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Background/Objectives. Obesity, type 2 diabetes (T2D), and Alzheimer's disease (AD) are pathologies that affect millions of people worldwide. They have no effective therapy and are difficult to prevent and control when they develop. It has been known for many years that these diseases have many pathogenic aspects in common. We highlight in this review that neuroglial cells (astroglia, oligodendroglia, and microglia) play a vital role in the origin, clinical–pathological development, and course of brain neurodegeneration. Moreover, we include the new results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we are investigating. Methods. Critical bibliographic revision and biochemical neuropathological study of neuroglia in a T2D-AD model. Results. T2D and AD are not only "connected" by producing complex pathologies in the same individual (obesity, T2D, and AD), but they also have many common pathogenic mechanisms. These include insulin resistance, hyperinsulinemia, hyperglycemia, oxidative stress, mitochondrial dysfunction, and inflammation (both peripheral and central—or neuroinflammation). Cognitive impairment and AD are the maximum exponents of brain neurodegeneration in these pathological processes. both due to the dysfunctions induced by metabolic changes in peripheral tissues and inadequate neurotoxic responses to changes in the brain. In this review, we first analyze the common pathogenic mechanisms of obesity, T2D, and AD (and/or cerebral vascular dementia) that induce transcendental changes and responses in neuroglia. The relationships between T2D and AD discussed mainly focus on neuroglial responses. Next, we present neuroglial changes within their neuropathological context in diverse scenarios: (a) aging involution and neurodegenerative disorders, (b) human obesity and diabetes and obesity/diabetes models, (c) human AD and in AD models, and (d) human AD-T2D and AD-T2D models. An important part of the data presented comes from our own studies on humans and experimental models over the past few years. In the T2D-AD section, we included the results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we investigated, which showed that neuroglial dysfunctions (astrocytosis and microgliosis) manifest before the appearance of amyloid neuropathology, and that the amyloid pathology is greater than that presented by mice fed a normal, non-high-caloric diet A broad review is finally included on pharmacological, cellular, genic, and non-pharmacological (especially diet and lifestyle) neuroglial-related treatments, as well as clinical trials in a comparative way between T2D and AD. These neuroglial treatments need to be included in the multimodal/integral treatments of T2D and AD to achieve greater therapeutic efficacy in many millions of patients. Conclusions. Neuroglial alterations (especially in astroglia and microglia, cornerstones of neuroinflammation) are markedly defining brain neurodegeneration in T2D and A, although there are some not significant differences between each of the studied pathologies. Neuroglial therapies are a very important and p. promising tool that are being developed to prevent and/or treat brain dysfunction in T2D-AD. The need for further research in two very different directions is evident: (a) characterization of the phenotypic changes of astrocytes and microglial cells in each region of the brain and in each phase of development of each isolated and associated pathology (single-cell studies are mandatory) to better understand the pathologies and define new therapeutic targets; (b) studying new therapeutic avenues to normalize the function of neuroglial cells (preventing neurotoxic responses and/or reversing them) in these pathologies, as well as the phenotypic characteristics in each moment of the course and place of the neurodegenerative process. [ABSTRACT FROM AUTHOR]

Introduction: Daily insulin administration can be burdensome for people with type 2 diabetes (PwT2D) and can impact treatment adherence. This study investigated preferences for once-weekly, long-acting basal insulin for treatment of PwT2D. Methods: An online discrete-choice experiment was administered to PwT2D in the USA. Qualitative interviews informed the selection of six attributes: reduction in A1c level after 6 months, amount of time spent in optimal blood sugar range each day, number of serious low blood sugar events, number of nighttime low blood sugar events, change in weight because of the insulin over 6 months, and frequency of administration. Each participant completed eight questions offering a choice between two long-acting insulins; questions varied according to an experimental design. A fixed treatment choice question asked about preferences for daily versus weekly insulin, holding other treatment features constant. Data were analyzed using random-parameters logit models, and heterogeneity was explored through subgroup analyses. Results: Four hundred sixty-six PwT2D completed the survey (mean age, 57; mean A1c, 7.5%; 59.0% female); 33.3% of these were currently on a basal/bolus regimen, 34.3% used basal only, and 32.4% were insulin naive. Respondents placed the most importance on avoiding a 10-pound weight change and equal importance on the largest change in the number of serious and nighttime low blood sugar events per year and achieving the longest time in range included in the choice questions. There was significant heterogeneity in preferences by experience: insulin-naive respondents had stronger preferences for scheduled and flexible weekly insulin over daily insulin; 67.6% preferred flexible weekly over daily insulin, all else being equal. Conclusion: PwT2D valued insulin efficacy and reducing treatment-related adverse events, with heterogeneity in the relative importance of administration frequency. All else being equal, respondents preferred weekly over daily basal insulin. These findings provide insights into the preferences of PwT2D considering weekly long-acting insulin. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2D) is related to intestinal microflora changes and immune inflammation. We aimed to investigate the pattern of intestinal flora-systematic T helper (Th) cell linkage in T2D patients. Methods: Participants with T2D diagnosed by physicians and healthy controls were enrolled in the study. The Th1, Th2, and Th17 cells from the peripheral blood were assessed by flow cytometry. The feces were collected. The V3-V4 variable region of 16S rRNA was sequenced and analyzed using bioinformatics. Principal coordinate analysis (PCoA) and non-metric multidimensional scaling (NMDS) analysis were performed to assess the beta diversity. The linear discriminant analysis (LDA) effect size (LEfSe) method was applied to identify amicrobial taxon specific to T2D. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was conducted to identify the metabolic pathways. A network analysis was conducted by constructing a co-occurrence network. Results: The percentages of the Th1 and Th17 cells in the peripheral blood were higher in patients with T2D than in controls. Among the top 30 genera of the intestinal microbiota, the levels of Lachnospiraceae_NK4A136_group, Ruminococcaceae_UCG002, and Eubacterium_hallii_group were lower in the patients with T2D than in controls. In the LEfSe analysis, it was observed that the Lachnospiraceae and Ruminococcaceae families were significantly different between patients with T2D and controls. Moreover, the Th1/Th2 ratio was positively correlated with the abundance of the Lachnoclostridium and Ruminococcus_torques_group genera. In the network analysis, the Th1/Th2 ratio, Ruminococcaceae_UCG-002, and Lachnospiraceae_NK4A136_group were the important nodes. Conclusion: This study provided a preliminary picture of the crosstalk between the intestinal microbiome and systematic Th cells in patients with T2D. The findings of the study suggested that the network relationship among the intestinalmicrobiota, metabolites, and CD4+T lymphocyte immunity was unbalanced in the patients with T2D, which might have promoted the development of T2D. This presents a therapeutic opportunity to modulate gut immune reaction and then chronic inflammation by manipulating microbiome-specific Th-cell response. [ABSTRACT FROM AUTHOR]

Several reports, including our previous studies, indicate that hyperglycemia and diabetes mellitus exert differential effects on vascular function in males and females. This study examines sex differences in the vascular effects of type 2 diabetes (T2D) in an established monogenic model of obesity-induced T2D, Zucker Diabetic Fatty (ZDF) rats. Acetylcholine (ACh) responses were assessed in phenylephrine pre-contracted rings before and after apocynin, a NADPH oxidase (NOX) inhibitor. The mRNA expressions of aortic endothelial NOS (eNOS), and key NOX isoforms were also measured. We demonstrated the following: (1) diabetes had contrasting effects on aortic vasorelaxation in ZDF rats, impairing relaxation to ACh in females while enhancing it in male ZDF rats; (2) inhibition of NOX, a major source of superoxide in vasculature, restored aortic vasorelaxation in female ZDF rats; and (3) eNOS and NOX4 mRNA expressions were elevated in female (but not male) ZDF rat aortas compared to their respective leans. This study highlights sexual dimorphism in ACh-mediated vasorelaxation in the aorta of ZDF rats, suggesting that superoxide may play a role in the impaired vasorelaxation observed in female ZDF rats. [ABSTRACT FROM AUTHOR]

