Diabetes Research and Clinical Practice

BackgroundType II diabetes (T2DM) is one of the most prevalent metabolic disorders, and its multisystemic health consequences are widely known. Due to skeletal muscles ability to sequester a vast amount of glucose, muscle function and exercise have become a subject of much research into strategies to prevent and treat T2DM. Myokines are bioactive molecules released by muscle during contraction and involved in several biological processes such as metabolism, inflammation and behavior. Irisin, a recently discovered myokine, has been implicated in a vast array of physiological roles, including the ability to induce fat beiging. Since beige and brown fat both serve important roles in metabolic regulation, irisins role in the context of T2DM is the subject of ongoing investigations. MethodsWe systematically reviewed articles indexed in PubMed, Scopus and Web of Science that were published between 2011 and 2024, and compared circulating irisin levels in patients affected by T2DM and healthy subjects. As part of our systematic review of the literature, we performed meta-analysis of the data across all included articles, as well as stratified by body mass index (BMI), country of origin and by average irisin concentration in the control group. ResultsWe discovered great variability across the included studies in the average irisin levels detected, which spanned four orders of magnitude, hence the attempt at reducing variability by stratifying based on average levels in the control group. While the statistical power of our meta-analysis was decreased by the great variability in reported irisin concentrations, we nonetheless detected a consistent trend of decreased irisin concentration in T2DM patients compared with healthy controls, regardless of BMI, country of origin or average irisin concentration in the control group. ConclusionWith almost 60 articles included, ours is the first extensive systematic review and meta-analysis of irisin in T2DM, yet a highly statistically significant association between circulating irisin levels and T2DM could not be established due to the great variability of the data across include articles. Nonetheless we noticed a trend that is independent of BMI, suggesting a direct relationship between T2DM and irisin that is likely not secondary to diabetic sarcopenia. While our work encourages further research into irisins potential role in T2DM pathogenesis, the reproducibility of irisin detection methods in biological samples should be determined and standardized protocols should be made available to the research and clinical communities.

BackgroundThe coronavirus disease 2019 (Covid-19) spreads rapidly around the world. ObjectiveTo evaluate the association between comorbidities and the risk of death in patients with COVID-19, and to further explore potential sex-specific differences. MethodsWe analyzed the data from 18,465 laboratory-confirmed cases that completed an epidemiological investigation in Hubei Province as of February 27, 2020. Information on death was obtained from the Infectious Disease Information System. The Cox proportional hazards model was used to estimate the association between comorbidities and the risk of death in patients with COVID-19. ResultsThe median age for COVID-19 patients was 50.5 years. 8828(47.81%) patients were females. Severe cases accounted for 20.11% of the study population. As of March 7, 2020, a total of 919 cases deceased from COVID-19 for a fatality rate of 4.98%. Hypertension (13.87%), diabetes (5.53%), and cardiovascular and cerebrovascular diseases (CBVDs) (4.45%) were the most prevalent comorbidities, and 27.37% of patients with COVID-19 reported having at least one comorbidity. After adjustment for age, gender, address, and clinical severity, patients with hypertension (HR 1.55, 95%CI 1.35-1.78), diabetes (HR 1.35, 95%CI 1.13-1.62), CBVDs (HR 1.70, 95%CI 1.43-2.02), chronic kidney diseases (HR 2.09, 95%CI 1.47-2.98), and at least two comorbidities (HR 1.84, 95%CI 1.55-2.18) had significant increased risks of death. And the association between diabetes and the risk of death from COVID-19 was prominent in women (HR 1.69, 95%CI 1.27-2.25) than in men (HR 1.16, 95%CI 0.91-1.46) (P for interaction = 0.036). ConclusionAmong laboratory-confirmed cases of COVID-19 in Hubei province, China, patients with hypertension, diabetes, CBVDs, chronic kidney diseases were significantly associated with increased risk of death. The association between diabetes and the risk of death tended to be stronger in women than in men. Clinicians should increase their awareness of the increased risk of death in COVID-19 patients with comorbidities.

