Lower Glucose Research Articles

Fluorinated thiazole–thiosemicarbazones hybrids as potential PPAR-γ agonist and α-amylase, α-glucosidase antagonists: Design, synthesis, in silico ADMET and docking studies and hypoglycemic evaluation

In addition to Peroxisome Proliferator-Activated Receptor-gamma (PPAR-γ), which is essential for controlling type-2 diabetes mellitus, α-amylase and α-glucosidase inhibition is a key strategy in managing postprandial hyperglycemia. In this work a series of 2-(1-(2-((4-fluorophenyl)amino)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carbothioamide derivatives (3–6) was designed and synthesized through theiosemicarbazide derivatives, the structural elucidation of the new synthesized compounds was established using elemental and spectroscopic analyses. The antidiabetic activities of the new thiazole-thiosemicarbazone hybrids were screened in vivo for blood glucose lowering activity in normal rats and compared with pioglitazone as antidiabetic standard. Male Sprague-Dawley rats had reduced blood sugar levels after exposure to compounds 5 and 6 compared to pioglitazone. Additionally, the PPAR-γ agonist activity of compounds 5 and 6 as well as their ability to inhibit α-amylase and α-glucosidase were assessed. When compared to standard acarbose, which had an IC50 value of 0.74 ± 0.15 mM/mL, compound 5 showed the highest α-glucosidase inhibitory activity with IC50 value of 0.446 ± 0.01 mM/mL, while compound 6 showed good activity with an IC50 value of 1. 914 ± 0.04 mM/mL. However, compound 5 and compound 6 had weak α-amylase inhibitory activity, with IC50 values of 11.78 ± 0.58 and 24.18 ± 1.2 µg/mL respectively. Furthermore, Peroxisome proliferator activated receptor γ [PPAR-γ] agonist activity for compound 5 and compound 6 was assessed and gave promising result as [PPAR-γ] agonist with IC50 value of 0.938 ± 0.023 and 0.947 ± 0.024 ng/mL respectively superior to that of pioglitazone with IC50 value of 1.912 ± 0.11 ng/mL. All the results supported compound 5 as promising candidates for construction of new antidiabetic agents. Also, in silico ADMET and docking studies for the most promising derivatives 5, 6, Acarbose, and Pioglitazone were done.

Post-Coronary Artery Bypass Grafting Outcomes of Patients with/without Type-2 Diabetes Mellitus and Chronic Kidney Disease Treated with SGLT2 Inhibitor Dapagliflozin: A Single-Center Experience Analysis.

Increasingly, SGLT2 inhibitors save patients with heart failure and comorbidities such as type-2 diabetes mellitus (T2DM) and chronic kidney disease (CKD); the inhibition of sodium-glucose cotransporter 2 (SGLT2) was first studied in patients with diabetes as a solution to lower glucose levels by preventing glucose reabsorption and facilitating its elimination; in the process, researchers took notice of how SGLT2 inhibitors also seemed to have beneficial cardiovascular effects in patients with both diabetes and cardiovascular disease. Our single-center prospective study assesses outcomes of post-coronary artery bypass grafting (CABG) rehabilitation and SLGT2 inhibition in CABG patients with/without T2DM and with/without CKD. One hundred twenty consecutive patients undergoing CABG were included in the analysis. Patients were divided into four subgroups: diabetes patients with chronic kidney disease (T2DM + CKD), diabetes patients without chronic kidney disease (T2DM-CKD), prediabetes patients with chronic kidney disease (PreD+CKD), and prediabetes patients without chronic kidney disease (PreD-CKD). Echocardiographic and laboratory investigations post-surgery (phase I) and 6 months later (phase II) included markers for cardiac ischemia, glycemic status, and renal function, and metabolic equivalents were investigated. One hundred twenty patients participated, mostly men, overweight/obese, hypertensive, smokers; 65 had T2DM (18 with CKD), and 55 were prediabetic (17 with CKD). The mean ejection fraction increased by 8.43% overall but significantly more in the prediabetes group compared to the T2DM group (10.14% vs. 6.98%, p < 0.05). Overall, mean heart-type fatty-acid-binding protein (H-FABP) levels returned to normal levels, dropping from 68.40 ng/mL to 4.82 ng/mL (p = 0.000), and troponin data were more nuanced relative to an overall, strongly significant decrease of 44,458 ng/L (p = 0.000). Troponin levels in patients with CKD dropped more, both in the presence of T2DM (by 82,500 ng/L, p = 0.000) and in patients without T2DM (by 73,294 ng/L, p = 0.047). As expected, the overall glycated hemoglobin (HbA1c) levels improved significantly in those with prediabetes (from 6.54% to 5.55%, p = 0.000); on the other hand, the mean HbA1c changed from 7.06% to 6.06% (p = 0.000) in T2DM, and the presence or absence of CKD did not seem to make any difference: T2DM+CKD 7.01-6.08% (p = 0.000), T2DM-CKD 7.08-6.04% (p = 0.000), PreD+CKD 5.66-4.98% (p = 0.014), and PreD-CKD 6.03-4.94% (p = 0.00). Compared to an overall gain of 11.51, the GFRs of patients with CKD improved by 18.93 (68.15-87.07%, p = 0.000) in the presence of established diabetes and 14.89 (64.75-79.64%, p = 0.000) in the prediabetes group. Regarding the patients' cardiac statuses, the results from our single-center analysis revealed a significant decrease in ischemic risk (H-FABP and hs-cTnI levels) with improvements in mean ejection fraction, glycemic status, and renal function in patients post-CABG with/without T2DM, with/without CKD, and with SGLT2 inhibitor dapagliflozin treatment while undergoing cardiac rehabilitation.