The primary cause of the pandemic scale of type 2 diabetes (T2D) is the excessive and/or abnormal accumulation of adiposity resulting from a chronic positive energy balance. Any form of weight loss dramatically affects the natural history of T2D, favoring prevention, treatment, and even remission in the case of significant weight loss. However, weight regain, which is often accompanied by the recurrence or worsening of obesity complications such as T2D, is an inevitable biological phenomenon that is an integral part of the pathophysiology of obesity. This can occur not only after weight loss, but also during obesity treatment if it is not effective enough to counteract the physiological responses aimed at restoring adiposity to its pre-weight-loss equilibrium state. Over the past few years, many controlled and randomized studies have suggested a superior efficacy of bariatric surgery compared to conventional therapy in terms of weight loss, glycemic control, and rates of T2D remission. Recently, the therapeutic armamentarium in the field of diabetology has been enriched with new antihyperglycemic drugs with considerable efficacy in reducing body weight, which could play a pathogenetic role in the remission of T2D, not through the classical incretin effect, but by improving adipose tissue functions. All these concepts are discussed in this position statement, which aims to deepen the pathogenetic links between obesity and T2D, shift the paradigm from a "simple" interaction between insulin resistance and insulin deficiency, and evaluate the efficacy of different therapeutic interventions to improve T2D management and induce diabetes remission whenever still possible. [ABSTRACT FROM AUTHOR]

Background and Objectives: In Italy, as in the rest of the world, government restrictions aimed at containing the spread of COVID-19 primarily imposed limitations on social relationships and personal behavior. This situation significantly affected the management of chronic illnesses, including type 2 diabetes (T2D). The objective was to evaluate the perceptions of patients with T2D regarding the quality of care received during the COVID-19 pandemic and the impact on dietary and physical activity behaviors. Materials and Methods: We conducted a retrospective cross-sectional survey. Data were collected from June to July 2023 using the convenience sampling of patients with T2D, and the Patient Assessment of Chronic Illness Care (PACIC) and Medi-Lite questionnaires were administered. Results: During the research period, out of the 130 subjects who met all enrollment criteria, 103 patients were included in this study (79.23%). The results of the administered questionnaires were heterogeneous. The average scores from the PACIC Questionnaire for each question displayed significant variability, indicating a range of experiences in the quality of care. In the Medi-Lite survey, fruit, cereals, and olive oil showed the highest adherence levels, with mean scores ranging from 2.58 (SD ± 1.18) for fruit to 1.89 (SD ± 0.34) for olive oil and 1.97 (SD ± 0.17) for cereals. Patients who reported increased food intake during the lockdown attributed it to having more time to prepare meals. Physical activity levels remained unchanged for 48 patients, decreased for 45 patients, and only 9 patients managed to exercise more during the COVID-19 restrictions. Conclusions: Healthcare systems must prioritize comprehensive care plans for T2D that address not only physical health, but also emotional and social well-being. Post-pandemic, promoting healthier lifestyles and empowering patients to manage their condition is crucial. A multidisciplinary and multidimensional approach could support the care of vulnerable individuals, such as patients with T2D, especially during crises like pandemics or other dramatic events. [ABSTRACT FROM AUTHOR]

Abstract Background A large proportion of skeletal muscle insulin resistance in type 2 diabetes (T2D) is caused by environmental factors. Methods By applying multiomics mRNA, microRNA (miRNA), and DNA methylation platforms in biopsies from 20 monozygotic twin pairs discordant for T2D, we aimed to delineate the epigenetic and transcriptional machinery underlying non-genetic muscle insulin resistance in T2D. Results Using gene set enrichment analysis (GSEA), we found decreased mRNA expression of genes involved in extracellular matrix organization, branched-chain amino acid catabolism, metabolism of vitamins and cofactors, lipid metabolism, muscle contraction, signaling by receptor tyrosine kinases pathways, and translocation of glucose transporter 4 (GLUT4) to the plasma membrane in muscle from twins with T2D. Differential expression levels of one or more predicted target relevant miRNA(s) were identified for approximately 35% of the dysregulated GSEA pathways. These include miRNAs with a significant overrepresentation of targets involved in GLUT4 translocation (miR-4643 and miR-548z), signaling by receptor tyrosine kinases pathways (miR-607), and muscle contraction (miR-4658). Acquired DNA methylation changes in skeletal muscle were quantitatively small in twins with T2D compared with the co-twins without T2D. Key methylation and expression results were validated in muscle, myotubes, and/or myoblasts from unrelated subjects with T2D and controls. Finally, mimicking T2D-associated changes by overexpressing miR-548 and miR-607 in cultured myotubes decreased expression of target genes, GLUT4 and FGFR4, respectively, and impaired insulin-stimulated phosphorylation of Akt (Ser473) and TBC1D4. Conclusions Together, we show that T2D is associated with non- and epigenetically determined differential transcriptional regulation of pathways regulating skeletal muscle metabolism and contraction.

This study aimed to close an evidence gap concerning the relative efficacy of finerenone versus SGLT2is in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). Canagliflozin was selected as a proxy for the SGLT2i class. Patient-level data of two randomized controlled trials (RCTs) of finerenone (FIDELIO-DKD and FIGARO-DKD) were used alongside aggregated data from CREDENCE, an RCT of canagliflozin. To account for meaningful between-study heterogeneity between each finerenone trial and CREDENCE, a matching-adjusted indirect comparison of a range of efficacy outcomes was undertaken for each finerenone study versus CREDENCE. These results were meta-analyzed, enabling the estimation of the relative effects of finerenone against canagliflozin. For the cardiorenal composite endpoint, the hazard ratio (HR) comparing finerenone to canagliflozin was 1.07 (95% CI: 0.83 to 1.36). The corresponding HRs for all-cause mortality, end-stage kidney disease and cardiovascular death were 0.99 (95% CI: 0.73 to 1.34), 1.03 (95% CI: 0.68 to 1.55) and 0.94 (95% CI: 0.64 to 1.37), respectively. The absence of statistically significant differences was consistent throughout the main analysis and a range of sensitivity analyses. Based on this study, using a large sample of data and adjusted for meaningful differences between the baseline characteristics of the included RCTs, there was no statistically significant evidence indicating a difference in the efficacy of finerenone compared to canagliflozin in the treatment of CKD in patients with T2D.

Objective: This study assessed the bioequivalence of a fixed-dose combination (FDC) therapy containing extended-release Metformin (Metformin XR), Dapagliflozin, and Sitagliptin for treating type 2 diabetes (T2D). The objective was to compare the absorption rate and extent of the FDC with two reference products: Sitagliptin 100mg tablets (R1) and a combination of Dapagliflozin 10mg plus Metformin 1000mg extended-release tablets (R2) in healthy adult males under fed conditions. Methods: An open-label, randomized, cross-over study was conducted with 24 healthy male participants. Each participant received a single dose of the test FDC and the reference products, with blood samples collected over 72 hours to evaluate pharmacokinetic parameters (Cmax, AUC0-t, AUC0-inf, Tmax, Kel, AUC_% Extrap_obs, and t1/2). Bioequivalence was determined based on the 90% confidence intervals (CIs) of the geometric mean ratios for AUC0-t and Cmax, within a predefined range of 80.00%-125.00%. Safety and tolerability were also assessed. Results: Pharmacokinetic analysis was performed on 22 subjects. The geometric mean ratios for the FDC compared to the reference products were within the predefined bioequivalence range, indicating that the absorption profiles of the FDC and the reference products were similar. The mean plasma concentration-time curves for Dapagliflozin, Sitagliptin, and Metformin XR were almost identical between the FDC and reference products, demonstrating consistent drug release and absorption. No significant differences were observed in Tmax, t1/2, or other pharmacokinetic parameters, further supporting bioequivalence. Additionally, the FDC was well-tolerated, with no serious adverse events reported, and all subjects completed the study without complications. Conclusion: The study confirmed that the FDC of Dapagliflozin, Sitagliptin, and Metformin XR is bioequivalent to the reference products in healthy adult males under fed conditions. This bioequivalence supports the use of the FDC as an effective treatment option to improve glycemic control in adults with T2D, particularly in the Indian context, promoting the benefits of combined therapy in managing diabetes. [ABSTRACT FROM AUTHOR]

