Human Diabetes Research Articles

The usefulness of HbA1c measurement in diabetic mouse models using various devices.

In most cases, the diagnosis of diabetes in animal models is based solely on blood glucose levels. While hemoglobin A1c (HbA1c) is widely used in the diagnosis of diabetes in humans, it is rarely measured in mice in diabetes research. This is thought to be because there are no established reference values for mouse HbA1c, as well as the fact that there are very few reports on the variability and reproducibility of measurements taken using different devices. In this study, we measured HbA1c levels in diabetic mouse models using different devices based on different principles, including capillary electrophoresis, high-performance liquid chromatography, and enzymatic methods, and compared the results. A positive correlation was observed between blood glucose and HbA1c levels in all measurement methods, and high reproducibility was confirmed in the measurement of HbA1c. However, HbA1c levels measured using the enzymatic method were slightly higher than those measured using the other two methods. In addition, an examination of diabetic mice given a sodium-glucose cotransporter 2 inhibitor, which is used to treat diabetes, revealed that there was a 2-week difference in the fluctuation of mouse HbA1c levels compared with the fluctuation of blood glucose levels. Based on these results, it is thought that HbA1c can be a reliable indicator in diabetic mouse models, and it is expected to make the evaluation of abnormal glucose metabolism in mice more reliable.

MiRNA-455-5p regulates the growth and development of adipose tissue by targeting IGF-1R gene

LAY SUMMARY Adipose tissue is an important factor that influences porcine quality, and adipose tissue is also an important endocrine regulator of metabolic homeostasis. Adipose tissue development involves a series of highly synergistic processes, including clone amplification, proliferation arrest and terminal differentiation. In recent years, microRNAs (miRNAs) are a class of non-coding endogenous RNA molecules that have been considered as a class of novel regulators of adipogenesis. In this study, we used the dorsal subcutaneous adipose tissue of Guangxi Bama mini-pigs and Landrace pigs as experimental materials to study the molecular mechanism of adipogenic differentiation of preadipocytes, and the regulatory mechanism of miRNA-455-5p and its target gene IGF-1R involved in the development of adipose tissue. These findings may improve our understanding of mechanism of the molecular regulation of miRNA-455-5p and IGF-1R in pigs, and provide a theoretical basis for increasing pork production. TEASER TEXT The miRNA-455-5p was involved in the negative regulation of adipose tissue development by inhibiting the expression of its target gene IGF-1R. ABSTRACT Adipose tissue is an organ with metabolic, endocrine and immune functions, affecting the life span of animals and their susceptibility to diseases. Previous studies have reported the relationship between many miRNAs and the development of adipose tissue. However, the regulation of miR-455-5p on the development of porcine adipose has not been reported. In this study, we used the dorsal subcutaneous adipose tissue of Guangxi Bama mini-pigs and Landrace pigs as experimental materials to study the regulatory mechanism of miRNA-455-5p and its target gene IGF-1R involved in the development of adipose tissue. Bioinformatic analysis with Targetscan predicted that IGF-1R might be a target gene of miRNA-455-5p. Moreover, mouse 3T3-L1 preadipocytes were transfected with chemically modified mimics and inhibitors to observe the expression of miR-455-5p and IGF-1R genes from 0 to 8 days after transfection. And the expression of adipogenic marker genes PPARγ and C/EBPα was examined. Additionally, the miRNA-455-5p may be involved in the negative regulation of adipose tissue development by inhibiting the expression of its target gene IGF-1R. These results provide a theoretical basis for increasing pork production and provide a new potential target for the treatment of obesity and type 2 diabetes in humans.

E3 ligase substrate adaptor SPOP fine-tunes the UPR of pancreatic β cells.

