The association of self-reported sleep and circadian measures with glycemic control and diabetes complications among young adults with type 2 diabetes.

We aim to examine the association of sleep duration, sleep quality, late chronotype, and circadian misalignment with glycemic control and risk of complications in young adults with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Self-reported sleep duration, quality, timing, and circadian misalignment were assessed via a modified Pittsburgh Sleep Quality Index (PSQI) questionnaire, and chronotype was assessed via the Morningness-Eveningness Questionnaire (MEQ). We examined diabetes complications including loss of glycemic control (defined as hemoglobin A1c ≥8%), hypertension, dyslipidemia, albuminuria, and diabetic peripheral neuropathy. Multivariable logistic regression models were constructed to assess associations between sleep and circadian measures with outcomes of interest, such as loss of glycemic control and diabetes complications. A total of 421 participants (34.2% male), mean age 23.6 ± 2.5 yr, mean body mass index (BMI) of 36.1 ± 8.3 kg/m2, and mean diabetes duration of 10.0 ± 1.5 yr were evaluated. Self-reported short sleep duration, daytime sleepiness, and sleep quality were not associated with loss of glycemic control or diabetes complications. Late self-reported bedtime (after midnight) on work/school nights, rather than self-expressed chronotype or circadian misalignment, was independently associated with loss of glycemic control. An association was seen between late bedtimes and albuminuria but was attenuated after adjusting for depression. In conclusion, late bedtime on work/school days, rather than short sleep duration, daytime sleepiness, or poor sleep quality, was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.NEW & NOTEWORTHY The prevalence of type 2 diabetes in youth is increasing at an alarming rate. Identifying potentially modifiable factors modulating glycemic control is critically important to reduce micro and macrovascular complications. In a large cohort of youth-onset type 2 diabetes, self-reported late bedtime on work/school days was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.

The causal relationship between plasma protein-to-protein ratios and type 2 diabetes and its complications: Proteomics mendelian randomization study.

AIM: In recent years, proteomics research has surged, with numerous observational studies identifying associations between plasma proteins and type 2 diabetes. However, research specifically focusing on the ratios of plasma proteins in type 2 diabetes remains relatively scarce. METHODS: This study primarily employed a two-sample, two-step Mendelian randomization (MR) approach, leveraging genetic data from several large, publicly accessible genome-wide association studies, wherein single nucleotide polymorphisms served as proxies for exposures and diseases. Within this framework, we applied two-sample MR to assess the associations between the 2821 plasma protein-to-protein ratios and type 2 diabetes along with its complications and utilized reverse MR to confirm the unidirectionality of these causal relationships. In addition, we employed two-step MR to investigate the potential mediating role of body mass index in these associations. To augment the robustness of our findings, we systematically implemented a series of sensitivity analyses. RESULTS: The results gleaned from the inverse-variance weighted method elucidated that a cumulative sum of 23 protein-to-protein ratios bore a causal nexus with type 2 diabetes across both sample cohorts. With each incremental elevation of 1 standard deviation in the genetically anticipated protein-to-protein ratio, the susceptibility to type 2 diabetes oscillated from 0.93 (95% confidence interval: 0.87, 1.00) for the CNTN3/NCSS1 protein level ratio to 1.13 (1.06, 1.22) for the DBNL/NCK2 protein level ratio. Moreover, a tally of eight protein-to-protein ratios correlated with a minimum of one complication linked to type 2 diabetes. Diverse sensitivity analyses corroborated the robustness of these observations. CONCLUSIONS: The outcomes of our investigation unveiled correlations between 23 plasma protein-to-protein ratios and type 2 diabetes, with eight of these ratios entwined with complications of type 2 diabetes. These discoveries offer novel perspectives on the diagnosis and management of type 2 diabetes and its associated complications.

Efficacy of 1-hour postload plasma glucose as a suitable measurement in predicting type 2 diabetes and diabetes-related complications: A post hoc analysis of the 30-year follow-up of the Da Qing IGT and Diabetes Study.

