Podocyte Apoptosis by Increasing Monocyte Release of TNF-α through ER Stress/ROS Activation of ADAM17/iRhom2 Expression

1783-LB: Acute Hyperglycemia Induces Human Podocyte Apoptosis by Increasing Monocyte Release of TNF-α through ER Stress/ROS Activation of ADAM17/iRhom2 Expression

1980-LB: Post-recovery of Acute Hyperglycemia during Hospitalization and Incident Cardiovascular Health Outcomes

1980-LB: Post-recovery of Acute Hyperglycemia during Hospitalization and Incident Cardiovascular Health Outcomes

Accuracy of acute hyperglycemia as a biomarker of severe brain damage in children with traumatic brain injury.

Biomarkers are substances measured at the systemic level to evaluate organic responses in certain situations, establishing diagnoses, disease staging, and prognosis. Blood glucose is a biomarker recognized as a predictor of prognosis in children victims of traumatic brain injury (TBI). The scope of this study was to identify the accuracy of blood glucose as a biomarker of severe brain injury. A retrospective analytical study was conducted through the consecutive review of medical records of children and teenage victims of TBI who underwent neurological surgery between 2016 and 2023 in a level 1 trauma center. Two groups were compared: children with Glasgow Coma Scale (GCS) score ≤ 8 and children with GCS > 8. We calculated the predictive values to define the accuracy of blood glucose as a biomarker of brain injury. Ninety-two medical records were included for analysis. Hyperglycemia predominated in cases with GCS ≤ 8 (48% vs 3%; p < 0.0001; OR, 30; 95% CI, 5.9902-150.2448). The glycemic measurement considering the cutoff point of 200 mg/dL or 11.1 mmol/L showed a specificity of 97%, a positive predictive value of 86%, an accuracy of 84%, and a likelihood ratio for a positive test of 16. Victims with GCS ≤ 8 are 16 times more likely to develop acute hyperglycemia after TBI when compared to those with GCS > 8. Blood glucose is a biomarker with an accuracy of 84% to predict severe brain injury, considering the cutoff point of 200 mg/dL or 11.1 mmol/L.

Renal handling of albumin in rats with early stage diabetes: A theoretical analysis.

In early diabetic nephropathy (DN), recent studies have shown that albuminuria stems mostly from alterations in tubular function rather than from glomerular damage. Several factors in DN, including hyperfiltration, hypertrophy and reduced abundance of the albumin receptors megalin and cubilin, affect albumin endocytosis in the proximal tubule (PT). To assess their respective contribution, we developed a model of albumin handling in the rat PT that couples the transport of albumin to that of water and solutes. Our simulations suggest that, under basal conditions, ∼75% of albumin is retrieved in the S1segment. The model predicts negligible uptake in S3, as observed experimentally. It also accurately predicts the impact of acute hyperglycaemia on urinary albumin excretion. Simulations reproduce observed increases in albumin excretion in early DN by considering the combined effects of increased glomerular filtration rate (GFR), osmotic diuresis, hypertrophy, and megalin and cubilin downregulation, without stipulating changes in glomerular permselectivity. The results indicate that in isolation, glucose-elicited osmotic diuresis and glucose transporter upregulation raise albumin excretion only slightly. Enlargement of PT diameter not only augments uptake via surface area expansion, but also reduces fluid velocity and thus shear stress-induced stimulation of endocytosis. Overall, our model predicts that downregulation of megalin and cubilin and hyperfiltration both contribute significantly to increasing albumin excretion in rats with early-stage diabetes. The results also suggest that acute sodium-glucose cotransporter 2 inhibition lowers albumin excretion only if GFR decreases sufficiently, and that angiotensin II receptor blockers mitigate urinary albumin loss in early DN in large part by upregulating albumin receptor abundance. KEY POINTS: The urinary excretion of albumin is increased in early diabetic nephropathy (DN). It is difficult to experimentally disentangle the multiple factors that affect the renal handling of albumin in DN. We developed a mathematical model of albumin transport in the rat proximal tubule (PT) to examine the impact of elevated plasma glucose, hyperfiltration, PT hypertrophy and reduced abundance of albumin receptors on albumin uptake and excretion in DN. Our model predicts that glucose-elicited osmotic diuresis per se raises albumin excretion only slightly. Conversely, increases in PT diameter and length favour reduced albumin excretion. Our results suggest that downregulation of the receptors megalin and cubilin in PT cells and hyperfiltration both contribute significantly to increasing albumin excretion in DN. The model helps to better understand the mechanisms underlying urinary loss of albumin in early-stage diabetes, and the impact of specific treatments thereupon.

