Insulin Research Articles

Pancreatic β-Cell TRAPδ Deficiency Reduces Insulin Production but Improves Insulin Sensitivity.

The translocon-associated protein-δ (TRAPδ) plays a role in insulin biosynthesis within pancreatic β cells. However, its pathophysiological significance in maintaining islet β cell function and glucose homeostasis remains unclear. In this study, we generated a mouse model featuring pancreatic β cell-specific deletion of TRAPδ (TRAPδ βKO). Our findings revealed that TRAPδ βKO resulted in decreased circulating insulin levels in mice fed either a normal chow diet or a high-fat diet. Multiple independent experiments established that, while TRAPδ deletion reduced insulin content in the islets, it had no discernible effect on insulin gene expression, the insulin/proinsulin ratio, or the expression and glycosylation of the prohormone enzymes involved in proinsulin processing. These data suggest that TRAPδ does not play a pivotal role in the transcription of the insulin gene or proinsulin processing. However, untranslocated preproinsulin levels were significantly increased when islets were treated with a proteasomal inhibitor, suggesting that TRAPδ deficiency may hinder preproinsulin translocation, resulting in a rapid degradation of untranslocated preproinsulin that accounts for the decreased insulin production. Remarkably, despite the moderate decrease in circulating insulin levels in TRAPδ βKO mice, their glucose levels remained unaffected, indicating the presence of compensatory mechanisms that help maintain glucose homeostasis. Insulin tolerance tests further revealed improved insulin sensitivity, accompanied by upregulation of phosphorylated AKT in the peripheral tissues of TRAPδ βKO mice. Collectively, these data highlight the important role of TRAPδ in insulin biosynthesis and β cell function. The moderate reduction in circulating insulin appears to promote insulin sensitivity in insulin target tissues.

EFFECTIVENESS OF THE COMBINATION OF METFORMIN AND INTRANASAL INSULIN FOR THE CORRECTION OF METABOLIC AND HORMONAL DISTURBANCES IN ADULT MALE RATS WITH METABOLIC SYNDROME INDUCED BY IMPAIRED BREASTFEEDING

Limitation or short-term interruption of breastfeeding can lead to the development of metabolic syndrome (MS) in adulthood, which requires the development of approaches for its prevention and correction. One of them is treatment with metformin (MF) or intranasally administered insulin (INI). Since the targets of MF and INI are different and these drugs can complement each other, it has been suggested that their combined use is effective. The aim of the work was to study the effect of a four-week co-administration of MF (orally, 120 mg/kg/day) and AI (1.2 IU/kg/day) to male rats with MS caused by interruption of breastfeeding on days 19-21 of postnatal development on their metabolic and hormonal indicators. The study was carried out in comparison with monotherapy with the same drugs. It was found that adult male rats with impaired breastfeeding had obesity, dyslipidemia and hyperleptinemia, impaired glucose tolerance, and a decrease in the number of β-cells and the area of pancreatic islets, which is characteristic of MS. Long-term treatment with MF and its combination with INI partially or completely normalized body weight and abdominal fat, metabolic and hormonal parameters, and the restorative effect of combination therapy in relation to indicators such as body weight and adipose tissue, glucose tolerance and the level of glycated hemoglobin in blood was more pronounced than that of MF monotherapy. This indicates the prospects of using a combination of MF and INI to normalize metabolic and hormonal disorders in MS caused by a deficiency of breastfeeding in early ontogenesis.

Structural insights into i-motif DNA structures in sequences from the insulin-linked polymorphic region

The insulin-linked polymorphic region is a variable number of tandem repeats region of DNA in the promoter of the insulin gene that regulates transcription of insulin. This region is known to form the alternative DNA structures, i-motifs and G-quadruplexes. Individuals have different sequence variants of tandem repeats and although previous work investigated the effects of some variants on G-quadruplex formation, there is not a clear picture of the relationship between the sequence diversity, the DNA structures formed, and the functional effects on insulin gene expression. Here we show that different sequence variants of the insulin linked polymorphic region form different DNA structures in vitro. Additionally, reporter genes in cellulo indicate that insulin expression may change depending on which DNA structures form. We report the crystal structure and dynamics of an intramolecular i-motif, which reveal sequences within the loop regions forming additional stabilising interactions that are critical to formation of stable i-motif structures. The outcomes of this work reveal the detail in formation of stable i-motif DNA structures, with potential for rational based drug design for compounds to target i-motif DNA.

