Glucagon-Like Peptide-1 Receptor Agonists and Risk for Suicidal Ideation and Behaviors in U.S. Older Adults With Type 2 Diabetes : A Target Trial Emulation Study.

BACKGROUND: A major concern has recently emerged about a potential link between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and increased risk for suicidal ideation and behaviors based on International Classification of Diseases codes. OBJECTIVE: To investigate the association between GLP-1 RAs, compared with sodium-glucose cotransporter-2 inhibitors (SGLT2is) or dipeptidyl peptidase-4 inhibitors (DPP4is), and risk for suicidal ideation and behaviors in older adults with type 2 diabetes (T2D). DESIGN: Two target trial emulation studies comparing propensity score (PS)-matched cohorts for GLP-1 RAs versus SGLT2is and GLP-1 RAs versus DPP4is. SETTING: U.S. national Medicare administrative data from January 2017 to December 2020. PATIENTS: Older adults (≥66 years) with T2D; no record of suicidal ideation or behaviors; and a first prescription for a GLP-1 RA, SGLT2i, or DPP4i. MEASUREMENTS: The primary end point was a composite of suicidal ideation and behaviors. New GLP-1 RA users were matched 1:1 on PS to new users of an SGLT2i or DPP4i in each pairwise comparison. A Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% CIs within matched groups. RESULTS: This study included 21 807 pairs of patients treated with a GLP-1 RA versus an SGLT2i and 21 402 pairs of patients treated with a GLP-1 RA versus a DPP4i. The HR of suicidal ideation and behaviors associated with GLP-1 RAs relative to SGLT2is was 1.07 (95% CI, 0.80 to 1.45; rate difference, 0.16 [CI, -0.53 to 0.86] per 1000 person-years); the HR relative to DPP4is was 0.94 (CI, 0.71 to 1.24; rate difference, -0.18 [CI, -0.92 to 0.57] per 1000 person-years). LIMITATIONS: Low event rate; imprecise estimates; unmeasured confounders, such as body mass index; and potential misclassification of outcomes. CONCLUSION: Among Medicare beneficiaries with T2D, this study found no clear increased risk for suicidal ideation and behaviors with GLP-1 RAs, although estimates were imprecise and a modest adverse risk could not be ruled out. PRIMARY FUNDING SOURCE: American Foundation for Pharmaceutical Education, Pharmaceutical Research and Manufacturers of America Foundation, National Institute on Aging, and National Institute of Diabetes and Digestive and Kidney Diseases.

Renal function as an effect modifier of intensive glucose control in delaying cognitive function decline among individuals with type 2 diabetes: A revisit to the ACCORD MIND trial.

AIM: Dysglycaemia accelerates cognitive decline. Intensive glucose control may help delay or prevent cognitive function decline (CFD). We aimed to determine how patient characteristics influence the effect of intensive glucose control [glycated haemoglobin (HbA1c) <6.0%] on delaying CFD in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this post-hoc analysis of 2977 type 2 diabetes participants from the ACCORD MIND trial, we applied the causal forest and causal tree algorithms to identify the effect modifier of intensive glucose control in delaying CFD from 68 variables (demographics, disease history, medications, vitals and baseline biomarkers). The exposure was intensive versus standard glucose control (HbA1c <6.0% vs. 7.0%-7.9%). The main outcome was cognitive function changes from baseline to the 40th month follow-up, which were evaluated using the digit symbol substitution test, Rey auditory verbal learning test, mini-mental state examination and Stroop test. We used Cohen's d, a measure of standardized difference, to quantify the effect size of intensive glucose control on delaying CFD. RESULTS: Among all the baseline characteristics, renal function was the most significant effect modifier. Participants with urinary albumin levels <0.4 mg/dl [absolute function change (AFC): 0.51 in mini-mental state examination, 95% confidence interval (CI): 0.04, 0.98, Cohen's d: 0.25] had slower CFD with intensive glucose control. Patients with preserved renal function (estimated glomerular filtration rate between 60 and 90 ml/min/1.73 m2) were associated with small benefits (AFC: 1.28 in Stroop, 95% CI: 0.28, 2.27, Cohen's d: 0.12) when undergoing intensive glucose control. Conversely, participants with an estimated glomerular filtration rate <60 ml/min/1.73 m2 (AFC: -0.57 in the Rey auditory verbal learning test, 95% CI: -1.09, -0.05, Cohen's d: -0.30) exhibited faster CFD when undergoing intensive glucose control. Participants who were <60 years old showed a significant benefit from intensive glucose control in delaying CFD (AFC: 1.08 in the digit symbol substitution test, 95% CI: 0.06, 2.10, Cohen's d: 0.13). All p < .05. CONCLUSIONS: Our findings linked renal function with the benefits of intensive glucose control in delaying CFD, informing personalized HbA1c goals for those with diabetes and at risk of CFD.