Blood Pressure Variability is Better Associated with Acute Relative Hyperglycemia Than the Heart Rate Variability in Healthy Young Adults.

Deranged cardiovascular autonomic functions are well-reported complications of diabetes mellitus, where chronic hyperglycemia is an important factor. The role of acute relative hyperglycemia on cardiovascular autonomic functions, particularly on blood pressure variability in healthy subjects, has been rarely explored. Therefore, this study aimed to examine the effect of acute relative hyperglycemia on cardiovascular autonomic functions in healthy young adults. Beat-to-beat blood pressure and electrocardiogram were recorded to assess the heart rate variability and blood pressure variability in 42 young, healthy subjects during fasting and relative hyperglycemic states. Recorded cardiovascular parameters were analyzed in time and frequency domains. Correlations among analyzed parameters of cardiovascular autonomic variabilities were explored during fasting and relative hyperglycemic state. A few of the systolic, mean, and diastolic blood-pressure-variability parameters were significantly altered during acute relative hyperglycemia when compared to the fasting state. However, no significant changes were observed in any of the heart-rate-variability parameters. Also, novel significant correlations were found among many of the parameters of cardiovascular autonomic variabilities during fasting and relative hyperglycemic states. The blood pressure variability is affected significantly during acute relative hyperglycemia in healthy young adults; however, the heart rate variability does not show such changes. Also, many blood pressure variability parameters show significant correlations with heart rate variability and baroreflex sensitivity. It may be hypothesized that although the variabilities in heart rate and blood pressure assess cardiovascular autonomic functions, blood pressure variability is a better indicator of cardiovascular autonomic effects of acute relative hyperglycemia.

Association between Glycemic Gap at Admission and In-Hospital Outcome in Patients with Diabetes with Acute Myocardial Infarction

Background: Acute hyperglycemia predicts adverse outcomes in patients with acute myocardial infarction (AMI), but it has a major disadvantage because the association is diminished in patients with diabetes mellitus (DM). Recent studies introduced a more accurate predictor, the glycemic gap (the difference between admission blood glucose and the estimated average glucose), that could anticipate adverse outcomes in patients with diabetes with AMI. Aims: This study aimed to determine the association between glycemic gap and clinical outcome in diabetic patients presenting with AMI to a tertiary hospital in Bangladesh. Methods: Two hundred twenty diabetic patients hospitalized with AMI were included in this study from the Department of Cardiology of Chittagong Medical College Hospital from March 2023 to February 2024. Admission blood glucose and HbA1c were measured, and the glycemic gap was calculated. Patients were prospectively followed during their hospital stay to obtain data regarding major adverse cardiac events (MACEs). Results: The mean (±SD) age of the patients was 56.5 (±10.1) years and 63.6% of them were male. MACEs included in-hospital death, cardiac arrest, cardiogenic shock, arrhythmia and left ventricular failure were observed in 6.4%, 3.6%, 19.5%, 5.5%, and 30.5% of the patients, respectively. Ninety-nine (45%) patients had one or more MACEs. Median (IQR) glycemic gap values were 38.5 (31.9-47.3) and 71.0 (61.0-84.3) in patients without any MACEs and patients with one or more MACEs, respectively (p&lt;0.001). Median (IQR) glycemic gap values were 90.6 (86.0-97.9) and 52.6 (36.1-69.3) in expired and survived patients, respectively (p&lt;0.001). The area under the receiver operating characteristics curve (AUROC) for admission glycemic gap values to predict in-hospital mortality was 0.895[95% confidence interval (CI) 0.768-1.000, p&lt;0.001] and with the best cut-off value of 80.16, glycemic gap had sensitivity and specificity of 92.9% and 89.8%, respectively.The Area Under ROC for admission glycemic gap values to predict MACEs was 0.926 (95% CI 0.874-0.958) and with the best cut-off value of 53.19, glycemic gap had a sensitivity and specificity of 94.9% and 84.3%, respectively. Glycemic gap was an independent predictor of MACEs [odds ratio (OR): 1.11, 95% CI 1.08-1.14, p &lt;0.001] and in-hospital mortality (OR: 1.09, 95% CI 1.05-1.14, p &lt;0.001). Conclusions: Elevated glycemic gap was significantly associated with an increased in-hospital mortality and other MACEs. So, glycemic gap can be used to assess the prognosis of hospitalized AMI patients with diabetes.

