Normal Glucose Levels Research Articles

A new upper limit for effective dose in patient administered with 18F-FDG for PET/CT whole-body imaging with diagnostic CT parameters

IntroductionThe aim of present study is to estimate effective dose in patient undergoing 18F-FDG for whole body PET/CT imaging with diagnostic CT parameters and identify the lowest achievable total effective dose. MethodA total of 2247 PET/CT patients with normal glucose level underwent 18F-FDG-whole body imaging procedures. The 18F-FDG dose of 3.7MBq per kg of patient weight administered via intravenous infusion. For CT parameters, kilovoltage of 140keV and current of 40 mAs were used for all studies. All the acquired images collected retrospectively and the effective dose was calculated for each patient using algorithm adapted from ICRP Publication 106, modified for patient weight and patient blood volume. The estimated effective doses were evaluated for patients’ body weight and BMI. ResultsThe mean of total effective dose and standard deviation is approximately 15.08(4.52) mSv using ICRP algorithm. 56% of total patient has normal BMI and their average total effective dose is 13.6mSv. Underweight patients’ effective dose can be as low as 9.6mSv even using diagnostic CT protocols. ConclusionThe effective dose of PET/CT procedure in present study is one of the lowest although using diagnostic parameters for CT acquisition compared to published data worldwide. This is due to the improved sensitivity of PET and complex reconstruction technique that maintains the image quality. A significant association between body weight, BMI and effective dose is reported in present study. Therefore, it is suggested that attention must be given for underweight and ideal BMI patients while prescribing FDG activity and CT imaging parameters in order to minimize the effective dose. The effective dose reported in present study can be considered as an upper limit for effective dose in PET/CT patients with normal BMI. This upper limit can be treated as a standard limit when optimizing imaging parameters, developing algorithm for image reconstruction and prescribing activity for patients. This practice could fulfill ALARA principle that could reduce cancer risk.

Sasang Constitution Type Combined with General Obesity May Act as a Risk Factor for Prediabetes Mellitus.

Sasang constitutional medicine is a traditional customized medicine in Korea that classifies people into four types: Taeeumin (TE), Taeyangin (TY), Soeumin (SE), and Soyangin (SY). This study explored whether Sasang constitution (SC) types combined with general obesity could be risk factors for prediabetes mellitus (pre-DM). This study was cross-sectional and was conducted from November 2007 to July 2011 in 23 Korean medical clinics. In total, 2185 eligible subjects participated. A t test, one-way ANOVA with Scheffé's post hoc analysis, the chi-square test and multinomial logistic regression were used. Significance was indicated by p < 0.05. The numbers of participants with normal fasting plasma glucose (FPG) levels and pre-DM were 405 (75.3%) and 133 (24.7%) in the SE, 516 (70.3%) and 218 (29.7%) in the SY, and 590 (64.6%) and 323 (35.4%) in the TE (p < 0.001) groups, respectively. There was a significant difference in the proportion of each SC type among people with pre-DM and normal FPG levels in the normal BMI group. The odds ratios (ORs) of the TE type were significantly different from those of the SE type in the crude and Model 1. The distribution of the normal FPG and pre-DM individuals between the obese and normal BMI groups only for the SY type was significantly different. The SY type combined with general obesity had a higher OR (1.846, 95% CI 1.286-2.649) than that combined with normal BMI among participants with pre-DM, and this higher OR remained after adjusting for covariates (OR, 1.604, 95% CI, 1.093-2.354). This study revealed that the TE type might be a risk factor for pre-DM in the normal BMI group, and the SY type with general obesity could be a risk factor for pre-DM compared with the SY type with normal BMI. Accordingly, SC and BMI should be considered when managing pre-DM. To clarify the risk of SC and BMI, further study including epigenetic factors is needed.

A Chemometric-Assisted Colorimetric-Based Inexpensive Paper Biosensor for Glucose Detection

This article reports a simple and inexpensive leak-proof paper pad with an initial selection of a paper substrate on the grounds of surface morphology and fluid absorption time. Herein, a drying method is used for glucose detection on a paper pad through colorimetric analysis, and the spot detection of glucose is analyzed by optimizing the HRP concentration and volume to obtain accurate results. The rapid colorimetric method for the detection of glucose on the paper pad was developed with a limit of detection (LOD) of 2.92 mmol L-1. Furthermore, the effects of the detection conditions were investigated and discussed comprehensively with the help of chemometric methods. Paper pads were developed for glucose detection with a range of 0.5-20 mM (apropos to the normal glucose level in the human body) and 0.1-0.5 M (to test the excessive intake of glucose). The developed concept has huge potential in the healthcare sector, and its extension could be envisioned to develop the reported paper pad as a point-of-care testing device for the initial screening of a variety of diseases.