Glucose tolerance two years after gestational diabetes classified by old Swedish or new WHO diagnostic criteria

AimTo explore how introduction of the lower WHO gestational diabetes (GDM) glucose criteria in Sweden affected prediabetes/type-2-diabetes (T2D) incidence two years postpartum. MethodsWomen included in the PREvention of PostPartum (PREPP) diabetes study were diagnosed with GDM according to EASD 1991 criteria (GDMOLD; n = 93) or only WHO 2013 criteria (GDMWHO; n = 174). Both groups were further stratified by BMI, and BMI-matched normoglycemic pregnancy controls were included (n = 88). Postpartum assessments included oral glucose tolerance tests (OGTT) and anthropometric measurements. ResultsThere was a higher postpartum incidence of T2D in GDMOLD versus GDMWHO (P < 0.001). Despite similar BMI, GDMOLD exhibited higher fasting and OGTT glucose levels, lower fat-free-mass, and hip circumference compared to GDMWHO. In normal-weight women, both GDM groups displayed higher HOMA-IR and lower fat-free-mass compared to controls, with GDMOLD additionally showing lower HOMA-β, slower insulin release during OGTT, and worse glucose tolerance than GDMWHO. Among obese women, the main differences were lower fat-free-mass and hip circumference in GDMOLD. ConclusionThe lower glucose cut-offs during pregnancy resulted in lower postpartum incidence of T2D, irrespective of BMI. Fat-free-mass emerged as a key determinant in glucose levels across BMI categories, while lower beta-cell function played a significant role in normal-weight women.

Nicotinamide N-methyltransferase inhibition mitigates obesity-related metabolic dysfunction.

To assess the effects of a small-molecule nicotinamide N-methyltransferase (NNMT) inhibitor, 5A1MQ, on body composition, metabolic variables, fatty liver pathologies, and circulating biomarkers in diet-induced obese (DIO) mice, and characterize its plasma pharmacokinetics (PK) and tissue distribution in vivo. DIO mice were administered vehicle or 5A1MQ once daily for 28 days. Longitudinal measures of body composition, blood glucose and plasma insulin levels, and terminal measures of liver histopathology and serum markers, were evaluated. Plasma and tissue PK were established in age- and strain-matched mice after intravenous, oral, and subcutaneous dosing of 5A1MQ. 5A1MQ treatment dose-dependently limited body weight and fat mass gains, improved oral glucose tolerance and insulin sensitivity, and suppressed hyperinsulinaemia in DIO mice. Liver histology from 5A1MQ-treated DIO mice showed attenuated hepatic steatosis and macrophage infiltration, and correspondingly reduced liver weight, size, and triglyceride levels. 5A1MQ treatment normalized circulating levels of alanine transaminase, aspartate transaminase, and ketone bodies, supporting an overall improvement in liver and metabolic functions. The pharmacodynamic effects of 5A1MQ were further corroborated by its high systemic exposure and effective distribution to metabolically active tissues, including adipose, muscle and liver, following subcutaneous dosing of mice. This work validates NNMT inhibition as a viable pharmacological approach to ameliorate metabolic imbalances and improve liver pathologies that develop with obesity.

Generation of Insulin-Producing Cells from Canine Bone Marrow-Derived Mesenchymal Stem Cells: A Preliminary Study.

Cell-based therapy using insulin-producing cells (IPCs) is anticipated as an alternative treatment option to insulin injection or pancreatic islet transplantation for the treatment of diabetes mellitus in both human and veterinary medicine. Several protocols were reported for the differentiation of mesenchymal stem cells (MSCs) into IPCs; to date, glucose-responsive IPCs have only been obtained from canine adipose tissue-derived MSCs (cAD-MSCs), but not from canine bone marrow-derived MSCs (cBM-MSCs). Therefore, this study aims to generate in vitro glucose-responsive IPCs from cBM-MSCs using two differentiation protocols: a two-step protocol using trichostatin (TSA) and a three-step protocol using mercaptoethanol to induce pancreatic and duodenal homeobox gene 1 (PDX-1) expression. A single experiment was carried out for each protocol. BM-MSCs from one dog were successfully cultured and expanded. Cells exposed to the two-step protocol appeared rarely grouped to form small clusters; gene expression analysis showed a slight increase in PDX-1 and insulin expression, but no insulin protein production nor secretion in the culture medium was detected either under basal conditions or following glucose stimulation. Conversely, cells exposed to the three-step protocol under a 3D culture system formed colony-like structures; insulin gene expression was upregulated compared to undifferentiated control and IPCs colonies secreted insulin in the culture medium, although insulin secretion was not enhanced by high-glucose culture conditions. The single experiment results suggest that the three-step differentiation protocol could generate IPCs from cBM-MSCs; however, further experiments are needed to confirm these data. The ability of IPCs from cBM- MSCs to produce insulin, described here for the first time, is a preliminary interesting result. Nevertheless, the IPCs' unresponsiveness to glucose, if confirmed, would affect its clinical application. Further studies are necessary to establish a differentiation protocol in this perspective.

