Study on the potential hypoglycemic flavonoids in Abrus precatorius leaves: purification process, quality profile and activity mechanisms by transcriptomics and network pharmacology.

The aim of the study was to investigate the relationship between flavonoids in Abrus precatorius leaves (APL) and their hypoglycaemic effects, which have not been studied before. An efficient purification process, transcriptomics and network pharmacology analysis were applied for the first time. High-performance liquid chromatography (HPLC) was used to determine the content of total flavonoids. The results showed that D101 resin was most suitable for purification of flavonoids of APL, which could increase its purity from 25.2% to 85.2% and achieve a recovery rate of 86.9%. The analysis of transcriptomics and network pharmacology revealed that flavonoids of APL could play a hypoglycaemic role by regulating 31 targets through AGE-RAGE and other signal pathways. Flavonoids of APL could exert hydroglycaemic effects by inhibiting AGEs, α-glucosidase and DPPH. This study provides a solid basis for hypoglycaemic product development and in-depth research of flavonoids in APL.

LD block disorder-specific pleiotropic roles of novel CRHR1 in type 2 diabetes and depression disorder comorbidity.

Major depressive disorder (MDD) and type 2 diabetes (T2D) are complex disorders whose comorbidity can be due to hypercortisolism and may be explained by dysfunction of the corticotropin-releasing hormone receptor 1 (CRHR1) and cortisol feedback within the hypothalamic-pituitary-adrenal axis (HPA axis). To investigate the role of the CRHR1 gene in familial T2D, MDD, and MDD-T2D comorbidity, we tested 152 CRHR1 single-nucleotide-polymorphisms (SNPs), via 2-point parametric linkage and linkage disequilibrium (LD; i.e., association) analyses using 4 models, in 212 peninsular families with T2D and MDD. We detected linkage/LD/association to/with MDD and T2D with 122 (116 novel) SNPs. MDD and T2D had 4 and 3 disorder-specific novel risk LD blocks, respectively, whose risk variants reciprocally confirm one another. Comorbidity was conferred by 3 novel independent SNPs. In silico analyses reported novel functional changes, including the binding site of glucocorticoid receptor-alpha [GR-α] on CRHR1 for transcription regulation. This is the first report of CRHR1 pleiotropic linkage/LD/association with peninsular familial MDD and T2D. CRHR1 contribution to MDD is stronger than to T2D and may antecede T2D onset. Our findings suggest a new molecular-based clinical entity of MDD-T2D and should be replicated in other ethnic groups.

Variation in responses to incretin therapy: Modifiable and non-modifiable factors.

Type 2 diabetes (T2D) and obesity have reached epidemic proportions. Incretin therapy is the second line of treatment for T2D, improving both blood glucose regulation and weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-stimulated insulinotropic polypeptide (GIP) are the incretin hormones that provide the foundations for these drugs. While these therapies have been highly effective for some, the results are variable. Incretin therapies target the class B G protein-coupled receptors GLP-1R and GIPR, expressed mainly in the pancreas and the hypothalamus, while some therapeutical approaches include additional targeting of the related glucagon receptor (GCGR) in the liver. The proper functioning of these receptors is crucial for incretin therapy success and here we review several mechanisms at the cellular and molecular level that influence an individual's response to incretin therapy.

Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment.