Impact of Protease Inhibitor-Based Highly Active Antiretroviral Therapy on Fetal Subcutaneous Fat Tissue in HIV-Pregnant Women in a Middle-Income Country.

HIV infection continues to be a global public health challenge, affecting approximately 1.7 million reproductive-aged women. Protease inhibitor-based highly active antiretroviral therapy (PI-HAART) has significantly reduced the risk of vertical transmission of HIV from mother to child. Nevertheless, concerns linger regarding the long-term effects, particularly on body composition, notably subcutaneous fat tissue (SFT). Although HIV-associated lipodystrophy syndrome (LS) has been well documented in adults and older children, its impact on fetuses exposed to PI-HAART remains underexplored. This study aims to evaluate SFT in the fetuses of HIV-pregnant women exposed to PI-HAART, assessing the potential clinical implications. We conducted a comparative study between HIV-pregnant women receiving PI-HAART and an HIV-negative control group. Fetometry measurements were obtained via 3D ultrasound. SFT in the fetal arm and thigh segments was assessed. Data were analyzed using lineal multivariate regression and receiver-operating characteristics (ROC)-curve analysis. Fetuses exposed to PI-HAART exhibited a significant reduction in subcutaneous fat, particularly in the proximal third-middle union of the femur (coefficient: -2.588, p = 0.042). This reduction was correlated with lower newborn serum glucose levels (65.7 vs. 56.1, p = 0.007; coefficient: -1.277, p = 0.045). Our study sheds light on the connection between PI-HAART, fetal subcutaneous fat, and neonatal health. These findings might reveal the long-lasting effects of PI-HAART on newborns and children's well-being. Our results emphasize the need for a more balanced approach to managing pregnant women with HIV in developing countries and open new venues for research on the impact of intrauterine PI-HAART exposure on energy metabolism and fetal programming.

The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development

BackgroundSolute carrier family 13 member 5 (SLC13A5) is a Na+-coupled citrate co-transporter that mediates entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a target for reducing progression of kidney disease. The aim of this study was to leverage the Mendelian randomization paradigm to gain insight into the effects of SLC13A5 inhibition in humans, towards prioritizing and informing clinical development efforts.MethodsThe primary Mendelian randomization analyses investigated the effect of SLC13A5 inhibition on measures of kidney function, including creatinine and cystatin C-based measures of estimated glomerular filtration rate (creatinine-eGFR and cystatin C-eGFR), blood urea nitrogen (BUN), urine albumin-creatinine ratio (uACR), and risk of chronic kidney disease and microalbuminuria. Secondary analyses included a paired plasma and urine metabolome-wide association study, investigation of secondary traits related to SLC13A5 biology, a phenome-wide association study (PheWAS), and a proteome-wide association study. All analyses were compared to the effect of genetically predicted plasma citrate levels using variants selected from across the genome, and statistical sensitivity analyses robust to the inclusion of pleiotropic variants were also performed. Data were obtained from large-scale genetic consortia and biobanks, with sample sizes ranging from 5023 to 1,320,016 individuals.ResultsWe found evidence of associations between genetically proxied SLC13A5 inhibition and higher creatinine-eGFR (p = 0.002), cystatin C-eGFR (p = 0.005), and lower BUN (p = 3 × 10−4). Statistical sensitivity analyses robust to the inclusion of pleiotropic variants suggested that these effects may be a consequence of higher plasma citrate levels. There was no strong evidence of associations of genetically proxied SLC13A5 inhibition with uACR or risk of CKD or microalbuminuria. Secondary analyses identified evidence of associations with higher plasma calcium levels (p = 6 × 10−13) and lower fasting glucose (p = 0.02). PheWAS did not identify any safety concerns.ConclusionsThis Mendelian randomization analysis provides human-centric insight to guide clinical development of an SLC13A5 inhibitor. We identify plasma calcium and citrate as biologically plausible biomarkers of target engagement, and plasma citrate as a potential biomarker of mechanism of action. Our human genetic evidence corroborates evidence from various animal models to support effects of SLC13A5 inhibition on improving kidney function.