Acute Hyperglycemia Induced by Hyperglycemic Clamp Affects Plasma Amyloid-β in Type 2 Diabetes.

Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer's disease (AD). Mis-metabolism with aggregation of amyloid-β peptides (Aβ) play a key role in AD pathophysiology. Therefore, human studies on Aβ metabolism and T2D are warranted. The objective of this study was to examine whether acute hyperglycemia affects plasma Aβ1-40 and Aβ1-42 concentrations in individuals with T2D and matched controls. Ten participants with T2D and 11 controls (median age, 69 years; range, 66-72 years) underwent hyperglycemic clamp and placebo clamp (saline infusion) in a randomized order, each lasting 4 hours. Aβ1-40, Aβ1-42, and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aβ1-40 and Aβ1-42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration. At baseline, Aβ1-40 and Aβ1-42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aβ decreased in the control group, compared to the placebo clamp (Aβ1-40: p = 0.034, Aβ1-42: p = 0.020), IDE increased (p = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aβ or IDE was noted in the T2D group. Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aβ40 and Aβ42 clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D.

From high dose Insulin therapy to dual oral therapy: recovery from glucotoxicity after acute pancreatitis and severe ketoacidotic hyperglycaemia

From high dose Insulin therapy to dual oral therapy: recovery from glucotoxicity after acute pancreatitis and severe ketoacidotic hyperglycaemia

Acute and chronic hyperglycemia blunts microvascular reactivity in postmenopausal women with type 2 diabetes

Type 2 diabetes (T2D) is strongly associated with increased risk of cardiovascular diseases via endothelial dysfunction. Hyperglycemia causes microvascular endothelial dysfunction and reduces muscle perfusion. Near-infrared spectroscopy (NIRS) measures microvascular reactivity in skeletal muscle during vascular occlusion/reperfusion. However, the impact of acute and chronic hyperglycemia on macrovascular endothelial function (brachial flow-mediated dilation, FMD) and microvascular reactivity (NIRS-derived tissue oxygen saturation index, TOI) has not been examined in postmenopausal women with and without T2D. We hypothesized that T2D women would have decreased FMD and TOI responsiveness in the fasted condition and greater vascular impairments during acute hyperglycemia compared to controls.Ten T2D (61 ± 5 years) and 10 normoglycemic postmenopausal women (CON, 62 ± 7 years) participated in the study. Hemoglobin A1C (HbA1C) and blood glucose were measured by finger prick at baseline (fasted condition). Brachial artery FMD was evaluated using ultrasound. Forearm muscle TOI magnitude and slope during arterial occlusion and reperfusion periods were measured using NIRS. An oral glucose tolerance test (OGTT) was performed to induce acute hyperglycemia. Blood glucose, FMD, and TOI were measure at baseline and 1 hour (1-h) after OGTT. Abdominal fat was assessed by waist circumference and visceral adipose tissue (VAT) obtained by a whole-body dual-energy X-ray absorptiometry scan.Fasting HbA1C and glucose, waist circumference, and VAT were higher in T2D compared to CON (all p &lt; 0.05). The increase in blood glucose at 1-h was higher in T2D (Δ143 ± 15 mg/dl) compared to CON (Δ49 ± 5 mg/dl) (p &lt; 0.01). FMD at baseline and the decreases in FMD at 1-h were similar in T2D (Δ-2.2 ± 0.2%) and CON groups (Δ-1.9 ± 0.4%) (all p &lt; 0.01). At baseline, T2D showed blunted TOI occlusion magnitude (T2D: -16 ± 1 vs. CON: -21 ± 2%), TOI occlusion slope (T2D: -0.05 ± 0.01 vs. CON: -0.07 ± 0.01), TOI reperfusion magnitude (T2D: 21 ± 2 vs. CON: 32 ± 3%), and TOI reperfusion slope (T2D: 0.79 ± 0.10 vs. CON: 1.19 ± 0.14) compared to CON (all p &lt; 0.05). At 1-h, T2D exhibited lower TOI occlusion magnitude (T2D: -17 ± 2 vs. CON: -24 ± 3%), TOI occlusion slope (T2D: -0.06 ± 0.01 vs. CON: -0.08 ± 0.01), TOI reperfusion magnitude (T2D: 23 ± 2 vs. CON: 33 ± 4%), and TOI reperfusion slope (T2D: 0.90 ± 0.19 vs. CON: 1.14 ± 0.15) compared to CON (all p &lt; 0.05). HbA1C, a measure of chronic hyperglycemia, was positively correlated with VAT (r = 0.514, p = 0.02) and TOI occlusion slope (r = 0.460, p = 0.04) and negatively correlated with TOI reperfusion magnitude (r = -0.506, p = 0.02) and slope at baseline (r = -0.493, p = 0.03). In conclusion, women with T2D exhibited blunted microvascular reactivity despite similar FMD compared with normoglycemic women in the fasted condition. Acute hyperglycemia further blunted microvascular function, but not macrovascular endothelial function, in women with T2D. Blunted microvascular reactivity was associated with chronic hyperglycemia and elevated VAT in postmenopausal women. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Histone Deacetylase Inhibition Increases Glycerol Uptake in Normal and Hyperglycemic Conditions in Human Corneal Epithelial Cells

