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Insulin resistance is a crucial factor in the development of type 2 diabetes mellitus (T2DM) and other metabolic disorders. Skeletal muscle, the body's largest insulin-responsive tissue, plays a significant role in the pathogenesis of T2DM due to defects in insulin signaling. Recently, there has been growing evidence that macrophages, immune cells essential for tissue homeostasis and injury response, also contribute to the development of skeletal muscle insulin resistance. This review aims to summarize the current understanding of the role of macrophages in skeletal muscle insulin resistance. Firstly, it provides an overview of the different macrophage populations present in skeletal muscle and their specific functions in the development of insulin resistance. Secondly, it examines the underlying mechanisms by which macrophages promote or alleviate insulin resistance in skeletal muscle, including inflammation, oxidative stress, and altered metabolism. Lastly, the review discusses potential therapeutic strategies targeting macrophages to improve skeletal muscle insulin sensitivity and metabolic health. [ABSTRACT FROM AUTHOR]

As diabetes continues to grow as major health problem, there has been great progress in understanding the important role of pancreatic beta-cells in its pathogenesis. Diabetes develops when the normal interplay between insulin secretion and the insulin sensitivity of target tissues is disrupted. With type 2 diabetes (T2D), glucose levels start to rise when beta-cells are unable to meet the demands of insulin resistance. For type 1 diabetes (T1D) glucose levels rise as beta-cells are killed off by autoimmunity. In both cases the increased glucose levels have a toxic effect on beta-cells. This process, called glucose toxicity, has a major inhibitory effect on insulin secretion. This beta-cell dysfunction can be reversed by therapies that reduce glucose levels. Thus, it is becoming increasingly apparent that an opportunity exists to produce a complete or partial remission for T2D, both of which will provide health benefit. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the predictors of medication adherence behavior and the role of self-efficacy in the medication adherence of people with diabetes. Materials and methods: This is a cross-sectional descriptive-analytical study. One hundred forty-eight samples were selected through the formula of difference of means. Measure tools consisted of a demographic questionnaire, Morisky Medication Adherence Scale, and psychological constructs questionnaires. SPSS20 software was used for descriptive statistics tests and calculation of correlation coefficients between variables. Amos 8.80 was used to implement the structural equation modeling method. Results: The mean age of participants was 54.1 ± 8.2 and mean of body mass index (BMI) was 28.3 ± 4.5. Correlation coefficients between medication compliance behavior and the constructs of knowledge (r = 0.382, p < 0.01), attitude (r = 0.422, p < 0.01), subjective norms (r = 0.312, 05 p < 0.05), self-efficacy (r = 0.481, p < 0.05) and fear (r = 0.305, p < 0.05) were positive and significant. In general, the strongest correlation coefficient was reported between attitude and self-efficacy (r = 0.516, p < 0.01). The fit indices generally showed that the data fitted well with the assumed model. Self-efficacy was the most important construct that directly influenced medication adherence (β = 0.585, p < 0.05), followed by attitude (β = 0.328, p < 0.05) and fear (β = 0.265, p < 0.05). Conclusions: According to the findings of this study, it was shown that various factors affect medication adherence behavior, among which self-efficacy is the most important reason, and subjective norms, attitude and norms and awareness of factors affecting medication adherence behavior. [ABSTRACT FROM AUTHOR]

A 34-year-old man with poorly controlled type 2 diabetes was admitted to our hospital because of fever, headache, vomiting, and impaired consciousness. His hemoglobin A1c level was as high as 11.0%. Abdominal computed tomography revealed a bacterial liver abscess, while head magnetic resonance imaging simultaneously showed a high-signal lesion on diffusion-weighted imaging and a low-signal lesion on the apparent diffusion coefficient map of the splenium of the corpus callosum. No significant findings were detected in the cerebrospinal fluid. The latter findings led to a diagnosis of mild encephalitis/encephalopathy with reversible splenial lesions. His impaired consciousness resolved on Day 5 after treatment with ceftriaxone and metronidazole infusion and intensive insulin therapy; magnetic resonance imaging on Day 20 showed that the lesion in the splenium of the corpus callosum had disappeared. We propose that when a person with poorly controlled diabetes develops a bacterial infection and presents with impaired consciousness and headache, clinicians should consider the complications of mild encephalitis/encephalopathy with reversible splenial lesion. [ABSTRACT FROM AUTHOR]

Abstract Background Although the relationship between type 2 diabetes (T2D) and the increased risk of colorectal carcinogenesis is widely defined in clinical studies, the therapeutic methods and molecular mechanism of T2D-induced colon cancer and how does hyperglycemia affect the progression is still unknown. Here, we studied the function of lactoferrin (LF) in suppressing the progression of colon cancer in T2D mice, and uncovered the related molecular mechanisms in DNA 5mC and RNA m6A levels. Methods We examined the effects of LF (50% iron saturation) on the migration and invasion of colon tumor cells under high concentration of glucose. Then, transcriptomics and DNA methylation profilings of colon tumor cells was co-analyzed to screen out the special gene (NT5DC3), and the expression level of NT5DC3 in 75 clinical blood samples was detected by q-PCR and western blot, to investigate whether NT5DC3 was a biomarker to distinguish T2D patients and T2D-induced colon cancer patients from healthy volunteers. Futhermore, in T2D mouse with xenografted colon tumor models, the inhibitory effects of LF and NT5DC3 protein on colon tumors were investigated. In addition, epigenetic alterations were measured to examine the 5mC/m6A modification sites of NT5DC3 regulated by LF. Utilizing siRNA fragments of eight m6A-related genes, the special gene (WTAP) regulating m6A of NT5DC was proved, and the effect of LF on WTAP/NT5DC3/HKDC1 axis was finally evaluated. Results A special gene NT5DC3 was screened out through co-analysis of transcriptomics and DNA methylation profiling, and HKDC1 might be a downstream sensor of NT5DC3. Mechanistically, LF-dependent cellular DNA 5mC and RNA m6A profiling remodeling transcriptionally regulate NT5DC3 expression. WTAP plays a key role in regulating NT5DC3 m6A modification and subsequently controls NT5DC3 downstream target HKDC1 expression. Moreover, co-treatment of lactoferrin and NT5DC3 protein restrains the growth of colon tumors by altering the aberrant epigenetic markers. Strikingly, clinical blood samples analysis demonstrates NT5DC3 protein expression is required to direct the distinction of T2D or T2D-induced colon cancer with healthy humans. Conclusions Together, this study reveals that lactoferrin acts as a major factor to repress the progression of colon cancer under hyperglycemia, thus, significantly expanding the landscape of natural dietary mediated tumor suppression. Graphical Abstract

Keypoints Prognostic value of pericardiac fat tissue assessed using CT to predict adverse outcomes for T2D patients admitted for COVID-19 infection A disctinct phenotypic pattern was found between diabetic patients and controls with respect to adverse outcom:. classicl risk factors such as age or sex adetermine the prognosis in controls whereas the metabolic and inflammatory profile determine outcome in diabetics. Fast and reliable measurement of cardiac adipose tissue using CT. The assessment of this parameter could be useful to better stratify individual risk in diabetic patients with COVID-19 and adapt patient management of patients in routine practice.

Atherosclerosis is a major risk factor for type 2 diabetes (T2D) mortality. We aim to investigate the changes in miR-21, miR-122, miR-33a and miR-3064-5p in circulation and the liver of ApoE-/- mice with streptozocin (STZ)-induced T2D. Twenty 5-week-old male ApoE-/- mice were randomly assigned to the control (n = 10) and T2D group (n = 10) and intraperitoneally injected with a citrate buffer and streptozotocin (STZ) (40 mg/kg BW) once a day for three consecutive days. The successfully STZ-induced T2D mice (n = 5) and control mice (n = 5) were then fed with a high-fat diet (HFD) for 34 weeks. Compared to the control mice, ApoE-/- mice with STZ-induced T2D had slower (p < 0.05) growth, increased (p < 0.05) total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), decreased (p < 0.05) high-density lipoprotein cholesterol (HDL-C) in serum, reduced (p < 0.05) TC and sterol regulatory element-binding protein-2 (Srebp-2), elevated (p < 0.05) ATP-binding-cassette-transporter-A1 (Abca1) in the liver, aggravated (p < 0.05) atherosclerotic lesions in the aorta, downregulated (p < 0.05) miR-21 and miR-33a, and upregulated (p < 0.05) miR-122 and miR-3064-5p in serum and the liver. In addition, the aortic lesions showed a positive correlation with miR-122 (r = 1.000, p = 0.001) and a negative correlation with miR-21 (r = −1.000, p = 0.001) in ApoE-/- mice with T2D. In conclusion, T2D-accelerated atherosclerosis correlates with a reduction in miR-21 and miR-33a and an elevation in miR-122 and miR-3064-5p in circulation and the liver of ApoE-/- mice.