Pharmacological screening of antidiabetic activity of ethanolic extracts of justicia tranquebarensis on streptozocin induced rats.

Non-communicable diseases like diabetes mellitus are becoming major health problem these days. There is an increasing demand by patients to use the natural products (plants) with anti-diabetic activity due to the severe side effects associated with the use of insulin and oral anti-diabetic drugs. One such plant is Justicia tranquebareinsis which has been traditionally used for the treatment of diabetes mellitus. The aim of this study was, therefore, to evaluate hypoglycemic activity of ethanol extract of Justicia tranquebareinsis in streptozotocin-induced diabetic rats, respectively and to carry out acute toxicity test. Two doses (200 mg/kg and 400 mg/kg) of the ethanol extract of Justicia tranquebareinsis were administered to normal glucose loaded and diabetic rat to study blood glucose lowering effect. Ethanol extract of Justicia tranquebareinsis (200mg/kg and 400mg/kg, p.o.) showed significant tolerance (P &lt; 0.05) to oral glucose load at 1 and 2 hrs after glucose load. The extract also produced significant (P &lt; 0.05) blood glucose reduction at 4 hours after its administration in normoglycemic mice. The extract at 400mg/kg dose level produced significant (P &lt; 0.05) reduction in blood glucose level at 2, 3 and 4 hours of treatment in streptozotocin (45 mg/kg) induced diabetic mice. Acute oral toxicity studies of ethanol extract of Justicia tranquebareinsis in rats showed no death or signs of toxicity at the dose of 2000 mg/kg indicating the safety nature of the extract. The results of the experiments showed that ethanol extract of Justicia tranquebareinsis has significant antihyperglycemic activity in streptozotocin induced diabetic rat and improvement in glucose tolerance and slight hypoglycemic activity in normal rat justifying the traditional claim for its use in diabetes.

Understanding atrazine elimination via treatment of the enzyme-based Fenton reaction: Kinetics, mechanism, reaction pathway, and metabolites toxicity

The degradation kinetics and mechanism of atrazine (ATZ) via an enzyme-based Fenton reaction were investigated at various substrate concentrations and pH values. Toxicological assessment was conducted on ATZ and its degradation products, and the associated reaction pathway was examined. The in situ production of hydrogen peroxide (H2O2) was monitored within the range of 3–15 mM, depending on the increase in glucose concentration, while decreasing the pH to 3.2–5.1 (initial pH of 5.8) or 6.5–7.4 (initial pH of 7.7). The degradation efficiency of ATZ was approximately 2–3 times higher at an initial pH of 5.8 with lower glucose concentrations than at an initial pH of 7.7 with higher substrate concentrations during the enzyme-based Fenton reaction. The apparent pseudo-first-order rate constant for H2O2 decomposition under various conditions in the presence of ferric citrate was 1.9–6.3 × 10−5 s−1. The •OH concentration ([•OH]ss) during the enzyme-based Fenton reaction was 0.5–4.1 × 10−14 M, and the second-order rate constant for ATZ degradation was 1.5–3.3 × 109 M−1 s−1. ATZ intrinsically hinders the growth and development of Arabidopsis thaliana, and its inhibitory effect is marginal, depending on the reaction time of the enzyme-based Fenton process. The ATZ transformation during this process occurs through dealkylation, hydroxylation, and dechlorination via •OH-mediated reactions. The degradation kinetics, mechanism, and toxicological assessment in the present study could contribute to the development and application of enzyme-based Fenton reactions for in situ pollutant abatement. Moreover, the enzyme-based Fenton reaction could be an environmentally benign and applicable approach for eliminating persistent organic matter, such as herbicides, using diverse H2O2-producing microbes and ubiquitous ferric iron with organic complexes.

The effects of glycemic index on prostate cancer progression in a xenograft mouse model.