LBODP031 Evaluation Of Artifactual Hypoglycemia: A Case-based Review

Abstract Background Artifactual Hypoglycemia (AH), is defined as a discrepancy between the measured and actual blood glucose level. The absence of classical symptoms of hypoglycemia in patients with low measured glucose levels should raise the suspicion of AH. Here we describe a case of AH in a patient with chronic myeloid leukemia (CML). Clinical Case A 47-year-old woman was hospitalized for the evaluation of a four-month history of headache, anorexia, and weight loss. After further workup, she was diagnosed with CML; and upon evaluation, she was found to have a very low serum glucose level of 22 mg/dL. She reported no symptoms of hypoglycemia at the time and no personal or family history of diabetes. She was not using any glucose-lowering medication. Physical examination findings, including vital signs, were unremarkable. Laboratory studies revealed a serum glucose of 22 mg/dL with a simultaneous point-of-care (POC) capillary glucose level of 81 mg/dL. This discrepancy in glucose levels raised the suspicion of artifactual hypoglycemia. To further explore this, we drew three simultaneous venous blood samples and processed them differently to examine the impact of sample processing on serum glucose level in this patient. Two samples were drawn in tubes with no antiglycolytic agent (one sample was centrifuged immediately after the blood draw, and the second one was processed 5 hours after the blood draw). Whereas, the third sample was drawn in a tube containing sodium fluoride, an inhibitor of aerobic glycolysis, and was processed after one hour of the blood draw. Glucose concentrations in the three samples were as follows: 79 mg/dl, 41.4 mg/dl, and 77.4 mg/dl, respectively. The diagnosis of artifactual hypoglycemia due to excessive glucose consumption by leukocytes was established based on the findings of normal capillary blood glucose and normal plasma glucose levels when a tube prefilled with a glycolysis inhibitor is used. Conclusion Artifactual hypoglycemia should be considered in patients with asymptomatic hypoglycemia, especially when there is a discrepancy between the capillary and venous glucose levels. Patients with marked leukocytosis can have artifactually low serum glucose, an erroneous finding that can be mitigated by a) rapid processing of the blood sample or b) utilization of tubes pre-filled with a glycolysis inhibitor. Presentation: No date and time listed

Potential new roles for glycogen in epilepsy.

Seizures often originate in epileptogenic foci. Between seizures (interictally), these foci and some of the surrounding tissue often show low signals with 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in many epileptic patients, even when there are no radiologically detectable structural abnormalities. Low FDG-PET signals are thought to reflect glucose hypometabolism. Here, we review knowledge about metabolism of glucose and glycogen and oxidative stress in people with epilepsy and in acute and chronic rodent seizure models. Interictal brain glucose levels are normal and do not cause apparent glucose hypometabolism, which remains unexplained. During seizures, high amounts of fuel are needed to satisfy increased energy demands. Astrocytes consume glycogen as an additional emergency fuel to supplement glucose during high metabolic demand, such as during brain stimulation, stress, and seizures. In rodents, brain glycogen levels drop during induced seizures and increase to higher levels thereafter. Interictally, in people with epilepsy and in chronic epilepsy models, normal glucose but high glycogen levels have been found in the presumed brain areas involved in seizure generation. We present our new hypothesis that as an adaptive response to repeated episodes of high metabolic demand, high interictal glycogen levels in epileptogenic brain areas are used to support energy metabolism and potentially interictal neuronal activity. Glycogenolysis, which can be triggered by stress or oxidative stress, leads to decreased utilization of plasma glucose in epileptogenic brain areas, resulting in low FDG signals that are related to functional changes underlying seizure onset and propagation. This is (partially) reversible after successful surgery. Last, we propose that potential interictal glycogen depletion in epileptogenic and surrounding areas may cause energy shortages in astrocytes, which may impair potassium buffering and contribute to seizure generation. Based on these hypotheses, auxiliary fuels or treatments that support glycogen metabolism may be useful to treat epilepsy.