Incretin-based therapies for the management of cardiometabolic disease in the clinic: Past, present, and future.

Among newer classes of drugs for type 2 diabetes mellitus (T2DM), glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are incretin-based agents that lower both blood sugar levels and promote weight loss. They do so by activating pancreatic GLP-1 receptors (GLP-1R) to promote glucose-dependent insulin release and inhibit glucagon secretion. They also act on receptors in the brain and gastrointestinal tract to suppress appetite, slow gastric emptying, and delay glucose absorption. Phase 3 clinical trials have shown that GLP-1 RAs improve cardiovascular outcomes in the setting of T2DM or overweight/obesity in people who have, or are at high risk of having atherosclerotic cardiovascular disease. This is largely driven by reductions in ischemic events, although emerging evidence also supports benefits in other cardiovascular conditions, such as heart failure with preserved ejection fraction. The success of GLP-1 RAs has also seen the evolution of other incretin therapies. Tirzepatide has emerged as a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA, with more striking effects on glycemic control and weight reduction than those achieved by isolated GLP-1R agonism alone. This consists of lowering glycated hemoglobin levels by more than 2% and weight loss exceeding 15% from baseline. Here, we review the pharmacological properties of GLP-1 RAs and tirzepatide and discuss their clinical effectiveness for T2DM and overweight/obesity, including their ability to reduce adverse cardiovascular outcomes. We also delve into the mechanistic basis for these cardioprotective effects and consider the next steps in implementing existing and future incretin-based therapies for the broader management of cardiometabolic disease.

Recent and Upcoming Therapies for Management of Type 2 Diabetes: A Review

abstract The article encompasses the present and future pharmacotherapies involved in managing type 2 diabetes (T2D). It is divided into three sections: recent treatment modalities of the last decade, upcoming approved drugs to be available in India, and near future drugs under clinical trials. It highlights the oral hyperglycaemic agents and insulin options available in India, their potential effects on diabetes outcomes and the clinical trials. India is a fast and dynamic adopter of novel treatments and newer technologies with off-patent and in-patent modalities. Medicinal novelties surround T2D, but technological advancements have touched newer heights with surreal support of artificial intelligence-based innovations, especially in type 1 diabetes management.

Effect of transcription factor MEOX on insulin gene expression in glucagon-like peptide 1-secreting cells.

Currently, the supply of beta cells for islet transplantation in the treatment of type 1 diabetes is limited. Enteroendocrine cells (EECs) are believed to have high potential as stem cells because they share significant developmental similarities with beta cells. In a previous study, we derived EEC cells that secrete individual gut hormones from STC-1 cells. This study aimed to examine intestinal hormone secretion and expression, investigate the expression of developmental-related transcription factors, and analyze the effect of MEOX on insulin gene expression in isolated EECs. The expression and secretion of enteroendocrine hormones were evaluated in L6 and K34 cells from STC-1 cells. Expression patterns of beta cell- and development-related genes in L6 and K34 cells were compared with beta cells. Comparisons of the MEOX-induced expression of Ins in beta cells and GLP-1-secreting cells were investigated. Both L6 and K34 cells predominantly expressed Glp1 and Gip, respectively. The secretion pattern of GLP-1 in L6 cells was similar to that of GLUTag cells. Previous microarray analysis confirmed MEOX as developmentally relevant transcription factors expressed in beta cells. Overexpression of MEOX showed a tendency to increase Ins expression in L6 and GLUTag cells, but not in MIN6 cells. However, when PDX1 and MEOX were co-expressed in GLUTag cells, insulin expression was suppressed, similar to that observed in MIN6 cells. These findings suggest a potential role for MEOX in regulating the expression of the Ins gene in both beta cells and GLP-1-secreting cells. Further studies are warranted to elucidate the underlying mechanism.