Previously, we found low-carbohydrate diets slowed prostate cancer (PC) growth and increased survival vs. a Western diet in mice, by inhibiting the insulin/IGF-1 axis. Thus, we tested whether modifying carbohydrate quality to lower glycemic index (GI) without changing quantity results in similar benefits as with reduced quantity. Male SCID mice injected with LAPC-4 cells were single-housed and randomized when their tumors reached 200 mm3 on average to a LoGI (48% carbohydrate kcal, from Hylon-VII) or HiGI Western diet (48% carbohydrate kcal, from sucrose). Body weight and tumor volume were measured weekly. Body composition was assessed 35 days after randomization. Blood glucose and serum insulin, IGF-1 and IGFBP3 were measured at study end when tumor volumes reached 800 mm3. We analyzed gene expression of mice tumors by RNA-sequencing and human tumors using the Prostate Cancer Transcriptome Atlas. There were no significant differences in tumor volume (P > 0.05), tumor proliferation (P = 0.29), and overall survival (P = 0.15) between groups. At 35 days after randomization, the LoGI group had 30% lower body fat (P = 0.007) despite similar body weight (P = 0.58). At sacrifice, LoGI mice had smaller livers (P < 0.001) and lower glucose (P = 0.15), insulin (P = 0.11), IGF-1 (P = 0.07) and IGF-1:IGFBP3 ratio (P = 0.05), and higher IGFBP3 (P = 0.09) vs. HiGI, although none of these metabolic differences reached statistical significance. We observed differential gene expression and pathway enrichment in mice tumors by diet. The most upregulated and downregulated gene in the LoGI group showed expression patterns more closely resembling expression in human benign prostate tissue vs. PC. In this single mouse xenograft model, consuming a low GI diet did not delay PC growth or survival vs. a high GI diet despite suggestions of decreased activation of the insulin/IGF-1 pathway. These data suggest that improving carbohydrate quality alone while consuming a high carbohydrate diet may not effectively slow PC growth.

Acute Activation of GFRAL in the Area Postrema Contributes to Glucose Regulation Independent of Weight.

GDF15 regulates energy balance and glucose homeostasis in rodents by activating its receptor GFRAL, expressed in the area postrema of the brain. However, whether GDF15-GFRAL signaling in the area postrema regulates glucose tolerance independent of changes in food intake and weight and contributes to the glucose-lowering effect of metformin remain unknown. Herein, we report that direct, acute GDF15 infusion into the area postrema of rats fed a high-fat diet increased intravenous glucose tolerance and insulin sensitivity to lower hepatic glucose production independent of changes in food intake, weight, and plasma insulin levels under conscious, unrestrained, and nonstressed conditions. In parallel, metformin infusion concurrently increased plasma GDF15 levels and glucose tolerance. Finally, a knockdown of GFRAL expression in the area postrema negated administration of GDF15, as well as metformin, to increase glucose tolerance independent of changes in food intake, weight, and plasma insulin levels. In summary, activation of GFRAL in the area postrema contributes to glucose regulation of GDF15 and metformin in vivo. Article Highlights

Analysis of Glucose Levels in White Glutinous Rice Bran: A Systematic Literature Review

White glutinous rice bran has lower glucose levels than white glutinous rice. This could be relevant for glycemic management in diabetes sufferers. Lower glucose levels can help reduce blood sugar spikes after food consumption. White glutinous rice bran, with its low glucose content, can be considered a safe and beneficial food alternative for diabetes sufferers. The literature search process was carried out on various databases (PubMed, Web of Sciences, EMBASE, Cochrane Libraries, and Google Scholar) regarding the analysis of glucose levels in white glutinous rice bran. This study follows the preferred reporting items for systematic reviews and meta-analysis (PRISMA) recommendations. The glucose content in rice bran ranges from 1.5 to 2.5%, a lower value compared to the glucose content in white glutinous rice which reaches around 7.5%. White glutinous rice bran has relatively low glucose levels, making it a potential food option for consumption by diabetes mellitus sufferers.

A cross-sectional study on the prevalence of cardiovascular disease in elderly patients with long-term type 2 diabetes mellitus mainly attended in private clinics in Mexico. The CAPTURE study

BackgroundTo estimate the contemporary prevalence of established cardiovascular disease (CVD) in adults with type 2 diabetes (T2D) in Mexico.MethodsCAPTURE was a multinational, non-interventional, cross-sectional study across 13 countries from five continents. Standardized demographic and clinical data were collected from adults with T2D attending a single routine healthcare visit in primary or specialized care between December 2018 and September 2019. Data from Mexico are analyzed in this study.ResultsOf the 9,823 patients included in the CAPTURE study, 820 (8.3%) participants were from Mexico, mainly attended in private centers (29.3% in 6 specialized diabetes treatment centers and 70.7% in 26 primary care centers). The median age was 63.0 years, 52.6% were women, the duration of diabetes was 11.8 years and the average HbA1c 7.5%. The weighted prevalence [95% CI] of CVD and atherosclerotic CVD was 36.9% [34.1–39.6] and 29.5% [26.7–32.3], respectively. Additionally, the prevalence of coronary heart disease, heart failure, peripheral arterial disease and cerebrovascular disease was 23.1% [20.6–25-7], 8.4% [6.8–10.0], 5.0% [3.5–6.5] and 3.9% [2.6–5.2], respectively. Glucose lowering drugs were used in 88.5% of patients, being metformin the most commonly drug used (79.4%), followed by sulfonylureas (26.3%). SGLT-2 inhibitors and GLP1 receptor agonists were used in 15.5% and 3.9%, respectively.ConclusionsIn Mexico, nearly four out of ten patients with T2D mainly attended in private centers have CVD, particularly atherosclerotic CVD. Most patients were not taking glucose lowering drugs with proven CV benefit.