Background: Functionally disruptive variants in the glucokinase gene (GCK) cause a form of mild non-progressive hyperglycemia, which does not require pharmacological treatment. A substantial proportion of patients with type 2 diabetes (T2D) carry GCK variants. We aimed to investigate whether carriers of rare GCK variants diagnosed with T2D have a glycemic phenotype and treatment response consistent with GCK-diabetes. Methods: Eight patients diagnosed with T2D from the Danish DD2 cohort who had previously undergone sequencing of GCK participated. Clinical examinations at baseline included an oral glucose tolerance test and continuous glucose monitoring. Carriers with a glycemic phenotype consistent with GCK-diabetes took part in a three-month treatment withdrawal. Results: Carriers of pathogenic and likely pathogenic variants had lower median fasting glucose and C-peptide levels compared to carriers of variants of uncertain significance and benign variants (median fasting glucose: 7.3 (interquartile range: 0.4) mmol/l vs. 9.5 (1.6) mmol/l, p = 0.04; median fasting C-peptide 902 (85) pmol/l vs. 1535 (295) pmol/l, p = 0.03). Four participants who discontinued metformin treatment and one diet-treated participant were reevaluated after three months. There was no deterioration of HbA1c or fasting glucose (median baseline HbA1c: 49 (3) vs. 51 (6) mmol/mol after three months, p = 0.4; median baseline fasting glucose: 7.3 (0.4) mmol/l vs. 7.0 (0.6) mmol/l after three months, p = 0.5). Participants did not consistently fulfill best practice guidelines for GCK screening nor clinical criteria for monogenic diabetes. Discussion: Carriers of pathogenic or likely pathogenic GCK variants identified by unselected screening in T2D should be reported, as they have a glycemic phenotype and treatment response consistent with GCK-diabetes. Variants of uncertain significance should be interpreted with care. Systematic genetic screening of patients with common T2D receiving routine care can lead to the identification and precise care of patients with misclassified GCK-diabetes who are not identifiable through common genetic screening criteria.

Effect of pegbelfermin on NASH and fibrosis-related biomarkers and correlation with histological response in the FALCON 1 trial.

Background & Aims: FALCON 1 was a phase IIb study of pegbelfermin in patients with non-alcoholic steatohepatitis (NASH) and stage 3 fibrosis. This FALCON 1 post hoc analysis aimed to further assess the effect of pegbelfermin on NASH-related biomarkers, correlations between histological assessments and non-invasive biomarkers, and concordance between the week 24 histologically assessed primary endpoint response and biomarkers. Methods: Blood-based composite fibrosis scores, blood-based biomarkers, and imaging biomarkers were evaluated for patients with available data from FALCON 1 at baseline through week 24. SomaSignal tests assessed protein signatures of NASH steatosis, inflammation, ballooning, and fibrosis in blood. Linear mixed-effect models were fit for each biomarker. Correlations and concordance were assessed between blood-based biomarkers, imaging, and histological metrics. Results: At week 24, pegbelfermin significantly improved blood-based composite fibrosis scores (ELF, FIB-4, APRI), fibrogenesis biomarkers (PRO-C3 and PC3X), adiponectin, CK-18, hepatic fat fraction measured by MRI-proton density fat fraction, and all four SomaSignal NASH component tests. Correlation analyses between histological and non-invasive measures identified four main categories: steatosis/metabolism, tissue injury, fibrosis, and biopsy-based metrics. Concordant and discordant effects of pegbelfermin on the primary endpoint vs. biomarker responses were observed; the most clear and concordant effects were on measures of liver steatosis and metabolism. A significant association between hepatic fat measured histologically and by imaging was observed in pegbelfermin arms. Conclusions: Pegbelfermin improved NASH-related biomarkers most consistently through improvement of liver steatosis, though biomarkers of tissue injury/inflammation and fibrosis were also improved. Concordance analysis shows that non-invasive assessments of NASH support and exceed the improvements detected by liver biopsy, suggesting that greater consideration should be given to the totality of available data when evaluating the efficacy of NASH therapeutics. Clinical trial number: Post hoc analysis of NCT03486899. Impact and implications: FALCON 1 was a study of pegbelfermin vs. placebo in patients with non-alcoholic steatohepatitis (NASH) without cirrhosis; in this study, patients who responded to pegbelfermin treatment were identified through examination of liver fibrosis in tissue samples collected through biopsy. In the current analysis, non-invasive blood- and imaging-based measures of fibrosis, liver fat, and liver injury were used to determine pegbelfermin treatment response to see how they compared with the biopsy-based results. We found that many of the non-invasive tests, particularly those that measured liver fat, identified patients who responded to pegbelfermin treatment, consistent with the liver biopsy findings. These results suggest that there may be additional value in using data from non-invasive tests, along with liver biopsy, to evaluate how well patients with NASH respond to treatment.