BackgroundParalytic ileus (PI), a condition characterized by reduced bowel motor activity without physical obstruction, can be affected by complications from type 2 diabetes (T2D) and anti-diabetic medications. It is unclear of the causal associations of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with the risk of PI in the context of T2D management. MethodsTo investigate the causal relationship of GLP-1RAs with PI, we conducted a 2-sample mendelian randomization (MR) study based on summary statistics from genome-wide association studies (GWAS). Genetic variants in the GLP1R were identified as genetical proxies of GLP-1RAs by the glycemic control therapy, based on genetic associations with glycated hemoglobin (GWAS n=344,182) and T2D (ncases/controls=228,499/1,178,783). The effects of GLP-1RAs were estimated for PI risk (ncases/controls=517/182,423) using GWAS data from the FinnGen project. ResultsBased on MR analysis, GLP-1RAs are causally associated with a decreased risk of PI (OR per 1 mmol/mol decrease in glycated hemoglobin: 0.21; 95% confidence interval [CI]=0.06-0.69). The magnitude of these benefit exceeded those expected from improved glycemic control more generally. ConclusionsOur studys findings show that GLP-1RAs are causally associated with a lower risk for PI, which provides information to guide clinicians in the selection of appropriate therapies for individuals with T2D while mitigating the risk of developing PI. Investigating the underlying mechanisms that contribute to the lower PI risk associated with GLP-1RAs is essential for a deeper understanding of these associations.

BackgroundTime-restricted eating (TRE) shows promise for metabolic health, but its effectiveness in glucose management among individuals with type 2 diabetes, and its role in modulating glucose responses to dietary intake remain poorly understood. ObjectiveWe aimed to identify temporal associations of TRE and dietary intake with 24-hour glucose dynamics. We further examined the interactions between eating windows and carbohydrate intake. MethodsClinical information, dietary records, and continuous glucose monitoring data from 90 Chinese adults with type 2 diabetes were analyzed. Two digital biomarkers were developed to characterize duration and regularity of eating patterns: a binary indicator for eating windows <10 hours (TRE10) and a continuous measure of deviation from an individuals median eating window (TWD). Linear mixed-effects models and functional data analysis were used to examine independent and temporal associations of glucose levels with TRE and dietary intakes. ResultsTRE10 was associated with reduced mean amplitude of glycemic excursions (MAGE) ({beta} = -7.15, P = 0.031) and glucose standard deviation (SD) ({beta} = -2.16, P = 0.035), with the strongest associations around 09:00. TWD was positively associated with glycemic coefficient of variation (CV) ({beta} = 0.36, P = 0.050) and higher glucose levels between 07:00 and 08:00. Carbohydrate intake was significantly associated with time in range (TIR) and glycemic variability, with notable glucose changes at 10:00 and 21:00. Dietary vitamin D intake was linked to reduced glycemic area under the curve (AUC) ({beta} = -0.29, P = 0.040), with pronounced effects at 12:00 and 20:00. Additionally, eating windows < 10 hours attenuated carbohydrate-induced glucose spikes in the morning but amplified glucose responses in the early afternoon. ConclusionsIn adults with type 2 diabetes, eating windows <10 hours and consistent eating windows improved glycemic control, with distinct time-of-day effects. These findings support integrating timing-based nutritional strategies into personalized diabetes management.

ObjectivePosttraumatic stress disorder (PTSD) is linked with metabolic disturbance and increased risk of Type 2 diabetes (DM2), yet mechanisms explaining this connection have yet to be defined. Here we examine commonly hypothesized risk factors influencing the strength and directionality of the relationship between PTSD and DM2 severity in trauma-exposed black women with DM2. MethodsWe examined the relationships among PTSD severity (Clinician-Administered PTSD Scale, CAPS), glycemic control (A1c), age, smoking, body mass index (BMI), depression (Beck Depression Inventory, BDI) and medications in trauma-exposed Black women with DM2 recruited from an urban hospital between 2013-2015 (n=95) as a part of the Grady Trauma Project. Missing data were handled with multiple imputation. Relationships were assessed using lasso regression performed on each imputed dataset. Mediation analysis tested whether BMI or depression mediated associations between PTSD severity and glycemic control. ResultsLasso regression identified BDI, ACE inhibitor/ARB/beta blocker use, and CAPS severity as predictors in the final model predicting A1c. In pooled linear regression analyses across imputed datasets, overall model fit was modest, and none of these predictors were statistically significant. Lasso regression in the reverse direction yielded BMI, BDI, ACE inhibitor/ARB use, and A1c for the final model predicting CAPS severity. In pooled analyses, model fit was substantially stronger and BDI emerged as the only statistically significant predictor (p<0.05). Mediation analyses indicated that BDI, but not BMI, significantly mediated the effect of A1c on CAPS severity, as well as to a lesser extent the reverse relationship, the effect of CAPS severity on A1c. ConclusionIn this examination of the relationships between PTSD and DM2 severity, CAPS severity and A1c were found to be bidirectionally correlated in lasso regression models, with BDI emerging as a significant predictor and mediator of these relationships. BMI was not found to be a mediator in either direction. These results suggest the possibility of a reciprocal relationship between PTSD and DM2, where worsening of either condition may influence worsening of the other, where treating one condition in isolation may not be sufficient to prevent increased overall morbidity and mortality. Further research should include physiological interventions to ascertain causality in these relationships.