Drug Therapies for Diabetes.

The treatment of type 2 diabetes (T2D) necessitates a multifaceted approach that combines behavioral and pharmacological interventions to mitigate complications and sustain a high quality of life. Treatment encompasses the management of glucose levels, weight, cardiovascular risk factors, comorbidities, and associated complications through medication and lifestyle adjustments. Metformin, a standard in diabetes management, continues to serve as the primary, first-line oral treatment across all age groups due to its efficacy, versatility in combination therapy, and cost-effectiveness. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) offer notable benefits for HbA1c and weight reduction, with significant cardiovascular benefits. Sodium-glucose cotransporter inhibitors (SGLT-2i) lower glucose levels independently of insulin while conferring notable benefits for cardiovascular, renal, and heart-failure outcomes. Combined therapies emphasizing early and sustained glycemic control are promising options for diabetes management. As insulin therapy remains pivotal, metformin and non-insulin agents such as GLP-1 RA and SGLT-2i offer compelling options. Notably, exciting novel treatments like the dual GLP-1/ glucose-dependent insulinotropic polypeptide (GIP) agonist show promise for substantially reducing glycated hemoglobin and body weight. This comprehensive review highlights the evolving landscape of pharmacotherapy in diabetes, the drugs currently available for treating diabetes, their effectiveness and efficacy, the impact on target organs, and side effects. This work also provides insights that can support the customization of treatment strategies.

The Effect of Intermittent Fasting and Caloric Restricted Diet on Diabetic Rats

The present study was aimed to investigate the effect of intermittent fasting and caloric restricted diet (RD) for 8 weeks on diabetic rats. Forty-nine adult male albino rats were divided into two main groups; the first main group was fed only on basal diet and served as negative control group and the second main group: diabetic rats were induced by a single intra-peritoneal injection of freshly prepared STZ (60 mg/kg BW) then divided into 6 subgroups: Subgroup (1) was fed only on basal diet and was served as positive cont. Subgroup (2) was fed on RD only. Subgroups (3, 4) were fed on basal diet and were deprived of food except water from 5 p.m. to 8 a.m. twice a week and every other day, respectively. Subgroups (5, 6): were fed on RD and intermittent fasting twice a week and every other day, respectively. The results indicated that RD and intermittent fasting significantly decreased the final body weight, feed intake and body weight gain % values as compared to the positive control rats. Diabetic treated rats had significant increase (p&lt;0.05) in insulin concentration and lower glucose levels as well as an improvement in liver functions and lipid profile as compared to the positive control group. Conclusion: the findings suggest that intermittent fasting and caloric restricted diet could have a potential role in managing diabetes.

Potentially modifiable factors explaining monozygotic twin discordance in amyloid pathology

AbstractBackgroundThe heritability of global amyloid burden in older adults was previously found to be moderate (41%), suggesting environmental factors to play an important role in early Alzheimer’s disease (AD) pathology. Identifying these factors may aid in the development of successful prevention strategies. Several, potentially modifiable, risk factors for dementia have been previously reported by Livingston and colleagues (Lancet, 2020). We here aim to identify which of these risk factors explain observed twin discordance in amyloid pathology in a sample of cognitively unimpaired monozygotic twin‐pairs.MethodsWe included 31 initially cognitively unimpaired twin‐pairs aged&gt;60 years from the EMIF‐AD PreclinAD study who were discordant on amyloid status (defined by visual read of dynamic [18F]flutemetamol‐PET images). Paired samples t‐tests (continuous measures) and McNemar’s tests (dichotomous measures) were applied to investigate which factors associated with twin discordance. Selected risk factors included comorbid diseases, lifestyle and vascular risk factors (see table 2).ResultsTwins were on average 72.7±7.0 years old, consisted of 48% females, and 58% Apoe‐ε4 carriers (table 1). Twins with a positive amyloid status showed lower body mass index (BMI) and glucose levels compared to their amyloid negative co‐twin (table 2, figure 1A&amp;B). We also observed a trend towards lower diastolic blood pressure in amyloid positive twins (table 2). In accordance with inclusion criteria for the study we observed very low prevalence of comorbid disorders in both groups. Further, no group differences were observed in lifestyle factors, such as smoking, alcohol use, physical activity and sleep quality.ConclusionsIn a sample of monozygotic twin‐pairs discordant for amyloid pathology, we found lower BMI and glucose levels to be associated with the presence of amyloid pathology. Although Livingston and colleagues reported high BMI (obesity) at mid‐life (age 45‐65) to increase the risk for dementia, effects of BMI have previously been found to differ in mid‐ and late‐age populations. In line with our results, lower BMI at later life (&gt;65 years) has previously been found to increase AD‐risk. For the development of prevention strategies, it would be of relevance to further investigate these dynamic age‐related effects.