Reduced volume of diabetic pancreatic islets in rodents detected by synchrotron X-ray phase-contrast microtomography and deep learning network.

The pancreatic islet is a highly structured micro-organ that produces insulin in response to rising blood glucose. Here we develop a label-free and automatic imaging approach to visualize the islets in situ in diabetic rodents by the synchrotron radiation X-ray phase-contrast microtomography (SRµCT) at the ID17 station of the European Synchrotron Radiation Facility. The large-size images (3.2 mm × 15.97 mm) were acquired in the pancreas in STZ-treated mice and diabetic GK rats. Each pancreas was dissected by 3000 reconstructed images. The image datasets were further analysed by a self-developed deep learning method, AA-Net. All islets in the pancreas were segmented and visualized by the three-dimension (3D) reconstruction. After quantifying the volumes of the islets, we found that the number of larger islets (=>1500 µm3) was reduced by 2-fold (wt 1004 ± 94 vs GK 419 ± 122, P < 0.001) in chronically developed diabetic GK rat, while in STZ-treated diabetic mouse the large islets were decreased by half (189 ± 33 vs 90 ± 29, P < 0.001) compared to the untreated mice. Our study provides a label-free tool for detecting and quantifying pancreatic islets in situ. It implies the possibility of monitoring the state of pancreatic islets in vivo diabetes without labelling.

Retinal Thickness and Morphology Changes on OCT in Youth with Type 2 Diabetes: Findings from the TODAY Study.

Objective: To evaluate changes in retinal thickness and morphology using OCT in youth with type 2 diabetes (T2D) and to identify systemic biomarkers correlating with these changes. Design: Retrospective subgroup analysis of a prospective study. Participants: Participants who underwent OCT imaging in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) trial and its follow-up study TODAY2. Methods: In 2010-2011 (TODAY) and 2017-2018 (TODAY2), 6 × 6-mm macular volume OCT scans were acquired, segmented, and analyzed to generate total retinal thickness, inner retinal thickness, and outer retinal thickness. The main retinal morphologies graded were intraretinal cystoid spaces, subretinal fluid, and posterior vitreous detachment (PVD). Main Outcome Measures: Changes in total and individual retinal layer thickness and development of abnormal vitreomacular morphology between TODAY and TODAY2. Results: Participants had a mean age of 17.9 ± 2.4 years and glycated hemoglobin (HbA1c) of 8.2 ± 2.8% in TODAY and a mean age of 25.0 ± 2.4 years and mean HbA1c of 9.5 ± 2.8% in TODAY2. Longitudinally between assessments, there were overall decreases in outer retinal thickness from 167.2 ± 11.5 microns to 158.4 ± 12.8 microns (P < 0.001) and in photoreceptor thickness from 30.3 ± 2.9 microns to 29.8 ± 4.1 microns (P = 0.04) in the central subfield, while in the inner subfield, we noted a decrease in outer retinal thickness from 150.5 ± 10.1 microns to 144.9 ± 10.5 microns (P < 0.001) and an increase in inner retinal thickness from 136.9 ± 11.5 microns to 137.4 ± 12.6 microns (P = 0.01). Multivariate analysis showed that in the center subfield, HbA1c increases were associated with increases in total retinal thickness (r: 0.67, P = 0.001), whereas fasting glucose was positively correlated with inner retinal thickness (r: 0.02, P = 0.02). In the inner subfield, both systolic (r: -0.22, P < 0.001) and diastolic (r: -0.22, P = 0.003) blood pressures were negatively correlated with total retinal thickness. There was an increase in PVD (18.9%) and cystoid spaces (4.2%). Conclusions: Youth with T2D develop retinal thickness changes on OCT, including increases in total retinal and inner retinal thickness in the center subfield that correlate with HbA1c and fasting glucose, respectively. Taken together with the increased prevalence of abnormal vitreomacular morphology in this cohort at risk, these findings emphasize the importance of controlling risk factors to prevent the development of sight-threatening retinal complications.