This study aimed to close an evidence gap concerning the relative efficacy of finerenone versus SGLT2is in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). Canagliflozin was selected as a proxy for the SGLT2i class. Patient-level data of two randomized controlled trials (RCTs) of finerenone (FIDELIO-DKD and FIGARO-DKD) were used alongside aggregated data from CREDENCE, an RCT of canagliflozin. To account for meaningful between-study heterogeneity between each finerenone trial and CREDENCE, a matching-adjusted indirect comparison of a range of efficacy outcomes was undertaken for each finerenone study versus CREDENCE. These results were meta-analyzed, enabling the estimation of the relative effects of finerenone against canagliflozin. For the cardiorenal composite endpoint, the hazard ratio (HR) comparing finerenone to canagliflozin was 1.07 (95% CI: 0.83 to 1.36). The corresponding HRs for all-cause mortality, end-stage kidney disease and cardiovascular death were 0.99 (95% CI: 0.73 to 1.34), 1.03 (95% CI: 0.68 to 1.55) and 0.94 (95% CI: 0.64 to 1.37), respectively. The absence of statistically significant differences was consistent throughout the main analysis and a range of sensitivity analyses. Based on this study, using a large sample of data and adjusted for meaningful differences between the baseline characteristics of the included RCTs, there was no statistically significant evidence indicating a difference in the efficacy of finerenone compared to canagliflozin in the treatment of CKD in patients with T2D. [ABSTRACT FROM AUTHOR]

This case report presents a novel, non-pharmacological treatment of Type 2 Diabetes in a 46-year-old male, demonstrating improvements in blood chemistry and psychometric markers after 8 treatments using a Mind-Body Intervention (MBI) called Neuro-Emotional Technique (NET). The patient presented with a diagnosis of Type 2 Diabetes (T2D), pain, psychosocial indicators of stress and anxiety, and a score of 4 on the ACE-Q (Adverse Childhood Experiences Questionnaire) that is consistent with a predisposition to chronic disease and autoimmune disorders. Glucose levels for this patient were above normal levels (typically between 10-15mmol/L where optimal range is between 4-10mmol/L) for at least two months prior to the 4-week NET intervention period, despite the standard use of conventional antidiabetic medications (insulin injections). The patient exhibited numerous indictors of chronic stress that were hypothesised to be underlying his medical diagnosis and a series of 8 NET treatments over a period of 4 weeks was recommended. Psychometric tests and glucose measurements were recorded at baseline (prior to treatment), 4 weeks (at the conclusion of treatment) and at 8 weeks (4 weeks following the conclusion of treatment). Results show that glucose levels were reduced, and self-reported measures of depression, anxiety, stress, distress and pain all decreased from high and extreme levels to within normal ranges after 4 weeks, with ongoing improvement at 8 weeks. McEwen described the concept of allostatic load and the disruptive effects that cumulative stress can have on both mental and physical health. It is hypothesized that NET reduces allostatic load thereby fortifying homeostasis and the salutogenic stress response mechanisms involved in recovery from chronic illness, possibly via the Psycho- Immune-Neuroendocrine (PINE) network. Further studies with larger sample sizes are required to establish whether these results could be extrapolated to a wider population, however the results of this case suggest that it may be beneficial to consider co-management of T2D with an MBI such as NET. [ABSTRACT FROM AUTHOR]

Infertility among women, particularly those living with obesity, presents a multifaceted challenge with implications for reproductive health worldwide. Lifestyle interventions, mainly focusing on weight loss, have emerged as promising strategies to improve fertility outcomes in this population. This review aims to explore the effectiveness of various lifestyle interventions, encompassing dietary modifications and exercise regimens, in enhancing fertility outcomes among women with obesity and associated conditions such as polycystic ovary syndrome, congenital adrenal hyperplasia, type 2 diabetesmellitus, premenopause, hypothyroidism and eating disorders. Methodology of study search encompass a broad spectrum, ranging from interventions targeting weight management through slow or rapid weight loss to dietary approaches emphasizing whole food groups, specific nutrients, and dietary patterns like low-carbohydrate or ketogenic diets, as well as the Mediterranean diet. By synthesizing existing findings and recommendations, this review contributes to the understanding of lifestyle interventions in addressing infertility, with an emphasis on the population of women of reproductive age with excess weight and known or unknown infertility issues, while promoting their integration into clinical practice to optimize reproductive health and overall well-being. [ABSTRACT FROM AUTHOR]

Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 (FOXA1), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy. [ABSTRACT FROM AUTHOR]

Hyperketonemia is a risk factor for prurigo pigmentosa; therefore, diabetic ketosis and ketoacidosis as background diseases are more frequent in prurigo pigmentosa. However, it is underrecognized by clinicians and easily missed. Herein, we present a case of diabetic ketoacidosis in which prurigo pigmentosa was recognized as a dermadrome. A 37-year-old woman with no medical history presented with thirst, polydipsia, and polyuria approximately 1 month prior to transport. and a pruritic skin rash on both shoulders 1 week later. After no diagnosis by a local dermatologist, the patient was diagnosed with diabetic ketoacidosis, and insulin therapy was initiated at our hospital. Based on the patient's history, post-hospitalization course, and pathological findings, the pruritic skin rash was diagnosed as prurigo pigmentosa. The clinical course suggested that prurigo pigmentosa is a dermadrome of diabetic ketosis and ketoacidosis. The medical clinicians' awareness of its relevance is crucial for designing therapeutic interventions for diabetic ketosis and ketoacidosis. [ABSTRACT FROM AUTHOR]

Abstract Background The impacts of long-term exposure to air pollution on the risk of subsequent non-alcoholic fatty liver disease (NAFLD) among participants with type 2 diabetes (T2D) is ambiguous. The modifying role of Life’s Essential 8 (LE8) remains unknown. Methods This study included 23,129 participants with T2D at baseline from the UK Biobank. Annual means of nitrogen dioxide (NO2), nitrogen oxides (NOX), and particulate matter (PM2.5, PM2.5–10, PM10) were estimated using the land-use regression model for each participant. The associations between exposure to air pollution and the risk of severe NAFLD were evaluated using Cox proportional hazard models. The effect modification of LE8 was assessed through stratified analyses. Results During a median 13.6 years of follow-up, a total of 1,123 severe NAFLD cases occurred. After fully adjusting for potential covariates, higher levels of PM2.5 (hazard ratio [HR] = 1.12, 95%CI:1.02, 1.23 per interquartile range [IQR] increment), NO2 (HR = 1.15, 95%CI:1.04, 1.27), and NOX (HR = 1.08, 95%CI:1.01, 1.17) were associated with an elevated risk of severe NAFLD. In addition, LE8 score was negatively associated with the risk of NAFLD (HR = 0.97, 95% CI: 0.97, 0.98 per point increment). Compared with those who had low air pollution and high LE8, participants with a high air pollution exposure and low LE8 had a significantly higher risk of severe NAFLD. Conclusions Our findings suggest that long-term exposure to air pollution was associated with an elevated risk of severe NAFLD among participants with T2D. A lower LE8 may increase the adverse impacts of air pollution on NAFLD.

Abstract Background//Objective Diabetes affects millions of people globally, despite treatment options, adherence and other factors pose obstacles. Once-weekly Insulin Icodec, a novel basal Insulin analog with a week-long half-life, offers potential benefits, enhancing convenience, adherence, and quality of life for improved glycemic control. This systematic review and meta-analysis aimed to assess the efficacy and safety of once-weekly Insulin Icodec compared to once-daily Insulin Glargine U-100 in individuals with type II diabetes (T2D). Methods A comprehensive literature search was conducted using PubMed, and Cochrane Library databases before September 2023 to identify relevant Randomized control trials (RCTs) with no language restrictions following PRISMA guidelines. The Cochrane risk-of-bias tool was used for quality assessment. All statistical analyses were conducted using RevMan (version 5.4; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Result Four RCTs published from 2020 to 2023 with a cumulative sample size of 1035 were included. The pooled mean difference (MD) revealed a 4.68% longer TIR (%) with Insulin Icodec compared to Insulin Glargine U-100 [{95% CI (0.69, 8.68), p = 0.02}], the estimated mean changes in HbA1c (%) and FPG (mg%) were found to be insignificant between the two groups [MD = − 0.12 {95% CI (− 0.26, 0.01), p = 0.07}] and [MD = − 2.59 {95% CI (− 6.95, 1.78), p = 0.25}], respectively. The overall OR for hypoglycemia was also nonsignificant between the two regimens 1.04 [{95% CI (0.71, 1.52), p = 0.84}]. Other safety parameters were similar between the two groups. Conclusions Switching from daily Insulin Glargine U-100 to weekly Insulin Icodec showed longer TIR (%) as well as similar blood glycemic control and safety profile. Hence, it may be a good alternate option for management of longstanding T2D.