Therapeutic Potential of Blocking Nephrin Phosphorylation to Improve Pancreatic β-cell Function.

The phosphorylation of the transmembrane protein nephrin has been shown to play an important role in signaling in kidney podocytes, and it has now been shown to also play a key role in regulating pancreatic β-cell function. Williamson et al have recently shown that the loss of nephrin tyrosine phosphorylation on its 3 cytoplasmic YDxV motifs can enhance insulin release in aged female mice. These studies suggest that blocking nephrin phosphorylation may be an effective treatment option for improving β-cell function.

Clinical Effects of Glucagon-Like Peptide-1 Agonist Use for Weight Loss in Women With Polycystic Ovary Syndrome: A Scoping Review.

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal regulatory hormone that stimulates insulin release from the pancreas. While GLP-1 receptor agonists (GLP-1 RAs) have traditionally been utilized to address insulin resistance, their potential application in treating polycystic ovary syndrome (PCOS) has recently garnered attention. This study aimed to investigate the therapeutic efficacy of GLP-1 RAs use for weight loss in women diagnosed with PCOS. We conducted a scoping review following the Joanna Briggs Institute (JBI) methodology and adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our investigation delved into the clinical effects experienced by women of diverse racial and ethnic backgrounds with PCOS who were prescribed GLP-1 RAs for weight loss. Peer-reviewed articles from Ovid Medline, Web of Science, CINAHL, Cochrane CENTRAL, SCOPUS, and ClinicalTrials.gov spanning from 2012 to 2023 were scrutinized. After eliminating duplicates, 811 articles were identified, and ultimately, eight met the eligibility criteria for inclusion. All studies were published in English and exhibited wide geographic diversity. The included studies uniformly reported reductions in weight and body mass index (BMI) among patients who were prescribed GLP-1 RAs, specifically liraglutide or exenatide. Additionally, evidence pointed towards improvements in anthropometric parameters (MF1) (including total body weight, BMI, reduction in waist circumference, and total fat percentage), glucose homeostasis, cardiovascular inflammatory markers (midregional pro-atrial natriuretic peptide (MR-proANP) and mid-regional pro-adrenomedullin (MR-proADM)), rates of pregnancy, and menstrual regulation. However, findings regarding the impact of GLP-1 RAs on lipid profiles were inconsistent. Although some short-term adverse effects were noted, long-term effects of GLP-1 RAs use remain undetermined. GLP-1 RA use demonstrated promising clinical outcomes for women with PCOS, including reduced BMI, improved metabolic parameters, menstrual regularity, and increased rates of natural pregnancy. While the current evidence is encouraging, further research is warranted to elucidate both short- and long-term adverse effects of GLP-1 RAtherapy for PCOS.

A homeostatic gut-to-brain insulin antagonist restrains neuronally stimulated fat loss

In C. elegans mechanisms by which peripheral organs relay internal state information to the nervous system remain unknown, although strong evidence suggests that such signals do exist. Here we report the discovery of a peptide of the ancestral insulin superfamily called INS-7 that functions as an enteroendocrine peptide and is secreted from specialized cells of the intestine. INS-7 secretion is stimulated by food withdrawal, increases during fasting and acts as a bona fide gut-to-brain peptide that attenuates the release of a neuropeptide that drives fat loss in the periphery. Thus, INS-7 functions as a homeostatic signal from the intestine that gates the neuronal drive to stimulate fat loss during food shortage. Mechanistically, INS-7 functions as an antagonist at the canonical DAF-2 receptor and functions via FOXO and AMPK signaling in ASI neurons. Phylogenetic analysis suggests that INS-7 bears greater resemblance to members of the broad insulin/relaxin superfamily than to conventional mammalian insulin and IGF peptides. The discovery of an endogenous insulin antagonist secreted by specialized intestinal cells with enteroendocrine functions suggests unexpected and important properties of the intestine and its role in directing neuronal functions.

High-Protein Mulberry Leaves Improve Glucose and Lipid Metabolism via Activation of the PI3K/Akt/PPARα/CPT-1 Pathway.