Aims/HypothesisType 2 diabetes has a well-established link to cognitive impairment in older adults; however, studies often do not control for adiposity and co-morbid conditions which might mediate this cognitive impairment. To overcome these limitations, we investigated the relation between prediabetes and cognition in youth with overweight/obesity while controlling for adiposity in a cross-sectional ancillary study to the Pathogenesis of Youth Onset Diabetes (PYOD) study. We reasoned that if glucose control directly impacts brain health, then cognitive function should be worse in youth with versus without prediabetes. We also predicted that this effect should be greater on tasks that depend on dopaminergic function, such as working memory and that it may be related to central insulin sensitivity. MethodsWe evaluated 69 youth with overweight/obesity for anthropomorphic and metabolic measures, abdominal adiposity, comprehensive cognitive testing, and the effects of intranasal insulin on cognition, resting state brain activity, and functional connectivity. Oral glucose tolerance tests classified 22 participants as having prediabetes (preT2D+) and 44 participants as having normal glucose control (preT2D-). ResultsGroups did not differ in age, sex, race, diet, or adiposity measures. IQ was significantly lower (p=0.032) in the preT2D+ group compared to the preT2D-group. The preT2D+ group performed worse than the preT2D-group in tasks of working memory (p<.0.001), reaction time (p=0.01), and visuospatial processing (p=0.02). After considering IQ as a model covariate, only spatial working memory showed a significant difference between groups (p=0.002). Insulin sensitivity across the entire sample was negatively correlated with processing speed in two tasks (reaction time index: p=0.022; and trail making test A: p=0.022) and with the sensitivity of the intraparietal sulcus to intranasal insulin administration. Administration of intranasal insulin showed no effect on cognition within or between groups. However, the extent to which intranasal insulin administration influenced caudate functional connectivity with the right intraparietal sulcus (p(FWE) =0.018) and bilateral medial precuneus (p(FWE) =0.03) was correlated with performance on the spatial working memory task. Conclusions/interpretationWe find evidence for the presence of global cognitive impairment in youth with prediabetes that cannot be accounted for by adiposity, as well as a specific deficit in spatial working memory that is not attributable to global cognitive impairment. We identified associations between central insulin sensitivity and both cognition and peripheral insulin sensitivity; however, central insulin sensitivity did not appear to account for the effect of prediabetes on cognition. These findings show that the association between peripheral glucose intolerance and cognition exists early in the course of the disease, prior to the onset of significant comorbid conditions and independently of adiposity. It also suggests the involvement of both generalized and specific mechanisms contributing to cognitive change. Research in ContextO_LIWhat is already known about this subject? (maximum of 3 bullet points) O_LIType 2 diabetes and prediabetes have been associated with an increased risk of dementia and cognitive impairment on dopaminergic tasks C_LIO_LIThe mechanism of this cognitive impairment and if it is dissociable from adiposity or comorbid conditions related to old age is unknown C_LIO_LIIt is unclear whether youth with prediabetes are at risk for cognitive impairment from impaired insulin sensitivity/glucose regulation C_LI C_LI O_LIWhat is the key question? (one bullet point only; formatted as a question) O_LIDo youth with prediabetes show cognitive impairment independent of adiposity, and is this related to insulin sensitivity of dopaminergic systems? C_LI C_LI O_LIWhat are the new findings? (maximum of 3 bullet points) O_LIYouth with prediabetes show global cognitive impairment, as well as particular impairment of spatial working memory, independent of adiposity C_LIO_LIInsulin sensitivity of caudate functional connectivity with right intraparietal sulcus and bilateral precuneus is correlated with prior performance on a spatial working memory task C_LI C_LI O_LIHow might this impact on clinical practice in the foreseeable future? (one bullet point only) O_LIThese findings provide evidence that suggests that youth with prediabetes are at risk for cognitive impairment, indicating early detection and treatment of impaired insulin sensitivity is crucial. C_LI C_LI

