Mannose-binding lectin does not explain the dismal prognosis after an acute coronary event in dysglycaemic patients. A report from the GAMI cohort.

BACKGROUND: Mannose binding lectin (MBL) has been suggested to be associated with an impaired cardiovascular prognosis in dysglycaemic conditions, but results are still contrasting. Our aims are (i) to examine whether MBL levels differ between patients with an acute myocardial infarction (MI) and healthy controls and between subgroups with different glucose tolerance status, and (ii) to investigate the relation between MBL and future cardiovascular events. METHODS: MBL levels were assessed at discharge and after 3 months in 161 AMI patients without any previously known glucose perturbations and in 183 age- and gender-matched controls from the Glucose metabolism in patients with Acute Myocardial Infarction (GAMI) study. Participants were classified as having dysglycaemia, i.e. type 2 diabetes or impaired glucose tolerance, or not by an oral glucose tolerance test. The primary outcome was a composite of cardiovascular events comprising cardiovascular death, AMI, stroke or severe heart failure during 11 years of follow-up. Total and cardiovascular mortality served as secondary outcomes. RESULTS: At hospital discharge patients had higher MBL levels (median 1246 µg/L) than three months later (median 575 µg/L; p < 0.01), the latter did not significantly differ from those in the controls (801 µg/L; p = 0.47). MBL levels were not affected by dysglycaemia either in patients or controls. Independent of glycaemic state, increasing MBL levels did not predict any of the studied outcomes in patients. In unadjusted analyses increasing MBL levels predicted cardiovascular events (hazard ratio HR: 1.67, 95% confidence interval CI 1.06-2.64) and total mortality (HR 1.53, 95% CI 1.12-2.10) in the control group. However, this did not remain in adjusted analyses. CONCLUSIONS: Patients had higher MBL levels than controls during the hospital phase of AMI, supporting the assumption that elevated MBL reflects acute stress. MBL was not found to be independently associated with cardiovascular prognosis in patients with AMI regardless of glucose state.

Comparison of treatment with insulin degludec and glargine U100 in patients with type 1 diabetes prone to nocturnal severe hypoglycaemia: The HypoDeg randomized, controlled, open-label, crossover trial.

AIM: To investigate whether the long-acting insulin analogue insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal symptomatic hypoglycaemia in patients with type 1 diabetes (T1D). METHODS: Adults with T1D and at least one episode of nocturnal severe hypoglycaemia during the last 2 years were included in a 2-year prospective, randomized, open, multicentre, crossover trial. A total of 149 patients were randomized 1:1 to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period lasted 1 year and consisted of 3 months of run-in or crossover followed by 9 months of maintenance. The primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycaemic episodes. Secondary endpoints included the occurrence of severe hypoglycaemia. We analysed all endpoints by intention-to-treat. RESULTS: Treatment with insulin degludec resulted in a 28% (95% CI: 9%-43%; P = .02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycaemia at level 1 (≤3.9 mmol/L), a 37% (95% CI: 16%-53%; P = .002) RRR at level 2 (≤3.0 mmol/L), and a 35% (95% CI: 1%-58%; P = .04) RRR in all-day severe hypoglycaemia compared with insulin glargine U100. CONCLUSIONS: Patients with T1D prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia and all-day severe hypoglycaemia with insulin degludec compared with insulin glargine U100.

Effect of dipeptidyl peptidase-4 inhibitors on complement activation.