Vitamin D and Swimming Exercise Prevent Obesity in Rats under a High-Fat Diet via Targeting FATP4 and TLR4 in the Liver and Adipose Tissue.

The prevalence of obesity has risen in the last decades, and it has caused massive health burdens on people's health, especially metabolic and cardiovascular issues. The risk of vitamin D insufficiency is increased by obesity, because adipose tissue alters both the requirements for and bioavailability of vitamin D. Exercise training is acknowledged as having a significant and long-term influence on body weight control; the favorable impact of exercise on obesity and obesity-related co-morbidities has been demonstrated via various mechanisms. The current work illustrated the effects of vitamin D supplementation and exercise on obesity induced by a high-fat diet (HFD) and hepatic steatosis in rats and explored how fatty acid transport protein-4 (FATP4) and Toll-like receptor-4 antibodies (TLR4) might be contributing factors to obesity and related hepatic steatosis. Thirty male albino rats were divided into five groups: group 1 was fed a normal-fat diet, group 2 was fed an HFD, group 3 was fed an HFD and given vitamin D supplementation, group 4 was fed an HFD and kept on exercise, and group 5 was fed an HFD, given vitamin D, and kept on exercise. The serum lipid profile adipokines, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were analyzed, and the pathological changes in adipose and liver tissues were examined. In addition, the messenger-ribonucleic acid (mRNA) expression of FATP4 and immunohistochemical expression of TLR4 in adipose and liver tissues were evaluated. Vitamin D supplementation and exercise improved HFD-induced weight gain and attenuated hepatic steatosis, along with improving the serum lipid profile, degree of inflammation, and serum adipokine levels. The expression of FATP4 and TLR4 in both adipose tissue and the liver was downregulated; it was noteworthy that the group that received vitamin D and was kept on exercise showed also improvement in the histopathological picture of this group. According to the findings of this research, the protective effect of vitamin D and exercise against obesity and HFD-induced hepatic steatosis is associated with the downregulation of FATP4 and TLR4, as well as a reduction in inflammation.

Clinical profile of patients with type 2 diabetes after COVID-19 vaccination: A prospective study.

The purpose of this study was to characterize the clinical profile of patients with type 2 diabetes after COVID-19 vaccination. This prospective study has involved 100 adult diabetic patients followed in the primary health care. SARS-CoV-2 infection after COVID-19 vaccination was the outcome indicator.

The extracellular matrix of human bone marrow adipocytes and glucose concentration differentially alter mineralization quality without impairing osteoblastogenesis.

Bone marrow adipocytes (BMAds) accrue in various states of osteoporosis and interfere with bone remodeling through the secretion of various factors. However, involvement of the extracellular matrix (ECM) produced by BMAds in the impairment of bone marrow mesenchymal stromal cell (BM-MSC) osteoblastogenesis has received little attention. In type 2 diabetes (T2D), skeletal fragility is associated with several changes in bone quality that are incompletely understood, and BMAd quantity increases in relationship to poor glycemic control. Considering their altered phenotype in this pathophysiological context, we aimed to determine the contribution of the ECM of mature BMAds to osteoblastogenesis and mineralization quality in the context of chronic hyperglycemia. Human BM-MSCs were differentiated for 21 days in adipogenic medium containing either a normoglycemic (LG, 5.5 mM) or a high glucose concentration (HG, 25 mM). The ECM laid down by BMAds were devitalized through cell removal to examine their impact on the proliferation and differentiation of BM-MSCs toward osteoblastogenesis in LG and HG conditions. Compared to control plates, both adipocyte ECMs promoted cell adhesion and proliferation. As shown by the unmodified RUNX2 and osteocalcin mRNA levels, BM-MSC commitment in osteoblastogenesis was hampered by neither the hyperglycemic condition nor the adipocyte matrices. However, adipocyte ECMs or HG condition altered the mineralization phase with perturbed expression levels of type 1 collagen, MGP and osteopontin. Despite higher ALP activity, mineralization levels per cell were decreased for osteoblasts grown on adipocyte ECMs compared to controls. Raman spectrometry revealed that culturing on adipocyte matrices specifically prevents type-B carbonate substitution and favors collagen crosslinking, in contrast to exposure to HG concentration alone. Moreover, the mineral to organic ratio was disrupted according to the presence of adipocyte ECM and the glucose concentration used for adipocyte or osteoblast culture. HG concentration and adipocyte ECM lead to different defects in mineralization quality, recapitulating contradictory changes reported in T2D osteoporosis. Our study shows that ECMs from BMAds do not impair osteoblastogenesis but alter both the quantity and quality of mineralization partly in a glucose concentration-dependent manner. This finding sheds light on the involvement of BMAds, which should be considered in the compromised bone quality of T2D and osteoporosis patients more generally.