Objectives: Though type 2 diabetes (T2D) has been known as a metabolic disease caused by multiple factors, the etiology remains insufficiently understood. Here, we aimed to figure out whether circulating immune cell profiles causally impact T2D liability. Methods: We applied one genome-wide association study (GWAS) summary statistics of blood traits in 563,085 participants from the Blood Cell Consortium and another GWAS of flow cytometric profile of lymphocyte subsets comprising 3,757 Sardinians to identify genetically predicted blood immune cells. We also obtained GWAS summary statistics in 898,130 individuals from the DIAGRAM Consortium to evaluate genetically predicted T2D. We primarily used inverse variance weighted (IVW) and weighted median methods to perform Mendelian randomization analyses and sensitivity analyses to evaluate heterogeneity and pleiotropy. Results: For circulating blood leukocyte and its subpopulations, the increase of genetically predicted circulating monocyte count was causally correlated with a higher risk of T2D [odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.02-1.10, p = 0.0048]. For lymphocyte subsets, CD8+ T cell and CD4+ CD8dim T cell count were identified with causal effect on T2D susceptibility (CD8+ T cell: OR = 1.09, 95% CI = 1.03-1.17, p = 0.0053; CD4+ CD8dim T cell: OR = 1.04, 95% CI = 1.01-1.08, p = 0.0070). No pleiotropy was determined. Conclusions: These findings demonstrated that higher circulating monocyte and T-lymphocyte subpopulation predicted increased T2D susceptibility, which confirmed the immunity predisposition for T2D. Our results may have the potential to provide new therapeutic targets for the diagnosis and treatment of T2D. [ABSTRACT FROM AUTHOR]

Objective: Sphingosine 1-phosphate (S1P) signaling pathway is involved in the pathogenesis of type 2 diabetes (T2D). So, targeting S1P signaling pathway could be considered as potential therapeutic target for T2D. The aim of this study was to investigate the effects of palmitate and chicoric acid (CA) on S1P signaling pathway in peripheral blood mononuclear cells (PBMCs) from newly diagnosed patients with T2D. Materials and methods: 20 newly diagnosed patients with T2D, aged 40–60 years, were enrolled in the study. PBMCs were isolated and then treated as follows: control groups (untreated, treated with BSA 1% for 12 h), CA groups (treated with 50 μM CA for 6 h), palmitate groups (treated with 500 μM palmitate for 12 h), palmitate + CA groups (treated with 500 μM palmitate for 12 h and then treated with 50 μM CA for 6 h). Finally, sphingosine kinase 1 (SPHK1) and sphingosine 1-phosphate receptor 1 (S1PR1) genes expression were evaluated by real-time PCR and S1PR1 protein levels were quantified using ELISA. Results: Palmitate significantly increased SPHK1 and S1PR1 genes expression and S1PR1 protein levels in PBMCs of patients with diabetes. However, CA ameliorates palmitate-increased SPHK1 and S1PR1 genes expression and S1PR1 levels in these cells. Conclusion: These data indicate that CA could be considered as a novel S1P signaling pathway inhibitor through down regulation of SPHK1 and S1PR1. [ABSTRACT FROM AUTHOR]

Objectives: The present study was designed to evaluate the effects of Tyrosol and Nano-tyrosol on the cellular arrangement, collagen disposition, protein level of insulin receptor (INSR), and superoxide dismutase (SOD) activity in both control and streptozotocin-induced diabetic rats. Methods: Type 2 Diabetes (T2D) was induced in rats by a single intraperitoneal injection of streptozotocin (50 mg/kg). Experimental rats were administered Tyrosol and Nano-tyrosol 1 ml intra-gastrically at a dose of 20 mg/kg once a day for 30 days. Then, rats were sacrificed according to ethical principles. Livers were removed and processed for histological studies using the paraffin technique. Furthermore, non-paraffin sections were used for the INSR-1 western blot technique. Results: At the end of the experiments, the rats in diabetic control and plain niosome groups exhibited a significant increase in collagen disposition (p < 0.001), and apoptotic cells (p < 0.001), as well as decreased total protein levels of INSR (p < 0.001), and SOD activity (p < 0.001) in the hepatic cells. Oral administration of Tyrosol and Nano-tyrosol to diabetic rats reversed all the above-mentioned parameters to near normal levels (p < 0.001). Nano-tyrosol showed the highest significant effect rather than Tyrosol. Conclusion: The results of the present study suggested the beneficial effects of Tyrosol and especially Nano-tyrosol on decreasing the adverse effects of diabetes. [ABSTRACT FROM AUTHOR]

Malaria remains a disease of public health importance globally, especially in sub-Saharan Africa. Malaria deaths reduced globally steadily between 2000-2019, however there was a 10% increase in 2020 due to disruptions in medical service during the COVID-19 pandemic. Globally, about 96% of malaria deaths occurred in 29 countries; out of which, four countries (Nigeria, the Democratic Republic of the Congo, the Niger, and the United Republic of Tanzania) accounted for just over half of the malaria deaths. Nigeria leads the four countries with the highest malaria deaths (accounting for 31% globally). Parallelly, sub-Saharan Africa is faced with a rise in the incidence of Type 2 diabetes (T2D). Until recently, T2D was a disease of adulthood and old age. However, this is changing as T2D in children and adolescents is becoming an increasingly important public health problem. Nigeria has been reported to have the highest burden of diabetes in Africa with a prevalence of 5.77% in the country. Several studies conducted in the last decade investigating the interaction between malaria and T2D in developing countries have led to the emergence of the intra-uterine hypothesis. The hypothesis has arisen as a possible explanation for the rise of T2D in malaria endemic areas; malaria in pregnancy could lead to intra-uterine stress which could contribute to low birth weight and may be a potential cause of T2D later in life. Hence, previous, and continuous exposure to malaria infection leads to a higher risk of T2D. Current and emerging evidence suggests that an inflammation-mediated link exists between malaria and eventual T2D emergence. The inflammatory process thus, is an important link for the coexistence of malaria and T2D because these two diseases are inflammatoryrelated. A key feature of T2D is systemic inflammation, characterized by the upregulation of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) which leads to impaired insulin signaling. Malaria infection is an inflammatory disease in which TNF-α also plays a major role. TNF-α plays an important role in the pathogenesis and development of malaria and T2D. We therefore hypothesize that TNF-α is an important link in the increasing coexistence of T2D. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) are worldwide chronic diseases that have strong relationships with one another and commonly exist together. Type 2 diabetes is considered one of the risk factors for NAFLD, so its occurrence in people with NAFLD is highly likely. As the high and increasing number of T2D and NAFLD, which potentially followed by existing together number, an analysis and assessment of T2D screening scores in people with NAFLD is necessary to be done. To prevent this potential case, an effective early prediction model is also required to be developed, which could help the patients avoid the dangers of both existing diseases. Therefore, in this study, analysis and assessment of T2D screening scores in people with NAFLD and the early prediction model utilizing a forward logistic regression-based feature selection method and multi-layer perceptrons are proposed. Our analysis and assessment results showed that the prevalence of T2D among patients with NAFLD was 8.13% (for prediabetes) and 37.19% (for diabetes) in two population-based NAFLD datasets. The variables related to clinical tests, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and systolic blood pressure (SBP), were found to be statistically significant predictors (p-values < 0.001) that indicate a strong association with T2D among patients with NAFLD in both the prediabetes and diabetes NAFLD datasets. Finally, our proposed model showed the best performance in terms of all performance evaluation metrics compared to existing various machine learning models and also the models using variables recommended by WHO/CDC/ADA, with achieved accuracy as much as 92.11% and 83.05% and its improvement scores after feature selection of 1.35% and 5.35%, for the first and second dataset, respectively. [ABSTRACT FROM AUTHOR]