AIM: To evaluate whether 1-hour plasma glucose (1hPG) can be a comparable measurement to 2-hour plasma glucose (2hPG) in identifying individuals at high risk of developing diabetes. METHODS: A total of 1026 non-diabetic subjects in the Da Qing IGT and Diabetes Study were included and classified according to baseline postload 1hPG. The participants were followed up and assessed at 6-, 20- and 30year follow-up for outcomes including diabetes, all-cause and cardiovascular mortality, cardiovascular disease (CVD) events, and microvascular disease. We then conducted a proportional hazards analysis in this post hoc study to determine the risks of developing type 2 diabetes and its complications in a '1hPG-normal' group (1hPG <8.6 mmol/L) and a '1hPG-high' group (≥8.6 mmol/L). The predictive values of 1hPG and 2hPG were evaluated using a time-dependent receiver-operating characteristic (ROC) curve. RESULTS: Compared with the 1hPG-normal group, the 1hPG-high group had increased risk of diabetes (hazard ratio [HR] 4.45, 95% CI 3.43-5.79), all-cause mortality (HR 1.46, 95% CI 1.07-2.01), CVD mortality (HR 1.84, 95% CI 1.16-2.95), CVD events (HR 1.39, 95% CI 1.03-1.86) and microvascular disease (HR 1.70, 95% CI: 1.03-2.79) after adjusting for confounders. 1hPG exhibited a higher area under the ROC curve (AUC) for predicting diabetes than 2hPG during the long-term follow-up (AUC [1hPG vs. 2hPG]: 10 years: 0.86 vs. 0.84, p = 0.08; 20 years: 0.88 vs. 0.87, p = 0.04; 30 years: 0.85 vs. 0.82, p = 0.009). CONCLUSIONS: Elevated 1hPG level (≥8.6 mmol/L) was associated with increased risk of developing type 2 diabetes and its long-term complications, and could be considered as a suitable measurement for identifying individuals at high risk of type 2 diabetes.

Deep Immune and RNA Profiling Revealed Distinct Circulating CD163+ Monocytes in Diabetes-Related Complications.

CD163, a scavenger receptor with anti-inflammatory function expressed exclusively on monocytes/macrophages, is dysregulated in cases of diabetes complications. This study aimed to characterize circulating CD163+ monocytes in the presence (D+Comps) or absence (D-Comps) of diabetes-related complications. RNA-sequencing and mass cytometry were conducted on CD163+ monocytes in adults with long-duration diabetes and D+Comps or D-Comps. Out of 10,868 differentially expressed genes identified between D+Comps and D-Comps, 885 were up-regulated and 190 were down-regulated with a ≥ 1.5-fold change. In D+Comps, 'regulation of centrosome cycle' genes were enriched 6.7-fold compared to the reference genome. MIR27A, MIR3648-1, and MIR23A, the most up-regulated and CD200R1, the most down-regulated gene, were detected in D+Comps from the list of 75 'genes of interest'. CD163+ monocytes in D+Comps had a low proportion of recruitment markers CCR5, CD11b, CD11c, CD31, and immune regulation markers CD39 and CD86. A gene-protein network identified down-regulated TLR4 and CD11b as 'hub-nodes'. In conclusion, this study reports novel insights into CD163+ monocyte dysregulation in diabetes-related complications. Enriched centrosome cycle genes and up-regulated miRNAs linked to apoptosis, coupled with down-regulated monocyte activation, recruitment, and immune regulation, suggest functionally distinct CD163+ monocytes in cases of diabetes complications. Further investigation is needed to confirm their role in diabetes-related tissue damage.

Circulating biomarkers, echocardiographic parameters, and incident subclinical atrial fibrillation in patients with diabetes and hypertension.