Report of Prolonged Neonatal Hypoglycemia in Three Infants of Mothers With Variants in HNF1A.

Background/Objective: Genetic variants in hepatic nuclear factor 1α (HNF1A) cause maturity-onset diabetes of the young (MODY). We sought to examine whether HNF1A MODY variants also cause neonatal hypoglycemia. Case Report: We present 3 infants with variants in HNF1A shared with their mothers. The infants experienced neonatal hypoglycemia, 2 extending beyond 1 year and the third resolving by 28 days, and all were large for gestational age (birth weights of >99th percentile). In 2 cases, genetic testing for neonatal hypoglycemia revealed pathogenic variants in HNF1A; 1 mother was previously diagnosed with HNF1A MODY, and the other's genetic testing and ultimate MODY diagnosis were prompted by her child's hypoglycemia workup. In the third case, the infant's persistent hypoglycemia prompted genetic testing, revealing an HNF1A variant of uncertain significance, which was then identified in the mother. Discussion: Genetic variants causing HNF1A MODY have not been definitively linked to neonatal hypoglycemia or fetal overgrowth in utero. MODY caused by HNF1A is clinically similar to that caused by HNF4A, for which a causal relationship with neonatal hypoglycemia is more certain. Case reports have previously implicated variants in HNF1A in congenital hyperinsulinism; however, these cases have generally not been in families with MODY. The cases presented here suggest that HNF1A variants causing MODY may also cause neonatal hypoglycemia. Conclusion: Although confounding factors make the assessment of neonatal hypoglycemia challenging, these cases offer potential support for single genetic variants in HNF1A causing both MODY and neonatal hypoglycemia, with associated fetal overgrowth in utero.

Impact of the COVID-19 pandemic on the care and outcomes of people with NAFLD-related cirrhosis.