Increased medial temporal lobe functional connectivity is critical in Alzheimer’s disease: evidences from longitudinal analyses across the whole cognitive continuum

AbstractBackgroundThe medial temporal lobe is extensively connected to the whole brain through two functional networks: the anterior‐temporal (AT) and posterior‐medial (PM) systems. While both increased and decreased functional connectivity (FC) have been reported in Alzheimer’s disease (AD), the specific changes in each network and their clinical relevance throughout AD stages remain to be elucidated. To fill this gap, we aimed to provide a comprehensive overview of AT‐ and PM‐FC changes, and links with AD imaging‐biomarkers, clinical severity and dementia onset, using longitudinal data covering the whole cognitive continuum.MethodLongitudinal data were acquired in 209 cognitively unimpaired (CU) adults aged 19‐85 (n = 56 Aβ‐ over 60), 26 Aβ+ patients with mild cognitive impairment (MCI) (n = 18 AD‐converters), and 26 Aβ+ AD‐demented patients, all followed up to 4 years. All underwent resting‐state (rs)‐fMRI, T1‐w MRI, Florbetapir‐ and FDG‐PET. Connectivity maps were generated from seed‐to‐voxels analyses applied to rs‐fMRI using individual ROIs (AT = perirhinal cortex, PM = parahippocampal cortex). The networks were defined by comparing baseline CU Aβ‐ AT to PM maps (and vice‐versa) using paired permutation t‐tests with FWE correction. Mean FC was then extracted from these masks for each participant. Generalized additive and linear mixed models were run to assess AT‐ and PM‐FC changes across the whole cognitive continuum, and their relationships with i)‐amyloid uptake, ii)‐glucose metabolism, iii)‐hippocampal volume and iv)‐cognitive deficit within participants&gt;60yo, and v)‐AD‐conversion time in MCI patients.ResultResults showed that AT‐FC linearly increased from younger to Aβ+ AD‐demented adults while PM‐FC decreased along the healthy lifespan and then remained stable across the AD continuum (Aβ+ individuals). Higher AT‐FC was associated with i)‐higher amyloid uptake, ii)‐lower glucose metabolism, iii)‐smaller hippocampal volume, iv)‐lower MMSE/Mattis scores and v)‐faster AD‐dementia onset. No such relationships were found with PM‐FC.ConclusionBy encompassing the whole cognitive continuum and assessing longitudinal changes, we highlighted that AT‐ and PM‐FC alterations differ in aging and AD. While reduced PM connectivity seems restricted to age‐related processes (corroborated by no correlation with AD‐signature changes), increased AT connectivity seems to result from specific AD‐related mechanisms. Importantly, we evidenced that AT hyper‐connectivity appears critical in AD and might predict clinical and pathological outcomes.

Comparative analysis of glucose and fructose tolerance in two marine fishes: effects on insulin secretion and acute hypoxia tolerance

Carbohydrates are a common and economical energy source in animal feeds. However, most fish show a persistent postprandial hyperglycemia after intake of a high-carbohydrate diet. Unfortunately, the mechanism of glucose metabolism in fish is still unclear. In the present study, tiger puffer (Takifugu rubripes) and turbot (Scophthalmus maximus) were intraperitoneally injected or orally administered with glucose or fructose (500 mg/kg body weight) to evaluate the ability of fish to utilize carbohydrates. Afterwards, serum glucose, fructose, pyruvate, insulin levels, and acute hypoxia tolerance were measured. Our results showed increased serum glucose level and then decreased post intraperitoneal injection with glucose, and reached a peak after 0.5 hours in turbot and 1 hour in tiger puffer. Tiger puffer had significantly lower liver glycogen, serum glucose, fructose, pyruvate, and insulin contents than turbot. Glucose and fructose only induced insulin secretion in turbot, but did not change serum insulin level in tiger puffer. Glucose was a stronger stimulator of insulin than fructose in the two marine species. Both intraperitoneal injection and oral fructose intake increased serum glucose level, while intraperitoneal or oral glucose also increased serum fructose level. Intraperitoneal injection of glucose promoted absorption and utilization of glucose in the blood more effectively than oral glucose intake. In addition, turbot and tiger puffer were intolerant to acute hypoxia, whereas supplementation with glucose or fructose improved hypoxia tolerance in the two marine fishes by activating anaerobic glycolysis. Taken together, our results provide important scientific information for understanding the mechanism for glucose and fructose utilization and improving hypoxia tolerance in fish.