BACKGROUND: Long-term rhythm monitoring (LTRM) can detect undiagnosed atrial fibrillation (AF) in patients at high risk of AF and stroke. Biomarkers and echocardiographic parameters could, however, help identify patients benefitting most from LTRM. The aim of this study was to investigate, whether circulating biomarkers of cardiac and vascular function (brain natriuretic peptide (BNP), cardiac troponin I (cTnI), copeptin, and mid-regional proadrenomedullin (MR-proADM)) and echocardiographic parameters were associated with incident subclinical AF (SCAF) in a population at high risk of stroke in the presence of AF. For this purpose, we investigated individuals ≥65 years of age with hypertension and diabetes mellitus, but no history or symptoms of AF or other cardiovascular disease (CVD). METHODS: We included 82 consecutive patients (median age 71.3 years (IQR 67.4-75.1)). All patients received an insertable cardiac monitor (ICM) and were followed for a median of 588 days (IQR 453-712). On the day of ICM implantation, a comprehensive echocardiogram and blood samples were obtained. RESULTS: During a median follow-up of 588 days (IQR: 453-712 days), incident SCAF occurred in 17 patients (20.7%) with a median time to first-detected episode of 91 days (IQR 41-251 days). MR-proADM (median 0.87 nmol/L (IQR 0.76-1.02) vs 0.78 nmol/L (IQR 0.68-0.98)) and copeptin (median 13 pmol/L (IQR 9-17) vs 8 pmol/L (IQR 4-18)) levels were insignificantly higher in patients with incident SCAF. BNP and cTnI concentrations and echocardiographic parameters were similar in the two groups. CONCLUSIONS: MR-proADM, BNP, cTnI, copeptin, and several echocardiographic parameters were not associated with incident SCAF in this cohort of patients with hypertension and diabetes, but without any underlying CVD.

Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes.

BACKGROUND: EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective. METHODS: Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions. RESULTS: Baseline glucose-lowering medications for the 14 752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% versus 28.8%), with metformin (6.1% versus 4.9%), sulfonylurea (8.7% versus 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% versus 7.5%), SGLT-2i (10.3% versus 8.1%), GLP-1 RA (3.4% versus 2.4%), and insulin (13.8% versus 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 (P=0.061) to 0.85 (P=0.008) and the ACM HR from 0.86 (P=0.016) to 0.81 (P=0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or P values, although simulations of substantially greater use of drop-in cardioprotective glucose-lowering agents demonstrated blunting of signal detection. CONCLUSIONS: EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01144338.

Variability of risk factors and diabetes complications.

Several studies suggest that, together with glucose variability, the variability of other risk factors, as blood pressure, plasma lipids, heart rate, body weight, and serum uric acid, might play a role in the development of diabetes complications. Moreover, the variability of each risk factor, when contemporarily present, may have additive effects. However, the question is whether variability is causal or a marker. Evidence shows that the quality of care and the attainment of the target impact on the variability of all risk factors. On the other hand, for some of them causality may be considered. Although specific studies are still lacking, it should be useful checking the variability of a risk factor, together with its magnitude out of the normal range, in clinical practice. This can lead to an improvement of the quality of care, which, in turn, could further hesitate in an improvement of risk factors variability.

Visit-to-visit variability of clinical risk markers in relation to long-term complications in type 1 diabetes.

BACKGROUND: Clinical characteristics such as HbA1c , systolic blood pressure (SBP), albuminuria and estimated glomerular filtration rate (eGFR) are important when treating type 1 diabetes. We investigated the variability in these measures as risk markers for micro- and macrovascular complications. METHODS: This prospective study included 1062 individuals with type 1 diabetes. Visit-to-visit variability of HbA1c , SBP, albuminuria and eGFR was calculated as the SD of the residuals in individual linear regression models using all available measures in a specified period of 3 years (VV). Endpoints included were as follows: cardiovascular events (CVE) defined as myocardial infarction, non-fatal stroke, or coronary or peripheral arterial intervention; end-stage kidney disease (ESKD) defined as eGFR <15 ml/min/1.73 m2 , chronic dialysis or kidney transplantation; eGFR decline ≥30%; and mortality. Adjustment included age, sex, cholesterol, HbA1c , SBP, body mass index, smoking, albuminuria, eGFR, and mean, intercept, slope of respective exposure variables and regression models. RESULTS: SBP VV was significantly associated with CVE (adjusted hazard ratio per 50% increase, (CI 95%); p: 1.21 [1.05-1.39]; p = 0.008), ESKD (1.51 [1.16-1.96]; p = 0.002) and mortality (1.25 [1.09-1.44]; p = 0.002). HbA1c VV was significantly associated with mortality (1.51 [1.30-1.75]; p < 0.001); albuminuria VV with eGFR decline (1.14 [1.08-1.20]; p = 0.024) and ESKD (1.14 [1.02-1.27]; p < 0.001), but neither CVE nor mortality. Adjusted eGFR VV was not associated with endpoints. CONCLUSION: In type 1 diabetes, higher variability of basic clinical risk markers adds important risk stratification information for the development of micro- and macrovascular complications.