Study protocol for a prospective, multicentre study of hypercortisolism in patients with difficult-to-control type 2 diabetes (CATALYST): prevalence and treatment with mifepristone.

INTRODUCTION: Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper c ortisolism in P at ients with Difficult to Control Type 2 Di a betes Despite Receiving Standard-of-Care Therapies: Preva l ence and Treatment with Korl y m® (Mifepri st one) (CATALYST) trial. METHODS AND ANALYSIS: In part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%-11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym®). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life. ETHICS AND DISSEMINATION: The study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05772169.

Cluster of differentiation molecules in the metabolic syndrome.

Metabolic syndrome (MetS) represents a significant public health concern due to its association with an increased risk of cardiovascular disease, type 2 diabetes, and other serious health conditions. Despite extensive research, the underlying molecular mechanisms contributing to MetS pathogenesis remain elusive. This review aims to provide a comprehensive overview of the molecular mechanisms linking MetS and cluster of differentiation (CD) markers, which play critical roles in immune regulation and cellular signaling. Through an extensive literature review with a systematic approach, we examine the involvement of various CD markers in MetS development and progression, including their roles in adipose tissue inflammation, insulin resistance, dyslipidemia, and hypertension. Additionally, we discuss potential therapeutic strategies targeting CD markers for the management of MetS. By synthesizing current evidence, this review contributes to a deeper understanding of the complex interplay between immune dysregulation and metabolic dysfunction in MetS, paving the way for the development of novel therapeutic interventions.

Cumulative effect of metabolic risk factors on left ventricular geometry in those with versus without early-onset type 2 diabetes or prediabetes: The Coronary Artery Risk Development in Young Adults (CARDIA) study.

AIM: To investigate metabolic risk factors (RFs) that accumulated over 20 years related to left ventricular mass index (LVMI), relative wall thickness (RWT) and LV remodelling patterns in participants with versus without early-onset type 2 diabetes (T2D) or prediabetes (pre-D). METHODS: A total of 287 early-onset T2D/pre-D individuals versus 565 sociodemographic-matched euglycaemic individuals were selected from the Coronary Artery Risk Development in Young Adults (CARDIA) study, years 0-25. We used the area under the growth curve (AUC) derived from quadratic random-effects models of four or more repeated measures of RFs (fasting glucose [FG], insulin, triglycerides [TG], low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-c), total cholesterol (total-c), blood pressure and body mass index) to estimate the cumulative burden, and their associations with LV outcomes. RESULTS: One standard deviation greater AUC of log (TG) (per 0.48) and HDL-c (per 13.5 mg/dL) were associated with RWT (ß 0.21 and -0.2) in the early-onset T2D/pre-D group, but not in the euglycaemia group (ß 0.01 and 0.05, P interactions .02 and .03). In both the early-onset T2D/pre-D and euglycaemia groups, greater AUCs of log (FG) (per 0.17) and log (insulin) (per 0.43) were associated with higher RWT (ß ranges 0.12-0.24). Greater AUCs of systolic blood pressure (per 10 mmHg) and diastolic blood pressure (per 7.3 mmHg) were associated with higher RWT and LVMI, irrespective of glycaemic status (ß ranges 0.17-0.28). Cumulative TG (odds ratio 3.4, 95% confidence interval: 1.8-6.3), HDL-c (0.23, 0.09-0.59), total-c (1.9, 1.1-3.1) and FG (2.2, 1.25-3.9) were statistically associated with concentric hypertrophy in the T2D/pre-D group only. CONCLUSIONS: Sustained hyperglycaemia and hyperinsulinaemia are associated with RWT, and those individuals with early T2D/pre-D are potentially at greater risk because of their higher levels of glucose and insulin. Dyslipidaemia was associated with LV structural abnormalities in those individuals with early-onset T2D/pre-D.

DCRM 2.0: Multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases.

The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes.

Acute severe hypoglycemia alters mouse brain microvascular proteome.