Type 2 diabetes (T2D) is a polygenic metabolic disorder characterized by insulin resistance in peripheral tissues and impaired insulin secretion by the pancreas. While the decline in insulin production and secretion was previously attributed to apoptosis of insulin-producing b-cells, recent studies indicate that b-cell apoptosis rates are relatively low in diabetes. Instead, b-cells primarily undergo dedifferentiation, a process where they lose their specialized identity and transition into non-functional endocrine progenitor-like cells, ultimately leading to b-cell failure. The underlying mechanisms driving b-cell dedifferentiation remain elusive due to the intricate interplay of genetic factors and cellular stress. Understanding these mechanisms holds the potential to inform innovative therapeutic approaches aimed at reversing b-cell dedifferentiation in T2D. This review explores the proposed drivers of b-cell dedifferentiation leading to b-cell failure, and discusses current interventions capable of reversing this process, thus restoring b-cell identity and function. [ABSTRACT FROM AUTHOR]

Introduction: Multiple daily injection insulin regimen (MDI) represents the most intensive insulin regimen used in the management of people with type 2 diabetes (PwT2D). Its efficacy regarding glycaemic control is counterbalanced by the increased risk of hypoglycaemia, frequently observed tendency to weight gain and necessity for frequent glucose monitoring. Recent introduction of novel antidiabetic medications with pleiotropic effects reaching far beyond the reduction of glycaemia (HbA1c), such as the glucagon-like peptide 1 receptor agonist (GLP-1 RA), has significantly widened the therapeutic options available for management of T2D. Consequently, there is currently a substantial number of PwT2D for whom the MDI regimen was initiated at a time when no other options were available. Yet, in present times, these individuals could benefit from simplified insulin regimens ideally taking advantage of the beneficial effects of the novel classes of antidiabetic medications. iGlarLixi (Suliqua®) is a once-daily fixed-ratio combination of basal insulin analogue glargine 100 U/ml and a GLP-1 RA lixisenatide. Methods: Insulin therapy DE-intensificAtion with iglarLixi (IDEAL) is a six-centre, open-label, parallel-group, active comparator, phase IV randomised controlled trial with a 24-week active treatment period examining the efficacy and safety of MDI regimen de-intensification with once-daily administration of iGlarLixi versus MDI regimen continuation in PwT2D on a backgroud therapy with metformin ± sodium-glucose cotransporter 2 inhibitor. Planned Outcomes: The primary objective is to compare the effects of MDI therapy de-intensification with iGlarLixi versus MDI regimen continuation regarding glycaemic control (HbA1c). Secondary objectives include detailed evaluation of the effects of MDI regimen de-intensification with iGlarLixi on glycaemic control using standardised continuous glucose monitoring (CGM) metrics and self-monitoring of plasma glucose. Furthermore, body weight and body composition analysis, quality of life and safety profile are evaluated. Trial Registration: ClinicalTrials.gov, identifier NCT04945070. [ABSTRACT FROM AUTHOR]

Background: The impacts of long-term exposure to air pollution on the risk of subsequent non-alcoholic fatty liver disease (NAFLD) among participants with type 2 diabetes (T2D) is ambiguous. The modifying role of Life's Essential 8 (LE8) remains unknown. Methods: This study included 23,129 participants with T2D at baseline from the UK Biobank. Annual means of nitrogen dioxide (NO2), nitrogen oxides (NOX), and particulate matter (PM2.5, PM2.5–10, PM10) were estimated using the land-use regression model for each participant. The associations between exposure to air pollution and the risk of severe NAFLD were evaluated using Cox proportional hazard models. The effect modification of LE8 was assessed through stratified analyses. Results: During a median 13.6 years of follow-up, a total of 1,123 severe NAFLD cases occurred. After fully adjusting for potential covariates, higher levels of PM2.5 (hazard ratio [HR] = 1.12, 95%CI:1.02, 1.23 per interquartile range [IQR] increment), NO2 (HR = 1.15, 95%CI:1.04, 1.27), and NOX (HR = 1.08, 95%CI:1.01, 1.17) were associated with an elevated risk of severe NAFLD. In addition, LE8 score was negatively associated with the risk of NAFLD (HR = 0.97, 95% CI: 0.97, 0.98 per point increment). Compared with those who had low air pollution and high LE8, participants with a high air pollution exposure and low LE8 had a significantly higher risk of severe NAFLD. Conclusions: Our findings suggest that long-term exposure to air pollution was associated with an elevated risk of severe NAFLD among participants with T2D. A lower LE8 may increase the adverse impacts of air pollution on NAFLD. [ABSTRACT FROM AUTHOR]

Experimental animal models of diabetes can be useful for identifying novel targets related to disease, for understanding its physiopathology, and for evaluating emerging antidiabetic treatments. This study aimed to characterize two rat diabetes models: HFD + STZ, a high-fat diet (60% fat) combined with streptozotocin administration (STZ, 35 mg/kg BW), and a model with a single STZ dose (65 mg/kg BW) in comparison with healthy rats. HFD + STZ- induced animals demonstrated a stable hyperglycemia range (350–450 mg/dL), whereas in the STZ-induced rats, we found glucose concentration values with a greater dispersion, ranging from 270 to 510 mg/dL. Moreover, in the HFD + STZ group, the AUC value of the insulin tolerance test (ITT) was found to be remarkably augmented by 6.2-fold higher than in healthy animals (33,687.0 ± 1705.7 mg/dL/min vs. 5469.0 ± 267.6, respectively), indicating insulin resistance (IR). In contrast, a more moderate AUC value was observed in the STZ group (19,059.0 ± 3037.4 mg/dL/min) resulting in a value 2.5-fold higher than the average exhibited by the control group. After microarray experiments on liver tissue from all animals, we analyzed genes exhibiting a fold change value in gene expression <−2 or >2 (p-value <0.05). We found 27,686 differentially expressed genes (DEG), identified the top 10 DEGs and detected 849 coding genes that exhibited opposite expression patterns between both diabetes models (491 upregulated genes in the STZ model and 358 upregulated genes in HFD + STZ animals). Finally, we performed an enrichment analysis of the 849 selected genes. Whereas in the STZ model we found cellular pathways related to lipid biosynthesis and metabolism, in the HFD + STZ model we identified pathways related to immunometabolism. Some phenotypic differences observed in the models could be explained by transcriptomic results; however, further studies are needed to corroborate these findings. Our data confirm that the STZ and the HFD + STZ models are reliable experimental models for human T1D and T2D, respectively. These results also provide insight into alterations in the expression of specific liver genes and could be utilized in future studies focusing on diabetes complications associated with impaired liver function. [ABSTRACT FROM AUTHOR]

Background//Objective: Diabetes affects millions of people globally, despite treatment options, adherence and other factors pose obstacles. Once-weekly Insulin Icodec, a novel basal Insulin analog with a week-long half-life, offers potential benefits, enhancing convenience, adherence, and quality of life for improved glycemic control. This systematic review and meta-analysis aimed to assess the efficacy and safety of once-weekly Insulin Icodec compared to once-daily Insulin Glargine U-100 in individuals with type II diabetes (T2D). Methods: A comprehensive literature search was conducted using PubMed, and Cochrane Library databases before September 2023 to identify relevant Randomized control trials (RCTs) with no language restrictions following PRISMA guidelines. The Cochrane risk-of-bias tool was used for quality assessment. All statistical analyses were conducted using RevMan (version 5.4; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Result: Four RCTs published from 2020 to 2023 with a cumulative sample size of 1035 were included. The pooled mean difference (MD) revealed a 4.68% longer TIR (%) with Insulin Icodec compared to Insulin Glargine U-100 [{95% CI (0.69, 8.68), p = 0.02}], the estimated mean changes in HbA1c (%) and FPG (mg%) were found to be insignificant between the two groups [MD = − 0.12 {95% CI (− 0.26, 0.01), p = 0.07}] and [MD = − 2.59 {95% CI (− 6.95, 1.78), p = 0.25}], respectively. The overall OR for hypoglycemia was also nonsignificant between the two regimens 1.04 [{95% CI (0.71, 1.52), p = 0.84}]. Other safety parameters were similar between the two groups. Conclusions: Switching from daily Insulin Glargine U-100 to weekly Insulin Icodec showed longer TIR (%) as well as similar blood glycemic control and safety profile. Hence, it may be a good alternate option for management of longstanding T2D. [ABSTRACT FROM AUTHOR]