LBSUN332 A Novel Drug To Modulate Auto-inflammation And Promote Glucose Control In Type 1 Diabetes Mellitus

Abstract Canine Diabetes (CD) is identical to human T1DM. Helper T cells expressing the CD40 receptor (TH40) are prominent in human T1DM. TH40 cell expansions occur regardless of HLA haplotype or auto-antibody status and remain elevated throughout disease. TH40 cells from T1DM respond to human islets, TH40 from healthy controls do not. At a Veterinary Hospital 6 female and 2 male dogs that met clinical criteria for T1DM were recruited. Physical exam, blood panels and CBC were done. Dogs were dosed with a OPT501 a drug targeting CD40 mediated inflammation by IV infusion. Doses were 2 and later 4 mg/kg, given on days 1, 4, 7, then weekly for 8 weeks. Diabetic dogs had significantly elevated TH40 numbers compared to non-diabetic dogs (p < 0. 0001). OPT501 reduced TH40 cell numbers to normal, following which insulin requirements reduced on average by 75% and up to 90%. The canine equivalent of HbA1c reduced 40.2% on average; 3 subjects were normal range. Daily blood glucose reduced significantly, 3 subjects maintained normal glucose levels. Time-in-range (TIR) increased to up to 90%, from a previous 10%. Increased c - peptide levels were universally detected after 8 weeks of treatment. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

A novel glucagon analog with an extended half-life, HM15136, normalizes glucose levels in rodent models of congenital hyperinsulinism

Congenital hyperinsulinism (CHI) is a rare genetic condition characterized by uncontrolled insulin secretion, resulting in hypoglycemia. Although glucagon has lately been regarded as a therapeutic option for CHI, its use is severely hampered by its poor solubility and stability at physiological pH, as well as its short duration of action. To address these constraints, we developed HM15136, a novel long-acting glucagon analog composed of a glucagon analog conjugated to the Fc fragment of human immunoglobulin G4 via a polyethylene glycol linker. In this study, we established that HM15136 was more soluble than natural glucagon (≥ 150 mg/mL vs 0.03 mg/mL). Next, we confirmed that HM15136 activated glucagon receptor in vitro and induced glycogenolysis and gluconeogenesis in rat primary hepatocytes. Pharmacokinetics (PK)/Pharmacodynamics (PD) analysis of HM15136 shows that HM15136 has a markedly longer half-life (36 h vs. < 5 min) and increased bioavailability (90%) compared to native glucagon in mice. Further, HM15136 could effectively reverse acute hypoglycemia induced by insulin challenge, and multiple doses of HM15136 could sustain increased blood glucose levels in CHI rats. In conclusion, our findings indicate that HM15136 promotes sustained elevation of blood glucose, demonstrating the potential for development as a once-weekly therapy for CHI.

A methylation-dependent checkpoint by SETD7 promotes myocardial ischemic injury in mice and men

Abstract Background Despite appropriate revascularization strategies, a significant number of patients with myocardial infarction (MI) develop ischemic heart failure suggesting that breakthrough therapies are yet to be approved in this setting. Methylation of non-histone proteins is emerging as a central regulatory mechanism in health and disease. The methyltransferase SETD7 has been shown to methylate and alter the function of a variety of proteins in vitro, however, its function in the heart is poorly understood. Purpose To determine the role of SETD7 in myocardial ischemic injury. Methods Neonatal rat ventricular myocytes (NRVM) were exposed to normal glucose levels or glucose deprivation (GD) for 15 h, in the presence of the selective SETD7 inhibitor (R)-PFI-2 or its inactive enantiomer (S)-PFI-2. Western blot and real-time PCR were employed to investigate the effects of energy stress on SETD7 and the Hippo pathway, while apoptosis and oxidative stress were assessed by Caspase-3 activity assay and mitoSOX staining. YAP transcriptional activity was assessed by chromatin immunoprecipitation assay (ChIP) while its localization and methylation were examined by confocal microscopy and immunoblotting, respectively. SETD7 knockout (SETD7−/−) mice and wild-type (WT) littermates underwent myocardial ischemia-reperfusion (I/R) injury (1h coronary ligation /24 h of reperfusion) followed by assessment of cardiac function by echocardiography. Left ventricular (LV) myocardial samples were collected from I/R mice and patients with ischemic cardiomyopathy (ICM), and isolated cardiomyocytes were treated with (R)-PFI-2. Finally, SETD7 expression was also assessed in peripheral blood mononuclear cells (PBMCs) from patients with ST-elevation MI (STEMI). Results SETD7 was activated upon energy deprivation in cultured NRVMs and methylated YAP, leading to its cytosolic retention and impaired transcription of antioxidant genes MnSOD and CAT. Pharmacological inhibition of SETD7 by (R)-PFI-2 restored YAP nuclear localization thus preventing mitochondrial reactive oxygen species (mtROS) and apoptosis. SETD7 deletion in mice attenuated I/R injury, mtROS and LV dysfunction by restoring YAP-dependent transcriptional programs. SETD7/YAP dysregulation was also observed in LV specimens from ICM patients. Moreover, in cardiomyocytes isolated from I/R mice and ICM patients, (R)-PFI-2 restored YAP nuclear localization, prevented mtROS accumulation while improving myofibrillar protein contractility and Ca2+ sensitivity. Finally, SETD7 was upregulated in PBMCs from STEMI patients and negatively correlated with the expression of MnSOD and CAT. Conclusions SETD7-dependent methylation of YAP is an important mechanism underpinning myocardial oxidative stress and apoptosis during ischemia. Pharmacological modulation of SETD7 by (R)-PFI-2 may represent a potential therapeutic approach to prevent myocardial ischemic damage through modulation of the Hippo pathway. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University of Zurich