High-Protein Mulberry is a novel strain of mulberry. High-Protein Mulberry leaves (HPM) were the subject of this study, which aimed to investigate its efficacy and underlying mechanisms in modulating glucose and lipid metabolism. A six-week intervention using db/db mice was carried out to assess the effects of HPM on serum lipid levels, liver function, and insulin (INS) levels. qRT-PCR and Western Blotting were employed to measure key RNA and protein expressions in the PI3K/Akt and PPARα/CPT-1 pathways. UHPLC-MS and the Kjeldahl method were utilized to analyze the component content and total protein. Additionally, network pharmacology was employed to predict regulatory mechanism differences between HPM and Traditional Mulberry leaves. The results of the study revealed significant improvements in fasting blood glucose, glucose tolerance, and insulin resistance in mice treated with HPM. HPM notably reduced serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and INS, while increasing high-density lipoprotein cholesterol (HDL-C) levels. The treatment also effectively mitigated liver fatty lesions, inflammatory infiltration, and islet atrophy. HPM activation of the PI3K/Akt/PPARα/CPT-1 pathway suggested its pivotal role in the regulation of glucose and lipid metabolism. With its rich composition and pharmacodynamic material basis, HPM displayed a greater number of targets associated with glucose and lipid metabolism pathways, underscoring the need for further research into its potential therapeutic applications.

Cystic fibrosis-related diabetes develops from a combination of insulin secretion defects and insulin resistance.

The relative contributions of insulin secretory defects and possible additional contribution of insulin resistance for the development of cystic fibrosis (CF)-related diabetes (CFRD) are poorly understood. We aimed to (a) determine which indices of insulin resistance predict progression to CFRD, and (b) to model the relative contributions of insulin secretory function and insulin resistance to predict the risk of CFRD. Three hundred and three individuals living with CF underwent a 2-h oral glucose tolerance test with blood sampling every 30 min at 12-24-month intervals until they developed CFRD or until the end of follow-up (up to 15 years). Indices of insulin resistance (e.g. Stumvoll) and insulin secretion were calculated from oral glucose tolerance test glucose and insulin measurements. CFRD-free survival was assessed by survival analysis. Estimated insulin resistance showed associations with glucose homeostasis and risk of progression to CFRD. The CFRD-free survival was significantly different between quartiles of insulin resistance (p < 0.0001). When patients were subdivided according to both insulin resistance and insulin secretion (insulinogenic index), CFRD-free survival was significantly lower in those with combined lowest insulin secretion and highest insulin resistance (Stumvoll) indices (hazard ratio: 11.2; p < 0.0001). There was no significant difference when the same analysis was performed for the nine other indices. Insulin resistance is correlated with glucose homeostasis and the risk of progression to CFRD. Patients combining low insulin secretion and high insulin resistance had the greatest odds of developing CFRD over a 15-year period.

Exploring pancreatic beta-cell subgroups and their connectivity.

Functional pancreatic islet beta cells are essential to ensure glucose homeostasis across species from zebrafish to humans. These cells show significant heterogeneity, and emerging studies have revealed that connectivity across a hierarchical network is required for normal insulin release. Here, we discuss current thinking and areas of debate around intra-islet connectivity, cellular hierarchies and potential "controlling" beta-cell populations. We focus on methodologies, including comparisons of different cell preparations as well as in vitro and in vivo approaches to imaging and controlling the activity of human and rodent islet preparations. We also discuss the analytical approaches that can be applied to live-cell data to identify and study critical subgroups of cells with a disproportionate role in control Ca2+ dynamics and thus insulin secretion (such as "first responders", "leaders" and "hubs", as defined by Ca2+ responses to glucose stimulation). Possible mechanisms by which this hierarchy is achieved, its physiological relevance and how its loss may contribute to islet failure in diabetes mellitus are also considered. A glossary of terms and links to computational resources are provided.

Ductal Intervention in Chronic Pancreatitis: Impact on Glycemic Control and Endocrine Insufficiency Management.