This qualitative research was conducted with main objective of examining the 'lived experiences' of individuals to manage and cope with type 2 diabetes (T2D). Twelve respondents (diagnosed with T2D) were shortlisted using purposive sampling technique from Lahore city Pakistan for this study. Data was collected through semi-structured interview method form the participants. Respondents' interview data were analyzed applying phenomenological analysis (IPA) to identify sub-themes and mega themes. IPA identified eleven identical themes from transcribed interviews. Findings highlighted individuals' causes of initial non-acceptance behavior, fears about disease, financial barriers, restrictive life styles, self-management strategies, role of their doctors, and family members to cope with disease. The study recommends that health practitioners should introduce diabetes management awareness programs as findings highlight the role of doctors' counselling to cope with disease and modify patient's life style after the disease. Additionally, patients' awareness about disease played vital role to adjust their life style and coping with it with support from family members. [ABSTRACT FROM AUTHOR]

The pathophysiology of Type 2 Diabetes (T2D) is intricate, involving three main processes that lead to elevated glucose levels. Insulin resistance hinders glucose utilization in muscles, adipose tissue, and the liver. Additionally, pancreatic dysfunction results in excessive glucose release and disrupts insulin and glucagon levels, contributing to hyperglycemia. Tailoring management strategies to individual needs and stages of the disease is crucial. Genetic factors play a significant role in the development of T2D and must be considered in treatment planning. Genome-Wide Association Studies (GWAS) have identified numerous genetic loci and Single Nucleotide Polymorphisms (SNPs) associated with T2D. A personalized approach considers a wide range of factors, such as patient characteristics, medical history, complications, and genetic makeup. By customizing treatment plans to suit each patient's unique needs, it may be possible to improve outcomes and reduce the impact of T2D on overall health. While some may argue that personalized diabetes care has been utilized for a long time, integrating it into the standard treatment of T2D remains a challenging task with numerous obstacles.The current review aims to describe the vision of personalized medicine in diabetes and offers helpful suggestions for a better understanding of this issue, as well as disseminating information about novel treatment approaches like Next Generation Sequencing (NGS) and pharmacotherapy.

Mulberry leaves can be processed into a tea rich in polyphenols and gamma-aminobutyric acid (GABA) with health benefits. This study aimed to investigate the anti-diabetic effects of mulberry leaf extracts. Potential hypoglycemic and anti-glycation activities were evaluated in vitro. The in vivo therapeutic efficacy was assessed in type 2 diabetic mice, with GABA and exendin-4 serving as reference anti-diabetic agents. The ethanol extract of mulberry leaves was found to contain higher levels of GABA and polyphenols than the water extract. Both extracts exhibited multiple anti-diabetic biological activities. Regarding in vivo therapeutic effects, incorporating 3% (g/g) mulberry leaf extract into the diet for 8 weeks improved glycemic control, insulin sensitivity, serum glucagon like peptide-1 levels, hepatic steatosis and xenobiotic metabolism abnormalities. Additionally, the ethanol extract had a more pronounced effect on immunity. In conclusion, mulberry leaves could be considered a sustainable dietary material to alleviate symptoms of type 2 diabetes.

This case report presents a novel, non-pharmacological treatment of Type 2 Diabetes in a 46-year-old male, demonstrating improvements in blood chemistry and psychometric markers after 8 treatments using a Mind-Body Intervention (MBI) called Neuro-Emotional Technique (NET). The patient presented with a diagnosis of Type 2 Diabetes (T2D), pain, psychosocial indicators of stress and anxiety, and a score of 4 on the ACE-Q (Adverse Childhood Experiences Questionnaire) that is consistent with a predisposition to chronic disease and autoimmune disorders. Glucose levels for this patient were above normal levels (typically between 10-15mmol/L where optimal range is between 4-10mmol/L) for at least two months prior to the 4-week NET intervention period, despite the standard use of conventional antidiabetic medications (insulin injections). The patient exhibited numerous indictors of chronic stress that were hypothesised to be underlying his medical diagnosis and a series of 8 NET treatments over a period of 4 weeks was recommended. Psychometric tests and glucose measurements were recorded at baseline (prior to treatment), 4 weeks (at the conclusion of treatment) and at 8 weeks (4 weeks following the conclusion of treatment). Results show that glucose levels were reduced, and self-reported measures of depression, anxiety, stress, distress and pain all decreased from high and extreme levels to within normal ranges after 4 weeks, with ongoing improvement at 8 weeks. McEwen described the concept of allostatic load and the disruptive effects that cumulative stress can have on both mental and physical health. It is hypothesized that NET reduces allostatic load thereby fortifying homeostasis and the salutogenic stress response mechanisms involved in recovery from chronic illness, possibly via the Psycho-Immune-Neuroendocrine (PINE) network. Further studies with larger sample sizes are required to establish whether these results could be extrapolated to a wider population, however the results of this case suggest that it may be beneficial to consider co-management of T2D with an MBI such as NET.

Background/Objectives. Obesity, type 2 diabetes (T2D), and Alzheimer’s disease (AD) are pathologies that affect millions of people worldwide. They have no effective therapy and are difficult to prevent and control when they develop. It has been known for many years that these diseases have many pathogenic aspects in common. We highlight in this review that neuroglial cells (astroglia, oligodendroglia, and microglia) play a vital role in the origin, clinical–pathological development, and course of brain neurodegeneration. Moreover, we include the new results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we are investigating. Methods. Critical bibliographic revision and biochemical neuropathological study of neuroglia in a T2D-AD model. Results. T2D and AD are not only “connected” by producing complex pathologies in the same individual (obesity, T2D, and AD), but they also have many common pathogenic mechanisms. These include insulin resistance, hyperinsulinemia, hyperglycemia, oxidative stress, mitochondrial dysfunction, and inflammation (both peripheral and central—or neuroinflammation). Cognitive impairment and AD are the maximum exponents of brain neurodegeneration in these pathological processes. both due to the dysfunctions induced by metabolic changes in peripheral tissues and inadequate neurotoxic responses to changes in the brain. In this review, we first analyze the common pathogenic mechanisms of obesity, T2D, and AD (and/or cerebral vascular dementia) that induce transcendental changes and responses in neuroglia. The relationships between T2D and AD discussed mainly focus on neuroglial responses. Next, we present neuroglial changes within their neuropathological context in diverse scenarios: (a) aging involution and neurodegenerative disorders, (b) human obesity and diabetes and obesity/diabetes models, (c) human AD and in AD models, and (d) human AD-T2D and AD-T2D models. An important part of the data presented comes from our own studies on humans and experimental models over the past few years. In the T2D-AD section, we included the results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we investigated, which showed that neuroglial dysfunctions (astrocytosis and microgliosis) manifest before the appearance of amyloid neuropathology, and that the amyloid pathology is greater than that presented by mice fed a normal, non-high-caloric diet A broad review is finally included on pharmacological, cellular, genic, and non-pharmacological (especially diet and lifestyle) neuroglial-related treatments, as well as clinical trials in a comparative way between T2D and AD. These neuroglial treatments need to be included in the multimodal/integral treatments of T2D and AD to achieve greater therapeutic efficacy in many millions of patients. Conclusions. Neuroglial alterations (especially in astroglia and microglia, cornerstones of neuroinflammation) are markedly defining brain neurodegeneration in T2D and A, although there are some not significant differences between each of the studied pathologies. Neuroglial therapies are a very important and p. promising tool that are being developed to prevent and/or treat brain dysfunction in T2D-AD. The need for further research in two very different directions is evident: (a) characterization of the phenotypic changes of astrocytes and microglial cells in each region of the brain and in each phase of development of each isolated and associated pathology (single-cell studies are mandatory) to better understand the pathologies and define new therapeutic targets; (b) studying new therapeutic avenues to normalize the function of neuroglial cells (preventing neurotoxic responses and/or reversing them) in these pathologies, as well as the phenotypic characteristics in each moment of the course and place of the neurodegenerative process.