BackgroundThe neutrophil-to-lymphocyte ratio (NLR) and immunoglobulin A (IgA) level are commonly used as biomarkers for inflammation. Patients with type 2 diabetes (T2D) may experience an imbalance of tear film and inflammation, which can result in dry eye disease (DED). This study aimed to assess the levels of IgA and explore its correlation with the NLR as potential inflammatory biomarkers for dry eye disease in patients with T2D.MethodsA retrospective study was conducted at the cornea clinic and diabetes centre of King Abdulaziz Medical City (Jeddah, Saudi Arabia). The study included patients with DED and the number of available T2D-DED patients determined the sample size. Neutrophil, lymphocyte, IgA and CRP (C-reactive protein) laboratory values were obtained from medical records and correlational analyses were performed.ResultsThe study included 85 patients with an average age of 54 ± 14.4 years for the DED group (n=32) and 62 ± 13.9 years for the T2D-DED group (n=53). The age difference between the two groups was statistically significant (p 0.0001). The NLR values of the T2D-DED and DED groups were 3.203 ± 0.66 and 2.406 ± 0.46, respectively, with no significant difference (p

The incidence of Diabetes Mellitus is increasing globally. Individuals who have been burdened with diabetes for many years often develop complications as a result of hyperglycemia. More and more research is being conducted highlighting inflammation as an important factor in disease progression. In all kinds of diabetes, hyperglycemia leads to activation of alternative glucose metabolic pathways, resulting in problematic by-products including reactive oxygen species and advanced glycation end products. This review takes a look into the pathogenesis of three specific diabetic complications; retinopathy, nephropathy and neuropathy as well as their current treatment options. By considering recent research papers investigating the effects of immunotherapy on relevant conditions in animal models, multiple strategies are suggested for future treatment and prevention of diabetic complications with an emphasis on molecular targets associated with the inflammation.

Type 2 diabetes (T2D) is a global public health issue characterized by excess weight, abdominal obesity, dyslipidemia, hyperglycemia, and a progressive increase in insulin resistance. Human population studies of T2D development and its effects on systemic metabolism are confounded by many factors that cannot be controlled, complicating the interpretation of results and the identification of early biomarkers. Aged, sedentary, and overweight/obese non-human primates (NHPs) are one of the best animal models to mimic spontaneous T2D development in humans. We sought to identify and distinguish a set of plasma and/or fecal metabolite biomarkers, that have earlier disease onset predictability, and that could be evaluated for their predictability in subsequent T2D studies in human cohorts. In this study, a single plasma and fecal sample was collected from each animal in a colony of 57 healthy and dysmetabolic NHPs and analyzed for metabolomics and lipidomics. The samples were comprehensively analyzed using untargeted and targeted LC/MS/MS. The changes in each animal’s disease phenotype were monitored using IVGTT, HbA1c, and other clinical metrics, and correlated with their metabolic profile. The plasma and fecal lipids, as well as bile acid profiles, from Healthy, Dysmetabolic (Dys), and Diabetic (Dia) animals were compared. Following univariate and multivariate analyses, including adjustments for weight, age, and sex, several plasma lipid species were identified to be significantly different between these animal groups. Medium and long-chain plasma phosphatidylcholines (PCs) ranked highest at distinguishing Healthy from Dys animals, whereas plasma triglycerides (TG) primarily distinguished Dia from Dys animals. Random Forest (RF) analysis of fecal bile acids showed a reduction in the secondary bile acid glycoconjugate, GCDCA, in diseased animals (AUC 0.76[0.64, 0.89]). Moreover, metagenomics results revealed several bacterial species, belonging to the genera Roseburia, Ruminococcus, Clostridium, and Streptococcus, to be both significantly enriched in non-healthy animals and associated with secondary bile acid levels. In summary, our results highlight the detection of several elevated circulating plasma PCs and microbial species associated with fecal secondary bile acids in NHP dysmetabolic states. The lipids and metabolites we have identified may help researchers to differentiate individual NHPs more precisely between dysmetabolic and overtly diabetic states. This could help assign animals to study groups that are more likely to respond to potential therapies where a difference in efficacy might be anticipated between early vs. advanced disease.

Abstract Background Many individuals living with chronic kidney disease (CKD) have comorbid Type 2 diabetes (T2D). We sought to explore if efficacious interventions that improve glycemic control may also have potential to reduce CKD progression. Methods REACH is a text message-delivered self-management support intervention, which focused on medication adherence, diet, and exercise that significantly improved glycemic control in N = 506 patients with T2D. Using data from the trial, we characterized kidney health in the full sample and explored the intervention’s effect on change in estimated glomerular filtration rate (eGFR) at 12 months in a subsample of N=271 patients with eGFR data. Results In a diverse sample with respect to race/ethnicity and socioeconomic status, 37.2% had presence of mild or heavy proteinuria and/or an eGFR

As diabetes continues to grow as major health problem, there has been great progress in understanding the important role of pancreatic beta-cells in its pathogenesis. Diabetes develops when the normal interplay between insulin secretion and the insulin sensitivity of target tissues is disrupted. With type 2 diabetes (T2D), glucose levels start to rise when beta-cells are unable to meet the demands of insulin resistance. For type 1 diabetes (T1D) glucose levels rise as beta-cells are killed off by autoimmunity. In both cases the increased glucose levels have a toxic effect on beta-cells. This process, called glucose toxicity, has a major inhibitory effect on insulin secretion. This beta-cell dysfunction can be reversed by therapies that reduce glucose levels. Thus, it is becoming increasingly apparent that an opportunity exists to produce a complete or partial remission for T2D, both of which will provide health benefit.

Malaria remains a disease of public health importance globally, especially in sub-Saharan Africa. Malaria deaths reduced globally steadily between 2000-2019, however there was a 10% increase in 2020 due to disruptions in medical service during the COVID-19 pandemic. Globally, about 96% of malaria deaths occurred in 29 countries; out of which, four countries (Nigeria, the Democratic Republic of the Congo, the Niger, and the United Republic of Tanzania) accounted for just over half of the malaria deaths. Nigeria leads the four countries with the highest malaria deaths (accounting for 31% globally). Parallelly, sub-Saharan Africa is faced with a rise in the incidence of Type 2 diabetes (T2D). Until recently, T2D was a disease of adulthood and old age. However, this is changing as T2D in children and adolescents is becoming an increasingly important public health problem. Nigeria has been reported to have the highest burden of diabetes in Africa with a prevalence of 5.77% in the country. Several studies conducted in the last decade investigating the interaction between malaria and T2D in developing countries have led to the emergence of the intra-uterine hypothesis. The hypothesis has arisen as a possible explanation for the rise of T2D in malaria endemic areas; malaria in pregnancy could lead to intra-uterine stress which could contribute to low birth weight and may be a potential cause of T2D later in life. Hence, previous, and continuous exposure to malaria infection leads to a higher risk of T2D. Current and emerging evidence suggests that an inflammation-mediated link exists between malaria and eventual T2D emergence. The inflammatory process thus, is an important link for the co-existence of malaria and T2D because these two diseases are inflammatory-related. A key feature of T2D is systemic inflammation, characterized by the upregulation of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) which leads to impaired insulin signaling. Malaria infection is an inflammatory disease in which TNF-α also plays a major role. TNF-α plays an important role in the pathogenesis and development of malaria and T2D. We therefore hypothesize that TNF-α is an important link in the increasing co-existence of T2D.