Delayed corneal wound healing, such as is seen in diabetes, can lead to visual impairment. Diabetes afflicts over 30 million Americans and leads to multiple comorbidities. Histone deacetylase (HDAC) expression and activity are increased in diabetes in correlation with an upregulation of inflammatory molecules and reactive oxygen species (ROS). HDACs have been previously found to suppress the expression of the glycerol channel aquaporin-3 (AQP3) in epithelial cells of the skin, the epidermal keratinocytes. Global deletion of AQP3 in mice has been found to delay corneal wound healing. We hypothesized that hyperglycemic conditions would decrease AQP3 levels and function while increasing the expression of HDAC(s), ROS scavenger proteins, and inflammatory mediators in human corneal epithelial cells (HCECs). HCECs were incubated for 48-hours in high glucose (25.5 mM) or normal glucose (~5.0 mM osmotically matched by mannitol) conditions. Under hyperglycemic conditions, the mRNA expression of interleukin-1α and -1β was significantly elevated, providing evidence for a pro-inflammatory effect of acute hyperglycemia in HCECs. Under these conditions, there was a significant increase in the mRNA expression of the ROS scavenger genes, superoxide dismutase-1 and -2 and peroxiredoxin-3 and -6, suggesting a compensatory response to an increase in ROS generation. Under acute hyperglycemic conditions, HDAC3 and HDAC8 mRNA expression also tended to increase while HDAC1 and HDAC2 mRNA levels remained unchanged. Although an upregulation of HDAC expression would be predicted to decrease AQP3 expression, AQP3 mRNA and protein expression levels were also unchanged. In addition, acute hyperglycemia (48 hours) did not alter glycerol transport into the HCECs, as measured by their uptake of radiolabeled [14C]-glycerol. However, HDAC inhibition using the broad-spectrum inhibitor SAHA for 24 hours increased [14C]-glycerol uptake under both normoglycemic and hyperglycemic conditions, suggesting that HDAC activity plays a role in AQP3 function. Overall, acute hyperglycemic conditions were pro-inflammatory and led to increased expression of ROS-scavenging genes; hyperglycemia also tended to upregulate HDAC expression, although without affecting AQP3 expression. On the other hand, HDAC inhibition increased glycerol uptake, an indicator of AQP3 function, suggesting an ability of HDAC activity to regulate AQP3 glycerol transport activity. National Institutes of Health/National Eye Institute award #R01EY030576 (to MW and WBB) VA Merit #BX005055 (to WBB). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hyperglycemia Is Associated With Computed Tomography Perfusion Core Volume Underestimation in Patients With Acute Ischemic Stroke With Large-Vessel Occlusion.