Background and Objectives: In Italy, as in the rest of the world, government restrictions aimed at containing the spread of COVID-19 primarily imposed limitations on social relationships and personal behavior. This situation significantly affected the management of chronic illnesses, including type 2 diabetes (T2D). The objective was to evaluate the perceptions of patients with T2D regarding the quality of care received during the COVID-19 pandemic and the impact on dietary and physical activity behaviors. Materials and Methods: We conducted a retrospective cross-sectional survey. Data were collected from June to July 2023 using the convenience sampling of patients with T2D, and the Patient Assessment of Chronic Illness Care (PACIC) and Medi-Lite questionnaires were administered. Results: During the research period, out of the 130 subjects who met all enrollment criteria, 103 patients were included in this study (79.23%). The results of the administered questionnaires were heterogeneous. The average scores from the PACIC Questionnaire for each question displayed significant variability, indicating a range of experiences in the quality of care. In the Medi-Lite survey, fruit, cereals, and olive oil showed the highest adherence levels, with mean scores ranging from 2.58 (SD ± 1.18) for fruit to 1.89 (SD ± 0.34) for olive oil and 1.97 (SD ± 0.17) for cereals. Patients who reported increased food intake during the lockdown attributed it to having more time to prepare meals. Physical activity levels remained unchanged for 48 patients, decreased for 45 patients, and only 9 patients managed to exercise more during the COVID-19 restrictions. Conclusions: Healthcare systems must prioritize comprehensive care plans for T2D that address not only physical health, but also emotional and social well-being. Post-pandemic, promoting healthier lifestyles and empowering patients to manage their condition is crucial. A multidisciplinary and multidimensional approach could support the care of vulnerable individuals, such as patients with T2D, especially during crises like pandemics or other dramatic events.

Diabetes mellitus, commonly referred to as diabetes, is a group of metabolic disorders characterized by chronic elevation in blood glucose levels, resulting from inadequate insulin production, defective cellular response to extracellular insulin, and/or impaired glucose metabolism. The two main types that account for most diabetics are type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), each with their own pathophysiological features. T1D is an autoimmune condition where the body's immune system attacks and destroys the insulin-producing beta cells in the pancreas. This leads to lack of insulin, a vital hormone for regulating blood sugar levels and cellular glucose uptake. As a result, those with T1D depend on lifelong insulin therapy to control their blood glucose level. In contrast, T2DM is characterized by insulin resistance, where the body's cells do not respond effectively to insulin, coupled with a relative insulin deficiency. This form of diabetes is often associated with obesity, sedentary lifestyle, and/or genetic factors, and it is managed with lifestyle changes and oral medications. Animal models play a crucial role in diabetes research. However, given the distinct differences between T1DM and T2DM, it is imperative for researchers to employ specific animal models tailored to each condition for a better understanding of the impaired mechanisms underlying each condition, and for assessing the efficacy of new therapeutics. In this review, we discuss the distinct animal models used in type 1 and type 2 diabetes mellitus research and discuss their strengths and limitations. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Trigonella foenum-graecum (Fenugreek) is an extensively researched phytotherapeutic for the management of Type 2 diabetes without any associated side effects. The major anti-diabetic bioactive constituents present in the plant are furostanolic saponins, which are more abundantly available in the seed of the plant. However, the bioavailability of these components depends on the method of extraction and hence formulation of the phytotherapeutic constitutes a critical step for its success. The present study reports the efficacy of a novel, patented fenugreek seed extract, Fenfuro®, containing significant amount of furostanolic saponins, in an open-labelled, two-armed, single centric study on a group of 204 patients with Type 2 diabetes mellitus over a period of twelve consecutive weeks. Administration of Fenfuro® in the dosage of 500 mg twice daily along with metformin and/or sulfonylurea-based prescribed antidiabetic drug resulted in a reduction of post-prandial glucose by more than 33% along with significant reduction in fasting glucose, both of which were greater than what resulted for the patient group receiving only Metformin and/or Sulfonylurea therapy. Fenfuro® also resulted in reduction in mean baseline HOMA index from 4.27 to 3.765, indicating restoration of insulin sensitivity which was also supported by a significant decrease in serum insulin levels by >10% as well as slight reduction in the levels of C-peptide. However, in the case of the Metformin and/or Sulfonylurea group, insulin levels were found to increase by more than 14%, which clearly indicated that drug-induced suppression of glucose levels instead of restoration of glucose homeostasis. Administration of the formulation was also found to be free from any adverse side effects as there were no changes in hematological profile, liver function and renal function. The study demonstrated the promising potential of this novel phytotherapeutic, Fenfuro®, in long-term holistic management of type-2 diabetes. [ABSTRACT FROM AUTHOR]

The UK Biobank has made general practitioner (GP) data (censoring date 2016–2017) available for approximately 45% of the cohort, whilst hospital inpatient and death registry (referred to as "HES/Death") data are available cohort-wide through 2018–2022 depending on whether the data comes from England, Wales or Scotland. We assessed the importance of case ascertainment via different data sources in UKB for three diseases that are usually first diagnosed in primary care: Parkinson's disease (PD), type 2 diabetes (T2D), and all-cause dementia. Including GP data at least doubled the number of incident cases in the subset of the cohort with primary care data (e.g. from 619 to 1390 for dementia). Among the 786 dementia cases that were only captured in the GP data before the GP censoring date, only 421 (54%) were subsequently recorded in HES. Therefore, estimates of the absolute incidence or risk-stratified incidence are misleadingly low when based only on the HES/Death data. For incident cases present in both HES/Death and GP data during the full follow-up period (i.e. until the HES censoring date), the median time difference between an incident diagnosis of dementia being recorded in GP and HES/Death was 2.25 years (i.e. recorded 2.25 years earlier in the GP records). Similar lag periods were also observed for PD (median 2.31 years earlier) and T2D (median 2.82 years earlier). For participants with an incident GP diagnosis, only 65.6% of dementia cases, 69.0% of PD cases, and 58.5% of T2D cases had their diagnosis recorded in HES/Death within 7 years since GP diagnosis. The effect estimates (hazard ratios, HR) of established risk factors for the three health outcomes mostly remain in the same direction and with a similar strength of association when cases are ascertained either using HES only or further adding GP data. The confidence intervals of the HR became narrower when adding GP data, due to the increased statistical power from the additional cases. In conclusion, it is desirable to extend both the coverage and follow-up period of GP data to allow researchers to maximise case ascertainment of chronic health conditions in the UK. [ABSTRACT FROM AUTHOR]

Context Fibroblast growth factor (FGF) 21 acts as a metabolic regulator and its therapeutic use is under investigation. FGF21 signaling requires binding to surface receptors, FGFR1c and β-klotho. FGF21 resistance is observed in metabolic diseases and FGF21 signaling is regulated by fibroblast activation protein (FAP). Metformin is reported to influence expression and secretion of FGF21 in preclinical models, but the effect of metformin on FGF21 in a clinical trial remains unknown. Objective To investigate how 12 weeks of treatment with metformin affects the FGF21 signaling pathway in patients with type 2 diabetes (T2D). Methods Randomized, placebo-controlled study in patients with T2D (n = 24) receiving either metformin (1000 mg twice daily) or placebo. A control group of body mass index- and age-matched healthy individuals (n = 12) received a similar dose of metformin. Blood samples and muscle and fat biopsies were collected at study entry and after 12 weeks. Methods Plasma levels of FGF21 (total and intact) and FAP (total and activity) were measured. Muscle and fat biopsies were analyzed for mRNA and protein expression of targets relevant for activation of the FGF21 signaling pathway. Results Circulating FAP activity decreased after metformin treatment compared with placebo (P =.006), whereas FGF21 levels were unchanged. Metformin treatment increased gene and protein expression of β-klotho, FGFR1c, and pFGFR1c in adipose tissue. FGF21 mRNA expression increased in muscle tissue after metformin and the FGF21 protein, but not mRNA levels, were observed in adipose tissue. Conclusion Our findings suggest that metformin suppresses the circulating FAP activity and upregulates the expression of FGFR1c and β-klotho for increased FGF21 signaling in adipose tissue, thus improving peripheral FGF21 sensitivity. [ABSTRACT FROM AUTHOR]