BACKGROUND: Adverse activation of the complement cascade in the innate immune system appears to be involved in development of vascular complications in diabetes. Dipeptidyl peptidase-4 (DPP-4) is a cell surface serine protease expressed in a variety of tissues. DPP-4 inhibitors are widely used in treatment of type 2 diabetes and appear to yield beneficial pleiotropic effects beyond their glucose-lowering action, for example, renoprotective and anti-inflammatory properties, but the exact mechanisms remain unknown. We hypothesised that DPP-4 inhibitors block adverse complement activation by inhibiting complement-activating serine proteases. MATERIALS AND METHODS: We analysed the effects of 7 different DPP-4 inhibitors on the lectin and classical pathway of the complement system in vitro by quantifying complement factor C4b deposition onto mannan or IgG coated surfaces, respectively. Furthermore, plasma concentrations of mannan-binding lectin (MBL), soluble membrane attack complex (sMAC), and C4b deposition were quantified in 71 patients with a recent acute coronary syndrome and glucose disturbances, randomly assigned to sitagliptin 100 mg (n = 34) or placebo (n = 37) for 12 weeks. RESULTS: All the 7 DPP-4 inhibitors tested in the study directly inhibited functional activity of the lectin pathway in a dose-dependent manner with varying potency in vitro. In vivo, MBL, sMAC, and C4b declined significantly during follow-up in both groups without significant effect of sitagliptin. CONCLUSIONS: We demonstrated an inhibitory effect of DPP-4 inhibitors on the lectin pathway in vitro. The clinical relevance of this effect of DPP-4 inhibitors remains to be fully elucidated.

Real-world use of cardioprotective glucose-lowering drugs in patients with type 2 diabetes and cardiovascular disease: A Danish nationwide cohort study, 2012 to 2019.

AIMS: To investigate temporal trends in time to initiation of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide 1 analogues (cardioprotective glucose-lowering drugs [GLDs]) in patients with a new dual diagnosis of type 2 diabetes (T2DM) and cardiovascular disease (CVD). MATERIALS AND METHODS: In a cohort study, we identified patients with a new dual diagnosis of T2DM and CVD using linked healthcare data from nationwide registries on drug prescriptions and diagnosis codes. For each calendar year between 2012 and 2018, we examined time to initiation and cumulative user proportions (CUPs) for cardioprotective GLD use 1 and 2 years after the dual diagnosis. RESULTS: Among all individuals living in Denmark in the period 2012 to 2018, 41 733 patients with a new dual diagnosis of T2DM and CVD were identified (median [interquartile range] age 71 [64-79] years, 61% male, and 57% with CVD as the latest diagnosis). Incidence curve slopes and 1- and 2-year CUPs for cardioprotective GLDs increased during the study period (1-year CUP 4.0%, 95% confidence interval [CI] 3.6-4.5) in 2012 to 14.7, 95% CI 13.7-15.7, in 2018; 2-year CUP 5.5, 95% CI 5.0-6.1, in 2012 to 16.7, 95% CI 15.8-17.7, in 2017). T2DM patients with CVD as the second (latest) diagnosis had higher 1-year CUPs than CVD patients with T2DM as the latest diagnosis: 2012: 7.0 (95% CI 6.2-8.0) versus 1.4 (95% CI 1.0-1.8); 2018: 18.1 (95% CI 16.8-19.6) versus 10.0 (95% CI 8.8-11.3). CONCLUSIONS: In patients with T2DM and CVD, the incidence of cardioprotective GLD initiation increased between 2012 and 2018, however, within 2 years of dual diagnosis, it remained low.

Effect of Intravenous 25OHD Supplementation on Bone Turnover and Inflammation in Prolonged Critically Ill Patients.