DNA damage in leukocytes and serum nitrite concentration are negatively associated in type 1 diabetes.

Chronic hyperglycaemia leads to DNA damage in diabetes and might be associated with nitrosative stress. In this study, we aimed at assessing the level of DNA strand breaks in leukocytes, serum nitrite and nitrate in patients with type 1 diabetes and healthy controls and associations of these parameters with diabetes-related outcomes in a prospective study. The level of DNA damage was determined in 71 patients with type 1 diabetes and 57 healthy controls by comet assay and scored with arbitrary units (AU). The chemiluminescence method was used to measure nitrite and nitrate. Clinical information and data on consumption of alcohol, physical activity and smoking were collected. Progression of complications in patients with diabetes was assessed after a follow-up time of 4-5 years. We observed a higher level of DNA damage in leukocytes of patients with type 1 diabetes compared with healthy subjects [type 1 diabetes AU 50 (36-74.5); control AU 30 (24.1-43), P < 0.001]. According to regression, type 1 diabetes leads to a 2-fold increase in DNA damage. In the group of type 1 diabetes, DNA damage correlated positively with total cholesterol (R = 0.262, P = 0.028) and negatively with serum glucose level (R = -0.284; P = 0.018) and serum nitrite (R = -0.335; P = 0.008). DNA damage was not significantly associated with HbA1c, diabetes duration, complications and lifestyle factors. However, DNA damage > 57 AU was associated with statistically significantly lower serum nitrite and 1.52 higher risk of progression of complications of diabetes over the follow-up period. The latter result was not statistically significant due to insufficient study power [relative risk 1.52 (95% confidence interval = 0.68, 3.42, P = 0.31)]. Our results confirm that type 1 diabetes is associated with a higher level of DNA strand breaks in leukocytes when compared with the reference group and demonstrate the negative association between DNA damage and serum nitrite concentration.

Alcohol use and dysglycemia among people living with human immunodeficiency virus (HIV) in the Alcohol & Metabolic Comorbidities in PLWH: Evidence Driven Interventions (ALIVE-Ex) study.

BACKGROUND: At-risk alcohol use is a common and costly form of substance misuse that is highly prevalent among people living with HIV (PLWH). The goal of the current analysis was to test the hypothesis that PLWH with at-risk alcohol use are more likely to meet the clinical criteria for prediabetes/diabetes than PLWH with low-risk alcohol use. METHODS: A cross-sectional analysis was performed on measures of alcohol and glycemic control in adult PLWH (n = 105) enrolled in a prospective, interventional study (the ALIVE-Ex Study (NCT03299205)) that investigated the effects of aerobic exercise on metabolic dysregulation in PLWH with at-risk alcohol use. The Alcohol Use Disorders Identification Test (AUDIT), Timeline Followback, and phosphatidylethanol (PEth) level were used to measure alcohol use. Participants were stratified into low-risk (AUDIT score < 5) and at-risk alcohol use (AUDIT  score ≥ 5). All participants underwent an oral glucose tolerance test and measures of glycemic control- the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and Matsuda Index - were correlated with alcohol measures and compared by AUDIT score group using mixed-effects linear and logistic regression models, adjusting for age, sex, race, body mass index (BMI), and viral load. RESULTS: In response to the glucose challenge, participants with at-risk alcohol use (n = 46) had higher glucose levels and were five times more likely to meet criteria for prediabetes/diabetes (OR: 5.3 (1.8, 15.9)) than participants with an AUDIT score < 5. Two-hour glucose values were positively associated with AUDIT score and PEth level and a higher percentage of PLWH with at-risk alcohol use had glucose values ≥140 mg/dl than those with low-risk alcohol use (34.8% vs. 10.2%, respectively). CONCLUSION: In this cohort of PLWH, at-risk alcohol use increased the likelihood of meeting the clinical criteria for prediabetes/diabetes (2-h glucose level ≥140 mg/dl). Established determinants of metabolic dysfunction (e.g., BMI, waist-hip ratio) were not associated with greater alcohol use and dysglycemia, suggesting that other mechanisms may contribute to the impaired glycemic control observed in this cohort.