Lifestyle disorders like obesity, type 2 diabetes (T2D), and cardiovascular diseases can be prevented and treated by regular physical activity. During exercise, skeletal muscles release signaling factors that communicate with other organs and mediate beneficial effects of exercise. These factors include myokines, metabolites, and extracellular vesicles (EVs). In the present study, we have examined how electrical pulse stimulation (EPS) of myotubes, a model of exercise, affects the cargo of released EVs. Chronic low frequency EPS was applied for 24 h to human myotubes isolated and differentiated from biopsy samples from six morbidly obese females with T2D, and EVs, both exosomes and microvesicles (MV), were isolated from cell media 24 h thereafter. Size and concentration of EV subtypes were characterized by nanoparticle tracking analysis, surface markers were examined by flow cytometry and Western blotting, and morphology was confirmed by transmission electron microscopy. Protein content was assessed by high-resolution proteomic analysis (LC-MS/MS), non-coding RNA was quantified by Affymetrix microarray, and selected microRNAs (miRs) validated by real time RT-qPCR. The size and concentration of exosomes and MV were unaffected by EPS. Of the 400 miRs identified in the EVs, EPS significantly changed the level of 15 exosome miRs, of which miR-1233- 5p showed the highest fold change. The miR pattern of MV was unaffected by EPS. Totally, about 1000 proteins were identified in exosomes and 2000 in MV. EPS changed the content of 73 proteins in exosomes, 97 in MVs, and of these four were changed in both exosomes and MV (GANAB, HSPA9, CNDP2, and ATP5B). By matching the EPS-changed miRs and proteins in exosomes, 31 targets were identified, and among these several promising signaling factors. Of particular interest were CNDP2, an enzyme that generates the appetite regulatory metabolite Lac-Phe, and miR-4433b-3p, which targets CNDP2. Several of the regulated miRs, such as miR-92b-5p, miR-320b, and miR-1233-5p might also mediate interesting signaling functions. In conclusion, we have used a combined transcriptome-proteome approach to describe how EPS affected the cargo of EVs derived from myotubes from morbidly obese patients with T2D, and revealed several new factors, both miRs and proteins, that might act as exercise factors. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance (IR) with associated compensatory hyperinsulinemia (HI) are early abnormalities in the etiology of prediabetes (preT2D) and type 2 diabetes (T2D). IR and HI also associate with increased erythrocytosis. Hemoglobin A1c (HbA1c) is commonly used to diagnose and monitor preT2D and T2D, but can be influenced by erythrocytosis independent of glycemia. Methods: We undertook bidirectional Mendelian randomization (MR) in individuals of European ancestry to investigate potential causal associations between increased fasting insulin adjusted for BMI (FI), erythrocytosis and its non-glycemic impact on HbA1c. We investigated the association between the triglyceride-glucose index (TGI), a surrogate measure of IR and HI, and glycation gap (difference between measured HbA1c and predicted HbA1c derived from linear regression of fasting glucose) in people with normoglycemia and preT2D. Results: Inverse variance weighted MR (IVWMR) suggested that increased FI increases hemoglobin (Hb, b=0.54 ± 0.09, p=2.7 x 10-10), red cell count (RCC, b=0.54 ± 0.12, p=5.38x10-6) and reticulocyte (RETIC, b=0.70 ± 0.15, p=2.18x10-6). Multivariable MR indicated that increased FI did not impact HbA1c (b=0.23 ± 0.16, p=0.162) but reduced HbA1c after adjustment for T2D (b=0.31 ± 0.13, p=0.016). Increased Hb (b=0.03 ± 0.01, p=0.02), RCC (b=0.02 ± 0.01, p=0.04) and RETIC (b=0.03 ± 0.01, p=0.002) might modestly increase FI. In the observational cohort, increased TGI associated with decreased glycation gap, (i.e., measured HbA1c was lower than expected based on fasting glucose, (b=- 0.09 ± 0.009, p<0.0001)) in people with preT2D but not in those with normoglycemia (b=0.02 ± 0.007, p<0.0001). Conclusions: MR suggests increased FI increases erythrocytosis and might potentially decrease HbA1c by non-glycemic effects. Increased TGI, a surrogate measure of increased FI, associates with lower-than-expected HbA1c in people with preT2D. These findings merit confirmatory studies to evaluate their clinical significance. [ABSTRACT FROM AUTHOR]

Insulin resistance (IR) is considered the precursor and the key pathophysiological mechanism of type 2 diabetes (T2D) and metabolic syndrome (MetS). However, the pathways that IR shares with T2D are not clearly understood. Meta-analysis of multiple DNA microarray datasets could provide a robust set of metagenes identified across multiple studies. These metagenes would likely include a subset of genes (key metagenes) shared by both IR and T2D, and possibly responsible for the transition between them. In this study, we attempted to find these key metagenes using a feature selection method, LASSO, and then used the expression profiles of these genes to train five machine learning models: LASSO, SVM, XGBoost, Random Forest, and ANN. Among them, ANN performed well, with an area under the curve (AUC) > 95%. It also demonstrated fairly good performance in differentiating diabetics from normal glucose tolerant (NGT) persons in the test dataset, with 73% accuracy across 64 human adipose tissue samples. Furthermore, these core metagenes were also enriched in diabetes-associated terms and were found in previous genome-wide association studies of T2D and its associated glycemic traits HOMA-IR and HOMA-B. Therefore, this metagenome deserves further investigation with regard to the cardinal molecular pathological defects/pathways underlying both IR and T2D. [ABSTRACT FROM AUTHOR]

Epidemiological evidence regarding the possible link between multiple essential metals levels and all-cause mortality and cardiovascular disease (CVD) mortality among type 2 diabetes (T2D) patients is sparse. Here, we aimed to evaluate the longitudinal associations between 11 essential metals levels in plasma and all-cause mortality and CVD mortality among T2D patients. Our study included 5278 T2D patients from the Dongfeng–Tongji cohort. LASSO penalized regression analysis was used to select the all-cause and CVD mortality-associated metals from 11 essential metals (iron, copper, zinc, selenium, manganese, molybdenum, vanadium, cobalt, chromium, nickel, and tin) measured in plasma. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: With a median follow-up of 9.8 years, 890 deaths were documented, including 312 deaths of CVD. LASSO regression models and the multiple-metals model revealed that plasma iron and selenium were negatively associated with all-cause mortality (HR: 0.83; 95%CI: 0.70, 0.98; HR: 0.60; 95%CI: 0.46, 0.77), whereas copper was positively associated with all-cause mortality (HR: 1.60; 95%CI: 1.30, 1.97). Only plasma iron has been significantly associated with decreased risk of CVD mortality (HR: 0.61; 95%CI: 0.49, 0.78). The dose-response curves for the association between copper levels and all-cause mortality followed a J shape (Pfor nonlinear = 0.01). Our study highlights the close relationships between essential metals elements (iron, selenium, and copper) and all-cause and CVD mortality among diabetic patients. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a complex disorder characterized by insufficient insulin production or insulin resistance, which results in a lifelong dependence on glucose-lowering drugs for almost all patients. During the fight with diabetes, researchers are always thinking about what characteristics the ideal hypoglycemic drugs should have. From the point of view of the drugs, they should maintain effective control of blood sugar, have a very low risk of hypoglycemia, not increase or decrease body weight, improve β-cell function, and delay disease progression. Recently, the advent of oral peptide drugs, such as semaglutide, brings exciting hope to patients with chronic diabetes. Legumes, as an excellent source of protein, peptides, and phytochemicals, have played significant roles in human health throughout human history. Some legume-derived peptides with encouraging anti-diabetic potential have been gradually reported over the last two decades. Their hypoglycemic mechanisms have also been clarified at some classic diabetes treatment targets, such as the insulin receptor signaling pathway or other related pathways involved in the progress of diabetes, and key enzymes including α-amylase, α-glucosidase, and dipeptidyl peptidase-IV (DPP-4). This review summarizes the anti-diabetic activities and mechanisms of peptides from legumes and discusses the prospects of these peptide-based drugs in type 2 diabetes (T2D) management. [ABSTRACT FROM AUTHOR]

Background: Although the relationship between type 2 diabetes (T2D) and the increased risk of colorectal carcinogenesis is widely defined in clinical studies, the therapeutic methods and molecular mechanism of T2D-induced colon cancer and how does hyperglycemia affect the progression is still unknown. Here, we studied the function of lactoferrin (LF) in suppressing the progression of colon cancer in T2D mice, and uncovered the related molecular mechanisms in DNA 5mC and RNA m6A levels. Methods: We examined the effects of LF (50% iron saturation) on the migration and invasion of colon tumor cells under high concentration of glucose. Then, transcriptomics and DNA methylation profilings of colon tumor cells was co-analyzed to screen out the special gene (NT5DC3), and the expression level of NT5DC3 in 75 clinical blood samples was detected by q-PCR and western blot, to investigate whether NT5DC3 was a biomarker to distinguish T2D patients and T2D-induced colon cancer patients from healthy volunteers. Futhermore, in T2D mouse with xenografted colon tumor models, the inhibitory effects of LF and NT5DC3 protein on colon tumors were investigated. In addition, epigenetic alterations were measured to examine the 5mC/m6A modification sites of NT5DC3 regulated by LF. Utilizing siRNA fragments of eight m6A-related genes, the special gene (WTAP) regulating m6A of NT5DC was proved, and the effect of LF on WTAP/NT5DC3/HKDC1 axis was finally evaluated. Results: A special gene NT5DC3 was screened out through co-analysis of transcriptomics and DNA methylation profiling, and HKDC1 might be a downstream sensor of NT5DC3. Mechanistically, LF-dependent cellular DNA 5mC and RNA m6A profiling remodeling transcriptionally regulate NT5DC3 expression. WTAP plays a key role in regulating NT5DC3 m6A modification and subsequently controls NT5DC3 downstream target HKDC1 expression. Moreover, co-treatment of lactoferrin and NT5DC3 protein restrains the growth of colon tumors by altering the aberrant epigenetic markers. Strikingly, clinical blood samples analysis demonstrates NT5DC3 protein expression is required to direct the distinction of T2D or T2D-induced colon cancer with healthy humans. Conclusions: Together, this study reveals that lactoferrin acts as a major factor to repress the progression of colon cancer under hyperglycemia, thus, significantly expanding the landscape of natural dietary mediated tumor suppression. [ABSTRACT FROM AUTHOR]