Critically ill patients have low circulating 25-hydroxyvitamin D (25OHD), vitamin D binding protein (DBP), and 1,25-dihydroxyvitamin D [1,25(OH)2D]. Low 25OHD is associated with poor outcomes, possibly explained by its effect on bone and immunity. In this prospective, randomized double-blind, placebo-controlled study, we investigated the feasibility of normalizing 25OHD in prolonged (>10 days) critically ill patients and the effects thereof on 1,25(OH)2D, bone metabolism, and innate immunity. Twenty-four patients were included and compared with 24 matched healthy subjects. Patients were randomized to either intravenous bolus of 200 µg 25OHD followed by daily infusion of 15 µg 25OHD for 10 days, or to placebo. Parameters of vitamin D, bone and mineral metabolism, and innate immune function were measured. As safety endpoints, ICU length of stay and mortality were registered. Infusion of 25OHD resulted in a sustained increase of serum 25OHD (from median baseline 9.2 -16.1 ng/ml at day 10), which, however, remained below normal levels. There was no increase in serum 1,25(OH)2D but a slight increase in serum 24,25(OH)2D. Mineral homeostasis, innate immunity and clinical safety endpoints were unaffected. Thus, intravenous 25OHD administration during critical illness increased serum 25OHD concentrations, though less than expected from data in healthy subjects, which suggests illness-induced alterations in 25OHD metabolism and/or increased 25OHD distribution volume. The increased serum 25OHD concentrations were not followed by a rise in 1,25(OH)2D nor were bone metabolism or innate immunity affected, which suggests that low 25OHD and 1,25OHD levels are part of the adaptive response to critical illness.

Morning blood pressure surge and target organ damage in newly diagnosed type 2 diabetic patients: a cross sectional study.

BACKGROUND: Type 2 diabetic patients display significantly higher incidence of cardiovascular (CV) events including stroke compared to non-diabetics. Morning blood pressure surge (MBPS) and blunted systolic night-day (SND) ratio have been associated with CV events in hypertensive patients. No studies have evaluated MBPS in newly diagnosed diabetic patients or studied the association with vascular target organ damage at this early time point of the diabetes disease. METHODS: Ambulatory blood pressure monitoring was performed in 100 patients with newly diagnosed type 2 diabetes and 100 age and sex matched controls. MBPS and SND-ratio were calculated. Markers of early vascular target organ damage included pulse wave velocity (PWV), white matter lesions (WML) on brain MRI, and urine albumin/creatinine ratio (UAE). RESULTS: No significant differences in MBPS were found between diabetic patients and controls. Neither MBPS or SND-ratio were associated with PWV, UAE or WML in the diabetic group independently of age, gender and 24-h systolic blood pressure. 40.2 % of diabetic patients and 25.8 % of controls were classified as non-dippers (p = 0.03). CONCLUSION: MBPS and SND-ratio are not associated with subclinical markers of vascular target organ damage in our study sample of newly diagnosed type 2 diabetic patients.

Association of the pattern recognition molecule H-ficolin with incident microalbuminuria in an inception cohort of newly diagnosed type 1 diabetic patients: an 18 year follow-up study.

AIMS/HYPOTHESIS: Increasing evidence links complement activation through the lectin pathway to diabetic nephropathy. Adverse complement recognition of proteins modified by glycation has been suggested to trigger complement auto-attack in diabetes. H-ficolin (also known as ficolin-3) is a pattern recognition molecule that activates the complement cascade on binding to glycated surfaces, but the role of H-ficolin in diabetic nephropathy is unknown. We aimed to investigate the association between circulating H-ficolin levels and the incidence of microalbuminuria in type 1 diabetes. METHODS: We measured baseline H-ficolin levels and tracked the development of persistent micro- and macroalbuminuria in a prospective 18 year observational follow-up study of an inception cohort of 270 patients with newly diagnosed type 1 diabetes. RESULTS: Patients were followed for a median of 18 years (range 1-22 years). During follow-up, 75 patients developed microalbuminuria, defined as a persistent urinary albumin excretion rate (UAER) above 30 mg/24 h. When H-ficolin levels were divided into quartile groups an unadjusted Cox proportional hazards regression model showed a significant association with risk of incident microalbuminuria during follow-up (HR, fourth vs first quartile, 2.45; 95% CI 1.24, 4.85) (p = 0.01). This remained significant after adjusting for HbA1c, systolic blood pressure, smoking and baseline UAER (HR 2.09; 95% CI 1.03, 4.25) (p = 0.04). CONCLUSIONS/INTERPRETATION: Our data suggest that high levels of the complement activating molecule H-ficolin are associated with an increased risk of future progression to microalbuminuria in patients with newly diagnosed type 1 diabetes.