Background and aim Pancreatic endotherapy has been established as a viable and effective modality for the management of pain in chronic pancreatitis (CP). However, its impact on endocrine insufficiency has been rarely reported. In this retrospective study, we aimed to assess the impact of endotherapy on glycemic status and the management of diabetes in these patients. Methods A retrospective review of a prospectively maintained database of patients with CP with pain presenting to the King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India, from December 2021 to May 2023 was done. Detailed clinical, laboratory, imaging, and treatment data were recorded. Endocrine dysfunction was defined as glycosylated hemoglobin (Hba1C) ≥6.5 g/dl. The status of endocrine function (Hba1C values) before and after endotherapy, as well as the requirement of oral hypoglycemic agent (OHA) and/or insulin, was recorded. Results One hundred forty-one patients underwent endoscopic retrograde cholangiopancreatography for the management of pain (mean age: 35 years, 74.5% males). Prior to endotherapy, pathological endocrine dysfunction was seen in 60 patients (42.5%). The mean HbA1c value was 8.46 g/dl (4.5-16.1g/dl). OHAs alone were used in 13/60 (21.6%), and 34/60 (56.6%) required insulin. A combination of OHA and insulin was required in 13/60 (21.6%) of patients. Post-endotherapy, none of the patients were on a combination of OHAs and insulin; 5/13 (38.4%) patients were on OHAs alone, while 8/13 (61.5%) patients were shifted to insulin. Out of the total 47 patients who required insulin, insulin could be stopped in 15/47 (31.9%) of patients. Patients who demonstrated improvement in endocrine dysfunction had significantly lower HbA1c values (6.38 vs. 8.07 g/dl, p < 0.001), a higher proportion of patients with idiopathic pancreatitis (73.3% vs. 22.2%, p = 0.004), and a lower proportion of patients with concomitant exocrine insufficiency (13.3% vs. 53.3%, p = 0.007). Conclusions One-third of the patients had improvements in endocrine dysfunction. Early ductal intervention in a selected subset of patients with CP may have the potential to improve glycemic status.

Role of age and sex in the incidence of adverse effects among diabetic patients treated with glipizide.

Glipizide is an antidiabetic drug that belongs to a class of medication known as sulfonylureas. It is considered one of the highly prescribed antidiabetic drugs for the treatment of type II diabetes in patients following a kidney transplant. It lowers blood glucose levels by causing the release of insulin from β-cells in the pancreas. Its main metabolizing pathway is through the liver. It has several adverse effects, which range from an upset stomach to glipizide-induced haemolytic anaemia and hypoglycaemia. These adverse effects may be spontaneous, or they could have a genetic cause. The present study aimed to assess and document the incidence of glipizide-induced adverse reactions among patients prescribed the drug. The present retrospective case-control study used the electronic medical records of patients prescribed glipizide for the past 3 years. These records were reviewed to extract and document cases and/or signs of glipizide-induced adverse reactions. The results revealed that the incidence of adverse effects was higher among female patients (odds ratio, 2.40, P<0.001). Moreover, the results revealed that the likelihood of developing adverse drug reactions among patients <40 years of age was higher than in older patients (P>0.05). The outcomes of the present study are expected to prompt future studies to take sex and age into consideration, in an aim to improve treatment outcomes, reduce adverse events and decrease the burden of unnecessary costs for healthcare systems. Recommendations also include genetic screening prior to administering the medication, educating the patients and caregivers on the possibility of adverse drug reactions, and routine follow-up. This issue is of utmost importance to achieve the optimal outcomes with the minimal detrimental effects.

Curcumin Treatment Ameliorates Hepatic Insulin Resistance Induced by Sub-chronic Oral Exposure to Cadmium LOAEL Dose via NF-κB and Nrf2 Pathways.

Cadmium (Cd) is a global pollutant, and its accumulation in the liver causes oxidative stress, inflammation, insulin resistance (IR), and metabolic complications. This study investigated whether curcumin treatment could alleviate hepatic IR in Wistar rats exposed to sub-chronic cadmium and explored the underlying molecular pathways. Male Wistar rats were divided into a control group (standard normocaloric diet + cadmium-free water) and a cadmium group (standard normocaloric diet + drinking water with 32.5ppm CdCl2) for 30days. Oral glucose tolerance, insulin response, and IR were assessed using mathematical models. Liver tissue was analyzed for markers of oxidative stress, inflammation, and key regulatory pathways, including NF-κB, Nrf2, MAPKs (JNK and p38), and the IRS1-Akt pathway. We established an effective curcumin dose of 250mg/kg for 5days orally. Results demonstrated that after 30days of exposure, cadmium accumulated in the liver, inducing an oxidative and inflammatory state. This was characterized by increased expression of NF-κB, JNK, and p38, along with diminished Nrf2 expression, hepatic IR, hyperglycemia, and hyperinsulinemia. Curcumin treatment effectively alleviated these metabolic disorders by restoring the balance between NF-κB and Nrf2 in the liver, modulating the MAPK pathway, and, consequently, improving oxidative and inflammatory balance. In conclusion, this study suggests that cadmium induces hepatic IR through an imbalance between NF-κB and Nrf2 signaling pathways. Curcumin treatment appears to improve these pathways, thereby ameliorating hepatic IR.