Background & Aims: The COVID-19 pandemic has had a major negative impact on health systems and many chronic diseases globally. We aimed to evaluate the impact of the first year of the pandemic on the outcomes of people with NAFLD cirrhosis. Methods: We conducted a before-after study in four University hospitals in Catalonia, Spain. Study subperiods were divided into Pre-pandemic (March/2019-February/2020) vs. Pandemic (March/2020-February/2021). The primary outcome was the rate of first liver-related event (LRE). Overall clinical outcomes (LREs plus cardiovascular plus all-cause mortality) were also assessed. Results: A total of 354 patients were included, all of whom were compensated at the beginning of the study period; 83 individuals (23.5%) had a history of prior hepatic decompensation. Mean age was 67.3 years and 48.3% were female. Median BMI was 31.2 kg/m2 and type 2 diabetes was present in 72.8% of patients. The rates of first LRE in the Pre-pandemic and Pandemic periods were 7.4% and 11.3% (p = 0.12), respectively. Whilst the rate of overall events was significantly higher in the Pandemic period (9.9% vs. 17.8%; p = 0.009), this was strongly associated with COVID-19-related deaths. The rate of worsened metabolic status was significantly higher in the Pandemic period (38.4% vs. 46.1%; p = 0.041), yet this was not associated with the risk of first LRE during the Pandemic period, whereas type 2 diabetes (odds ratio [OR] 3.77; 95% CI 1.15-12.32; p = 0.028), albumin <4 g/L (OR 4.43; 95% CI 1.76-11.17; p = 0.002) and Fibrosis-4 score >2.67 (OR 15.74; 95% CI 2.01-123.22; p = 0.009) were identified as risk factors in the multivariable analysis. Conclusion: Overall, people with NAFLD cirrhosis did not present poorer liver-related outcomes during the first year of the pandemic. Health system preparedness seems key to ensure that people with NAFLD cirrhosis receive appropriate care during health crises. Lay summary: Mobility restrictions and social stress induced by the COVID-19 pandemic have led to increased alcohol drinking and worsened metabolic control (e.g., weight gain, poor control of diabetes) in a large proportion of the population in many countries. We aimed to analyze whether people with cirrhosis due to non-alcoholic fatty liver disease, who are particularly vulnerable to such lifestyle modifications, were significantly impacted during the first year of the pandemic. We compared the clinical situation of 354 patients one year before the pandemic and one year after. We found that although metabolic control was indeed worse after the first year of the pandemic and patients presented worse clinical outcomes, the latter was mostly due to non-liver causes, namely COVID-19 itself. Moreover, the care provided to these patients did not worsen during the first year of the pandemic.

The incidence of fractures at various sites in newly treated patients with type 2 diabetes mellitus.

Purpose: In this descriptive study, we examined the incidence of fractures in patients with newly treated type 2 diabetes mellitus (T2D) compared to matched reference population. Methods: Participants from the UK Clinical Practice research datalink (CPRD) GOLD (1987-2017), aged ≥30 years, with a T2D diagnosis code and a first prescription for a non-insulin anti-diabetic drug (n = 124,328) were included. Cases with T2D were matched by year of birth, sex and practice to a reference population (n = 124,328), the mean follow-up was 7.7 years. Crude fracture incidence rates (IRs) and incidence rate ratios (IRRs) were calculated. Analyses were stratified by fracture site and sex and additionally adjusted for BMI, smoking status, alcohol use and history of any fracture at index date. Results: The IR of all fractures and major osteoporotic fractures was lower in T2D compared to the reference population (IRR 0.97; 95%CI 0.94-0.99). The IRs were lower for clavicle (IRR 0.67; 0.56-0.80), radius/ulna (IRR 0.81; 0.75-0.86) and vertebral fractures (0.83; 0.75-0.92) and higher for ankle (IRR 1.16; 95%CI 1.06-1.28), foot (1.11; 1.01-1.22), tibia/fibula (1.17; 1.03-1.32) and humerus fractures (1.11; 1.03-1.20). Differences in IRs at various fracture sites between T2D and the reference population were more pronounced in women than in men. In contrast, BMI adjusted IRs for all fractures (IRR 1.07; 1.04-1.10) and most individual fracture sites were significantly higher in T2D, especially in women. Conclusion: The crude incidence of all fractures was marginally lower in patients with newly treated T2D compared to the matched reference population but differed according to fracture site, especially in women. BMI adjusted analyses resulted in higher incidence rates in T2D at almost all fracture sites compared to crude incidence rates and this was more pronounced in women than in men. This implies that BMI may have a protective impact on the crude incidence of fractures, especially in women with newly treated T2D.

The burden of non-alcoholic steatohepatitis: A systematic review of health-related quality of life and patient-reported outcomes.