Black bean (Phaseolus vulgaris L.) protein hydrolysates reduce acute postprandial glucose levels in adults with prediabetes and normal glucose tolerance

This study evaluated the acute effect of black bean protein hydrolysate (BPH) on postprandial glucose and insulin levels in adults with normal glucose tolerance (NGT) or prediabetes. First, an in silico predictive digestion was performed on twenty peptides identified in BPH. Then, 28 adults with NGT or prediabetes were randomized to a parallel double-blind, placebo-controlled trial. Following consent, participants were randomly assigned to one of two groups, placebo, or 5 g of BPH. To evaluate the acute effects of BPH, an oral glucose tolerance test was administered, and blood samples were collected at 60, 120, and 150 min. In the 5 g BPH group, the area under the curve for glucose, and glucose levels at 120 min were statistically lower compared to the placebo group (p = 0.04, p = 0.02). In this study, BPH had an acute glucose lowering effect after an oral glucose tolerance test in subjects with NGT or prediabetes.

A Ketone Monoester with Carbohydrate Improves Cognitive Measures Postexercise, but Not Performance in Trained Females.

The acute ingestion of a ketone monoester with the coingestion of a carbohydrate (KME + CHO) compared with carbohydrate (CHO) was investigated on cycling performance and cognitive performance in trained females. Using a two condition, placebo-controlled, double-blinded and crossover design, 12 trained females (mean ± SD: age, 23 ± 3 yr; height, 1.64 ± 0.08 m; mass, 65.2 ± 12.7 kg) completed a baseline assessment of cognitive performance (psychomotor vigilance testing (PVT), task switching, and incongruent flanker), followed by 6 × 5-min intervals at 40%, 45%, 50%, 55%, 60%, and 65% of their maximal power output (W max ) and then a 10-km time trial, concluding with the same assessments of cognitive performance. Participants consumed either 375 mg·kg -1 body mass of KME with a 6% CHO solution (1 g·min -1 of exercise) or CHO alone, across three boluses (50:25:25). Blood β-hydroxybutyrate concentrations averaged 1.80 ± 0.07 and 0.13 ± 0.01 mM during exercise in KME + CHO and CHO, respectively. Blood glucose decreased after drink 1 of KME + CHO (~15%; P = 0.01) but not CHO, and lactate concentrations were lower in KME + CHO at 50%, 55%, 60%, and 65% W max (all P < 0.05) compared with CHO. Despite these changes, no differences were found between conditions for time trial finishing times (KME + CHO, 29.7 ± 5.7 min; CHO, 29.6 ± 5.7 min; P = 0.92). However, only KME + CHO resulted in increases in psychomotor vigilance testing speed (~4%; P = 0.01) and faster reaction times (~14%; P < 0.01), speed (~15%; P < 0.01), and correct responses (~13%; P = 0.03) in the incongruent flanker during posttesting compared with CHO. The acute ingestion of a KME + CHO elevated blood β-hydroxybutyrate and lowered glucose and lactate across multiple time points during exercise compared with CHO. Although these changes did not affect physical performance, several markers of cognitive performance were improved by the addition of a KME in trained females.

Predictors of devastating functional outcome despite successful basilar thrombectomy.

Basilar thrombosis frequently leads to poor functional outcomes, even with good endovascular reperfusion. We studied factors associated with severe disability or death in basilar thrombectomy patients achieving revascularization. We retrospectively analyzed records from a health system's code stroke registry, including successful basilar thrombectomy patients from January 2017 to May 2023 who were evaluated with pretreatment computed tomography perfusion. The primary outcome was devastating functional outcome (90-day modified Rankin Scale [mRS] score 5-6). A multivariable logistic regression model was constructed to determine independent predictors of the primary outcome. The area under the receiver operator characteristics curve (AUC) was calculated for the model distinguishing good from devastating outcome. Among 64 included subjects, with mean (standard deviation) age 65.6 (14.1) years and median (interquartile range) National Institutes of Health Stroke Scale (NIHSS) 18 (5.75-24.5), the primary outcome occurred in 28 of 64 (43.8%) subjects. Presenting NIHSS (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.01-1.14, p = 0.02), initial glucose (OR 0.99, 95% CI 0.97-1.00, p < 0.05), and proximal occlusion site (OR 7.38, 95% CI 1.84-29.60, p < 0.01) were independently associated with 90-day mRS 5-6. The AUC for the multivariable model distinguishing outcomes was 0.81 (95% CI 0.70-0.92). We have identified presenting stroke severity, lower glucose, and proximal basilar occlusion as predictors of devastating neurological outcome in successful basilar thrombectomy patients. These factors may be used in medical decision making or for patient selection in future clinical trials.