Aim: The study we are conducting aims to establish a validated method for measuring empagliflozin in plasma using UPLC MS/MS. Materials and Methods: Sodium-Glucose co Transporter inhibitors (SGLTi), a novel class of diabetes medication. Non-insulin dependent diabetes and adult-onset diabetes were the prior names for type 2 diabetes. Empagliflozin was the first SGLT2-inhibitor a drug used that reduced the risk of cardiovascular risk those with type 2 diabetes and pre-existing cardiovascular disease. The empagliflozin D4 as Internal Solution (IS). Liquid-liquid extraction was used to achieve separation on Synergi 2.5µ Fusion-Reverse phase 100A (100 mm×2.0 mm), 2.5 µm column. Mixture of Methanol: As a mobile phase, 0.2% formic acid in a 75:25 volumetric ratio is utilised. The flow rate is set at 0.3µl/min. The calibration curve is linear and plotted. Results: The developed method is accurate, precise, sensitive method for determination of empagliflozin from human plasma solution. Ethyl acetate and water in HPLC grade are preferred solvent for empagliflozin. Performing LLE extraction with centrifuge and LV Nitrogen Evaporator it with Ethyl acetate and water. Ethyl acetate is used as non-polar solvent and water is used as polar solvent for liquid-liquid extraction. LLE is a low cost extraction process compare to solid liquid extraction. The reported method is suitable for bioequivalence and pharmacokinetic studies. [ABSTRACT FROM AUTHOR]

The mammalian target of rapamycin complex 1 syndrome (Tors), paradigm implies an exhaustive cohesive disease entity driven by a hyperactive mTORC1, and which includes obesity, type 2 diabetic hyperglycemia, diabetic dyslipidemia, diabetic cardiomyopathy, diabetic nephropathy, diabetic peripheral neuropathy, hypertension, atherosclerotic cardiovascular disease, non‐alcoholic fatty liver disease, some cancers, neurodegeneration, polycystic ovary syndrome, psoriasis and other. The TorS paradigm may account for the efficacy of standard‐of‐care treatments of type 2 diabetes (T2D) in alleviating the glycaemic and non‐glycaemic diseases of TorS in T2D and non‐T2D patients. The TorS paradigm may generate novel treatments for TorS diseases. [ABSTRACT FROM AUTHOR]

Context Misclassification of diabetes type occurs in people with atypical presentations of type 1 diabetes (T1D) or type 2 diabetes (T2D). Although current clinical guidelines suggest clinical variables and treatment response as ways to help differentiate diabetes type, they remain insufficient for people with atypical presentations. Objective This work aimed to assess the clinical utility of 2 polygenic scores (PGSs) in differentiating between T1D and T2D. Methods Patients diagnosed with diabetes in the UK Biobank were studied (N = 41 787), including 464 (1%) and 15 923 (38%) who met the criteria for classic T1D and T2D, respectively, and 25 400 (61%) atypical diabetes. The validity of 2 published PGSs for T1D (PGST1D) and T2D (PGST2D) in differentiating classic T1D or T2D was assessed using C statistic. The utility of genetic probability for T1D based on PGSs (GenProb-T1D) was evaluated in atypical diabetes patients. Results The joint performance of PGST1D and PGST2D for differentiating classic T1D or T2D was outstanding (C statistic = 0.91), significantly higher than that of PGST1D alone (0.88) and PGST2D alone (0.70), both P less than.001. Using an optimal cutoff of GenProb-T1D, 23% of patients with atypical diabetes had a higher probability of T1D and its validity was independently supported by clinical presentations that are characteristic of T1D. Conclusion PGST1D and PGST2D can be used to discriminate classic T1D and T2D and have potential clinical utility for differentiating these 2 types of diseases among patients with atypical diabetes. [ABSTRACT FROM AUTHOR]

IntroductionType 2 diabetes (T2D) has been linked to cognitive impairment and dementia, but its impact on brain cortical structures in individuals prior to or without cognitive impairment remains unclear.MethodsWe conducted a systematic review of 2,331 entries investigating cerebral cortical thickness changes in T2D individuals without cognitive impairment, 55 of which met our inclusion criteria.ResultsMost studies (45/55) reported cortical brain atrophy and reduced thickness in the anterior cingulate, temporal, and frontal lobes between T2D and otherwise cognitively healthy controls. However, the balance of studies (10/55) reported no significant differences in either cortical or total brain volumes. A few reports also noticed changes in the occipital cortex and its gyri. As part of the reports, less than half of studies (18/55) described a correlation between T2D and hippocampal atrophy. Variability in sample characteristics, imaging methods, and software could affect findings on T2D and cortical atrophy.DiscussionIn conclusion, T2D appears linked to reduced cortical thickness, possibly impacting cognition and dementia risk. Microvascular disease and inflammation in T2D may also contribute to this risk. Further research is needed to understand the underlying mechanisms and brain health implications.

Type 2 diabetes (T2D) is a polygenic metabolic disorder characterized by insulin resistance in peripheral tissues and impaired insulin secretion by the pancreas. While the decline in insulin production and secretion was previously attributed to apoptosis of insulin-producing β-cells, recent studies indicate that β-cell apoptosis rates are relatively low in diabetes. Instead, β-cells primarily undergo dedifferentiation, a process where they lose their specialized identity and transition into non-functional endocrine progenitor-like cells, ultimately leading to β-cell failure. The underlying mechanisms driving β-cell dedifferentiation remain elusive due to the intricate interplay of genetic factors and cellular stress. Understanding these mechanisms holds the potential to inform innovative therapeutic approaches aimed at reversing β-cell dedifferentiation in T2D. This review explores the proposed drivers of β-cell dedifferentiation leading to β-cell failure, and discusses current interventions capable of reversing this process, thus restoring β-cell identity and function.

Diabetes mellitus, commonly referred to as diabetes, is a group of metabolic disorders characterized by chronic elevation in blood glucose levels, resulting from inadequate insulin production, defective cellular response to extracellular insulin, and/or impaired glucose metabolism. The two main types that account for most diabetics are type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), each with their own pathophysiological features. T1D is an autoimmune condition where the body’s immune system attacks and destroys the insulin-producing beta cells in the pancreas. This leads to lack of insulin, a vital hormone for regulating blood sugar levels and cellular glucose uptake. As a result, those with T1D depend on lifelong insulin therapy to control their blood glucose level. In contrast, T2DM is characterized by insulin resistance, where the body’s cells do not respond effectively to insulin, coupled with a relative insulin deficiency. This form of diabetes is often associated with obesity, sedentary lifestyle, and/or genetic factors, and it is managed with lifestyle changes and oral medications. Animal models play a crucial role in diabetes research. However, given the distinct differences between T1DM and T2DM, it is imperative for researchers to employ specific animal models tailored to each condition for a better understanding of the impaired mechanisms underlying each condition, and for assessing the efficacy of new therapeutics. In this review, we discuss the distinct animal models used in type 1 and type 2 diabetes mellitus research and discuss their strengths and limitations.