ImportanceAlthough diabetes mellitus (DM) is a well-established determinant of dementia risk, most studies have evaluated type 2 DM (T2DM) or any DM without considering type 1 DM (T1DM) separately. Questions remain about the influence of T1DM on risk of dementia. ObjectiveTo evaluate associations of T1DM and T2DM with incident dementia using linked electronic health records (EHRs). Design, Setting, ParticipantsThis cohort study used data from the All of Us (AoU) cohort, a convenience sample of US adults. Eligible participants were [&ge;] 50 years, completed baseline surveys, and had EHR information. Enrollment began in 2017, with data available through October 2023, including records prior to enrollment in AoU. Mean follow-up was 2.4 years. ExposuresWe developed and validated an algorithm to distinguish DM type using three reference measures: (1) self-report diabetes type; (2) C-peptide values; and (3) islet-specific autoantibodies (ISAs). Participants were classified as no DM, T1DM, or T2DM based on number of T1DM encounters. Main Outcomes and MeasuresIncident dementia was identified based on ICD-9, ICD-10, and SNOMED codes in participants EHRs. ResultsAmong 283,965 participants (mean [SD] age 64.62 [8.96] years; 56.7% women); 60.3% identified as Non-Hispanic White; 13.3% as Hispanic/Latino; and 26.4% as Non-Hispanic Other. Optimal DM classification algorithm cutoas varied by reference standard: (1) self-reported diabetes: [&ge;] 1 T1DM EHR encounter (sensitivity: 0.59; specificity: 0.90); (2) C-peptide: [&ge;] 3 T1DM EHR encounters (sensitivity: 0.76; specificity: 0.79); and (3) ISAs: [&ge;] 4 T1DM EHR encounters (sensitivity: 0.48; specificity: 0.74). Using at least one T1DM encounter cutoa, 5,444 participants were classified with T1DM. Compared with those without DM, participants with T1DM had higher incidence of dementia (sociodemographic-adjusted HR = 2.79; 95% CI: 2.26-3.45); those with T2DM also had elevated risk (sociodemographic-adjusted HR = 2.09; 95% CI: 1.88-2.33). Results were similar across gender and race and ethnicity stratified groups. Conclusion and RelevanceIn this cohort, participants with diabetes had a higher dementia risk than did those without DM, with the highest risk among those with T1DM. These findings highlight the need to better understand mechanisms linking T1DM and dementia in aging populations.

Type 2 diabetes (T2D) affects 11.1% of the global population, underscoring the need for biomarkers that inform treatment response and glycemic outcomes. We evaluated the association between the FTO variant rs9939609-A and glycemic control in a Mexican population. A total of 174 individuals living with T2D from Merida and Sisal, Yucatan, were included, of whom 85% were receiving oral hypoglycemic agents as main treatment. Glycemic control was defined cross-sectionally as good ([&le;]130 mg/dL, n=63) or poor (>130 mg/dL, n= 111) with fasting glucose. Linear mixed models incorporating relevant covariates and a family random intercept were used. Effect size estimates were transformed to logit odds ratios. After adjustment for age, sex, BMI, years with T2D, and treatment, we observed a significant association in the additive (OR = 1.15 [1.003-1.31]) and recessive (OR = 1.51 [1.03-2.23]) models. To conclude, rs9939609-A may be associated with poorer glycemic control despite pharmacologic therapy.

Objective: Patients and physicians frequently focus on HbA1c and weight alone. We hypothesized that individuals with similar HbA1c and BMI may present markedly distinct metabolic backgrounds. We investigated whether the adipo-B index- composite of adipose insulin resistance (adipo-IR) and beta-cell function (HOMA-B)-can uncover hidden heterogeneity in this clinically homogeneous population. Methods: A total of 399 newly diagnosed, drug-naive Japanese subjects with T2DM were analyzed. Histograms of HbA1c and BMI demonstrated peak distributions within HbA1c 8-10% and BMI 24-26. Based on these distributions, a clinically homogeneous subgroup was defined to minimize confounding by glycemic severity and adiposity. Metabolic parameters including FBG, insulin, FFA, HOMA-R, HOMA-B, adipo-IR, adipo-B, T-C, TG, HDL-C and non-HDL-C were analyzed. Simple regression, multivariable linear regression, and subgroup stratification analyses were performed. Results: Despite comparable HbA1c and BMI by design, adipo-B stratification revealed significant differences in HOMA-B, FFA, non-HDL-C, and TG, whereas HOMA-R stratification identified only higher insulin and adipo-IR without differences in lipids or HOMA-B. Thus, adipo-B-but not HOMA-R-identified a lipotoxic, beta-cell-stressed phenotype invisible to conventional markers. Simple regression showed significant positive correlations between adipo-B and HbA1c, FBG, FFA, T-C, TG, and non-HDL-C, and negative correlations with insulin and HOMA-B. Multivariable linear regression confirmed that adipo-B was independently associated with non-HDL cholesterol, TG, and FFA after adjustment for HbA1c and BMI. Conclusion: Even among patients with identical HbA1c and BMI, the adipo-B index uncovers clinically relevant metabolic heterogeneity, supporting its role as a functional marker of the adipose-pancreas axis and a potential tool for precision phenotyping in early T2DM.