The Cullin-3 E3 ligase adaptor protein SPOP targets proteins for ubiquitination and proteasomal degradation. We previously established the β-cell transcription factor (TF) and human diabetes gene PDX1 as an SPOP substrate, suggesting a functional role for SPOP in the β cell. Here, we generated a β-cell-specific Spop deletion mouse strain (Spop βKO) and found that Spop is necessary to prevent aberrant basal insulin secretion and for maintaining glucose-stimulated insulin secretion through impacts on glycolysis and glucose-stimulated calcium flux. Integration of proteomic, TF-regulatory gene network, and biochemical analyses identified XBP1 as a functionally important SPOP substrate in pancreatic β cells. Furthermore, loss of SPOP strengthened the IRE1α-XBP1 axis of unfolded protein response (UPR) signaling. ER stress promoted proteasomal degradation of SPOP, supporting a model whereby SPOP fine-tunes XBP1 activation during the UPR. These results position SPOP as a regulator of β-cell function and proper UPR activation.

Why do they use bhat chew sticks? An experiment to demonstrate the antihyperglycemic activity of Clerodendrum infortunatum Linn.

Introduction: The rise in blood glucose than the recommended level is called hyperglycemia, mainly caused by diabetes mellitus (DM). DM is in turn a consequence of decreased insulin secretion or action or both. This experiment is intended to evaluate the effect of Clerodendrum infortunatum Linn. (bhat) chew sticks in controlling diabetes in humans. Method: The fasting blood sugar was measured twice with the help of a glucometer. First, all participants were requested to measure their blood sugar on an empty stomach in the morning without using a bhat chew stick. The next morning, their fasting plasma sugar was again accessed after the use of the bhat chew sticks as a toothbrush. The fall in blood sugar value was recorded and the efficiency of the stimulus was tested using student t-test at α level of significance and n-1 degree of freedom. Result: A total of 27 individuals participated in the study and all responded to the stimulus. A fall in blood glucose was observed between 3-59 mg/dL and the response was not found to be significant at 0.05 level of significance. Conclusion: Rural people use chew sticks as toothbrushes and prefer C. infortunatum twigs to control diabetes. The present experiment shows that bhat lowers the blood sugar level in both diabetic and non-diabetic individuals. However, chronic impacts should also be monitored by conducting large-scale studies on humans to establish proper dosage, indications, and side effects of C. infortunatum. Keywords: Clerodendrum infortunatum, diabetes, hyperglycemia, random blood sugar, chew stick.

Targeting mTOR Kinase with Natural Compounds: Potent ATP-Competitive Inhibition Through Enhanced Binding Mechanisms.

Background/Objectives: The mammalian target of the rapamycin (mTOR) signaling pathway is a central regulator of cell growth, proliferation, metabolism, and survival. Dysregulation of mTOR signaling contributes to many human diseases, including cancer, diabetes, and obesity. Therefore, inhibitors against mTOR's catalytic kinase domain (KD) have been developed and have shown significant antitumor activities, making it a promising therapeutic target. The ATP-KD interaction is particularly important for mTOR to exert its cellular functions, and such inhibitors have demonstrated efficient attenuation of overall mTOR activity. Methods: In this study, we screened the Traditional Chinese Medicine (TCM) database, which enlists natural products that capture the relationships between drugs targets and diseases. Our aim was to identify potential ATP-competitive agonists that target the mTOR-KD and compete with ATP to bind the mTOR-KD serving as potential potent mTOR inhibitors. Results: We identified two compounds that demonstrated interatomic interactions similar to those of ATP-mTOR. The conformational stability and dynamic features of the mTOR-KD bound to the selected compounds were tested by subjecting each complex to 200 ns molecular dynamic (MD) simulations and molecular mechanics/generalized Born surface area (MM/GBSA) to extract free binding energies. We show the effectiveness of both compounds in forming stable complexes with the mTOR-KD, which is more effective than the mTOR-KD-ATP complex with more robust binding affinities. Conclusions: This study implies that both compounds could serve as potential therapeutic inhibitors of mTOR, regulating its function and, therefore, mitigating human disease progression.

Identifying the Role of Individual Seal IAPP Amino Acids in Inhibiting the Aggregation of Human IAPP.