The Role of 5' Adenosine Monophosphate-Activated Protein Kinase in the Chemo-Sensitivity and Metabolic Behaviour of Breast Cancer Cells Exposed to Hypoxia and Hyperglycaemia

Background: 5' adenosine monophosphate-activated protein kinase (AMPK) is a key enzyme for maintaining energy homeostasis in the cell and is associated with many downstream targets of metabolic processes such as mTORC1, p53 and fatty acid synthase (FASN) and insulin-like growth factor binding protein-2 (IGFBP-2).&#x0D; Aim: To investigate the interactions between AMPK, FASN and IGFBP-2 and how the activity of AMPK affects the metabolism and response of breast cancer cells to chemotherapy with changes in oxygenation and under different glucose concentrations.&#x0D; Methods: MCF-7 breast cancer cells were exposed to different glucose levels (5mM and 25mM) in the presence or absence of doxorubicin under normoxic and hypoxic conditions with and without AMPK silenced using siRNA. Changes in protein abundance were monitored using Western Immunoblotting. Cell death was measured by the Muse® Cell Analyser using a count and viability assay. Hypoxia was chemically induced using cobalt chloride or with low levels of oxygen (2%). Lactate and citrate levels were measured using commercially available kits.&#x0D; Results: In normoxic conditions, AMPK activity was higher in normal levels of glucose (5mM) compared with high levels of glucose (25mM). Under hypoxic conditions, AMPK phosphorylation remained high in 5mM glucose with levels in 25 mM glucose being equivalent. Upregulation of AMPK in normoxic and hypoxic conditions was associated with a reduction in FASN and IGFBP-2, which resulted in a better response to chemotherapy. Moreover, the cells increased the production of lactate and reduced production of citrate under normoxic conditions in 25mM glucose compared to 5mM glucose. Silencing AMPK under normoxic conditions or inducing hypoxia promoted a more glycogenic phenotype. However, silencing AMPK under hypoxic conditions reduced levels of lactate comparable to normoxic levels. The citrate profile was unaffected by silencing AMPK or altering levels of oxygen.&#x0D; Conclusions: AMPK plays an important role in regulating metabolic signalling and this alters the sensitivity of breast cancer cells to chemotherapy.