Introduction. Diabetes is a growing global health challenge, necessitating effective management strategies. Glycosylation, a highly regulated post-translational protein modification, has emerged as a pivotal factor in diabetes pathophysiology. However, the modulation of protein glycosylation by antidiabetic treatment is still largely unknown. This study explored the longitudinal effects of four distinct antidiabetic therapies - metformin, insulin, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 receptor agonists (GLP-1RA) - on plasma protein and immunoglobulin G (IgG) glycosylation in patients with type 2 diabetes (T2D). Research Design and Methods. Plasma protein and IgG N-glycans were enzymatically released, purified and chromatographically profiled in a cohort of 124 patients, examined at four time points, to assess therapy-induced glycan alterations. Linear mixed models adjusting for covariates and multiple testing (FDR<0.05) were used to investigate the associations between plasma protein and IgG N-glycosylation and antidiabetic therapy. Results. Our findings reveal that metformin, SGLT2 inhibitors, and GLP-1RA induce significant alterations in IgG glycosylation, including the increased core fucosylation and galactosylation, features associated with a reduced inflammatory IgG potential. Notably, IgG monogalactosylation, previously linked to cardioprotective effects in women, was elevated in response to GLP-1RA and SGLT2 inhibitor treatments. Plasma protein glycosylation changes were more limited, with distinct alterations observed for each therapy. Metformin and GLP-1RA similarly reduced certain fucosylated and sialylated glycans, while SGLT2 inhibitors decreased a high-mannose glycan, previously positively associated with diabetes progression. Insulin therapy had a minimal effect on protein glycosylation, with only one plasma glycan significantly altered. Conclusions. Our findings emphasise the importance of protein glycosylation as a dynamic and responsive marker in T2D treatment. The distinct glycan alterations observed in response to metformin, SGLT2 inhibitors, and GLP-1 receptor agonists provide novel insights into the molecular effects of these therapies, potentially contributing to the development of glycan-based biomarkers for personalized diabetes management.

AIMSUsing machine learning integrated with clinical and metabolomic data to identify biomarkers associated with diabetic kidney disease (DKD) and diabetic retinopathy (DR), and to improve the performance of DKD/DR detection models beyond traditional risk factors. METHODSWe examined a population-based cross-sectional sample of 2,772 adults with type 1 or type 2 diabetes from Singapore Epidemiology of Eye Diseases study (SEED, 2004-2011). LASSO logistic regression (LASSO) and gradient boosting decision tree (GBDT) were used to select markers of prevalent DKD (defined as an eGFR < 60ml/min/1.73m2) and prevalent DR (defined as an ETDRS severity level [&ge;] 20) from an expanded set of 19 established risk factors and 220 NMR-quantified circulating metabolites. Risk assessment models were developed based on the variable selection results and externally validated in UK Biobank (n=5,843, 2007-2010). Model performance (AUC with 95% CI, sensitivity, and specificity) of machine learning was compared to that of traditional logistic regression adjusted for age, gender, diabetes duration, HbA1c%, systolic BP, and BMI. RESULTSSEED participants had a median age of 61.7 years, with 49.1% female, 20.2% having DKD, and 25.4% having DR. UK Biobank participants had a median age of 61.0 years, with 39.2% female, 6.4% having DKD, and 5.7% having DR. Both algorithms identified diabetes duration, insulin usage, age, and tyrosine as the most important factors of both DKD and DR. DKD was additionally associated with CVD, hypertension medication, and three metabolites (lactate, citrate, and cholesterol esters to total lipids ratio in intermediate-density-lipoprotein); While DR was additionally associated with HbA1c, blood glucose, pulse pressure, and alanine. Machine-learned models for DKD and DR detection outperformed traditional logistic regression in both internal (AUC: 0.832-0.838 vs. 0.743 for DKD, and 0.779-0.790 vs. 0.764 for DR) and external validation (AUC: 0.737-0.790 vs. 0.692 for DKD, and 0.778 vs. 0.760 for DR). CONCLUSIONSMachine-learned biomarkers suggested insulin resistance to be a primary factor associated with diabetic microvascular complications. Integrating machine learning with biomedical big data enabled biomarker discovery from a wide range of correlated variables, which may facilitate our understanding of the disease mechanisms and improve disease screening.