Aim: To evaluate continuous glucose monitoring (CGM) metrics for use as alternatives to glycated haemoglobin (HbA1c) to evaluate therapeutic efficacy. Methods: We re‐analysed correlations among CGM metrics from studies involving 545 people with type 1 diabetes (T1D), 5910 people with type 2 diabetes (T2D) and 98 people with T1D during pregnancy and the postpartum period. Results: Three CGM metrics, interstitial fluid Mean Glucose level, proportion of time above range (%TAR) and proportion of time in range (%TIR), were correlated with HbA1c and provided metrics that can be used to evaluate therapeutic efficacy. Mean Glucose showed the highest correlation with %TAR (r = 0.98 in T1D, 0.97 in T2D) but weaker correlations with %TIR (r = −0.92 in T1D, −0.83 in T2D) or with HbA1c (r = 0.78 in T1D). %TAR and %TIR were highly correlated (r = −0.96 in T1D, −0.91 in T2D). After 6 months of use of real‐time CGM by people with T1D, changes in Mean Glucose level were more highly correlated with changes in %TAR (r = 0.95) than with changes in %TIR (r = −0.85) or with changes in HbA1c level (r = 0.52). These metrics can be combined with metrics of hypoglycaemia and/or glycaemic variability to provide a more comprehensive assessment of overall quality of glycaemic control. Conclusion: The CGM metrics %TAR and %TIR show much higher correlations with Mean Glucose than with HbA1c and provide sensitive indicators of efficacy. Mean glucose may be the best metric and shows consistently higher correlations with %TAR than with %TIR. [ABSTRACT FROM AUTHOR]

Development of the Italian clinical practice guidelines on bariatric and metabolic surgery, as well as design and methodological aspects. Background: Obesity and its complications are a growing problem in many countries. Italian Society of Bariatric and Metabolic Surgery for Obesity (Società Italiana di Chirurgia dell'Obesità e delle Malattie Metaboliche—SICOB) developed the first Italian guidelines for the treatment of obesity. Methods: The creation of SICOB Guidelines is based on an extended work made by a panel of 24 members and a coordinator. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology has been used to decide the aims, reference population, and target health professionals. Clinical questions have been created using the PICO (Patient, Intervention, Comparison, Outcome) conceptual framework. The definition of questions used the two-step web-based Delphi method, made by repeated rounds of questionnaires and a consensus opinion from the panel. Results: The panel proposed 37 questions. A consensus was immediately reached for 33 (89.2%), with 31 approved, two rejected and three which did not reach an immediate consensus. The further discussion allowed a consensus with one approved and two rejected. Conclusions: The areas covered by the clinical questions included indications of metabolic/bariatric surgery, types of surgery, and surgical management. The choice of a surgical or a non-surgical approach has been debated for the determination of the therapeutic strategy and the correct indications. [ABSTRACT FROM AUTHOR]

The effectiveness and safety of preoperative oral carbohydrate (POC) for people with diabetes remain controversial. We systematically reviewed studies comparing POC to fasting or placebo in elective surgery for diabetic adults, focusing on gastric volume, postoperative complications, hospital stay, and glycemic control. Fourteen studies (n = 1870 patients) were included. POC did not significantly increase gastric volume or aspiration risk in well-controlled type 2 diabetes. Effects on perioperative glucose control varied. POC improved patient comfort and reduced preoperative hypoglycemia in gestational diabetes. Limited evidence suggested potential benefits in cardiac surgery patients. POC is safe for well-controlled type 2 diabetics, enhancing comfort and reducing preoperative hypoglycemia without increasing aspiration risk. However, its effects on glucose control and postoperative outcomes vary. Personalized approaches are crucial, particularly for poorly controlled diabetes. • 200–400 mL of 12.5 % carbohydrate solution 2–3 h preoperatively appears safe for well-controlled type 2 diabetes. • POC may be applicable to previously excluded populations, including gestational diabetes and morbidly obese patients. • Comprehensive outcome assessment beyond traditional safety indicators provides robust clinical decision-making support. [ABSTRACT FROM AUTHOR]

BackgroundInsulin resistance (IR) with associated compensatory hyperinsulinemia (HI) are early abnormalities in the etiology of prediabetes (preT2D) and type 2 diabetes (T2D). IR and HI also associate with increased erythrocytosis. Hemoglobin A1c (HbA1c) is commonly used to diagnose and monitor preT2D and T2D, but can be influenced by erythrocytosis independent of glycemia.MethodsWe undertook bidirectional Mendelian randomization (MR) in individuals of European ancestry to investigate potential causal associations between increased fasting insulin adjusted for BMI (FI), erythrocytosis and its non-glycemic impact on HbA1c. We investigated the association between the triglyceride-glucose index (TGI), a surrogate measure of IR and HI, and glycation gap (difference between measured HbA1c and predicted HbA1c derived from linear regression of fasting glucose) in people with normoglycemia and preT2D.ResultsInverse variance weighted MR (IVWMR) suggested that increased FI increases hemoglobin (Hb, b=0.54 ± 0.09, p=2.7 x 10-10), red cell count (RCC, b=0.54 ± 0.12, p=5.38x10-6) and reticulocyte (RETIC, b=0.70 ± 0.15, p=2.18x10-6). Multivariable MR indicated that increased FI did not impact HbA1c (b=0.23 ± 0.16, p=0.162) but reduced HbA1c after adjustment for T2D (b=0.31 ± 0.13, p=0.016). Increased Hb (b=0.03 ± 0.01, p=0.02), RCC (b=0.02 ± 0.01, p=0.04) and RETIC (b=0.03 ± 0.01, p=0.002) might modestly increase FI. In the observational cohort, increased TGI associated with decreased glycation gap, (i.e., measured HbA1c was lower than expected based on fasting glucose, (b=-0.09 ± 0.009, p

Background: Portulaca oleracea L. (PO) is a herb widely used in folk medicine as antioxidant and mainly as an anti-diabetic. However, scientific evidence of its effects remains very limited. Here we aim to unravel the effect of the host genetic background on the PO treatment in the development of obesity and type 2 diabetes (T2D) using the genetically diverse Collaborative Cross (CC) mouse model, which could contribute to better understand and design personalized medical treatment. Results: We have studied the PO treatments efficacy on reduction of body weight (BW) and glucose tolerance ability in 221 mice of 13 different CC lines as a response to two different diets: the control match diet (CMD – 10% fat) as a control group and the high-fat diet (HFD – 60% fat) as the experiment group. Glucose tolerance ability was determined by a 180 minutes Intraperitoneal Glucose Tolerance Test (IPGTT) and the calculation of the area under the curve (AUC) was made. PO treatments started in week 12 of the dietary challenge and lasted for 4 weeks. PO was given to the mice every other day by intraperitoneal (IP) injection at concentration of 200mg/kg. The results showed significant sex effect across the different lines and assessed traits; therefore, male and female mice data was analyzed separately. Sex differences among lines were analyzed by ANOVA and shown to be significant (P