ANALYSIS OF LIVER FUNCTION DISORDERS IN CRUMB RUBBER FACTORY WORKERS IN PALEMBANG CITY, SOUTH SUMATRA

Workers are required to receive Occupational Safety and Health protection. Work accidents can be influenced by physical, chemical, biological, ergonomic and psychological factors. Natural rubber factory is one of the industries that have risks to these factors. This study used a cross-sectional design. Data analysis used the CHAID (Chi-Square Automatic Interaction) method. P value &lt; 0.05 was considered statistically significant. The results of the study showed that the average concentration of H2S in the air and in solids was above the quality standard and the average concentration of H2S in water was still below the quality standard. The average concentration of NH3 in water and in solids is above the quality standard and the average concentration of NH3 in the air is still below the quality standard. The results of the CHAID method analysis showed that glucose levels were associated with impaired liver function (p = 0.000; chi square = 48.766) and the risk of H2S exposure in the air with impaired liver function (p = 0.007; chi square = 7.944). In addition, 3 segments of liver function disorders were also found, namely Segment 1: Workers with abnormal BBS levels, high air exposure H2S; segment 2: Workers with abnormal glucose levels, low air exposure H2S; segment 3: Workers with normal glucose levels. Based on this segment, it was also found that the percentage of risk of experiencing liver function disorders were workers in segment 2 (36.3%) and segment 1 (17.4%).

Flexible, disposable, and portable self-powered glucose biosensors visible to the naked eye

Diabetic patients need to measure their blood glucose level ∼5 times a day using glucose sensor. However, typical glucose sensors require additional power supply and equipment to interpret glucose concentration. In this study, flexible, disposable, and portable self-powered glucose biosensor is suggested to quickly measure glucose concentration with the naked eye. The theory of enzymatic biofuel cell is adopted for its self-powered operation. This glucose biosensor includes glucose dehydrogenase (GDH) and Prussian blue (PB) as biocatalysts for anode and cathode, while glucose oxidation reaction and reduction reaction of PB are utilized as the main reactions. In electrochemical evaluations, maximum current density and onset potential of anodic and cathodic reactions are 0.39 and – 0.53 mA/cm2, and 0 and 0.3 V vs. Ag/AgCl. Furthermore, when many interfering compounds are included, anodic catalyst is only sensitive to glucose, while this shows linearity even at a low glucose range of 0.5 – 10 mM (R2 = 0.999). When 3, 5, and 10 mM glucose solutions corresponding to low, normal, and high glucose level are prepared and injected into glucose biosensor, each glucose is well recognized by the naked eye through the number of PB bars whose color is automatically changed after one min. Ultimately, this glucose biosensor, which can quickly estimate glucose concentration without external power source, offers strong potential as commercial glucose sensor

241.3: Generation of Prevascularized Endocrine Constructs to Treat Type 1 Diabetes

Introduction: The goal of our study was to generate a functional, prevascularized endocrine constructs utilizing amniotic membrane derived hydrogel, islets and blood outgrowth endothelial cells (BOECs) to be transplanted in diabetic hosts. Methods: Human amniotic membranes were dissected from placentas decellularized, lyophilized, and solubilized to obtain hydrogels. DNA quantification and scanning electron microscopy showed complete removal of cellular components and preserved extracellular matrix. Characterization studies demonstrated widespread distribution of all essential structural proteins, including collagen, GAGs and laminin. The islets and BOECs were admixed in amnion derived hydrogels and cultured in specially designed media to enhance endothelial cell assembly into tubular, vascular-like structures. Constructs were kept under culture for 3 days. Glucose stimulated insulin secretion (GSIS) tests showed an adequate insulin secretion in response to high glucose stimulation, confirming the functional activity of the prevascularized endocrine constructs. Results: To test in vivo biocompatibility and function, the vascularized constructs generated from 500 IEQ rat islets and 2× 105 human derived BOECs were implanted under the skin of the diabetic NSG mice. Transplantation of the constructs led to rapid and long-term (90 days) normalization of blood glucose levels. Removal of the grafts led to recurrence of hyperglycemia within 24 hours, indicating that the transplanted constructs was responsible for normalized glucose levels. Histological analysis of the explanted grafts revealed healthy islet morphology and perfect revascularization. Grafts stained positive for insulin and human specific CD 31 indicating presence of human endothelial cells in newly formed intra-islet micro vessels. Conclusion: Our findings show that amnion derived hydrogel seeded with endocrine pancreatic tissue and endothelial cells could be used for functional, preveascularized endocrine construct bioengineering. This work is supported by grants from the European Commission (Horizon 2020 Framework Program; VANGUARD grant 874700), the European Foundation for the Study of Diabetes (EFSD), the Juvenile Diabetes Research Foundation (JDRF; grant 3-SRA-2020-926-S-B) and the Shota Rustaveli National Science Foundation (grant FR-19-19760).