Correlational study on the levels of 25-hydroxyvitamin D and non-alcoholic fatty liver disease in type 2 diabetic patients.

BACKGROUND: It is widely acknowledged that nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus(T2DM) are all chronic metabolic diseases. The objective of this study is to retrospectively probe the association between the 25-hydroxyvitamin D (25-(OH)D) and NAFLD in type 2 diabetic patients. METHODS: Three hundred thirty-nine T2DM patients participated in this research and from November 2018 to September 2019 and were divided into simple T2DM group (108 cases) and T2DM with NAFLD group (231 cases) in conformity with abdominal ultrasound diagnosis. The NAFLD fibrosis score (NFS) ≥0.676 was defined as progressive liver fibrosis.231 T2DM with NAFLD patients were categorized into two subgroups: progressive liver fibrosis subgroup (48 cases) and without progressive liver fibrosis subgroup (183 cases). RESULTS: The prevalence of NAFLD by Abdominal ultrasonography was 68%.The results indicated that the levels of 25-(OH) D were significantly lower in T2DM with NAFLD group than that in simple T2DM group(P < 0.01). The levels of 25-(OH) D were significantly lower in progressive liver fibrosis subgroup than that in patients without progressive liver fibrosis and simple T2DM,and 25-(OH) D levels were lower in without progressive liver fibrosis subgroup than that in simple T2DM group(p < 0.01 or p < 0.05). Multivariate logistic regression analysis showed that levels of 25-(OH) D were negative correlation with risk of NAFLD and progressive liver fibrosis(p = 0.011、p = 0.044,respectively). CONCLUSIONS: we could come to a conclusion that low levels of 25-(OH) D was a risk factor for NAFLD and progressive liver fibrosis in T2DM patients.

The association of glycemic level and prevalence of tuberculosis: a meta-analysis.

BACKGROUND: Diabetes is a well-known risk factor for tuberculosis and poorly glycemic control may increase the risk of tuberculosis. We performed a meta-analysis to explore the association of glycemic control in diabetic patients and their tuberculosis prevalence. METHODS: We included observational studies that investigated the prevalence of tuberculosis associated with glycemic control. The markers of glycated hemoglobin A1c (HbA1c) and fasting plasma glucose were used to evaluate the exposure of interest in the study. We searched related articles in PubMed, EMBASE and Web of Science through 14 December 2019. The Newcastle-Ottawa scale was used to assess the risk of bias of included studies. RESULTS: Seventeen studies (four cohort studies, five case-control studies and eight cross-sectional studies) were included, involving 1,027,074 participants. The meta-analysis found the pooled odds ratio of prevalent tuberculosis increased a 2.05-fold (95%CI: 1.65, 2.55) for the patients with HbA1c ≥7.0% compared to those with HbA1c concentration < 7.0%. Furthermore, we found the mean of HbA1c was higher in the diabetes mellitus with tuberculosis group than the diabetes-only group (P = 0.002). In the sensitivity analysis, the finding remains consistent. CONCLUSION: Our study provides the evidence that poorly controlled diabetes in diabetics may be associated with increased prevalence of tuberculosis. More efforts should focus on screening tuberculosis in uncontrolled diabetes.

Glycemic and lipid variability for predicting complications and mortality in diabetes mellitus using machine learning.