Background & Aims: Non-alcoholic steatohepatitis (NASH) is associated with increased mortality and a high clinical burden. NASH adversely impacts patients' health-related quality of life (HRQoL), but published data on the humanistic burden of disease are limited. This review aimed to summarise and critically evaluate studies reporting HRQoL or patient-reported outcomes (PROs) in populations with NASH and identify key gaps for further research. Methods: Medline, EMBASE, the Cochrane Library and PsycINFO were searched for English-language publications published from 2010 to 2021 that reported HRQoL/PRO outcomes of a population or subpopulation with NASH. Results: Twenty-five publications covering 23 unique studies were identified. Overall, the data showed a substantial impact of NASH on HRQoL, particularly in terms of physical functioning and fatigue, with deterioration of physical and mental health as NASH progresses. Prevalent symptoms, including fatigue, abdominal pain, anxiety/depression, cognition problems, and poor sleep quality, adversely impact patients' ability to work and perform activities of daily living and the quality of relationships. However, some patients fail to attribute symptoms to their disease because of a lack of patient awareness and education. NASH is associated with high rates of comorbidities such as obesity and type 2 diabetes, which contribute to reduced HRQoL. Studies were heterogeneous in terms of diagnostic methods, population, outcomes, follow-up time, and measures of HRQoL/utility. Most studies were rated 'moderate' at quality assessment, and all evaluable studies had inadequate control of confounders. Conclusions: NASH is associated with a significant HRQoL burden that begins early in the disease course and increases with disease progression. More robust studies are needed to better understand the humanistic burden of NASH, with adequate adjustment for confounders that could influence outcomes. Lay summary: Non-alcoholic steatohepatitis (NASH) has a significant impact on quality of life, with individuals experiencing worse physical and mental health compared with the general population. NASH and its symptoms, which include tiredness, stomach pain, anxiety, depression, poor focus and memory, and impaired sleep, affect individuals' relationships and ability to work and perform day-to-day tasks. However, not all patients are aware that their symptoms may be related to NASH. Patients would benefit from more education on their disease, and the importance of good social networks for patient health and well-being should be reinforced. More studies are needed to better understand the patient burden of NASH.

Mendelian randomization supports the causal role of fasting glucose on periodontitis.

Purpose: The effect of hyperglycemia on periodontitis is mainly based on observational studies, and inconsistent results were found whether periodontal treatment favors glycemic control. The two-way relationship between periodontitis and hyperglycemia needs to be further elucidated. This study aims to evaluate the causal association of periodontitis with glycemic traits using bi-directional Mendelian randomization (MR) approach. Methods: Summary statistics were sourced from large-scale genome-wide association study conducted for fasting glucose (N = 133,010), HbA1c (N = 123,665), type 2 diabetes (T2D, N = 659,316), and periodontitis (N = 506,594) among European ancestry. The causal relationship was estimated using the inverse-variance weighted (IVW) model and further validated through extensive complementary and sensitivity analyses. Results: Overall, IVW showed that a genetically higher level of fasting glucose was significantly associated with periodontitis (OR = 1.119; 95% CI = 1.045-1.197; PFDR= 0.007) after removing the outlying instruments. Such association was robust and consistent through other MR models. Limited evidence was found suggesting the association of HbA1C with periodontitis after excluding the outliers (IVW OR = 1.123; 95% CI = 1.026-1.229; PFDR= 0.048). These linkages remained statistically significant in multivariate MR analyses, after adjusting for body mass index. The reverse direction MR analyses did not exhibit the causal association of genetic liability to periodontitis with any of the glycemic trait tested. Conclusions: Our MR study reaffirms previous findings and extends evidence to substantiate the causal effect of hyperglycemia on periodontitis. Future studies with robust genetic instruments are needed to confirm the causal association of periodontitis with glycemic traits.

FunOMIC: Pipeline with built-in fungal taxonomic and functional databases for human mycobiome profiling.

While analysis of the bacterial microbiome has become routine, that of the fungal microbiome is still hampered by the lack of robust databases and bioinformatic pipelines. Here, we present FunOMIC, a pipeline with built-in taxonomic (1.6 million marker genes) and functional (3.4 million non-redundant fungal proteins) databases for the identification of fungi. Applied to more than 2,600 human metagenomic samples, the tool revealed fungal species associated with geography, body sites, and diseases. Correlation network analysis provided new insights into inter-kingdom interactions. With this pipeline and two of the most comprehensive fungal databases, we foresee a fast-growing resource for mycobiome studies.