Type 2 diabetes mellitus (T2DM) is a global burgeoning health problem that increases the risk of atherosclerotic cardiovascular disease (ASCVD). Infiltration and oxidative modification of low-density lipoprotein (LDL) cholesterol in the arterial wall and chronic inflammation comprise central pathogenetic mechanisms in ASCVD. Scavenger receptors, particularly Stabilin-1 (Stab1) and Stabilin-2 (Stab2), are pivotal in the clearance of oxidized LDL (oxLDL) cholesterol and pro-atherogenic ligands from circulation. However, their role in atherosclerosis development in the spectrum of T2DM remains poorly characterized. We assessed circulating levels of Stab1, Stab2, and their ligands (TGFbI, Periostin and Reelin) in a cohort of 33 T2DM and 21 non-diabetic individuals, stratified by their atherosclerotic plaque burden as assessed by high-resolution vascular ultrasound. Associations between stabilins, their ligands and conventional cardiovascular risk factors were evaluated. Stab1 levels were significantly elevated in individuals with higher atherosclerotic plaque burden (p<0.05), while Reelin levels were marginally elevated, both in the total study cohort and among T2DM patients. Stab1 levels positively correlated with body mass index and inversely correlated with total cholesterol, LDL, and high-density lipoprotein (HDL) cholesterol levels. Our findings indicate that Stab1 may serve as a marker of dysregulated lipid metabolism and increased atherosclerotic plaque burden in individuals with T2DM. Larger prospective studies are warranted to establish the prognostic and potentially therapeutic value of Stab1 and to clarify its mechanistic role in diabetic atherosclerosis.

IntroductionType 2 diabetes (T2D) is associated with significant neurological and nephrological complications, leading to high morbidity and mortality. GLP-1 receptor agonists (GLP-1 RAs), such as liraglutide, semaglutide, and tirzepatide, have been shown to effectively control glycemia, with additional neuroprotective and nephroprotective effects. This systematic review and network meta-analysis (NMA) aimed to evaluate the impact of GLP-1 RAs on neurological and nephrological outcomes in T2D patients. MethodsA literature search was conducted across PubMed, Cochrane, and ClinicalTrials.gov for randomized controlled trials (RCTs) published between 2010 and 2023. Studies were included if they evaluated the effects of GLP-1 RAs on neurological and nephrological outcomes in T2D patients. A total of 17 studies, involving 96,460 patients (60,190 males, 36,199 females, average age 62.99 {+/-} 7 years), were selected. Network meta-analysis was performed to compare the efficacy and safety of different GLP-1 RAs on outcomes such as neuropathy, cognitive function, albuminuria, and glomerular filtration rate (GFR). ResultsAmong the 17 studies, GLP-1 RAs showed significant improvements in neurological and nephrological outcomes. Neurological benefits included a 24% improvement in cognitive function and a 31% reduction in neuropathic pain. Nephrological benefits included a 27% reduction in albuminuria and a 19% improvement in GFR. Tirzepatide demonstrated the most significant renal improvement, with a mean difference in GFR of 2.50 (95% CI: 0.36, 4.64). Subgroup analyses showed consistent efficacy across age, gender, and ethnicity, with no significant differences in treatment effects. Adverse events were generally mild, with gastrointestinal issues (nausea, vomiting) occurring in 11% of patients, but discontinuation rates were low (5%). ConclusionGLP-1 RAs significantly improve both neurological and nephrological outcomes in T2D patients. While variability in effects exists, these agents offer substantial benefits in managing T2D complications, with a favorable safety profile.

Background: Metabolic syndrome (MetS) has been associated with cognitive decline. Considering its increasing prevalence worldwide, the goal of this study was to evaluate the feasibility and efficacy of a short-term, self-administered computerized cognitive training programme in individuals with metabolic syndrome and low cognitive performances. Methods: Thirty six participants, aged 40-72 years (mean age: 57.8 years), were randomly assigned to the cognitive training or the passive control group. The cognitive training component of Long Lasting Memories (LLM) Care was used as an interactive software to enhance participants' cognitive functions. Up to 24 sessions, each lasting 45 minutes, were self-administered at home twice per week for 3 months. Thorough cognitive assessments with were performed at baseline (randomization), at the end of intervention, and 12 months after baseline. The primary outcome was performance at nine neuropsychological tests, and the secondary outcome was a self-reported questionnaire assessing everyday functional abilities. Primary analyses were performed employing mixed-effect models using the intention-to-treat principle. Results: Low adherence was observed in the study, as only 9 participants (50%) completed at least 8 sessions of the cognitive training programme (range 9-24 sessions, median 15 sessions). No statistically significant effect of the cognitive training programme on performance in neuropsychological tests or everyday functioning was found. At the end of the 3-month intervention programme, effect for visual memory enhancement in immediate ({beta} = 1.58, 95% CI = -1.84 to 4.99, Cohen's d = 0.39) and delayed recall ({beta} = 2.17, 95% CI = -1.68 to 6.01, Cohen's d = 0.45) was moderate in favour of the intervention group, and at 12-month follow-up, semantic verbal fluency gains for the intervention group were detected ({beta} = 2.78, 95% CI = -0.92 to 6.49, Cohen's d = 0.70), though with wide confidence intervals. Conclusions: Despite some small effects observed in memory and verbal fluency, cognitive training did not yield statistically significant improvements. The observed low adherence and limited benefits on mild cognitive deficits in mostly middle-aged individuals with MetS are likely associated with the self-administered and short-term nature of the computerized intervention. This highlights the need for more intensive and clinician-delivered approaches to enhance engagement. Registry: ClinicalTrials.gov, TRN: NCT05658354, Registration date: 08 December 2022. Keywords: Metabolic syndrome, cognitive deficits, cognitive training, computerized, adults