Background: Patients with type 2-diabetes mellitus (T2D), are characterized by visceral and ectopic adipose tissue expansion, leading to systemic chronic low-grade inflammation. As visceral adiposity is associated with severe COVID-19 irrespective of obesity, we aimed to evaluate and compare the predictive value for early intensive care or death of three fat depots (cardiac, visceral and subcutaneous) using computed tomography (CT) at admission for COVID-19 in consecutive patients with and without T2D. Methods: Two hundred and two patients admitted for COVID-19 were retrospectively included between February and June 2020 and distributed in two groups: T2D or non-diabetic controls. Chest CT with cardiac (CATi), visceral (VATi) and subcutaneous adipose tissue (SATi) volume measurements were performed at admission. The primary endpoint was a composite outcome criteria including death or ICU admission at day 21 after admission. Threshold values of adipose tissue components predicting adverse outcome were determined. Results: One hundred and eight controls [median age: 76(IQR:59–83), 61% male, median BMI: 24(22–27)] and ninety-four T2D patients [median age: 70(IQR:61–77), 70% male, median BMI: 27(24–31)], were enrolled in this study. At day 21 after admission, 42 patients (21%) had died from COVID-19, 48 (24%) required intensive care and 112 (55%) were admitted to a conventional care unit (CMU). In T2D, CATi was associated with early death or ICU independently from age, sex, BMI, dyslipidemia, CRP and coronary calcium (CAC). (p = 0.005). Concerning T2D patients, the cut-point for CATi was > 100 mL/m2 with a sensitivity of 0.83 and a specificity of 0.50 (AUC = 0.67, p = 0.004) and an OR of 4.71 for early ICU admission or mortality (p = 0.002) in the fully adjusted model. Other adipose tissues SATi or VATi were not significantly associated with early adverse outcomes. In control patients, age and male sex (OR = 1.03, p = 0.04) were the only predictors of ICU or death. Conclusions: Cardiac adipose tissue volume measured in CT at admission was independently predictive of early intensive care or death in T2D patients with COVID-19 but not in non-diabetics. Such automated CT measurement could be used in routine in diabetic patients presenting with moderate to severe COVID-19 illness to optimize individual management and prevent critical evolution. Keypoints: Prognostic value of pericardiac fat tissue assessed using CT to predict adverse outcomes for T2D patients admitted for COVID-19 infection A disctinct phenotypic pattern was found between diabetic patients and controls with respect to adverse outcom:. classicl risk factors such as age or sex adetermine the prognosis in controls whereas the metabolic and inflammatory profile determine outcome in diabetics. Fast and reliable measurement of cardiac adipose tissue using CT. The assessment of this parameter could be useful to better stratify individual risk in diabetic patients with COVID-19 and adapt patient management of patients in routine practice. [ABSTRACT FROM AUTHOR]

Although increasing evidence shows the association between type 2 diabetes (T2D) and colorectal cancer, the related mechanism remains unclear. This study examined the suppressive effect of lactoferrin (LF) on the development of T2D-induced colon cancer. First, a co-cultured cell model consisting of NCM460 and HT29 cells was constructed to mimic the progression of T2D into colon cancer. The migration ability of NCM460 cells increased significantly (p < 0.05) after cultivation in HT29 cell medium (high glucose), while LF suppressed the progression of T2D to colon cancer by regulating the 5′-nucleotidase domain-containing 3 (NT5DC3) protein and the PI3K/AKT/mTOR signaling pathway in diabetic BALB/c mice and in cell models. A mutation assay of the phosphorylation site in the NT5DC3 protein and a surface plasmon resonance (SPR) protein binding test were performed to further ascertain a mechanistic link between LF and the NT5DC3 protein. The results indicated that LF specifically bound to the NT5DC3 protein to activate its phosphorylation at the Thr6 and Ser11 sites. Next, metabolic-specific staining and localization experiments further confirmed that LF acted as a phosphate donor for NT5DC3 protein phosphorylation by regulating the downstream metabolic pathway in T2D-induced colon tumors, which was specifically accomplished by controlling Thr6/Ser11 phosphorylation in NT5DC3 and its downstream effectors. These data on LF and NT5DC3 protein may suggest a new therapeutic strategy for cancer prevention, especially in T2D patients susceptible to colon cancer. [ABSTRACT FROM AUTHOR]

Purpose: In people with diabetes, one of the problems for patients is muscle wasting and inhibition of the protein synthesis pathway. This study aimed to evaluate the effects of HIIT on protein expression in two skeletal muscles, flexor hallucis longus (FHL) and soleus (SOL) in rats with type 2 diabetes mellitus (T2DM). Materials and methods: Diabetes initially was induced by streptozotocin (STZ) and nicotinamide. Rats with type 2 diabetes were randomly and equally divided into control (n = 6) and HIIT groups (n = 6). After 8 weeks of training, the content of total and phosphorylated proteins of serine/threonine-protein kinases (AKT1), mammalian target of rapamycin (mTOR), P70 ribosomal protein S6 kinase 1 (P70S6K1), and 4E (eIF4E)-binding protein 1 (4E-BP1) in FHL and SOL muscles were measured by Western blotting. While body weight and blood glucose were also controlled. Results: In the HIIT training group, compared to the control group, a significant increase in the content of AKT1 (0.003) and mTOR (0.001) proteins was observed in the FHL muscle. Also, after 8 weeks of HIIT training, protein 4E-BP1 (0.001) was increased in SOL muscle. However, there was no significant change in other proteins in FHL and SOL muscle. Conclusions: In rats with type 2 diabetes appear to HIIT leading to more protein expression of fast-twitch muscles than slow-twitch muscles. thus likely HIIT exercises can be an important approach to increase protein synthesis and prevent muscle atrophy in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Introduction: Previous research indicates that the salivary microbiota may be a biomarker of oral as well as systemic disease. However, clarifying the potential bias from general health status and lifestyle-associated factors is a prerequisite of using the salivary microbiota for screening. Materials & Methods: ADDDITION-PRO is a nationwide Danish cohort, nested within the Danish arm of the Anglo-Danish-Dutch Study of Intensive treatment in People with Screen-Detected Diabetes in Primary Care. Saliva samples from n=746 individuals from the ADDITION-PRO cohort were characterized using 16s rRNA sequencing. Alpha- and beta diversity as well as relative abundance of genera was examined in relation to general health and lifestyle-associated variables. Permutational multivariate analysis of variance (PERMANOVA) was performed on individual variables and all variables together. Classification models were created using sparse partial-least squares discriminant analysis (sPLSDA) for variables that showed statistically significant differences based on PERMANOVA analysis (p < 0.05). Results: Glycemic status, hemoglobin-A1c (HbA1c) level, sex, smoking and weekly alcohol intake were found to be significantly associated with salivary microbial composition (individual variables PERMANOVA, p < 0.05). Collectively, these variables were associated with approximately 5.8% of the observed differences in the composition of the salivary microbiota. Smoking status was associated with 3.3% of observed difference, and smoking could be detected with good accuracy based on salivary microbial composition (AUC 0.95, correct classification rate 79.6%). Conclusions: Glycemic status, HbA1c level, sex, smoking and weekly alcohol intake were significantly associated with the composition of the salivary microbiota. Despite smoking only being associated with 3.3% of the difference in overall salivary microbial composition, it was possible to create a model for detection of smoking status with a high correct classification rate. However, the lack of information on the oral health status of participants serves as a limitation in the present study. Further studies in other cohorts are needed to validate the external validity of these findings. [ABSTRACT FROM AUTHOR]

Current treatments for type 2 diabetes (T2D) mainly rely on exercise, dietary control, and anti-diabetic drugs to enhance insulin secretion and improve insulin sensitivity. However, there is a need for more therapeutic options, as approved drugs targeting different pharmacological objectives are still unavailable. One potential target that has attracted attention is the protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the insulin signaling pathway. In this work, a comprehensive computational screening was carried out using cheminformatics and molecular docking on PTP1B, employing a rigorous repurposing approach. The screening involved approved drugs and compounds under research as anti-diabetics that bind to targets such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and α-glucosidase. Several computational hits were then meticulously tested in vitro against PTP1B, with 13-cis-retinoic acid (3a) showing an IC 50 of 0.044 mM and competitive inhibition. Molecular dynamics studies further confirmed that 3a can bind to the catalytic binding site of PTP1B. Finally, 3a is the first time it has been reported as an inhibitor of PTP1B, making it a potentially valuable candidate for further studies in D2T treatment., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

IntroductionPrevious research indicates that the salivary microbiota may be a biomarker of oral as well as systemic disease. However, clarifying the potential bias from general health status and lifestyle-associated factors is a prerequisite of using the salivary microbiota for screening.Materials & MethodsADDDITION-PRO is a nationwide Danish cohort, nested within the Danish arm of the Anglo-Danish-Dutch Study of Intensive treatment in People with Screen-Detected Diabetes in Primary Care. Saliva samples from n=746 individuals from the ADDITION-PRO cohort were characterized using 16s rRNA sequencing. Alpha- and beta diversity as well as relative abundance of genera was examined in relation to general health and lifestyle-associated variables. Permutational multivariate analysis of variance (PERMANOVA) was performed on individual variables and all variables together. Classification models were created using sparse partial-least squares discriminant analysis (sPLSDA) for variables that showed statistically significant differences based on PERMANOVA analysis (p < 0.05).ResultsGlycemic status, hemoglobin-A1c (HbA1c) level, sex, smoking and weekly alcohol intake were found to be significantly associated with salivary microbial composition (individual variables PERMANOVA, p < 0.05). Collectively, these variables were associated with approximately 5.8% of the observed differences in the composition of the salivary microbiota. Smoking status was associated with 3.3% of observed difference, and smoking could be detected with good accuracy based on salivary microbial composition (AUC 0.95, correct classification rate 79.6%).ConclusionsGlycemic status, HbA1c level, sex, smoking and weekly alcohol intake were significantly associated with the composition of the salivary microbiota. Despite smoking only being associated with 3.3% of the difference in overall salivary microbial composition, it was possible to create a model for detection of smoking status with a high correct classification rate. However, the lack of information on the oral health status of participants serves as a limitation in the present study. Further studies in other cohorts are needed to validate the external validity of these findings.