The progression of type 2 diabetes in humans appears to be linked to the loss of insulin-producing β-cells. One of the major contributors to β-cell loss is the formation of toxic human IAPP amyloid (hIAPP, Islet Amyloid Polypeptide, amylin) in the pancreas. Inhibiting the formation of toxic hIAPP amyloid could slow, if not prevent altogether, the progression of type 2 diabetes. Many non-human organisms also express amyloidogenic IAPP variants known to kill pancreatic cells and give rise to diabetes-like symptoms. Surprisingly, some of these non-human IAPP variants function as inhibitors of hIAPP aggregation, raising the possibility of developing non-human IAPP peptides into anti-diabetic therapeutic peptides. One such inhibitory IAPP variant is seal IAPP, which has been shown to inhibit hIAPP aggregation. Seal IAPP only differs from hIAPP by three amino acids. In this study, each of the six seal/human IAPP permutations was analyzed to identify the role of each of the three amino acid positions in inhibiting hIAPP aggregation. This study aimed toidentify the minimal amino acid substitutions to yield a peptide inhibitor of human IAPP aggregation. The goal of the study was to determine the minimal amino acid substitutions necessary to convert human IAPP into an amyloid-inhibiting peptide. The formation of toxic hIAPP amyloid was monitored using Thioflavin T binding assays, atomic force microscopy, and MTT cell rescue studies. One seal IAPP variant retained amyloid-inhibition activity, and two variants appeared to be more amyloidogenic and toxic than wild-type human IAPP. These results suggest that inhibition of hIAPP requires both the H18R and F23L substitutions of hIAPP.

Feline Diabetes Is Associated with Deficits in Markers of Insulin Signaling in Peripheral Tissues.

Like humans, cats have a strong relationship between decreasing insulin sensitivity and the development of diabetes with obesity. However, the underlying molecular mechanisms of impaired insulin secretion and signaling in cats remain largely unknown. A total of 54 client-owned nondiabetic lean (n = 15), overweight (n = 15), and diabetic (n = 24) cats were included in the study. The pancreas, liver, and skeletal muscle were quantified for mRNA and protein abundances of insulin and incretin signaling markers. Diabetic cats showed increased liver and muscle adiposity. The pancreas of diabetic cats had decreased transcript abundances of insulin, insulin receptor, insulin-receptor substrate (IRS)-1, glucose transporters (GLUT), and protein abundance of mitogen-activated protein kinase. In treated diabetics, protein abundance of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide receptors, total and phosphorylated Akt, and GLUT-1 were increased in the pancreas, whereas untreated diabetics had downregulation of markers of insulin and incretin signaling. In the muscle and liver, diabetic cats had reduced mRNA abundances of insulin receptor, IRS-1/2, and phosphatidylinositol-3-kinase, and reduced protein abundances of GLUT-4 and phosphatidylinositol-3-kinase-p85α in muscle. We demonstrate that feline diabetes is associated with ectopic lipid deposition in the liver and skeletal muscle, deficits in insulin synthesis and incretin signaling in the pancreas, and impaired insulin signaling in the muscle and liver. These findings have implications for understanding the pathophysiological mechanisms of obesity and diabetes in humans and pets.

Glucocorticoids reduce Slc2a2 (GLUT2) gene expression through HNF1 in pancreatic β-cells.

Glucose transporter type 2 (GLUT2), encoded by the Slc2a2 gene, is essential for glucose-stimulated insulin secretion (GSIS) in pancreatic islet β-cells, and low expression of GLUT2 is associated with β-cell dysfunction during the progression of type 2 diabetes in humans and animal models. Glucocorticoids are stress hormones that regulate inflammation and metabolism through glucocorticoid receptor (GR), a member of the nuclear receptor superfamily, and synthetic glucocorticoids are widely used for the treatment of inflammatory disorders. Prolonged exposure to glucocorticoids induces β-cell dysfunction and diabetes, but the effects of Slc2a2 gene repression in β-cells, if any, and the mechanisms involved, remains unclear. In the present study, we measured the expression of GSIS-related genes in the MIN6 β-cell line, and found that Slc2a2 mRNA expression was selectively reduced by dexamethasone (DEX), a synthetic glucocorticoid. Using bioinformatics and reporter assays, we identified two β-cell enhancers of the Slc2a2 gene, one within the first intron and another located approximately 40 kbp downstream of the transcription start site. The latter enhancer (designated as E3c) was responsible for the DEX-induced repression of the Slc2a2 gene. Of the previously identified β-cell-enriched transcription factors (NEUROD1, MAFA, HNF1α, and HNF1β) that activate the E3c enhancer, the transcriptional activity of HNF1α and HNF1β, responsible for maturity-onset diabetes of the young types 3 and 5, respectively, was repressed by DEX and GR. This functional link between HNF1α/HNF1β and GR should help elucidate the mechanism of glucocorticoid-induced β-cell dysfunction and diabetes.