Prescription of sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) among patients with guideline-directed indications remains limited with substantial inter-prescriber variability. In this prospective study of US adults, we used administrative claims database of individuals with type 2 diabetes and compelling indications for SGLT-2i and GLP-1RA to evaluate the impact of healthcare visits with certain specialty providers on the initiation of these medications. These specialties included family medicine, internal medicine, cardiology, endocrinology, and nephrology. Overall, 294,988 individuals eligible for SGLT-2i and 198,525 for GLP-1RA were identified. In 2019-2020, SGLT-2i and GLP-1RA were initiated in 10.4% and 16.7% of eligible individuals, respectively. After accounting for patient characteristics and comorbidities, healthcare visit with endocrinologists was associated with the highest rate of initiation of either drug across specialties (OR=2.16 [2.08-2.24] for SGLT-2i, and 2.76 [2.64-2.88] for GLP-1RA). Healthcare visits with cardiologists and with family medicine and internal medicine physicians were only modestly associated with initiation of SGLT-2i and GLP-1RA. The study highlights the need for broad education for expansion of the use of these medications rather than focus on dedicated specialty clinics.

Background & AimsDiabetes mellitus has been associated with both intestinal barrier dysfunction and peripheral neuropathy leading to increased risk of infection. The mucus layer forms a physical barrier against pathogens and is a critical component of the intestinal barrier that may be impaired in diabetes. This study aimed to assess how diabetes impacts goblet cells (GCs), mucus layer integrity, and innervation in the colon. MethodsFluorescence microscopy was used to investigate GCs, the mucus layer, and innervation in the colon of db/db mice. Custom open-access image analysis pipelines were developed to quantify GC numbers, location and content, mucus thickness, bacterial colonization, and innervation density in intestinal tissue sections. We also treated mice with the clinically used glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide to assess its capacity to reverse pathological changes to GCs and the mucus layer in a model of established type 2 diabetes (T2DM). ResultsThe mucus layer was significantly thinner in the colon of db/db mice with established diabetes and bacteria more readily colonized the epithelium and crypts. Intercrypt GC numbers were significantly reduced in db/db mice. However, there were significantly more GCs per crypt, and crypts were elongated in the db/db colon. Innervation was reduced in the mucosa and external muscle of the colon, consistent with diabetic neuropathic changes. Liraglutide treatment increased the size of GCs but had no effect on GC numbers, mucus thickness, or innervation in this model of established T2DM. ConclusionsMucus barrier dysfunction and GC hyperplasia is evident in the db/db colon. Increased microbial penetrability through the mucus layer suggests potential implications for the increased risk of gastrointestinal infection in diabetes.

BackgroundThe prevalence of childhood obesity continues to rise worldwide. Obesity leads to major health risks already early in life, including insulin resistance (IR) and type 2 diabetes mellitus (T2DM). The pathogenesis of these conditions includes mitochondrial alterations, however, data on mitochondrial health in pediatric populations are scarce to date. MethodsThe study evaluated mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) from children and adolescents (6-18 years) with obesity with different stages of IR or T2DM, respectively. Participants were stratified according to pubertal stage and metabolic status. Mitochondrial health was determined by key parameters of mitochondrial respiration (ATP production, coupling efficiency, proton leak), and the Bioenergetic Health Index (BHI) served as an integrative marker of mitochondrial performance. ResultsA total of 162 participants were included. The Bioenergetic Health Index (BHI) was significantly lower in postpubertal T2DM adolescents compared to postpubertal IR participants, despite of equal pubertal stage and BMI (p=0,0126). The mitochondrial respiration rates and BHI between prepubertal and peripubertal children with obesity and IR showed no statistical differences. However, GlycoATP was correlated to higher insulin and HbA1c levels in children with obesity and IR. In line, the T2DM group demonstrated significantly reduced coupling efficiency (p = 0.003), reduced mitoATP and elevated glycoATP production, indicating impaired mitochondrial efficiency. ConclusionThese data suggest for the first time, that progression of IR towards manifest T2DM in children with obesity leads to impaired mitochondrial function. Thus, mitochondrial alterations in PBMCs may detect early metabolic impairment in young people with obesity and altered glucose metabolism. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/25336982v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@a70e3aorg.highwire.dtl.DTLVardef@1970646org.highwire.dtl.DTLVardef@1ce5a9org.highwire.dtl.DTLVardef@129bc5b_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- GlycoATP is correlated to higher insulin and HbA1c levels in children with obesity and - Insulin resistance (IR) - Adolescents with T2DM have significantly reduced coupling efficiency, reduced mito- - ATP and elevated glycoATP production, indicating impaired mitochondrial efficiency - Data suggest for the first time, that progression of IR towards manifest T2DM in children with obesity leads to impaired mitochondrial function - Mitochondrial alterations in PBMCs may detect early metabolic impairment in young - people with obesity and altered glucose metabolism.