Corelation of pharmaceutical services with the incidence of side effects of phase III COVID vaccination participants in RS Tingkat II Udayana

Background Presiden Regulation No. 99 of 2020 requires Indonesian citizens to vaccinate against COVID-19 to prevent the transmission and severity of COVID-19. Pharmaceutical services are a tangible manifestation in realizing a comfortable and safe COVID-19 vaccination to reduce the risk of side effects Objective: this study aims to study the relationship of pharmaceutical services to the incidence of side effects of covid-19 vaccination after III at RS Tingkat II Udayana. Method: The reseach desaign was cross-sectional study which used analytical survey The population in the study was all participants of the COVID-19 vaccine in June at RS Tingkat II Udayana as many as 500 people. The sample in this study used a total sampling technique. Data collection in this study used primary data. Data analysis is carried out univariately and bivariately. Results: Participants in the third phase of vaccination were dominated by Astrazeneca vaccination users 245 people (49%), no history of comorbidities 435 people (87%), vaccination participants had a normal BMI of 310 people (62%),normal glucose level of 490 (98%), and normal tension of 450 people (90%). The results showed that patients were satisfied with pharmaceutical services related to handling side effects of fever, muscle pain and fatigue.

Effects of low-protein-high-starch diet on growth performance, glucose and lipid metabolism of Amur sturgeon (Acipenser schrenckii) during feeding and starvation phases

An 8-week growth (8 w) and 1-week starvation (S1 w) trial were conducted to investigate the effects of low-protein-high-starch diet on the growth performance, glucose and lipid metabolism in Amur sturgeon (initial body weight, 69.99 ± 0.06 g). Two diets with equal protein-to-energy ratios were fed, one diet contained 43.0% protein and 11.5% starch (HPLS) and the other contained 38.9% protein and 23.6% starch (LPHS). The results showed that LPHS diet did not compromise growth performance of Amur sturgeon, while the feeding rate increased significantly suggesting the keep of energy supplement. The LPHS diet also promoted the deposition of whole-body protein in Amur sturgeon after S1 w. An effective glucose metabolism response was observed that the transcript levels of glycolysis-related genes (gk) was upregulated significantly, suggesting that glucose catabolism was accelerated to maintain normal glycemic homeostasis and avoid hyperglycemia and glycogen accumulation during long-term feeding phase. Moreover, hepatic gluconeogenesis pathway (PEPCK, G6P) was upregulated to maintain normal plasma glucose levels of sturgeon in the LPHS group during S1 w phase. In addition, activated chrebp by high-starch intake induced excess glucose conversion to TG in the liver, which led to inhibit lipogenesis and accelerate lipolysis to prevent excessive fat accumulation after fed LPHS diet during feeding phase. Hepatic lipolysis (HSL) and β-oxidation (PPARα) were upregulated to satisfy energetic requirements, thereby promoting whole-body protein deposition. Our findings suggested that low-protein-high-starch diet could conserve dietary protein, and mitigate the excessive consumption of whole-body protein during starvation.

Amyloid [Formula: see text] (1-42) peptide impairs mitochondrial respiration in primary human brain microvascular endothelial cells: impact of dysglycemia and pre-senescence.

Diabetes increases the risk of Alzheimer's disease (AD). We investigated the impact of glucose concentrations on the β-amyloid (Aβ)-induced alteration of mitochondrial/cellular energetics in primary human brain microvascular endothelial cells (HBMECs). HBMECs were grown and passaged in media containing 15mmol/l glucose (normal) based on which the glucose levels in the media were designated as high (25mmol/L) or low (5mmol/L). HBMECs were treated with Aβ (1-42) (5µmol/l) or a scrambled peptide for 24h and mitochondrial respiratory parameters were measured using Seahorse Mito Stress Test. Aβ (1-42) decreased the mitochondrial ATP production at normal glucose levels and decreased spare respiratory capacity at high glucose levels. Aβ (1-42) diminished all mitochondrial respiratory parameters markedly at low glucose levels that were not completely recovered by restoring normal glucose levels in the media. The addition of mannitol (10mmol/l) to low and normal glucose-containing media altered the Aβ (1-42)-induced bioenergetic defects. Even at normal glucose levels, pre-senescent HMBECs (passage 15) displayed greater Aβ (1-42)-induced mitochondrial respiratory impairments than young cells (passages 7-9). Thus, hypoglycemia, osmolarity changes, and senescence are stronger instigators of Aβ (1-42)-induced mitochondrial respiration and energetics in HBMECs and contributors to diabetes-related increased AD risk than hyperglycemia.