The generation of PD-L1 and PD-L2 in cancer cells: From nuclear chromatin reorganization to extracellular presentation.

The immune checkpoint blockade (ICB) targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers. However, the low response rate and frequently observed severe side effects limit its broad benefits. It is partially due to less understanding of the biological regulation of PD-L1. Here, we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation. In PD-L1 and PD-L2 highly expressed cancer cells, a new TAD (topologically associating domain) (chr9: 5,400,000-5,600,000) around CD274 and CD273 was discovered, which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2. The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1. After transcription, the PD-L1 is tightly regulated by miRNAs and RNA-binding proteins via the long 3'UTR. At translational level, PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination. In addition, PD-L1 can be secreted via exosome to systematically inhibit immune response. Therefore, fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy.

Exendin-4 inhibits small intestinal glucose sensing and absorption through repression of T1R2/T1R3 sweet taste receptor signalling in streptozotocin diabetic mice.

The small intestine, which is the area where sugars are absorbed, should be considered in the approaches developed for the treatment of diabetes. However, studies on small intestine damage in diabetic individuals, and the effects of current treatments on the small intestine are very limited. This is the first study to investigate the effects of exendin-4, a GLP-1 receptor agonist, on small intestine injury in diabetic mice. BALB/c male mice were divided into 4 groups for this study. The first group was given citrate buffer, the second group was given exendin-4, the third group was given streptozotocin (STZ), and the fourth group was given both exendin-4, and STZ. As the results, we determined a decrease in the edema and deterioration in the integrity of the villi, disruption in continuity of the brush border, fibrosis and enterocyte apoptosis, while the TNFα level and crypt cell proliferation were increased in the small intestinal tissue of exendin-4 treated STZ diabetic mice. Furthermore, the levels of duodenal tissue glucose, SGLT1, and GLUT2 were decreased, whereas there was an increase in GIP level in diabetic mice administered with exendin-4. Moreover, we determined that the sweet taste receptors T1R2/T1R3, downstream molecules PLCß2, α-gustducin and associated secondary messengers IP3, cAMP, which were increased in the duodenal tissue of STZ-diabetic mice, decreased with exendin-4 administration. These findings were evaluated as that exendin-4 reduces glucose absorption by suppressing the T1R2/T1R3 sweet taste signal perception pathway in duodenum of STZ diabetic mice.

Herbal medications and natural products for patients with covid-19 and diabetes mellitus: Potentials and challenges.

Background: The presence of diabetes mellitus (DM) among COVID-19 patients is associated with increased hospitalization, morbidity, and mortality. Evidence has shown that hyperglycemia potentiates SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection and plays a central role in severe COVID-19 and diabetes comorbidity. In this review, we explore the therapeutic potentials of herbal medications and natural products in the management of COVID-19 and DM comorbidity and the challenges associated with the preexisting or concurrent use of these substances. Methods: Research papers that were published from January 2016 to December 2021 were retrieved from PubMed, ScienceDirect, and Google Scholar databases. Papers reporting clinical evidence of antidiabetic activities and any available evidence of the anti-COVID-19 potential of ten selected natural products were retrieved and analyzed for discussion in this review. Results: A total of 548 papers (73 clinical trials on the antidiabetic activities of the selected natural products and 475 research and review articles on their anti-COVID-19 potential) were retrieved from the literature search for further analysis. A total of 517 articles (reviews and less relevant research papers) were excluded. A cumulative sum of thirty-one (31) research papers (20 clinical trials and 10 others) met the criteria and have been discussed in this review. Conclusion: The findings of this review suggest that phenolic compounds are the most promising phytochemicals in the management of COVID-19 and DM comorbidity. Curcumin and propolis have shown substantial evidence against COVID-19 and DM in humans and are thus, considered the best potential therapeutic options.