INTRODUCTION: Recent studies have reported that HbA1c and lipid variability is useful for risk stratification in diabetes mellitus. The present study evaluated the predictive value of the baseline, subsequent mean of at least three measurements and variability of HbA1c and lipids for adverse outcomes. METHODS: This retrospective cohort study consists of type 1 and type 2 diabetic patients who were prescribed insulin at outpatient clinics of Hong Kong public hospitals, from 1st January to 31st December 2009. Standard deviation (SD) and coefficient of variation were used to measure the variability of HbA1c, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglyceride. The primary outcome is all-cause mortality. Secondary outcomes were diabetes-related complications. RESULT: The study consists of 25,186 patients (mean age = 63.0, interquartile range [IQR] of age = 15.1 years, male = 50%). HbA1c and lipid value and variability were significant predictors of all-cause mortality. Higher HbA1c and lipid variability measures were associated with increased risks of neurological, ophthalmological and renal complications, as well as incident dementia, osteoporosis, peripheral vascular disease, ischemic heart disease, atrial fibrillation and heart failure (p <  0.05). Significant association was found between hypoglycemic frequency (p <  0.0001), HbA1c (p <  0.0001) and lipid variability against baseline neutrophil-lymphocyte ratio (NLR). CONCLUSION: Raised variability in HbA1c and lipid parameters are associated with an elevated risk in both diabetic complications and all-cause mortality. The association between hypoglycemic frequency, baseline NLR, and both HbA1c and lipid variability implicate a role for inflammation in mediating adverse outcomes in diabetes, but this should be explored further in future studies.

Improvement of glycemic control in type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials.

AIM: Different guidelines provide similar, but not identical, therapeutic targets for HbA1c in type 2 diabetes. These targets can also depend from the different pharmacological strategies adopted for intensifying glycemic control. DATA SYNTHESIS: This meta-analysis includes randomized trials adopting any pharmacological regimen for intensifying glycemic control in T2DM (versus standard of care/placebo), with a trial duration ≥2 years and a between-group HbA1c difference≥0.5%. The primary outcome was to assess the effects of the improvement of glycemic control on major cardiovascular events (MACE), ocular and renal complications, and severe hypoglycemia. Mantel-Haenszel odds ratios (MH-OR) with 95% Confidence Intervals were calculated for all the outcomes considered. We included 13 trials fulfilling the inclusion criteria. The improvement of glycemic control was associated with a lower risk of MACE (MH-OR:0.89 [95%CI 0.85-0.94]) and renal adverse events (MH-OR 0.73 [0.65-0.82]), but not all-cause mortality (MH-OR 0.95 [0.88-1.01]) and ocular adverse complications (MH-OR 0.94 [0.72-1.22]). For glucose-lowering drugs inducing hypoglycemia, a protective effect on the risk of microvascular complications, but not of MACE and all-cause mortality, was observed only for HbA1c ≤ 48 mmol/mol, but with higher risk of severe hypoglycaemia (MH-OR 2.72 [1.79-4.13]). Drugs not inducing hypoglycaemia were associated with a reduction of MACE, renal adverse events, and all-cause mortality, for HbA1c< 7% (no data for lower targets). CONCLUSIONS: The present meta-analysis show that the improvement of glycemic control with drugs not inducing hypoglycemia is associated with a reduction in the risk of long-term chronic vascular and renal complications, and all-cause mortality.

High prevalence of Afro-Caribbean ethnicity and hypoglycaemia in patients with diabetes and end stage renal disease hospitalized with COVID-19.

End stage renal disease (ESRD) is associated with a high mortality rate among patients hospitalized with COVID-19. To the best of our knowledge, there is limited data on the clinical features, ethnicity, inpatient glycaemic control and outcomes in patients with diabetes related ESRD in the literature. We report the clinical features and outcomes of 39 consecutive ESRD patients (28 on haemodialysis [HD] and 11 with renal transplant) secondary to diabetic kidney disease admitted to a university hospital with COVID-19. We observed a high prevalence of patients of Afro-Caribbean ethnicity hospitalized with COVID-19 with a 73% and 54% prevalence in renal transplant and HD groups respectively. The mortality rate of our cohort was 36%. Nearly a one-third of HD patients and one-fifth of transplant patients had hypoglycaemic events during COVID-19 hospitalization. Adjustment of diabetes treatment was frequently required. Our data highlight the importance of integrated multidisciplinary care of patients with diabetes related ESRD hospitalized with COVID-19.