Introduction: The development of continuous glucose monitoring (CGM) over the last decade has provided access to many consecutive glucose concentration measurements from patients. A standard method for estimating glycated hemoglobin (HbA1c), already established in the literature, is based on its relationship with the average blood glucose concentration (aBG). We showed that the estimates obtained using the standard method were not sufficiently reliable for an Indian population and suggested two new methods for estimating HbA1c. Methods: Two datasets providing a total of 128 CGM and their corresponding HbA1c levels were received from two centers: Health Centre, Savitribai Phule Pune University, Pune and Joshi Hospital, Pune, from patients already diagnosed with diabetes, non-diabetes, and pre-diabetes. We filtered 112 data-sufficient CGM traces, of which 80 traces were used to construct two models using linear regression. The first model estimates HbA1c directly from the average interstitial fluid glucose concentration (aISF) of the CGM trace and the second model proceeds in two steps: first, aISF is scaled to aBG, and then aBG is converted to HbA1c via the Nathan model. Our models were tested on the remaining 32 datasufficient traces. We also provided 95% confidence and prediction intervals for HbA1c estimates. Results: The direct model (first model) for estimating HbA1c was HbA1cmmol/mol = 0.319 × aISFmg/dL + 16.73 and the adapted Nathan model (second model) for estimating HbA1c is HbA1cmmol/dL = 0.38 × (1.17 × ISFmg/dL) − 5.60. Discussion: Our results show that the new equations are likely to provide better estimates of HbA1c levels than the standard model at the population level, which is especially suited for clinical epidemiology in Indian populations. [ABSTRACT FROM AUTHOR]

Atypical antipsychotics (AAPs) are commonly prescribed drugs in the treatment of schizophrenia, bipolar disorder and other mental diseases with psychotic traits. Although the use of AAPs is associated with beneficial effects in these patients, they are also associated with undesired metabolic side effects, including metabolic syndrome (MetS). MeS is defined by the presence of metabolic abnormalities such as large waist circumference, dyslipidemia, fasting hyperglycemia and elevated blood pressure, which predispose to type 2 diabetes (T2D) and cardiovascular disease. In this review, the molecular and cellular mechanisms involved in these undesired metabolic abnormalities induced by AAPs are described. These mechanisms are complex as AAPs have multiple cellular targets which significantly affect the activities of several hormones and neuromodulators. Additionally, AAPs affect all the relevant metabolic organs, namely the liver, pancreas, adipose tissue, skeletal muscle and intestine, and the central and peripheral nervous system as well. A better understanding of the molecular targets linking AAPs with MetS and of the mechanisms responsible for clinically different side effects of distinct AAPs is needed. This knowledge will help in the development of novel AAPs with less adverse effects as well as of adjuvant therapies to patients receiving AAPs. [ABSTRACT FROM AUTHOR]

This study was designed to assess the effect of Centratherum anthelminticum seeds administration on blood and serum risk factor markers in type 2 diabetic (T2D) patients using metformin. It was a randomized non-blinded, controlled, 3month trial. T2D patients were registered from Sindh Government Hospital New Karachi, Karachi. There were 3 groups, DT (Diabetic Test, n=20), DC (Diabetic Control, n=20) HC (Healthy Control n=20, healthy individuals of similar age were selected). DC (metformin 500mg), DT (capsule of C. anthelminticum seeds powder CAPca + metformin 500mg each) and HC (CAPca 500mg) were given daily. Fasting blood glucose, body weights were monitored weekly while blood samples were collected on first and final day of the trial for biochemistry. Administration of CAPca showed significant decrease in % glycaemia (p<0.0001) and % Hb glycosylation (p<0.05) values. Serum risk factor markers including direct bilirubin & uric acid (p<0.01), creatine kinase & alanine aminotransferase (p<0.0001) and creatinine (p<0.05) were reduced significantly. CAPca administration improved blood and serum markers in healthy volunteers too. These improved blood & serum markers in T2D patients indorsed synergistic effect of CAPca with metformin to manage secondary challenges of T2D. [ABSTRACT FROM AUTHOR]

Abstract Background Type 2 diabetes (T2D) is a polygenic metabolic disease, characterized by high fasting blood glucose (FBG). The ability of cranberry (CRN) fruit to regulate glycemia in T2D patients is well known. Here, a cohort of 13 lines of the genetically diverse Collaborative Cross (CC) mouse model was assessed for the effect of non‐dialyzable material (NDM) of cranberry extract in lowering fasting blood glucose. Methods Eight‐week‐old mice were maintained on either a standard chow diet (control group) or a high‐fat diet (HFD) for 12 weeks, followed by injections of intraperitoneal (IP) NDM (50 mg/kg) per mouse, three times a week for the next 6 weeks. Absolute FBG (mg/dl) was measured bi‐weekly and percentage changes in FBG (%FBG) between weeks 0 and 12 were calculated. Results Statistical analysis showed a significant decrease in FBG between weeks 0 and 12 in male and female mice maintained on CHD. However, a non‐significant increase in FBG values was observed in male and female mice maintained on HFD during the same period. Following administration of NDM during the following 6 weeks, the results show a variation in significant levels of FBG lowering between lines, male and female mice and under the different diets. Conclusion The results suggest that the efficacy of NDM treatment in lowering FGB depends on host genetic background (pharmacogenetics), sex of the mouse (pharmacosex), and diet (pharmacodiet). All these results support the need for follow‐up research to better understand and implement a personalized medicine approach/utilization of NDM for reducing FBG.

IntroductionThe development of continuous glucose monitoring (CGM) over the last decade has provided access to many consecutive glucose concentration measurements from patients. A standard method for estimating glycated hemoglobin (HbA1c), already established in the literature, is based on its relationship with the average blood glucose concentration (aBG). We showed that the estimates obtained using the standard method were not sufficiently reliable for an Indian population and suggested two new methods for estimating HbA1c.MethodsTwo datasets providing a total of 128 CGM and their corresponding HbA1c levels were received from two centers: Health Centre, Savitribai Phule Pune University, Pune and Joshi Hospital, Pune, from patients already diagnosed with diabetes, non-diabetes, and pre-diabetes. We filtered 112 data-sufficient CGM traces, of which 80 traces were used to construct two models using linear regression. The first model estimates HbA1c directly from the average interstitial fluid glucose concentration (aISF) of the CGM trace and the second model proceeds in two steps: first, aISF is scaled to aBG, and then aBG is converted to HbA1c via the Nathan model. Our models were tested on the remaining 32 data- sufficient traces. We also provided 95% confidence and prediction intervals for HbA1c estimates.ResultsThe direct model (first model) for estimating HbA1c was HbA1cmmol/mol = 0.319 × aISFmg/dL + 16.73 and the adapted Nathan model (second model) for estimating HbA1c is HbA1cmmol/dL = 0.38 × (1.17 × ISFmg/dL) − 5.60.DiscussionOur results show that the new equations are likely to provide better estimates of HbA1c levels than the standard model at the population level, which is especially suited for clinical epidemiology in Indian populations.

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. [ABSTRACT FROM AUTHOR]

Aim: The lack of longitudinal metabolomics data and the statistical techniques to analyse them has limited the understanding of the metabolite levels related to type 2 diabetes (T2D) onset. Thus, we carried out logistic regression analysis and simultaneously proposed new approaches based on residuals of multiple logistic regression and geometric angle‐based clustering for the analysis in T2D onset‐specific metabolic changes. Materials and methods: We used the sixth, seventh and eighth follow‐up data from 2013, 2015 and 2017 among the Korea Association REsource (KARE) cohort data. Semi‐targeted metabolite analysis was performed using ultraperformance liquid chromatography/triple quadrupole‐mass spectrometry systems. Results: As the results from the multiple logistic regression and a single metabolite in a logistic regression analysis varied dramatically, we recommend using models that consider potential multicollinearity among metabolites. The residual‐based approach particularly identified neurotransmitters or related precursors as T2D onset‐specific metabolites. By using geometric angle‐based pattern clustering studies, ketone bodies and carnitines are observed as disease‐onset specific metabolites and separated from others. Conclusion: To treat patients with early‐stage insulin resistance and dyslipidaemia when metabolic disorders are still reversible, our findings may contribute to a greater understanding of how metabolomics could be used in disease intervention strategies during the early stages of T2D. [ABSTRACT FROM AUTHOR]

Background: The 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. Methods: A 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. Results: The 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<0.285). Similarly, there were no significant differences in neutrophil and lymphocyte values between the two groups. The IgA levels showed no significant variation between T2D-DED and DED groups (p<0.364). Spearman’s correlation analysis in the DED group showed a significant negative correlation between IgA and lymphocyte (p=0.011; r= - 0.471) values and significant positive correlations between IgA and neutrophil (p=0.014; r=0.309) and NLR (p=0.052; r= - 0.283) values. In the T2D-DED group, a significant correlation was found between IgA and CRP values (p=0.032; r=0.33). Conclusion: Although diabetic patients may exhibit higher levels of NLR and IgA that correlate with disease severity, our study did not find significant differences in NLR and IgA values between the two groups. These findings may guide future research and enhance understanding of the disease’s underlying mechanisms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]