CT Perfusion (CTP) predictions of infarct core play an important role in the determination of treatment eligibility in large vessel occlusion (LVO) acute ischemic stroke (AIS). Prior studies have demonstrated that blood glucose can affect cerebral blood flow (CBF). Here we examine the influence of acute and chronic hyperglycemia on CTP estimations of infarct core. From our prospectively collected multi-center observational cohort, we identified patients with LVO AIS who underwent CTP with RAPID (IschemaView, Stanford, CA) post-processing, followed by endovascular therapy with substantial reperfusion (TICI 2b-3) within 90 minutes, and final infarct volume (FIV) determination by MRI 48-72 hours post-treatment. Core volume over- and under-estimations were defined as a difference of at least 20 mL between CTP-RAPID predicted infarct core and DWI FIV. Primary outcome was the association of presentation glucose and HgbA1c with underestimation (UE) of core volume and was measured using multivariable logistic regression adjusted for comorbidities and presentation characteristics. Secondary outcomes included frequency of overestimation (OE) of infarct core. Among 256 patients meeting inclusion criteria, median age was 67 [IQR 57-77], 51.6% were female, and 132 (51.6%) and 93 (36.3%) had elevated presentation glucose and elevated HgbA1c, respectively. Median CTP-predicted core was 6 mL [IQR 0-30], median DWI FIV was 14 mL [IQR 6-43] and median difference was 12 mL [IQR 5-35]. Twenty-eight (10.9%) patients had infarct core OE and 68 (26.6%) had UE. Compared to those with no UE, patients with UE had elevated blood glucose (median 119 [103-155] vs 138 [117-195], p=0.002) and HgbA1c (median 5.80 [5.40-6.40] vs 6.40 [5.50-7.90], p=0.009). In multivariable analysis, UE was independently associated with elevated glucose (aOR 2.10, p=0.038) and HgbA1c (aOR 2.37, p=0.012). OE was associated with lower presentation blood glucose (median 109 [ 99-132] in OE vs 127 [107-172] in no OE, p=0.003) and HgbA1c (5.6 [IQR 5.1 - 6.2] in OE vs 5.90 [5.50-6.70] in no OE, p=0.012). Acute and chronic hyperglycemia were strongly associated with CTP UE in patients with LVO AIS undergoing EVT. Glycemic state should be considered when interpreting CTP findings in patients with LVO AIS.

The Knowledge, Attitudes, and Practices Regarding Diabetic Ketoacidosis Among Diabetic Patients in the Northern and Western Regions of Saudi Arabia.

Background and objective Diabetes mellitus (DM) is a chronic debilitating metabolic diseasecaused by insulin deficiency. Diabetic ketoacidosis (DKA) is a potentially fatal complicationcharacterized by acute hyperglycemia and metabolic acidosis. In light of the high prevalence of DM in Saudi Arabia, we sought to investigate the knowledge, attitudes, and practices of the Saudi general population about DKA. Methods An online self-administered questionnaire was distributed through popular social media platforms among diabetics in the Saudi population. The survey questions involved demographic data; diabetesstatusincluding the time of diagnosis, current medications, and the latest HbA1c level; and an assessment of theknowledge about DKA through queries related to diagnostic criteria, definition, risk factors, symptoms, and preventive measures. Results Our study involved 400 participants, and 42.5% of them were able to correctly identify DKA as an emergency requiring immediate medical attention. Regarding the awareness of DKA's symptoms among the participants, 33.8% correctly identified excessive thirst as a key indicator, followed closely by frequent urination (31.8%), and the characteristic fruity breath odor (31.3%). As for the awareness of the participants of the causes of DKA, 33.8%correctly linked forgetting insulin injections to DKA development. Encouragingly, 39.8% of participants identified regular blood sugar monitoring as the most effective way to prevent DKA. Conclusions Most patients in our study demonstrated limited knowledge of DKA. However, a significant portion of them was able to identify it as an emergency. To prevent such events, raising awareness about DM and its complications may serve as the first step toward better outcomes in diabetic patients. We believe our findings can be used to devise quality-improving interventions in this field.