Hypoxia mimetics restore bone biomineralisation in hyperglycaemic environments

Diabetic patients have an increased risk of fracture and an increased occurrence of impaired fracture healing. Diabetic and hyperglycaemic conditions have been shown to impair the cellular response to hypoxia, via an inhibited hypoxia inducible factor (HIF)-1α pathway. We investigated, using an in vitro hyperglycaemia bone tissue engineering model (and a multidisciplinary bone characterisation approach), the differing effects of glucose levels, hypoxia and chemicals known to stabilise HIF-1α (CoCl2 and DMOG) on bone formation. Hypoxia (1% O2) inhibited bone nodule formation and resulted in discrete biomineralisation as opposed to the mineralised extracellular collagen fibres found in normoxia (20% O2). Unlike hypoxia, the use of hypoxia mimetics did not prevent nodule formation in normal glucose level. Hyperglycaemic conditions (25 mM and 50 mM glucose) inhibited biomineralisation. Interestingly, both hypoxia mimetics (CoCl2 and DMOG) partly restored hyperglycaemia inhibited bone nodule formation. These results highlight the difference in osteoblast responses between hypoxia mimetics and actual hypoxia and suggests a role of HIF-1α stabilisation in bone biomineralisation that extends that of promoting neovascularisation, or other system effects associated with hypoxia and bone regeneration in vivo. This study demonstrates that targeting the HIF pathway may represent a promising strategy for bone regeneration in diabetic patients.

Metabolic and Genetic Markers Improve Prediction of Incident Type 2 Diabetes: A Nested Case-Control Study in Chinese.

It is essential to improve the current predictive ability for type 2 diabetes (T2D) risk. We aimed to identify novel metabolic markers for future T2D in Chinese individuals of Han ethnicity and to determine whether the combined effect of metabolic and genetic markers improves the accuracy of prediction models containing clinical factors. A nested case-control study containing 220 incident T2D patients and 220 age- and sex- matched controls from normoglycemic Chinese individuals of Han ethnicity was conducted within the Wuxi Non-Communicable Disease cohort with a 12-year follow-up. Metabolic profiling detection was performed by high-performance liquid chromatography‒mass spectrometry (HPLC-MS) by an untargeted strategy and 20 single nucleotide polymorphisms (SNPs) associated with T2D were genotyped using the Iplex Sequenom MassARRAY platform. Machine learning methods were used to identify metabolites associated with future T2D risk. We found that abnormal levels of 5 metabolites were associated with increased risk of future T2D: riboflavin, cnidioside A, 2-methoxy-5-(1H-1, 2, 4-triazol-5-yl)- 4-(trifluoromethyl) pyridine, 7-methylxanthine, and mestranol. The genetic risk score (GRS) based on 20 SNPs was significantly associated with T2D risk (OR = 1.35; 95% CI, 1.08-1.70 per SD). The area under the receiver operating characteristic curve (AUC) was greater for the model containing metabolites, GRS, and clinical traits than for the model containing clinical traits only (0.960 vs 0.798, P = 7.91 × 10-16). In individuals with normal fasting glucose levels, abnormal levels of 5 metabolites were associated with future T2D. The combination of newly discovered metabolic markers and genetic markers could improve the prediction of incident T2D.

Biochemical assessment of uric acid and magnesium in prediabetic patients in Peshawar-KP: A case-control study.

Background: Background: There is a lack of information regarding serum uric acid (SUA) and magnesium levels among the pre-diabetics population. This study aimed to assess the biochemical assessment of both uric acid and magnesium in prediabetics of the Peshawar-KP region.&#x0D; Methodology: In this case-control study, patients having normal glucose levels were considered as control, and prediabetics were cases. Fasting blood glucose (FPG) levels between 100-125 mg/dl or HbA1c levels between 5.7 to 6.4% were considered pre-diabetic. SUA was assessed by the Uricase method, serum Mg+ by the Calmagite calorimetric method, and fasting glucose was assessed by the GOD-POD enzymatic method.&#x0D; Results: According to our findings, mean values of serum magnesium were 2.12 ± 0.60 mg/dl (p=0.026) and 1.10 ± 0.82 mg/dl (p=0.001) in male and female of control group whereas, 1.60 ± 0.44 mg/dl (p=0.004) and 0.90 ± 0.22 mg/dl (p=0.002) in male and female of cases group respectively. Correspondingly, mean value of SUA was recorded as 4.14 ± 0.66 mg/dl (p=0.008) and 3.12 ± 0.38 mg/dl (p=0.004) in male and female of control group whereas 8.10 ± 1.00 mg/dl (p=0.002) and 6.22 ± 0.44 mg/dl (p=0.003) in male and female of cases and subjects group respectively. It is noticeable that mean serum magnesium and SUA values were higher in the male of both groups compared to females.&#x0D; Conclusion: The study concluded that lower serum magnesium levels in prediabetics might result from the closure of K+ channels, defective phosphorylation of insulin receptors, or diminished glucokinase activity. Higher uric acid levels in prediabetics might result from inflammation, oxidative stress, and hypertrophy of the tubules.