Mitigating methylglyoxal-induced glycation stress: the protective role of iron, copper, and manganese coordination compounds in Saccharomyces cerevisiae.

Glycation-induced stress (G-iS) is a physiological phenomenon that leads to the formation of advanced glycation end-products, triggering detrimental effects such as oxidative stress, inflammation, and damage to intracellular structures, tissues, and organs. This process is particularly relevant because it has been associated with various human pathologies, including cancer, neurodegenerative diseases, and diabetes. As therapeutic alternatives, coordination compounds with antioxidant activity show promising potential due to their versatility in attenuating oxidative stress and inflammation. Herein, we investigated the antioxidant-related protective potential of a series of complexes: [Cu(II)(BMPA)Cl2] (1), [Fe(III)(BMPA)Cl3] (2), and [Cl(BMPA)MnII-(μ-Cl)2-MnII(BMPA)-(μ-Cl)- MnII(BMPA)(Cl)2]•5H2O (3), all synthesized with the ligand bis-(2-pyridylmethyl)amine (BMPA) in Saccharomyces cerevisiae exposed to G-iS caused by methylglyoxal (MG). Pre- treatment with complexes 1-3 proved highly effective, increasing yeast tolerance to G-iS and attenuating mitochondrial dysfunction. This observed phenotype appears to result from a reduction in intracellular oxidation, lipid peroxidation levels, and glycation. Additionally, an increase in the activity of the antioxidant enzymes superoxide dismutase and catalase was observed following treatment with complexes 1-3. Notably, although complexes 1-3 provided significant protection against oxidative stress induced by H2O2 and menadione, their protective role was more effective against MG-induced glycation stress. Our results indicate that these complexes possess both antiglycation and antioxidant properties, warranting further investigation as potential interventions for mitigating glycation and oxidative stress-related pathologies.

Transcriptomic heterogeneity of non-beta islet cells is associated with type 2 diabetes development in mouse models

Aims/hypothesisThe aim of this work was to understand the role of non-beta cells in pancreatic islets at early stages of type 2 diabetes pathogenesis.MethodsSpecific clustering was employed to single-cell transcriptome data from islet cells of obese mouse strains differing in their diabetes susceptibility (diabetes-resistant B6.V.Lepob/ob [OB] and diabetes-susceptible New Zealand Obese [NZO] mice) on a diabetogenic diet.ResultsRefined clustering analysis revealed several heterogeneous subpopulations for alpha cells, delta cells and macrophages, of which 133 mapped to human diabetes genes identified by genome-wide association studies. Importantly, a similar non-beta cell heterogeneity was found in a dataset of human islets from donors at different stages of type 2 diabetes. The predominant alpha cell cluster in NZO mice displayed signs of cellular stress and lower mitochondrial capacity (97 differentially expressed genes [DEGs]), whereas delta cells from these mice exhibited higher expression levels of maturation marker genes (Hhex and Sst) but lower somatostatin secretion than OB mice (184 DEGs). Furthermore, a cluster of macrophages was almost twice as abundant in islets of OB mice, and displayed extensive cell–cell communication with beta cells of OB mice. Treatment of beta cells with IL-15, predicted to be released by macrophages, activated signal transducer and activator of transcription (STAT3), which may mediate anti-apoptotic effects. Similar to mice, humans without diabetes possess a greater number of macrophages than those with prediabetes (39 mmol/mol [5.7%] < HbA1c < 46 mmol/mol [6.4%]) and diabetes.Conclusions/interpretationOur study indicates that the transcriptional heterogeneity of non-beta cells has an impact on intra-islet crosstalk and participates in beta cell (dys)function.Data availabilityscRNA-seq data from the previous study are available in gene expression omnibus under gene accession number GSE159211 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE159211).Graphical

Prospective clinical surveillance for severe acute respiratory illness and COVID-19 vaccine effectiveness in Kenyan hospitals during the COVID-19 pandemic.