Hypoglycemia increases the risk related to stroke and neurodegenerative diseases, however, the underlying mechanisms are unclear. For the first time, we studied the effect of a single episode (acute) of severe (ASH) and mild (AMH) hypoglycemia on mouse brain microvascular proteome. After four-hour fasting, insulin was administered (i.p) to lower mean blood glucose in mice and induce ∼30 minutes of ASH (∼30 mg/dL) or AMH (∼75 mg/dL), whereas a similar volume of saline was given to control mice (∼130 mg/dL). Blood glucose was allowed to recover over 60 minutes either spontaneously or by 20% dextrose administration (i.p). Twenty-four hours later, the brain microvessels (BMVs) were isolated, and tandem mass tag (TMT)-based quantitative proteomics was performed using liquid chromatography-mass spectrometry (LC/MS). When compared to control, ASH significantly downregulated 13 proteins (p ≤ 0.05) whereas 23 proteins showed a strong trend toward decrease (p ≤ 0.10). When compared to AMH, ASH significantly induced the expression of 35 proteins with 13 proteins showing an increasing trend. AMH downregulated only 3 proteins. ASH-induced downregulated proteins are involved in actin cytoskeleton maintenance needed for cell shape and migration which are critical for blood-brain barrier maintenance and angiogenesis. In contrast, ASH-induced upregulated proteins are RNA-binding proteins involved in RNA splicing, transport, and stability. Thus, ASH alters BMV proteomics to impair cytoskeletal integrity and RNA processing which are critical for cerebrovascular function.

Ethnic disparities of vascular complications in pre-diabetes, undiagnosed diabetes, and newly diagnosed diabetes.

In the U.S., ethnic minorities with pre-diabetes, undiagnosed type 2 diabetes (T2D), and newly diagnosed T2D had a higher prevalence of microvascular complications than non-Hispanic Whites and exhibited distinct risk factors, whereas Whites had a higher rate of cardiovascular disease.

Dietary intake during a pragmatic cluster-randomized weight loss trial in an underserved population in primary care.

BACKGROUND: Currently there are limited data as to whether dietary intake can be improved during pragmatic weight loss interventions in primary care in underserved individuals. METHODS: Patients with obesity were recruited into the PROPEL trial, which randomized 18 clinics to either an intensive lifestyle intervention (ILI) or usual care (UC). At baseline and months 6, 12, and 24, fruit and vegetable (F/V) intake and fat intake was determined. Outcomes were analyzed by repeated-measures linear mixed-effects multilevel models and regression models, which included random cluster (clinic) effects. Secondary analyses examined the effects of race, sex, age, and food security status. RESULTS: A total of 803 patients were recruited. 84.4% were female, 67.2% African American, 26.1% received Medicaid, and 65.5% made less than $40,000. No differences in F/V intake were seen between the ILI and UC groups at months 6, 12, or 24. The ILI group reduced percent fat at months 6, 12, and 24 compared to UC. Change in F/V intake was negatively correlated with weight change at month 6 whereas change in fat intake was positively associated with weight change at months 6, 12, and 24 for the ILI group. CONCLUSIONS: The pragmatic weight loss intervention in primary care did not increase F/V intake but did reduce fat intake in an underserved population with obesity. F/V intake was negatively associated with weight loss at month 6 whereas percent fat was positively correlated with weight loss throughout the intervention. Future efforts better targeting both increasing F/V intake and reducing fat intake may promote greater weight loss in similar populations. TRIAL REGISTRATION: NCT Registration: NCT02561221.

Sex differences in cardiometabolic biomarkers during the pre-diabetes stage.

Using two large prospective epidemiological studies in the U.S., we examined biomarkers that reflect sex-specific pathophysiological pathways to cardiovascular complications among people with pre-diabetes. Women with pre-diabetes exhibited higher levels of adipokines, while men had lower eGFR. Sex differences in lipoproteins and vascular inflammatory markers during pre-diabetes indicate sex-specific lipoprotein and inflammatory mechanisms to cardiovascular complications.

Glycated Albumin Correlates With Time-in-Range Better Than HbA1c or Fructosamine.