Separate and combined effect of visit-to-visit glycaemic variability and mean fasting blood glucose level on all-cause mortality in patients with type 2 diabetes: A population-based cohort study.

To assess the independent and combined impacts of visit-to-visit fasting blood glucose variability (VVV-FBG) and mean fasting blood glucose level (M-FBG) on all-cause mortality. This prospective cohort study included 48 843 Chinese patients with type 2 diabetes. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to evaluate the association of VVV-FBG and M-FBG with all-cause mortality. The potential nonlinear associations were examined using restricted cubic splines, and additive interaction was evaluated using relative excess risk due to interaction (RERI). Cox generalized additive models (CGAMs) and bivariate response surface models were further used to assess the combined effects of VVV-FBG and M-FBG. A total of 4087 deaths were observed during a median follow-up of 6.99 years. Compared with patients with values at the 5th percentile of average real variability (ARV) and M-FBG, we observed a 23% and 38% increased risk of premature deaths among those with values at the 95th percentile of ARV (HR 1.23, 95% CI 1.10, 1.37) and M-FBG (HR 1.38, 95% CI 1.26, 1.51), respectively. The interaction between glycaemic variability (ARV) and M-FBG was significant on both the additive scale (RERI 0.80 [0.29, 1.32]) and the multiplicative scale (HR 1.90 [1.10, 3.28]). High VVV-FBG and high M-FBG conferred the highest risk of all-cause mortality (HR 1.89, 95% CI 1.64, 2.17), compared to low VVV-FBG and low M-FBG. The CGAMs showed significant synergistic effects between glycaemic variability and M-FBG (P < 0.05). Moreover, a bivariate surface plot showed that risk of death increased more rapidly in type 2 diabetes patients with lower M-FBG combined with lower VVV-FBG. The coexistence of high glycaemic variability and high glucose level might exacerbate the independent risk of premature mortality in type 2 diabetes patients, highlighting the importance of achieving normal and stable glucose levels simultaneously in the management of glucose.

Early-Phase Changes in Serum Free Fatty Acid Levels After Glucose Intake Are Associated With Type 2 Diabetes Incidence: The Hiroshima Study on Glucose Metabolism and Cardiovascular Diseases.

Experimental studies suggest that excess serum free fatty acid (FFA) levels result in impaired glucose metabolism. This study investigated the relationship between changes in serum FFA levels after glucose intake and type 2 diabetes risk. This observational study included 6,800 individuals without diabetes who underwent a 75-g oral glucose tolerance test. Serum FFA levels were measured before and 30 and 60 min after glucose intake. The percentages of changes in serum FFA levels from 0 to 30 and from 30 to 60 min were compared, and a low rate of change in FFA levels was determined using the receiver operating characteristic curve analysis. Over a mean 5.3-year follow-up period, 485 participants developed type 2 diabetes. After adjusting for plasma glucose levels and indices of insulin resistance and β-cell function, low rates of change in FFA levels at 0-30 min (adjusted odds ratio [aOR] 1.91; 95% CI 1.54-2.37) and 30-60 min (aOR 1.48; 95% CI 1.15-1.90) were associated with the incidence of type 2 diabetes. Stratified analysis revealed that the low rate of change in FFA levels at 30-60 min (aOR 1.97; 95% CI 1.05-3.69) was associated with the incidence of type 2 diabetes even in participants with normal fasting glucose levels or glucose tolerance. Changes in serum FFA levels within the 1st h after glucose intake could be a primary predictor of type 2 diabetes. This change may occur prior to the onset of impaired glucose metabolism.