There are limited data from sub-Saharan Africa describing the demographic characteristics, clinical features and outcome of patients admitted to public hospitals with severe acute respiratory infections during the COVID-19 pandemic. We conducted a prospective longitudinal hospital-based sentinel surveillance between May 2020 and December 2022 at 16 public hospitals in Kenya. All patients aged above 18 years admitted to adult medical wards in the participating hospitals were included. We collected data on demographic and clinical characteristics, SARS-CoV-2 infection and COVID-19 vaccination status and, admission episode outcomes. We determined COVID-19 vaccine effectiveness (VE) against admission with SARS-CoV-2 positive severe acute respiratory illness (SARI) (i.e., COVID-19) andprogression to inpatient mortality among patients admitted with SARI, using a test-negative case control design. Of the 52,636 patients included in the study, 17,950 (34.1%) were admitted with SARI. The median age was 50 years. Patients were equally distributed across sexes. Pneumonia was the most common diagnosis at discharge. Hypertension, Human Immunodeficiency Virus (HIV) infection and Diabetes Mellitus were the most common chronic comorbidities. SARS-CoV-2 test results were positive in 2,364 (27.9%) of the 8,471 patients that underwent testing. After adjusting for age, sex and presence of a chronic comorbidity, SARI patients were more likely to progress to inpatient mortality compared to non-SARI patients regardless of their SARS-CoV-2 infection status (adjusted odds ratio (aOR) for SARI and SARS-CoV-2 negative patients 1.22, 95% CI 1.10-1.37; and aOR for SARI and SARS-CoV-2 positive patients 1.32, 95% CI 1.24-1.40). After adjusting for age, sex and presence of a chronic comorbidity, COVID-19 VE against progression to inpatient mortality following admission with SARI for those with a confirmed vaccination status was 0.59 (95% CI 0.27-0.77). We have provided a comprehensive description of the demographic and clinical pattern of admissions with SARI in Kenyan hospitals during the COVID-19 pandemic period as well as the COVID-19 VE for these patients. These data were useful in providing situational awareness during the first three years of the pandemic in Kenya and informing national response measures.

Tapered coreless optical fiber-based refractive index sensor for acetone concentration detection

A fast-response optical fiber sensor is designed and fabricated to detect different concentrations of volatile acetone. The proposed sensor structure was fabricated by splicing a segment of tapered coreless fiber (CLF) amid two single-mode fibers (SMF). Herein, tuned tapered diameters and lengths of CLF’s cladding were immersed in various concentrations of the acetone solutions to sense the effective refractive index (RI) variations. Accordingly, the sensor’s performance with tuned diameters at different lengths of the CLF was optimized to realize the suitable size of amplified evanescent fields. The sensor responded remarkably towards acetone concentrations, with a superior sensitivity of 336.102 nm/RIU, 0.163 nm/%, and 27.531 × 10−5 nm/ppm at 5 cm length and 60 µm taper diameter of CLF. The examined sensor possesses a fast response time with a minimum detection limit of 0.244 RIU, 5.025%vol, and 2.9 ppm. Though the rapid evaporation (volatility) of the acetone compound exempted it from air pollutants, many industrial and human body processes produce acetone which needs to be detected. The examined sensor may have the potential to detect in a non-invasive approach with high accuracy and rapid diabetes in humans, lung cancer, etc.

The combination of metformin and high glucose increased longevity of Caenorhabditis elegans a DAF-16/FOXO-independent manner: cancer/diabetic model via C. elegans.

Sedentary lifestyles and diets with high glycemic indexes are considered to be contributing factors to the development of obesity, type 2 diabetes in humans. Metformin, a biguanide medication commonly used to treat type 2 diabetes, has been observed to be associated with longevity; however, the molecular mechanisms underlying this observation are still unknown. The effects of metformin and high glucose, which have important roles in aging-related disease such as diabetes and cancer, were studied in lin-35 worms because they are associated with cancer-associated pRb function in mammals and have a tumour suppressor property. According to our results, the negative effect of high glucose on egg production of lin-35 worms was greater than that of N2 worms. High glucose shortened lifespan and increased body length and width in individuals of both strains. Metformin treatment alone extended the lifespan of N2 and lin-35 worms by reducing fertilization efficiency. However, when metformin was administered in the presence of high glucose, the lifespan of lin-35 worms was clearly longer compared to N2 worms. Additionally, we conclude that glucose and metformin in lin35 worms can extend life expectancy through a DAF-16/FOXO-independent mechanism. Furthermore, the results of this study will provide a new perspective on extending mammalian lifespan through the model organism C. elegans.