Four weeks SGLT2 inhibition improves beta cell function and glucose tolerance without affecting muscle free fatty acid or glucose uptake in subjects with type 2 diabetes.

AIMS: Sodium glucose co-transporter-2 (SGLT2) inhibition lowers glucose levels independently of insulin, leading to reduced insulin secretion and increased lipolysis, resulting in elevated circulating free fatty acids (FFAs). While SGLT2 inhibition improves tissue insulin sensitivity, the increase in circulating FFAs could reduce insulin sensitivity in skeletal muscle and the liver. We aimed to investigate the effects of SGLT2 inhibition on substrate utilization in skeletal muscle and the liver and to measure beta-cell function and glucose tolerance. METHODS: Thirteen metformin-treated individuals with type 2 diabetes were randomized to once-daily empagliflozin 25 mg or placebo for 4 weeks in a crossover design. Skeletal muscle glucose and FFA uptake together with hepatic tissue FFA uptake were measured using [18F]FDG positron emission tomography/computed tomography (PET/CT) and [11C]palmitate PET/CT. Insulin secretion and action were estimated using the oral minimal model. RESULTS: Empagliflozin did not affect glucose (0.73 ± 0.30 vs. 1.16 ± 0.64, µmol/g/min p = 0.11) or FFA (0.60 ± 0.30 vs. 0.56 ± 0.3, µmol/g/min p = 0.54) uptake in skeletal muscle. FFA uptake in the liver (21.2 ± 10.1 vs. 19 ± 8.8, µmol/100 ml/min p = 0.32) was unaffected. Empagliflozin increased total beta-cell responsivity (20 ± 8 vs. 14 ± 9, 10-9 min-1, p < 0.01) and glucose effectiveness (2.6 × 10-2 ± 0.3 × 10-2 vs. 2.4 × 10-2 ± 0.3 × 10-2, dL/kg/min, p = 0.02). CONCLUSIONS: Despite improved beta-cell function and glucose tolerance, empagliflozin does not appear to affect skeletal muscle FFA or glucose uptake.

Circulating levels of the shed scavenger receptor sCD163 and association with outcome of critically ill patients.

PURPOSE: CD163, a scavenger receptor for haptoglobin-hemoglobin complexes, is almost exclusively expressed by monocytes and macrophages and is shedded (as sCD163) by inflammatory stimuli. Thus, high serum levels of sCD163 predicted mortality in certain inflammatory diseases. We investigated baseline levels, time course of sCD163 levels and CD163 gene expression in relation to mortality and clinical complications in a large heterogeneous cohort of critically ill patients. METHODS: In this pre-planned secondary analysis of two randomized clinical studies, critically ill patients (n = 1657) were randomized to "conventional" (insulin administered only for blood glucose levels above 215 mg/dL) or "intensive" insulin therapy (glycemia maintained at 80-110 mg/dL) and compared with healthy controls (n = 112). RESULTS: Upon admission, critically ill patients had 1.6-fold higher sCD163 levels than controls (P < 0.0001). Long-stay patients (ICU stay >5 days), non-survivors and patients who developed liver dysfunction or kidney injury had higher baseline sCD163 levels. In multivariable analyses, elevated baseline sCD163 levels were independently associated with ICU mortality, liver dysfunction, and time to discharge from ICU and hospital. sCD163 further increased during ICU stay in patients who developed organ dysfunction and in non-survivors. Avoiding hyperglycemia with insulin slightly reduced circulating sCD163 levels. Hepatic CD163 gene expression in patients was higher than in controls (P = 0.002) and correlated positively with sCD163 levels (P = 0.345, P < 0.0001). CONCLUSIONS: This study hallmarks the association of elevated sCD163 with organ dysfunction and adverse outcome of critical illness and may point to the liver as a potential source.

Reproducibility of pulse wave analysis and pulse wave velocity in patients with type 2 diabetes.