The prognostic value of the stress hyperglycemia ratio for all-cause and cardiovascular mortality in patients with diabetes or prediabetes: insights from NHANES 2005–2018

BackgroundThe Stress hyperglycemia ratio (SHR) is a novel marker reflecting the true acute hyperglycemia status and is associated with clinical adverse events. The relationship between SHR and mortality in patients with diabetes or prediabetes is still unclear. This study aimed to investigate the predictive value of the SHR for all-cause and cardiovascular mortality in patients with diabetes or prediabetes.MethodsThis study included 11,160 patients diagnosed with diabetes or prediabetes from the National Health and Nutrition Examination Survey (2005–2018). The study endpoints were all-cause and cardiovascular mortality, and morality data were extracted from the National Death Index (NDI) up to December 31, 2019. Patients were divided into SHR quartiles. Cox proportion hazards regression was applied to determine the prognostic value of SHR. Model 1 was not adjusted for any covariates. Model 2 was adjusted for age, sex, and race. Model 3 was adjusted for age, sex, race, BMI, smoking status, alcohol use, hypertension, CHD, CKD, anemia, and TG.ResultsDuring a mean follow-up of 84.9 months, a total of 1538 all-cause deaths and 410 cardiovascular deaths were recorded. Kaplan-Meier survival analysis showed the lowest all-cause mortality incidence was in quartile 3 (P < 0.001). Multivariate Cox regression analyses indicated that, compared to the 1st quartile, the 4th quartile was associated with higher all-cause mortality (model 1: HR = 0.89, 95% CI 0.74–10.7, P = 0.226; model 2: HR = 1.24, 95% CI 1.03-1.49, P = 0.026; model 3: HR = 1.30, 95% CI 1.08–1.57, P = 0.006). The 3rd quartile was associated with lower cardiovascular mortality than quartile 1 (model 1: HR = 0.47, 95% CI 0.32–0.69, P < 0.001; model 2: HR = 0.66, 95% CI 0.45–0.96, P = 0.032; model 3: HR = 0.68, 95% CI 0.46–0.99, P = 0.049). There was a U-shaped association between SHR and all-cause mortality and an L-shaped association between SHR and cardiovascular mortality, with inflection points of SHR for poor prognosis of 0.87 and 0.93, respectively.ConclusionSHR is related to all-cause and cardiovascular mortality in patients with diabetes or prediabetes. SHR may have predictive value in those patients.

Prognostic effect of stress hyperglycemia ratio on patients with severe aortic stenosis receiving transcatheter aortic valve replacement: a prospective cohort study

BackgroundStress hyperglycemia ratio (SHR) has recently been recognized as a novel biomarker that accurately reflects acute hyperglycemia status and is associated with poor prognosis of heart failure. We evaluated the relationship between SHR and clinical outcomes in patients with severe aortic stenosis receiving transcatheter aortic valve replacement (TAVR).MethodsThere were 582 patients with severe native aortic stenosis who underwent TAVR consecutively enrolled in the study. The formula used to determine SHR was as follows: admission blood glucose (mmol/L)/(1.59×HbA1c[%]–2.59). The primary endpoint was defined as all-cause mortality, while secondary endpoints included a composite of cardiovascular mortality or readmission for heart failure, and major adverse cardiovascular events (MACE) including cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke. Multivariable Cox regression and restricted cubic spline analysis were employed to assess the relationship between SHR and endpoints, with hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsDuring a median follow-up of 3.9 years, a total of 130 cases (22.3%) of all-cause mortality were recorded. Results from the restricted cubic spline analysis indicated a linear association between SHR and all endpoints (p for non-linearity > 0.05), even after adjustment for other confounding factors. Per 0.1 unit increase in SHR was associated with a 12% (adjusted HR: 1.12, 95% CI: 1.04–1.21) higher incidence of the primary endpoint, a 12% (adjusted HR: 1.12, 95% CI: 1.02–1.22) higher incidence of cardiovascular mortality or readmission for heart failure, and a 12% (adjusted HR: 1.12, 95% CI: 1.01–1.23) higher incidence of MACE. Subgroup analysis revealed that SHR had a significant interaction with diabetes mellitus with regard to the risk of all-cause mortality (p for interaction: 0.042). Kaplan-Meier survival analysis showed that there were significant differences in the incidence of all endpoints between the two groups with 0.944 as the optimal binary cutoff point of SHR (all log-rank test: p < 0.05).ConclusionsOur study indicates linear relationships of SHR with the risk of all-cause mortality, cardiovascular mortality or readmission for heart failure, and MACE in patients with severe aortic stenosis receiving TAVR after a median follow-up of 3.9 years. Patients with an SHR exceeding 0.944 had a poorer prognosis compared to those with lower SHR values.