Euglycemic Diabetic Ketoacidosis: Experience with 44 Patients and Comparison to Hyperglycemic Diabetic Ketoacidosis.

Euglycemic diabetic ketoacidosis (DKA) (glucose <250milligrams per deciliter (mg/dL) has increased in recognition since introduction of sodium-glucose co-transporter 2 (SGLT2) inhibitors but remains challenging to diagnose and manage without the hyperglycemia that is otherwise central to diagnosing DKA, and with increased risk for hypoglycemia with insulin use. Our objective was to compare key resource utilization and safety outcomes between patients with euglycemic and hyperglycemic DKA from the same period. This is a retrospective review of adult emergency department patients in DKA at an academic medical center. Patients were included if they were >18years old, met criteria for DKA on initial laboratories (pH ≤7.30, serum bicarbonate ≤18millimoles per liter [mmol/L], anion gap ≥10), and were managed via a standardized DKA order set. Patients were divided into euglycemic (<250milligrams per deciliter [mg/dL]) vs hyperglycemic (≥250mg/dL) cohorts by presenting glucose. We extracted and analyzed patient demographics, resource utilization, and safety outcomes. Etiologies of euglycemia were obtained by manual chart review. For comparisons between groups we used independent-group t-tests for continuous variables and chi-squared tests for binary variables, with alpha 0.05. We identified 629 patients with DKA: 44 euglycemic and 585 hyperglycemic. Euglycemic patients had milder DKA on presentation (higher pH and bicarbonate, lower anion gap; P < 0.05) and lower initial glucose (195 vs 561mg/dL, P < 0.001) and potassium (4.3 vs 5.3mmol/L, P < 0.001). Etiologies of euglycemia were insulin use prior to arrival (57%), poor oral intake with baseline insulin use (29%), and SGLT2 inhibitor use (14%). Mean time on insulin infusion was shorter for those with euglycemic DKA: 13.5 vs 19.4 hours, P = 0.003. Mean times to first bicarbonate >18mmol/L and first long-acting insulin were similar. Incidence of hypoglycemia (<70mg/dL) while on insulin infusion was significantly higher for those with euglycemic DKA (18.2 vs 4.8%, P = 0.02); incidence of hypokalemia (<3.3mmol/L) was 27.3 vs 19.1% (P = 0.23). Compared to hyperglycemic DKA patients managed in the same protocolized fashion, euglycemic DKA patients were on insulin infusions 5.9 hours less, yet experienced hypoglycemia over three times more frequently. Future work can investigate treatment strategies for euglycemic DKA to minimize adverse events, especially iatrogenic hypoglycemia.

The anti-diabetic effects of metformin are mediated by regulating long non-coding RNA.

Type 2 diabetes (T2D) is a metabolic disease with complex etiology and mechanisms. Long non-coding ribonucleic acid (LncRNA) is a novel class of functional long RNA molecules that regulate multiple biological functions through various mechanisms. Studies in the past decade have shown that lncRNAs may play an important role in regulating insulin resistance and the progression of T2D. As a widely used biguanide drug, metformin has been used for glucose lowering effects in clinical practice for more than 60years. For diabetic therapy, metformin reduces glucose absorption from the intestines, lowers hepatic gluconeogenesis, reduces inflammation, and improves insulin sensitivity. However, despite being widely used as the first-line oral antidiabetic drug, its mechanism of action remains largely elusive. Currently, an increasing number of studies have demonstrated that the anti-diabetic effects of metformin were mediated by the regulation of lncRNAs. Metformin-regulated lncRNAs have been shown to participate in the inhibition of gluconeogenesis, regulation of lipid metabolism, and be anti-inflammatory. Thus, this review focuses on the mechanisms of action of metformin in regulating lncRNAs in diabetes, including pathways altered by metformin via targeting lncRNAs, and the potential targets of metformin through modulation of lncRNAs. Knowledge of the mechanisms of lncRNA modulation by metformin in diabetes will aid the development of new therapeutic drugs for T2D in the future.