CONTEXT: Intermediate-term glycemic control metrics may represent a viable alternative to continuous glucose monitoring (CGM) in patients without access to CGM. OBJECTIVE: This work aimed to compare the relationship between CGM parameters and glycated albumin (GA), glycated hemoglobin A1c (HbA1c), and fructosamine for 24 weeks. METHODS: We conducted exploratory comparative analyses of CGM subgroup data from a previously published 24-week prospective study of assay performance in 8 US clinics. Participants included 34 individuals with type 1 (n = 18) and type 2 diabetes (n = 16) undergoing changes to improve glycemic control (n = 22; group 1) or with stable diabetes therapy (n = 12; group 2). Main outcome measures included Pearson correlations between CGM and glycemic indices and receiver operating characteristic (ROC) analysis of glycemic index values predictive of time in range (TIR) greater than 70%. RESULTS: At weeks 4 and 8, GA correlations with TIR were higher than HbA1c correlations in group 1. In group 2, GA correlations with TIR were statistically significant, whereas HbA1c correlations were not. In both groups over the first 12 weeks, GA correlations with TIR were higher than fructosamine-TIR correlations. In the ROC analysis, GA predicted a TIR greater than 70% during weeks 2 to 24 (area under the curve >0.80); HbA1c was predictive during weeks 12 to 24. Cutoff values for TIR greater than 70% were 17.5% (sensitivity and specificity, 0.88) for GA and 7.3% (0.86) for HbA1c. CONCLUSION: GA is the most accurate predictor of TIR over 8 weeks compared with other glycemic indices, which may assist in clinical evaluation of changes in treatment where CGM is not possible and it is too early to use HbA1c (NCT02489773).

Pax4 in Health and Diabetes.

Paired box 4 (Pax4) is a key transcription factor involved in the embryonic development of the pancreatic islets of Langerhans. Consisting of a conserved paired box domain and a homeodomain, this transcription factor plays an essential role in early endocrine progenitor cells, where it is necessary for cell-fate commitment towards the insulin-secreting ß cell lineage. Knockout of Pax4 in animal models leads to the absence of ß cells, which is accompanied by a significant increase in glucagon-producing α cells, and typically results in lethality within days after birth. Mutations in Pax4 that cause an impaired Pax4 function are associated with diabetes pathogenesis in humans. In adulthood, Pax4 expression is limited to a distinct subset of ß cells that possess the ability to proliferate in response to heightened metabolic needs. Upregulation of Pax4 expression is known to promote ß cell survival and proliferation. Additionally, ectopic expression of Pax4 in pancreatic islet α cells or δ cells has been found to generate functional ß-like cells that can improve blood glucose regulation in experimental diabetes models. Therefore, Pax4 represents a promising therapeutic target for the protection and regeneration of ß cells in the treatment of diabetes. The purpose of this review is to provide a thorough and up-to-date overview of the role of Pax4 in pancreatic ß cells and its potential as a therapeutic target for diabetes.

Sex Differences in Cardiovascular Risk Associated With Prediabetes and Undiagnosed Diabetes.

INTRODUCTION: Women with Type 2 diabetes (T2D) face up to 50% higher risk of cardiovascular disease than men. This study evaluated the extent to which prediabetes and undiagnosed T2D are associated with a greater excess risk of cardiovascular disease in women versus in men. METHODS: Data were pooled from 18,745 cardiovascular disease-free individuals from the Atherosclerosis Risk in Communities Study, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study. The risk of coronary heart disease, ischemic stroke, and atherosclerotic cardiovascular disease (coronary heart disease or stroke) associated with prediabetes or undiagnosed T2D was estimated using Cox models adjusting for sociodemographic factors, concomitant risk factors, medication use, and menopausal status. Data were collected in 2022, and the analysis was performed in 2023. RESULTS: During a median follow-up of 18.6 years, the associations between prediabetes and risk of atherosclerotic cardiovascular disease were only significant in women (hazard ratio=1.18, 95% CI=1.01, 1.34, p=0.03) but not in men (hazard ratio=1.08, 95% CI=1.00, 1.28, p=0.06) (p-interaction=0.18). The associations between undiagnosed T2D and cardiovascular disease outcomes were significant in both sexes, but the effect was more pronounced in women (coronary heart disease: hazard ratio=1.83, 95% CI=1.4, 2.41, p<0.0001 in women vs hazard ratio=1.6, 95% CI=1.38, 2.07, p=0.007 in men; stroke: hazard ratio=1.99, 95% CI=1.39, 2.72, p<0.0001 vs hazard ratio=1.81, 95% CI=1.36, 2.6, p<0.0001; atherosclerotic cardiovascular disease: hazard ratio=1.86, 95% CI=1.5, 2.28, p<0.0001 vs hazard ratio=1.65, 95% CI=1.4, 1.98, p<0.0001) (all p-interactions≤0.2). Both White and Black patients exhibit similar sex differences. CONCLUSIONS: Prediabetes or undiagnosed T2D was associated with a greater excess risk of cardiovascular disease in women than in men. The sex differential in cardiovascular disease risk among those without the T2D diagnosis suggests the need for sex-specific guidelines in T2D screening and treatment.