Abstract WMP115: Rapid Vascular Complement Activation: A Key Driver of Blood-Brain Barrier Disruption in Ischemic Stroke With Acute Hyperglycemia

Background: Acute hyperglycemia, which occurs in over 40% of ischemic stroke patients irrespective of pre-existing diabetes, exacerbates stroke injury. Understanding its mechanisms is vital for innovative treatments. Here we investigate the role of complement in hyperglycemia-exacerbated damage after stroke. Method: Male C57/BL6 mice (10-11 weeks) underwent 30-min suture-induced middle cerebral artery occlusion followed by reperfusion, resembling clinical thrombectomy. Acute hyperglycemia was induced 10 min pre-stroke via glucose injection. Mice were sacrificed at 4.5h and 24h post-stroke to analyze brain swelling, blood-brain barrier (BBB) leakage and hemorrhagic transformation (HT). Mortality, neurological deficits, and motor-sensory functions were assessed at 14 days post-stroke. Complement activation was visualized via C3d immunostaining. Complement C3's role was examined using knock-out mice and the targeted complement inhibitor CR2-Crry fusion protein. Result: Hyperglycemia rapidly worsens BBB leakage (p&lt;0.0001), brain swelling (p&lt;0.05), and HT (p&lt;0.0001) at 4.5 hr after stroke. Hyperglycemic stroke mice exhibit higher mortality (100% vs 25%, p=0.0008), body weight loss, and behavior impairment at the sub-acute phase compared to normoglycemic mice. Notably, acute hyperglycemia rapidly increased plasma C3 levels at 1hr after stroke (p&lt;0.01), accompanied by rapid and time-dependent activation of C3 in ischemic brain vessels, as marked by increased vascular C3d; and this co-localized with autoantibody (IgM/IgG) vessel buildup and vessel leakage. Additionally, C3d levels positively correlated with brain swelling and HT (p&lt;0.01). Vascular C3d and leakage into parenchyma were markedly reduced in the absence of reperfusion. Blocking complement via C3 knock-out or post-reperfusion systemic injection of C3 inhibitor CR2-Crry mitigates hyperglycemia's detrimental effects, including BBB leakage. Conclusion: Rapid vascular activation of complement C3 is a significant driver of hyperglycemic-exacerbated pathology in experimental stroke. Inhibiting C3 activation could be a potential therapeutic approach to improve hyperglycemic stroke outcome.

Abstract WP3: Serum Glucose Fluctuations is an Independent Predictor of Adverse Outcomes in Patients With Acute Ischemic Stroke Undergoing Endovascular Treatment

Background: Acute hyperglycemia may increase the rate of death or disability among acute ischemic stroke patients undergoing endovascular procedures. Objective: To explore the association between serum glucose fluctuation on post treatment symptomatic intracranial hemorrhage (sICH) and mortality. Methods: We analyzed consecutive acute ischemic stroke patients who underwent endovascular treatment over 30 months at a comprehensive stroke center. Serum glucose levels within the initial 24 hours were used to calculate the mean and standard deviation (SD). Patients were grouped by the standard deviation [SD] of the mean value of serum glucose, whether above or below 25%. Outcomes included sICH, and inpatient mortality, adjusted for confounders which included age, gender, baseline NIHSS, perfusion grade (TICI) intravenous thrombolysis, history of diabetes and HBA1c. Results: A total of 224 patients (mean age was 68.7 years (±14.3); 44.2% were women) underwent endovascular treatment. The proportion of sICH (16.7% vs. 3.28%; p=0.0006) and inpatient mortality (18.6% vs. 7.4%; p=0.0112) were higher in patients with SD exceeding 25. After adjusting for potential confounders, serum glucose SD above 25 was significantly associated with increased rate of sICH (odds ratio [OR] 5.2; 95% confidence interval [CI] 1.5-18.5; p=0.0112) and inpatient mortality (OR 3.5; 95% CI 1.3-9.8; p=0.0154). Conclusion: Serum glucose fluctuations within first 24 hours maybe be therapeutic target due to its association with increased risks of sICH and inpatient mortality following endovascular treatment in acute ischemic stroke.