Mitochondrial Bioenergetics Deficiency in cisd-1 Mutants is Linked to AMPK-Mediated Lipid Metabolism

BackgroundCISD-1 is a mitochondrial iron-sulfate [2Fe-2S] protein known to be associated with various human diseases, including cancer and diabetes. Previously, we demonstrated that CISD-1 deficiency in worms lowers glucose and ATP levels. In this study, we further explored how worms compensate for lower ATP levels by analyzing changes in cytoplasmic and mitochondrial iron content, AMPK activities, and total lipid profiles. Materials and MethodsExpression levels of CISD-1 and CISD-1::GFP fusion proteins in wild-type worms (N2), cisd-1-deletion mutants (tm4993 and syb923) and GFP insertion transgenic worms (PHX953 and SJL40) were examined by western blot. Fluorescence microscopy analyzed CISD-1::GFP pattern in PHX953 embryos and adults, and lipid droplet sizes in N2, cisd-1, aak-2 and aak-2;cisd-1 worms. Total and mitochondrial iron content, electron transport complex profiles, and AMPK activity were investigated in tm4993 and syb923 mutants. mRNA levels of mitochondrial β-oxidation genes, acs-2, cpt-5, and ech-1, were quantified by RT-qPCR in various genetic worm strains. Lipidomic analyses were performed in N2 and cisd-1(tm4993) worms. ResultsDefects in cisd-1 lead to an imbalance in iron transport and cause proton leak, resulting in lower ATP production by interrupting the mitochondrial electron transport chain. We identified a signaling pathway that links ATP deficiency-induced AMPK (AMP activated protein kinase) activation to the expression of genes that facilitate lipolysis via β-oxidation. ConclusionOur data provide a functional coordination between CISD-1 and AMPK constitutes a mitochondrial bioenergetics quality control mechanism that provides compensatory energy resources.

Endothelial KLF11 is a novel protector against diabetic atherosclerosis

BackgroundAtherosclerotic cardiovascular diseases remain the leading cause of mortality in diabetic patients, with endothelial cell (EC) dysfunction serving as the initiating step of atherosclerosis, which is exacerbated in diabetes. Krüppel-like factor 11 (KLF11), known for its missense mutations leading to the development of diabetes in humans, has also been identified as a novel protector of vascular homeostasis. However, its role in diabetic atherosclerosis remains unexplored.MethodsDiabetic atherosclerosis was induced in both EC-specific KLF11 transgenic and knockout mice in the Ldlr−/− background by feeding a diabetogenic diet with cholesterol (DDC). Single-cell RNA sequencing (scRNA-seq) was utilized to profile EC dysfunction in diabetic atherosclerosis. Additionally, gain- and loss-of-function experiments were conducted to investigate the role of KLF11 in hyperglycemia-induced endothelial cell dysfunction.ResultsWe found that endothelial KLF11 deficiency significantly accelerates atherogenesis under diabetic conditions, whereas KLF11 overexpression remarkably inhibits it. scRNA-seq profiling demonstrates that loss of KLF11 increases endothelial-to-mesenchymal transition (EndMT) during atherogenesis under diabetic conditions. Utilizing gain- and loss-of-function approaches, our in vitro study reveals that KLF11 significantly inhibits EC inflammatory activation and TXNIP-induced EC oxidative stress, as well as Notch1/Snail-mediated EndMT under high glucose exposure.ConclusionOur study demonstrates that endothelial KLF11 is an endogenous protective factor against diabetic atherosclerosis. These findings indicate that manipulating KLF11 could be a promising approach for developing novel therapies for diabetes-related cardiovascular complications.