Early intervention and intensive management of patients with diabetes, cardiorenal, and metabolic diseases.

Increasing rates of obesity and diabetes have driven corresponding increases in related cardiorenal and metabolic diseases. In many patients, these conditions occur together, further increasing morbidity and mortality risks to the individual. Yet all too often, the risk factors for these disorders are not addressed promptly in clinical practice, leading to irreversible pathologic progression. To address this gap, we convened a Task Force of experts in cardiology, nephrology, endocrinology, and primary care to develop recommendations for early identification and intervention in obesity, diabetes, and other cardiorenal and metabolic diseases. The recommendations include screening and diagnosis, early interventions with lifestyle, and when and how to implement medical therapies. These recommendations are organized into primary and secondary prevention along the continuum from obesity through the metabolic syndrome, prediabetes, diabetes, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), atherosclerotic cardiovascular disease (ASCVD) and atrial fibrillation, chronic kidney disease (CKD), and heart failure (HF). The goal of early and intensive intervention is primary prevention of comorbidities or secondary prevention to decrease further worsening of disease and reduce morbidity and mortality. These efforts will reduce clinical inertia and may improve patients' well-being and adherence.

Rising Prediabetes, Undiagnosed Diabetes, and Risk Factors in Young Women.

INTRODUCTION: Women of reproductive age are less prone to cardiovascular disease than men. However, diabetes mellitus negates this female advantage. The prevalence change of prediabetes (prediabetes mellitus) and diabetes mellitus and diabetes mellitus‒associated cardiovascular risk factors have not been clearly described in women before menopause. METHODS: Using National Health and Nutrition Examination Survey data (1999-2018), this study estimated the age-adjusted prevalence of prediabetes mellitus (2005-2018), diagnosed diabetes mellitus, and undiagnosed diabetes mellitus in premenopausal women. Logistic regression was used to examine cardiovascular risk factors, including obesity, central obesity, hypercholesterolemia, hypertension, and hypertriglyceridemia, associated with prediabetes mellitus, diagnosed diabetes mellitus, or undiagnosed diabetes mellitus in premenopausal women. The magnitude of the association among age-matched men and postmenopausal women was compared. The analysis was conducted in 2022. RESULTS: Premenopausal women experienced an increased prevalence of prediabetes mellitus and undiagnosed diabetes mellitus, contrasting with steady trends in all U.S. adults over the last 2 decades. Premenopausal women with prediabetes mellitus or diabetes mellitus (versus those with normoglycemia) have significant obesity risk, and the risk is equivalent to that among age-matched men and higher than that among postmenopausal women. The association between prediabetes mellitus and hypercholesterolemia or hypertriglyceridemia was significant in premenopausal women only. Hypercholesterolemia and hypertension associated with undiagnosed diabetes mellitus were significant in premenopausal women and men of the same age, respectively. Diagnosed and undiagnosed diabetes mellitus was associated with hypertriglyceridemia in men and postmenopausal women, respectively. CONCLUSIONS: Premenopausal women had increased prediabetes mellitus and undiagnosed diabetes mellitus in the past 2 decades. They face a considerable cardiovascular risk burden associated with prediabetes mellitus and diabetes mellitus. Cardiometabolic risk screening and patient education should be improved in young and early middle-aged adults, particularly in women.

Amyloid [Formula: see text] (1-42) peptide impairs mitochondrial respiration in primary human brain microvascular endothelial cells: impact of dysglycemia and pre-senescence.