Integrated analysis of intestinal microbial community and muscle transcriptome profile in rabbits

Intestinal microbial community plays an important part in maintaining health and skeletal muscle development in livestock. This study is the first of its kind in the world. In order to better understand the relationship between gut microbiota and gene expression in skeletal muscle of rabbits, caecum contents and longissimus dorsi tissues of rabbits at 0 d (S1), 35 d (S2) and 70d (S3) were collected and subjected for 16S rRNA sequencing and transcriptome sequencing. Our results showed that, among three groups of rabbits, Firmicutes and Bacteroidetes were the dominant phyla at the phylum level, while Akmansia, Bacteroides and Ruminobacter were the dominant genera at the genus level, and the relative abundance of Akmansia and Bacteroides increased firstly and then decreased from 0 d to 70 d. By analyzing the transcriptome sequencing data, we identified 2866, 2446 and 4541 differentially expressed genes (DEGs) in S1 vs S2, S2 vs S3 and S1 vs S3 groups, respectively. Finally, we performed correlation analysis between gut microbiota and the expression levels of muscle development-related genes of rabbits at 0 d and 70 d. Compared with 0 day old rabbits, in 70 day old rabbits Acinetobacter and Cronbacter with decreased abundance, and Ruminococcaceae_UCG-014 and Ruminococcus_1 with increase abundance is beneficial to caecum health in rabbits. These results will lay a foundation for further re-searches about the relationship between caecum microflora and muscle development in rabbits.

Assessment of Health-Related Quality of Life and Its Determinants in Type 2 Diabetes Mellitus Patients: A Cross-Sectional Study.

Background Type 2 diabetes mellitus is a complex metabolic disorder associated with several complications that determine the quality of life of the patients. Health-related quality of life (HRQoL) is a measurable outcome of the self-perception of a patient's health which is affected due to age, lifestyle changes, medication, and treatment modalities. This study was undertaken to understand the impact of individual parameters of age, medication type and duration, diabetes-associated complications, and levels of glycated hemoglobin (HbA1c) on the quality of life (QoL) of the patient. Methodology This single-center prospective, cross-sectional study was conducted at the Indira Gandhi Institute of Medical Sciences (IGIMS), Patna, Bihar, India. Participants were recruited from the Outpatient Department of General Medicine, IGIMS.HRQoL was measured using a validated and reliable EuroQol 5-dimensions 5-levels (EQ-5D-5L) questionnaire developed by the EuroQol Research Foundation, along with the EuroQol-Visual Analogue Scale (EQ-VAS). The eligibility criteria included adult diabetic patients above 18 years of age with complete medical records, who had been treated at the outpatient department for a minimum of three months and could be interviewed. Results The results from this study show that 46% of the patients belonged to the age group of 45-65 years. The quality of health index scores and EQ-VAS scores significantly correlated withage (p-values: 1.11 e-4 and 3.09 e-5; <0.05). Of the subjects,66.4%, 6.7%, and 26.8% were under oral hypoglycaemic agents (OHA), insulin, and both insulin with OHA medications respectively. HbA1C levels werestatistically significantly correlated with mobility, self-care, usual activities, pain or discomfort, and anxiety or depression (p-value 0.032; <0.05), along with self-perception of the patient's health (p-value 0.00026; <0.05).Also, the perception of having slight problems in mobility, self-care, usual activities, pain or discomfort, and anxiety or depression was similar irrespective of gender (EQ-5D-5L score for males: 9.47 and females: 9.3). Despite suffering from diabetes-associated chronic complications, 60.5% of the subjects perceived their overall health to be good as indicated by the scores. Conclusion The self-perception of HRQoL concerning mobility, self-care, usual activities, pain or discomfort, and anxiety or depression was correlated with age, duration of anti-diabetic medication, and HbA1C level. Good mobility, self-care, and performing usual activities reduce anxiety or depression as opposed to age, pain, and discomfort. However, the subjects in this study cohort perceived overall good health in themselves in terms of EQ-VAS and 5D-5L scores, indicating effective diabetic care and management options available to them.