Assessing the Arsenic Contents and Associated Risks in Groundwater of Vehari and Lodhran Districts, Pakistan

Exposure to arsenic (As) can induce numerous lethal diseases, such as cancer, cardiovascular issues, skin diseases, and diabetes in humans. The major route of human and animal exposure to As is through drinking As-rich groundwater. This study assessed As occurrence in the groundwater of two districts in the Punjab (Vehari and Lodhran) provinces of Pakistan. Groundwater analysis revealed an average As concentration of 7.7 µg/L (n = 79) in the study area, with a maximum As concentration up to 41.4 µg/L (33% of samples exceeding the WHO limit of 10 µg/L). Arsenic traces were found in animal milk (n = 15, mean: 0.79 µg/L, 17% exceeding 2.0 µg/L), human hair (n = 12, mean: 0.36 µg/g, 17% exceeding 1.0 µg/g), and human nails (n = 8, mean: 0.03 µg/g, none of the samples exceeded 1.0 µg/g). Health risk assessment indices revealed that about 33% of the hazard quotient and 54% of the cancer risk factor exceeded their thresholds. Despite the low–moderate As concentration in groundwater and the accumulation of As in a few biological samples, there is a possibility of potential As poisoning via the long-term and continuous use of groundwater for drinking. Monitoring and blanket testing of wells for As in well water can provide baseline data to minimize the threat of As-mediated arsenicosis in As-affected areas of Pakistan. Moreover, a detailed study of potential As accumulation in biological samples with a higher number of samples is recommended in the area.

End tuberculosis strategy also requires initiation and integration of a national silicosis control program with the ongoing tuberculosis elimination activities: A review of the silicotuberculosis situation in India.

Earlier studies conducted by Indian researchers have demonstrated that the elimination of tuberculosis (TB) requires proactive control of silicosis, given India's significant burden of silicosis and its common comorbidity, pulmonary TB, also known as silicotuberculosis. The TB Control Indian Health Authority saw human immunodeficiency virus infection, diabetes, and malnutrition, among others, as important risk factors for case findings, but overlooked the significance of silicosis. Silicotuberculosis control is often confronted with challenges of detecting microorganisms, uncertain treatment outcomes, a higher likelihood of mono-drug and multi-drug resistance, and increased mortality due to treatment failure. In addition, silicosis has a long latent period, typically 15 years or more, from the onset of silica dust exposure to the appearance of opacities on radiological examination, which is the conventional method of diagnosis of the condition. Facing the aforementioned situation, scientists of the Indian Council of Medical Research-National Institute of Occupational Health have identified a useful biomarker, Club cell secretory protein 16 (CC-16) (a lung protein), that might serve as a surrogate marker for early detection of silicosis among silica dust-exposed workers. An added benefit of CC-16 is its ability to detect sub-radiological silicosis, which is recognized as a risk factor for TB and multi-drug-resistant TB. At present, two researchers have developed point-of-care devices for detecting silica-dust-induced lung damage using serum CC-16, to support its further application. The present review highlights possible mechanisms for the early detection of silicosis and silicotuberculosis by assessing several relevant research publications, and the findings suggest that a national silicosis control program, to be integrated with existing TB elimination activities for sustainable and improved outcomes, should be initiated.

Pentachlorophenol increases diabetes risk by damaging β-cell secretion and disrupting gut microbial-related amino acids and fatty acids biosynthesis

Pentachlorophenol (PCP), a ubiquitous environmental pollutant, has been reported as a possible contributor to diabetes. However, evidence for general population is scarce while related mechanisms are largely unknown. Using a representative population-based case-control study in Beijing (n = 1796), we found a positive association between PCP exposure and diabetes risk with the odds ratio reaching 1.68 (95 % confidence interval: 1.30 to 2.18). A further rat experiment revealed that low-dose PCP mimicking real-world human exposure can significantly impair glycemic homeostasis by inducing pancreatic β-cell dysfunction, with non-linear dose-response relationships. Subsequent multi-omics analysis suggested that low-dose PCP led to notable gut microbiota dysbiosis (especially the species from genus Prevotella, such as intermedia, dentalis, ruminicola, denticola, melaninogenica, and oris), decreased serum amino acids (L-phenylalanine, L-tyrosine, and L-tryptophan) and increased serum fatty acids (oleic and palmitic acid) in rats, while strong correlations were observed among alterations of gut microbes, serum metabolites and glycemic-related biomarkers (e.g., fasting blood glucose and insulin). Collectively, these results imply PCP may increase diabetes risk by disrupting gut microbial-related amino acids and fatty acids biosynthesis. This will help guide future in-depth studies on the roles of PCP in the development of human diabetes.