Diabetes increases the risk of Alzheimer's disease (AD). We investigated the impact of glucose concentrations on the ß-amyloid (Aß)-induced alteration of mitochondrial/cellular energetics in primary human brain microvascular endothelial cells (HBMECs). HBMECs were grown and passaged in media containing 15 mmol/l glucose (normal) based on which the glucose levels in the media were designated as high (25 mmol/L) or low (5 mmol/L). HBMECs were treated with Aß (1-42) (5 µmol/l) or a scrambled peptide for 24 h and mitochondrial respiratory parameters were measured using Seahorse Mito Stress Test. Aß (1-42) decreased the mitochondrial ATP production at normal glucose levels and decreased spare respiratory capacity at high glucose levels. Aß (1-42) diminished all mitochondrial respiratory parameters markedly at low glucose levels that were not completely recovered by restoring normal glucose levels in the media. The addition of mannitol (10 mmol/l) to low and normal glucose-containing media altered the Aß (1-42)-induced bioenergetic defects. Even at normal glucose levels, pre-senescent HMBECs (passage 15) displayed greater Aß (1-42)-induced mitochondrial respiratory impairments than young cells (passages 7-9). Thus, hypoglycemia, osmolarity changes, and senescence are stronger instigators of Aß (1-42)-induced mitochondrial respiration and energetics in HBMECs and contributors to diabetes-related increased AD risk than hyperglycemia.

Progression of retinopathy with glucagon-like peptide-1 receptor agonists with cardiovascular benefits in type 2 diabetes - A systematic review and meta-analysis.

AIMS: The effect of Glucagon-like peptide 1 receptor agonists (GLP1 RA) on diabetic retinopathy (DR) remains controversial. Previous reviews combined data from randomized clinical trials (RCTs) with or without cardiovascular (CV) benefits and did not address confounders, therefore may have generated misleading results. The study aimed to examine the effect of GLP1RA on DR in type 2 diabetes (T2DM) in RCTs with or without CV benefits and distinguish the effect by major confounders. METHODS: We conducted electronic searches of multiple databases and a manual search using references lists. We included 13 RCTs examining the effect of GLP1 RA on health outcomes/adverse events including DR or DR complications in T2DM. We performed a random-effects model meta-analysis. RESULTS: GLP1RA was associated with an elevated risk of rapidly worsening DR in four major RCTs with CV benefits in T2DM (OR 1.23, 95 % CI 1.05-1.44). The association between GLP1 RA and DR was significant in subgroups of RCTs with length over 52 weeks (1.2, 1.00-1.43), using placebo as a comparator (1.22, 1.05-1.42). In subgroups with patients who had T2DM ≥10 years (1.19, 0.99-1.42) or with subjects enrolled from multiple countries (1.2, 0.99-1.46), the association appeared to be evident but did not reach statistical significance. CONCLUSIONS: GLP1 RA including liraglutide, semaglutide, and dulaglutide are associated with an increased risk of rapidly worsening DR in RCTs with CV benefits. Further data from clinical studies with longer follow-up purposefully designed for DR risk assessment, particularly including patients of established DR are warranted.

Menopausal hormone therapy and risk of cardiovascular events in women with prediabetes or type 2 diabetes: A pooled analysis of 2917 postmenopausal women.

BACKGROUND AND AIMS: The effect of MHT on cardiovascular disease (CVD) risk among women with prediabetes or type 2 diabetes (PreDM or T2DM) is unclear. We examined the association between ever or early use MHT and CVD risk in postmenopausal women with PreDM or T2DM, and the potential modifying effect of race. METHODS: 2,917 postmenopausal women with PreDM or T2DM were pooled from 3 prospective CVD cohorts (the Atherosclerosis Risk in Communities, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study). Ever (yes vs no) or early use of MHT (MHT initiated ≤5 vs > 5 years since menopause), and their associations with ischemic stroke, coronary heart disease (CHD), and atherosclerotic cardiovascular disease (ASCVD) were assessed using Cox proportional hazards models. RESULTS: During a median follow-up of 15 years, 264 stroke, 484 CHD, and 659 ASCVD events were observed. In fully adjusted models, ever use of MHT was associated with reduced risk of stroke (hazard ratio 0.86, 95% CI 0.76-0.98), CHD (0.85, 0.74-0.98), and ASCVD (0.83, 0.73-0.95) in white women with PreDM or T2DM. Early use of MHT was associated with reduced risk of stroke (0.82, 0.72-0.95), CHD (0.85, 0.74-0.98), and ASCVD (0.82, 0.70-0.96) in the white group. No risk reduction with ever or early use of MHT was found for black women with PreDM or T2DM. CONCLUSIONS: MHT is associated with statistically reduced CVD risk among white but not black women with PreDM or DM. Race is an effect modifier in the association between MHT use and CVD.