Clinical characteristics and outcomes of patients admitted with COVID-19 at a public-sector hospital over the first two waves of SARS-CoV-2 infection in Harare, Zimbabwe: A prospective cohort study.

We investigated the clinical profile, complications, and outcomes of inpatients with COVID-19 at Parirenyatwa Hospital, Harare, across the first two waves of SARS-CoV-2 infection, and factors associated with mortality. We conducted a prospective cohort study on all patients admitted to the COVID-19 unit. Data were extracted from medical records and negative binomial regression with robust standard errors was used to assess the association between sociodemographic and clinical characteristics and mortality. Cox Regression was used for sensitivity analysis. Of 563 people admitted with COVID-19 between 2 July 2020 and 19 March 2021, 214 (38.0%) died, 340 were discharged and 9 transferred. The median age was 56 (IQR 44-68) years and 53.8% were male. Overall, 38.8% experienced a complication, the most common being acute kidney injury (17.9%) and hyperglycaemia (13.1%). The most common comorbidity was hypertension (41.3%) followed by diabetes (28.6%), HIV (12.1%), cardiovascular disease (10.9%) and chronic kidney disease (7.8%). Among participants who stayed in the ward for more than 1 night, mortality was higher in patients with comorbidity compared to those without any comorbidity (38.7% vs 25.5%, risk ratio (RR) = 1.52 (95% CI 1.11, 2.07), p = 0.008). After adjusting for oxygen saturation, comorbidities, sex and pregnancy, mortality was higher in the second wave than in the first (adjusted RR 1.23, 95% CI 1.00-1.51, p = 0.05). In the second wave 57/161 (35.4%) deaths were attributed to lack of resources, mainly human resources. The mortality rate was high and clinical COVID-19 care needs to pay careful attention to patient monitoring for complications and management of comorbidities. This will require addressing the critical health workforce shortage issues. Prevention of COVID-19 including vaccination particularly among individuals with comorbidities remains a high priority.

Two Prenylated Chalcones, 4-Hydroxyderricin, and Xanthoangelol Prevent Postprandial Hyperglycemia by Promoting GLUT4 Translocation via the LKB1/AMPK Signaling Pathway in Skeletal Muscle Cells.

Stimulation of glucose uptake in the skeletal muscle is crucial for the prevention of postprandial hyperglycemia. Insulin and certain polyphenols enhance glucose uptake through the translocation of glucose transporter 4 (GLUT4) in the skeletal muscle. The previous study reports that prenylated chalcones, 4-hydroxyderricin (4-HD), and xanthoangelol (XAG) promote glucose uptake and GLUT4 translocation in L6 myotubes, but their underlying molecular mechanism remains unclear. This study investigates the mechanism in L6 myotubes and confirms antihyperglycemia by 4-HD and XAG. In L6 myotubes, 4-HD and XAG promote glucose uptake and GLUT4 translocation through the activation of adenosine monophosphate-activated protein kinase (AMPK) and liver kinase B1 (LKB1) signaling pathway without activating phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and Janus kinases (JAKs)/signal transducers and activators of transcriptions (STATs) pathways. Moreover, Compound C, an AMPK-specific inhibitor, as well as siRNA targeting AMPK and LKB1 completely canceled 4-HD and XAG-increased glucose uptake. Consistently, oral administration of 4-HD and XAG to male ICR mice suppresses acute hyperglycemia in an oral glucose tolerance test. In conclusion, LKB1/AMPK pathway and subsequent GLUT4 translocation in skeletal muscle cells are involved in Ashitaba chalcone-suppressed acute hyperglycemia.