Type 2 diabetes mellitus (T2DM) in adolescents is a more rapidly progressive disease, associated with earlier and higher rates of microvascular complications than in adults. As obesity is a significant risk factor for T2DM development and progression, the American Diabetes Association (ADA) recommends anti-obesity medications (AOMs) as adjuvant therapy for adults with both T2DM and overweight/obesity. In adults, the addition of AOMs to a diabetes regimen can improve glycemic control, reduce weight, and decrease anti-diabetes medication use. The ADA recommends considering bariatric surgery for adolescents with T2DM who have a BMI >35 kg/m2, but did not mention the use of AOMs in their 2022 updated guidelines. Currently, there are three FDA-approved AOMs available for chronic use in adolescents with obesity. Other medications are used in an “off-label” fashion for appetite suppression and BMI reduction. As additional AOMs are being developed and FDA-approved for the pediatric population, new treatment options with novel mechanisms of action will become available for adolescents with T2DM and obesity. In this review, we will discuss the evidence for the use of AOMs in the treatment of T2DM in adolescents, including lessons learned from the adult T2DM literature.

ObjectiveTo investigate the status of glycemic control and analyze its influencing factors in patients with type 2 diabetes (T2D) in Anhui, China.Methods1,715 T2D patients aged 18–75 years old were selected from 4 counties or districts in Anhui Province in 2018, using a convenience sampling method. All patients have undergone a questionnaire survey, physical examination, and a glycosylated hemoglobin (HbA1c) test. According to the 2022 American Diabetes Association criteria, HbA1c was used to evaluate the glycemic control status of patients, and HbA1c < 7.0% was defined as good glycemic control. The influencing factors of glycemic control were analyzed by multivariate unconditional logistic regression.ResultsThe prevalence of good glycemic control among people with T2D in the Anhui Province was low (22.97%). On univariate analysis, gender, education level, occupation, region, smoking, drinking, waist circumference and disease duration (all P < 0.05) were significantly associated with glycemic control. The factors associated with pool glycemic control were female gender [OR = 0.67, 95%CI (0.52, 0.86), P = 0.001], higher level of education [OR = 0.47, 95%CI (0.27, 0.83), P = 0.001], living in rural areas [OR = 1.77, 95%CI (1.39, 2.26), P < 0.001], central obesity [OR = 1.58, 95%CI (1.19, 2.09), P = 0.001] and longer duration of disease [OR = 2.66, 95%CI (1.91, 3.69), P < 0.001].ConclusionsThe prevalence of good glycemic control in people with T2D in Anhui Province was relatively low, and gender, region, education level, central obesity and course of the disease were influencing factors. The publicity and education on the importance of glycemic control should be further strengthened in T2D patients, and targeted intervention measures should be carried out for risk groups.

Background: This study aimed to validate the application of CT texture analysis in estimating Bone Mineral Density (BMD) in patients with Type 2 Diabetes (T2D) and comparing it with the results of dual-energy X-ray absorptiometry (DXA) in a normative cohort. Methods: We analyzed a total of 510 cases (145 T2D patients and 365 normal patients) from a single institution. DXA-derived BMD and CT texture analysis-estimated BMD were compared for each participant. Additionally, we investigated the correlation among 45 different texture features within each group. Results: The correlation between CT texture analysis-estimated BMD and DXA-derived BMD in T2D patients was consistently high (0.94 or above), whether measured at L1 BMD, L1 BMC, total hip BMD, or total hip BMC. In contrast, the normative cohort showed a modest correlation, ranging from 0.66 to 0.75. Among the 45 texture features, significant differences were found in the Contrast V 64 and Contrast V 128 features in the normal group. Conclusion: In essence, our study emphasizes that the clinical assessment of bone health, particularly in T2D patients, should not merely rely on traditional measures, such as DXA BMD. Rather, it may be beneficial to incorporate other diagnostic tools, such as CT texture analysis, to better comprehend the complex interplay between various factors impacting bone health.

Osteoporosis is defined as a systemic skeletal disease characterized by decreased bone mass and micro-architectural deterioration leading to increased fracture risk. Osteoporosis incidence increases with age in both post-menopausal women and aging men. Among other important contributing factors to bone fragility observed in osteoporosis, that also affect the elderly population, are metabolic disturbances observed in obesity and Type 2 Diabetes (T2D). These metabolic complications are associated with impaired bone homeostasis and a higher fracture risk. Expansion of the Bone Marrow Adipose Tissue (BMAT), at the expense of decreased bone formation, is thought to be one of the key pathogenic mechanisms underlying osteoporosis and bone fragility in obesity and T2D. Our review provides a summary of mechanisms behind increased Bone Marrow Adiposity (BMA) during aging and highlights the pre-clinical and clinical studies connecting obesity and T2D, to BMA and bone fragility in aging osteoporotic women and men. [ABSTRACT FROM AUTHOR]

The corticotropin-releasing hormone receptor 2 (CRHR2) gene encodes CRHR2, contributing to the hypothalamic–pituitary–adrenal stress response and to hyperglycemia and insulin resistance. CRHR2−/− mice are hypersensitive to stress, and the CRHR2 locus has been linked to type 2 diabetes and depression. While CRHR2 variants confer risk for mood disorders, MDD, and type 2 diabetes, they have not been investigated in familial T2D and MDD. In 212 Italian families with type 2 diabetes and depression, we tested 17 CRHR2 single nucleotide polymorphisms (SNPs), using two-point parametric-linkage and linkage-disequilibrium (i.e., association) analysis (models: dominant-complete-penetrance-D1, dominant-incomplete-penetrance-D2, recessive-complete-penetrance-R1, recessive-incomplete-penetrance-R2). We detected novel linkage/linkage-disequilibrium/association to/with depression (3 SNPs/D1, 2 SNPs/D2, 3 SNPs/R1, 3 SNPs/R2) and type 2 diabetes (3 SNPs/D1, 2 SNPs/D2, 2 SNPs/R1, 1 SNP/R2). All detected risk variants are novel. Two depression-risk variants within one linkage-disequilibrium block replicate each other. Two independent novel SNPs were comorbid while the most significant conferred either depression- or type 2 diabetes-risk. Although the families were primarily ascertained for type 2 diabetes, depression-risk variants showed higher significance than type 2 diabetes-risk variants, implying CRHR2 has a stronger role in depression-risk than type 2 diabetes-risk. In silico analysis predicted variants' dysfunction. CRHR2 is for the first time linked to/in linkage-disequilibrium/association with depression-type 2 diabetes comorbidity and may underlie the shared genetic pathogenesis via pleiotropy. [ABSTRACT FROM AUTHOR]