Glucose Metabolism-Modifying Natural Materials for Potential Feed Additive Development.

Glucose, a primary energy source derived from animals' feed ration, is crucial for their growth, production performance, and health. However, challenges such as metabolic stress, oxidative stress, inflammation, and gut microbiota disruption during animal production practices can potentially impair animal glucose metabolism pathways. Phytochemicals, probiotics, prebiotics, and trace minerals are known to change the molecular pathway of insulin-dependent glucose metabolism and improve glucose uptake in rodent and cell models. These compounds, commonly used as animal feed additives, have been well studied for their ability to promote various aspects of growth and health. However, their specific effects on glucose uptake modulation have not been thoroughly explored. This article focuses on glucose metabolism is on discovering alternative non-pharmacological treatments for diabetes in humans, which could have significant implications for developing feed additives that enhance animal performance by promoting insulin-dependent glucose metabolism. This article also aims to provide information about natural materials that impact glucose uptake and to explore their potential use as non-antibiotic feed additives to promote animal health and production. Further exploration of this topic and the materials involved could provide a basis for new product development and innovation in animal nutrition.

Branched-chain amino acids supplementation induces insulin resistance and pro-inflammatory macrophage polarization via INFGR1/JAK1/STAT1 signal pathway

BackgroundObesity is a global epidemic, and the low-grade chronic inflammation of adipose tissue in obese individuals can lead to insulin resistance and type 2 diabetes. Adipose tissue macrophages (ATMs) are the main source of pro-inflammatory cytokines in adipose tissue, making them an important target for therapy. While branched-chain amino acids (BCAA) have been strongly linked to obesity and type 2 diabetes in humans, the relationship between BCAA catabolism and adipose tissue inflammation is unclear. This study aims to investigate whether disrupted BCAA catabolism influences the function of adipose tissue macrophages and the secretion of pro-inflammatory cytokines in adipose tissue, and to determine the underlying mechanism. This research will help us better understand the role of BCAA catabolism in adipose tissue inflammation, obesity, and type 2 diabetes.MethodsIn vivo, we examined whether the BCAA catabolism in ATMs was altered in high-fat diet-induced obesity mice, and if BCAA supplementation would influence obesity, glucose tolerance, insulin sensitivity, adipose tissue inflammation and ATMs polarization in mice. In vitro, we isolated ATMs from standard chow and high BCAA-fed group mice, using RNA-sequencing to investigate the potential molecular pathway regulated by BCAA accumulation. Finally, we performed targeted gene silence experiment and used immunoblotting assays to verify our findings.ResultsWe found that BCAA catabolic enzymes in ATMs were influenced by high-fat diet induced obesity mice, which caused the accumulation of both BCAA and its downstream BCKA. BCAA supplementation will cause obesity and insulin resistance compared to standard chow (STC) group. And high BCAA diet will induce pro-inflammatory cytokines including Interlukin-1beta (IL-1β), Tumor Necrosis Factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) secretion in adipose tissue as well as promoting ATMs M1 polarization (pro-inflammatory phenotype). Transcriptomic analysis revealed that a high BCAA diet would activate IFNGR1/JAK1/STAT1 pathway, and IFNGR1 specific silence can abolish the effect of BCAA supplementation-induced inflammation and ATMs M1 polarization.ConclusionsThe obesity mice model reveals the catabolism of BCAA was disrupted which will cause the accumulation of BCAA, and high-level BCAA will promote ATMs M1 polarization and increase the pro-inflammatory cytokines in adipose tissue which will cause the insulin resistance in further. Therefore, reducing the circulating level of BCAA can be a therapeutic strategy in obesity and insulin resistance patients.