Hyperglycemia and Correlated High Levels of Inflammation Have a Positive Relationship with the Severity of Coronavirus Disease 2019.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a considerable global public health threat. This study sought to investigate whether blood glucose (BG) levels or comorbid diabetes are associated with inflammatory status and disease severity in patients with COVID-19. METHODS: In this retrospective cohort study, the clinical and biochemical characteristics of COVID-19 patients with or without diabetes were compared. The relationship among severity of COVID-19, inflammatory status, and diabetes or hyperglycemia was analyzed. The severity of COVID-19 in all patients was determined according to the diagnostic and treatment guidelines issued by the Chinese National Health Committee (7th edition). RESULTS: Four hundred and sixty-one patients were enrolled in our study, and 71.58% of patients with diabetes and 13.03% of patients without diabetes had hyperglycemia. Compared with patients without diabetes (n = 366), patients with diabetes (n = 95) had a higher leucocyte count, neutrophil count, neutrophil to lymphocyte ratio (NLR), and erythrocyte sedimentation rate (ESR). There was no association between severity of COVID-19 and known diabetes adjusted for age, sex, body mass index (BMI), known hypertension, and coronary heart disease. The leucocyte count, NLR, and C-reactive protein (CRP) level increased with increasing BG level. Hyperglycemia was an independent predictor of critical (OR 4.00, 95% CI 1.72-9.30) or severe (OR 3.55, 95% CI 1.47-8.58) COVID-19, and of increased inflammatory levels (high leucocyte count (OR 4.26, 95% CI 1.65-10.97), NLR (OR 2.76, 95% CI 1.24-6.10), and CRP level (OR 2.49, 95% CI 1.19-5.23)), after adjustment for age, sex, BMI, severity of illness, and known diabetes. CONCLUSION: Hyperglycemia was positively correlated with higher inflammation levels and more severe illness, and it is a risk factor for the increased severity of COVID-19. The initial measurement of plasma glucose levels after hospitalization may help identify a subset of patients who are predisposed to a worse clinical course.

A systematic review and meta-analysis of effects of spironolactone on blood pressure, glucose, lipids, renal function, fibrosis and inflammation in patients with hypertension and diabetes.

PURPOSE: Hypertension commonly co-exists with diabetes mellitus (DM), and both are closely related to adverse health outcomes. The activation of aldosterone and mineralocorticoid receptor (MR) may play important roles in this process. Therefore, we aim to evaluate the efficacy of MR antagonists on cardiovascular risk factors, including blood pressure (BP), glucose, lipids, renal function, fibrosis and inflammatory and its safety in patients with both hypertension and DM. METHODS: We searched PubMed, Embase, Web of Science and Cochrane databases for clinical trials published until December 31, 2019. Studies comparing the effect of spironolactone to placebo in patients with hypertension and DM were included. Mean difference with 95% confidence intervals was used to report outcomes. RESULTS: Eleven randomised placebo-controlled trials with 640 participants were finally included with mean follow-up of 5 months. Compared to placebo, spironolactone significantly reduced office systolic (-6.57, 95%CI: -9.21, -3.93) and diastolic BP (-2.63, 95%CI: -4.25, -1.02) as well as ambulatory BP; increased glycosylated haemoglobin by 0.3 but no clear effect on fasting glucose. Spironolactone induced a significantly reduction of urinary albumin but increased serum creatinine (7.60, 95%CI: 4.94, 10.27) and decreased glomerular filtration rate (-4.28, 95%CI: -6.38, -2.18). Markers of fibrosis and inflammation, including NIIINP, PICP, hs-CRP and TNF-α were also decreased after spironolactone therapy. For lipid metabolism, there was no significant difference between groups. Spironolactone mildly increased serum potassium (0.30, 95%CI: 0.23, 0.37). 2.5% subjects treated with spironolactone experienced mild to moderate hyperkalaemia and received medication or dietary advice and another 1.6% developed severe hyperkalaemia and withdrawn from the studies. CONCLUSION: Spironolactone reduced BP and urinary albumin, improve fibrosis and inflammation, whereas slightly increases the glycosylated haemoglobin and serum creatinine in patients with hypertension and diabetes. Long-term RCTs to assess the effects of spironolactone on cardiovascular events in this population are warranted.

Association between Hb A1c and Severity of COVID-19 Patients.