Objective To examine the relationship between bone metabolism biomarker and glycated hemoglobin（HbA1c） in patients with type 2 diabetes（T2D）. Methods A total of 372 patients with T2D in Department of Endocrinology，Shanghai Pudong Hospital were retrospectively analyzed，all of them were post-menopausal women or men age 45 years or older，with 192 males and 180 females.General data of the patients were collected as well as blood lipid，liver function，renal function，HbA1c，bone metabolism indexes including 25-hydroxy vitamin D（25（OH）D），β -C-terminal telopeptide of type Ⅰ collagen（β - CTX），N-terminal osteocalcin （N-MID），calcium（Ca）and phosphorus （P）indexes. Patients were categorized into three groups based on the level of glycated hemoglobin （HbA1c） for inter-group comparison：group A（HbA1c<7.5%），group B（HbA1c 7.5%-8.9%），and group C（HbA1c≥9.0%）. Results There were no statistically significant differences in 25（OH）D，β -CTX，Ca and P among the three groups. However，variations in N-MID（female：P<0.001；male：P=0.048）was significant. Pearson correlation analysis showed that HbA1c was negatively correlated with N-MID（female：r=-0.302；P< 0.001；male：r =-0.207；P=0.004）. Multiple linear regression showed that N-MID was an influencing factor of HbA1c after adjusting for age and BMI（female：β =-0.321，P<0.001；male：β =-0.339，P<0.001）. Conclusion In postmenopausal women and middle-aged and elderly men with T2D，N-MID is inversely related with HbA1c，implying that a higher serum N-MID level may benefit in blood glucose control in T2D patients. [ABSTRACT FROM AUTHOR]

Introduction: Type 2 diabetes mellitus (T2DM) is a chronic condition associated with substantial clinical and economic burden. As multiple therapeutic options are available, patient preferences on treatment characteristics are key in T2DM therapeutic decision-making. This study aimed to determine the preferences of US patients with T2DM for therapies recommended for first pharmacologic intensification after metformin.Methods: As part of a discrete choice experiment, an online survey was designed using literature review and qualitative interview findings. Eligibility was met by US patients with T2DM who were aged 18 years or older with an HbA1c ≥ 6.5%. Anonymized therapy profiles were created from six antidiabetic therapies including oral and injectable semaglutide, dulaglutide, empagliflozin, sitagliptin, and thiazolidinediones.Results: Eligible patients (n = 500) had a mean HbA1c of 7.4%, and a mean BMI of 32.0 kg/m2, the majority of which (72.2%) were injectable-naïve. The treatment characteristic with greatest importance was mode and frequency of administration (35.5%), followed by body weight change (29.2%), cardiovascular event risk (19.1%), hypoglycemic event risk (9.9%), and HbA1c change (6.5%). An oral semaglutide-like profile was preferred by 91.9-70.1% of respondents depending on the comparator agent, and preference was significant in each comparison (p < 0.05); an injectable semaglutide-like profile was preferred by 89.3-55.7% of respondents in each comparison depending on the comparator agent.Conclusion: Patients with T2DM in the USA are significantly more likely to prefer oral or injectable semaglutide-like profiles over those of key comparators from the glucagon-like peptide 1 receptor agonist, sodium-glucose cotransporter 2 inhibitor, dipeptidyl peptidase 4 inhibitor, and thiazolidinedione classes. [ABSTRACT FROM AUTHOR]

Background: Many individuals living with chronic kidney disease (CKD) have comorbid Type 2 diabetes (T2D). We sought to explore if efficacious interventions that improve glycemic control may also have potential to reduce CKD progression.Methods: REACH is a text message-delivered self-management support intervention, which focused on medication adherence, diet, and exercise that significantly improved glycemic control in N = 506 patients with T2D. Using data from the trial, we characterized kidney health in the full sample and explored the intervention's effect on change in estimated glomerular filtration rate (eGFR) at 12 months in a subsample of N=271 patients with eGFR data.Results: In a diverse sample with respect to race/ethnicity and socioeconomic status, 37.2% had presence of mild or heavy proteinuria and/or an eGFR < 60 mL/min/1.73 m2. There was a trending interaction effect between intervention and presence of proteinuria at baseline (b = 6.016, p = .099) such that patients with proteinuria at baseline who received REACH had less worsening of eGFR.Conclusions: Future research should examine whether diabetes directed self-management support reduces CKD progression in ethnically diverse individuals with albuminuria. In highly comorbid populations, such as T2D and CKD, text-based support can be further tailored according to individuals' multimorbid disease self-management needs and is readily scalable for individuals with limited resources.Trial Registration: This study was registered with ClinicalTrials.gov ( NCT02409329 ). [ABSTRACT FROM AUTHOR]

The melanocortin receptors are G-protein-coupled receptors, which are essential components of the hypothalamic–pituitary–adrenal axis, and they mediate the actions of melanocortins (melanocyte-stimulating hormones: α-MSH, β-MSH, and γ-MSH) as well as the adrenocorticotropin hormone (ACTH) in skin pigmentation, adrenal steroidogenesis, and stress response. Three melanocortin receptor genes (MC1R, MC2R, and MC5R) contribute to the risk of major depressive disorder (MDD), and one melanocortin receptor gene (MC4R) contributes to the risk of type 2 diabetes (T2D). MDD increases T2D risk in drug-naïve patients; thus, MDD and T2D commonly coexist. The five melanocortin receptor genes might confer risk for both disorders. However, they have never been investigated jointly to evaluate their potential contributing roles in the MDD-T2D comorbidity, specifically within families. In 212 Italian families with T2D and MDD, we tested 11 single nucleotide polymorphisms (SNPs) in the MC1R gene, 9 SNPs in MC2R, 3 SNPs in MC3R, 4 SNPs in MC4R, and 2 SNPs in MC5R. The testing used 2-point parametric linkage and linkage disequilibrium (LD) (i.e., association) analysis with four models (dominant with complete penetrance (D1), dominant with incomplete penetrance (D2), recessive with complete penetrance (R1), and recessive with incomplete penetrance (R2)). We detected significant (p ≤ 0.05) linkage and/or LD (i.e., association) to/with MDD for one SNP in MC2R (rs111734014) and one SNP in MC5R (rs2236700), and to/with T2D for three SNPs in MC1R (rs1805007 and rs201192930, and rs2228479), one SNP in MC2R (rs104894660), two SNPs in MC3R (rs3746619 and rs3827103), and one SNP in MC4R genes (Chr18-60372302). The linkage/LD/association was significant across different linkage patterns and different modes of inheritance. All reported variants are novel in MDD and T2D. This is the first study to report risk variants in MC1R, MC2R, and MC3R genes in T2D. MC2R and MC5R genes are replicated in MDD, with one novel variant each. Within our dataset, only the MC2R gene appears to confer risk for both MDD and T2D, albeit with different risk variants. To further clarity the role of the melanocortin receptor genes in MDD-T2D, these findings should be sought among other ethnicities as well. [ABSTRACT FROM AUTHOR]

Diabetes is considered to influence the severity and length of hospital stay (LOS) in COVID-19 patients. It is not known whether lack of diabetes management may magnify the severity and LOS in COVID-19 patients with diabetes. The purpose of the study was to determine the impact of unmanaged diabetes and acute glycemia on severity and LOS among hospitalized COVID-19 patients. This retrospective study used medical records from patients admitted to the University Medical Center, El Paso, TX with COVID-19. Glycemic control was assessed by fasting blood glucose (acute) and HbA1c (chronic); COVID-19 severity was measured by quick sepsis-related organ failure assessment (qSOFA) and the LOS was determined by the number of days spent in the hospital. Diabetes management with medication was self-reported by patients. There was no significant difference in severity and LOS between patients with and without diabetes. However, patients with unmanaged diabetes showed significantly greater severity and LOS compared to patients who managed diabetes. Patients with an elevated fasting blood glucose level also had a greater COVID-19 severity and LOS. In conclusion, unmanaged diabetes and blood glucose showed worsened severity and prolonged hospitalization in COVID-19 patients. Diabetes management should be considered in treatment of COVID-19 patients. [ABSTRACT FROM AUTHOR]

Type 2 diabetes causes substantial long-term damage in several organs including the brain. Cognitive decline is receiving increased attention as diabetes has been established as an independent risk factor along with the identification of several other pathophysiological mechanisms. Early detection of detrimental changes in cerebral blood flow regulation may represent a useful clinical marker for development of cognitive decline for at-risk persons. Technically, reliable evaluation of neurovascular coupling is possible with several caveats but needs further development before it is clinically convenient. Different modalities including ultrasound, positron emission tomography and magnetic resonance are used preclinically to shed light on the many influences on vascular supply to the brain. In this narrative review, we focus on the complex link between type 2 diabetes, cognition, and neurovascular coupling and discuss how the disease-related pathology changes neurovascular coupling in the brain from the organ to the cellular level. Different modalities and their respective pitfalls are covered, and future directions suggested. [ABSTRACT FROM AUTHOR]