Type 2 diabetes mellitus (T2DM) is a major health and economic burden because of the seriousness of the disease and its complications. Improvements in short- and long-term glycemic control is the goal of diabetes treatment. To investigate the longitudinal management of T2DM at Geisinger, we interrogated the electronic health record (EHR) information and identified a T2DM cohort including 125,477 patients using the Electronic Medical Records and Genomics Network (eMERGE) T2DM phenotyping algorithm. We investigated the annual anti-diabetic medication usage and the overall glycemic control using hemoglobin A1c (HbA1c). Metformin remains the most frequently medication despite the availability of the new classes of anti-diabetic medications. Median value of HbA1c decreased to 7% in 2002 and since remained stable, indicating a good glycemic management in Geisinger population. Using metformin as a pilot study, we identified three groups of patients with distinct HbA1c trajectories after metformin treatment. The variabilities in metformin response is mainly explained by the baseline HbA1c. The pharmacogenomic analysis of metformin identified a missense variant rs75740279 (Leu/Val) for STAU2 associated with the metformin response. This strategy can be applied to study other anti-diabeticmedications. Such research will facilitate the translational healthcare for better T2DM management.

ObjectiveTo investigate the relationship between history of metformin use and delirium risk, as well as long-term mortality. MethodsIn this retrospective cohort study, subjects recruited between January 2016 and March 2020 were analyzed. Logistic regression analysis was performed to investigate the relationship between metformin use and delirium. Log-rank analysis and Cox proportional hazards model were used to investigate the relationship between metformin use and 3-year mortality. ResultsThe data from 1404 subjects were analyzed. 242 subjects were categorized into a DM-without-metformin group, and 264 subjects were categorized into a DM-with-metformin group. Prevalence of delirium was 36.0% in the DM-without-metformin group, and 29.2% in the DM-with-metformin group. A history of metformin use reduced the risk of delirium in patients with DM (OR, 0.50 [95% CI, 0.32 to 0.79]) after controlling for age, sex, and dementia status, body mass index (BMI), and insulin use. The 3-year mortality in the DM-without-metformin group (survival rate, 0.595 [95% CI, 0.512 to 0.669]) was higher than in the DM-with-metformin group (survival rate, 0.695 [95% CI, 0.604 to 0.770]) (p=0.035). A history of metformin use decreased the risk of 3-year mortality after adjustment for age, sex, Charlson Comorbidity Index, BMI, history of insulin use, and delirium status (HR, 0.69 [95% CI, 0.48 to 0.98]). ConclusionsIt was found that metformin usage was associated with decreased delirium prevalence and lower 3-year mortality. The potential benefit of metformin on delirium risk and mortality were shown.

Background Besides hyperglycemia, type 2 diabetes (T2D) is characterized by dyslipidemia, which is typically assessed using traditional clinical lipid measurements. However, molecular plasma lipids beyond these traditional markers can provide additional information about an individuals health status. For molecular lipids to be used effectively, certain characteristics, such as their temporal variability, need to be determined. Methods We analyzed the plasma lipidome for three consecutive time points, each three months apart, of 51 individuals with T2D using targeted liquid chromatography coupled to mass spectrometry (LC-MS). 513 lipid species across 25 (sub)classes were quantified by this approach and the temporal variability were calculated. Moreover, to identify sex differences in the plasma lipidome, we analyzed 914 samples of a cross-sectional T2D cohort with the same approach. Results Neutral lipids and phosphatidylserine had the highest temporal variability which was independent of their platform-specific variability. In contrast, glycosphingolipids were found to be relatively stable over time in individuals with T2D. Acyl-chain analysis revealed generally similar variability in the acyl-chain groups but indicated a higher temporal variability in medium-length acyl-chains. Lipid-sex association analysis showed markedly higher sphingomyelins, phosphatidylcholines, and phosphatidylethanolamines in women and higher acylcarnitines in men. Overall, approximately one-third of measured lipids showed significant sex differences independent of age, BMI, diabetes duration, glycemic control, and medication use. Conclusions Our findings provide insights into temporal variability of molecular lipids. This variability should be considered when assessing novel lipid biomarkers. Likewise, sex differences in these lipids need to be considered in precision medicine for diabetes management.