This study aimed to examine the relationship between Hb A1c levels and the clinical course of coronavirus-19 (COVID-19) patients. Sixty-six COVID-19(+) patients with high Hb A1c and 46 with average Hb A1c and 30 COVID-19(-) patients with average Hb A1c were included. Hb A1c levels and parameters examined in COVID-19(+) patients were compared between groups, and correlation analysis was performed between these parameters and Hb A1c levels. The effect of Hb A1c levels on intensive care unit (ICU) admission and mortality rate in COVID-19 patients was analyzed with the χ2 test. It was observed that hemoglobin (Hb) and arterial oxygen saturation (SaO2) levels of the COVID-19 (+) groups was lower than the COVID-19 (-) group, while ferritin, D-dimer, procalcitonin (PCT), and C-reactive protein (CRP) levels were higher. The COVID-19 (+) group with high Hb A1c had higher lactate dehydrogenase (LDH), PCT and D-dimer levels than the other two groups, while Hb, partial arterial oxygen pressure (PaO2) levels were lower. The Hb A1c levels of the COVID-19 (+) groups were positively correlated with absolute neutrophil count (ANC), LDH, PCT and (K+) levels, while negatively correlated with Hb and PaO2 levels. Hb A1c was found to be associated with the inflammation process, coagulation disorders and low PaO2 in COVID-19 patients. The COVID-19 patients with high Hb A1c levels had a higher mortality rate than other COVID-19 patients. Using Hb A1c measurements with other prognostic markers would contribute to the patient's risk of death assessment.

PAI-1 in Diabetes: Pathophysiology and Role as a Therapeutic Target.

Hypofibrinolysis is a key abnormality in diabetes and contributes to the adverse vascular outcome in this population. Plasminogen activator inhibitor (PAI)-1 is an important regulator of the fibrinolytic process and levels of this antifibrinolytic protein are elevated in diabetes and insulin resistant states. This review describes both the physiological and pathological role of PAI-1 in health and disease, focusing on the mechanism of action as well as protein abnormalities in vascular disease with special focus on diabetes. Attempts at inhibiting protein function, using different techniques, are also discussed including direct and indirect interference with production as well as inhibition of protein function. Developing PAI-1 inhibitors represents an alternative approach to managing hypofibrinolysis by targeting the pathological abnormality rather than current practice that relies on profound inhibition of the cellular and/or acellular arms of coagulation, and which can be associated with increased bleeding events. The review offers up-to-date knowledge on the mechanisms of action of PAI-1 together with the role of altering protein function to improve hypofirbinolysis. Developing PAI-1 inhibitors may form for the basis of future new class of antithrombotic agents that reduce vascular complications in diabetes.

Circulating Soluble ACE2 and Upstream microRNA Expressions in Serum of Type 2 Diabetes Mellitus Patients.

The global coronavirus disease 2019 (COVID-19) pandemic was associated with multiple organ failure and comorbidities, such as type 2 diabetes mellitus (T2DM). Risk factors, such as age, gender, and obesity, were associated with COVID-19 infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to use several host receptors for viral entry, such as angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) in the lung and other organs. However, ACE2 could be shed from the surface to be soluble ACE2 (sACE2) in the circulation. The epigenetic factors affecting ACE2 expression include a type of small non-coding RNAs called microRNAs (miRNAs). In this study, we aimed at exploring the status of the sACE2 as well as serum levels of several upstream novel miRNAs as non-invasive biomarkers that might have a potential role in T2DM patients. Serum samples were collected from 50 T2DM patients and 50 healthy controls, and sACE2 levels were quantified using enzyme-linked immunosorbent assay (ELISA). Also, RNA was extracted, and TaqMan miRNA reverse transcription quantitative PCR (RT-qPCR) was performed to measure serum miRNA levels. Our results revealed that sACE2 is decreased in the T2DM patients and is affected by age, gender, and obesity level. Additionally, 4 miRNAs, which are revealed by in silico analysis to be potentially upstream of ACE2 were detectable in the serum. Among them, miR-421 level was found to be decreased in the serum of diabetic patients, regardless of the presence or absence of diabetic complications, as well as being differential in various body mass index (BMI) groups. The other 3 miRNAs (miR-3909, miR-212-5p, and miR-4677-3p) showed associations with multiple factors including age, gender, BMI, and serum markers, in addition to being correlated to each other. In conclusion, our study reveals a decline in the circulating serum levels of sACE2 in T2DM patients and identified 4 novel miRNAs that were associated with T2DM, which are influenced by different clinical and demographic factors.