AIMS: Patients with type 2 diabetes have increased arterial stiffness and a high incidence of cardiovascular disease compared with non-diabetics. Arterial stiffness and central waveforms can be assessed by carotid-femoral pulse wave velocity (PWV) and pulse wave analysis (PWA) using the SphygmoCor device. These methods can potentially improve cardiovascular risk stratification in the future. However, a prerequisite is acceptable reproducibility. The objective of this study was to assess the intra- and inter-observer reproducibility of PWV and PWA indices in patients with type 2 diabetes using the SphygmoCor device. METHODS: Two trained observers (A and B) each undertook two PWA and two carotid-femoral PWV recordings in random order in 20 patients with type 2 diabetes under standardized conditions on the right side of the patients. Observer A also made double recordings on the left side. The mean of the two recordings was used for inter-observer comparison. Data were analyzed by Bland-Altman plots. RESULTS: The mean intra-observer differences (± 2SD) on the right side for observer A and B, respectively, were 0.0 ± 2.8 mmHg and 0.3 ± 3.2 mmHg (aortic systolic blood pressue (BP)), 0.0 ± 1.2 mmHg and 0.1 ± 1.0 mmHg (aortic diastolic BP), - 1.1 ± 3.2% and 1.1 ± 9.6% (central augmentation index (Aix)), - 1.6 ± 6.6% and 0.1 ± 9.0% (Aix normalized to heart rate 75 beats/min (Aix@HR75)) and 0.1 ± 1.8 m/s and 0.0 ± 1.6 m/s (PWV). The mean inter-observer differences (± 2SD) were - 2.6 ± 13.0 mmHg (aortic systolic BP), - 2.1 ± 7.4 mmHg (aortic diastolic BP), - 0.8 ± 8.4% (Aix), - 1.5 ± 7.4% (Aix@HR75) and - 0.3 ± 1.6 m/s (PWV). Left-vs-right comparison showed comparable results (observer A). CONCLUSIONS: PWA and PWV assessed with the SphygmoCor device are characterized by good reproducibility in patients with type 2 diabetes.

Effects of SGLT2 inhibition on lipid transport in adipose tissue in type 2 diabetes.

SGLT2 inhibition induces an insulin-independent reduction in plasma glucose causing increased lipolysis and subsequent lipid oxidation by energy-consuming tissues. However, it is unknown whether SGLT2 inhibition also affects lipid storage in adipose tissue. Therefore, we aimed to determine the effects of SGLT2 inhibition on lipid storage and lipolysis in adipose tissue. We performed a randomized, double-blinded, placebo-controlled crossover design of 4 weeks of empagliflozin 25 mg and placebo once-daily in 13 individuals with type 2 diabetes treated with metformin. Adipose tissue fatty acid uptake, lipolysis rate and clearance were measured by 11C-palmitate PET/CT. Adipose tissue glucose uptake was measured by 18F-FDG PET/CT. Protein and gene expression of pathways involved in lipid storage and lipolysis were measured in biopsies of abdominal s.c. adipose tissue. Subjects were weight stable, which allowed us to quantify the weight loss-independent effects of SGLT2 inhibition. We found that SGLT2 inhibition did not affect free fatty acids (FFA) uptake in abdominal s.c. adipose tissue but increased FFA uptake in visceral adipose tissue by 27% (P < 0.05). In addition, SGLT2 inhibition reduced GLUT4 protein (P = 0.03) and mRNA content (P = 0.01) in abdominal s.c. adipose tissue but without affecting glucose uptake. In addition, SGLT2 inhibition decreased the expression of genes involved in insulin signaling in adipose tissue. We conclude that SGLT2 inhibition reduces GLUT4 gene and protein expression in abdominal s.c. adipose tissue, which could indicate a rebalancing of substrate utilization away from glucose oxidation and lipid storage capacity through reduced glycerol formation.

Longitudinal measurement of cytokines in pre-eclamptic and normotensive pregnancies.

OBJECTIVE: To evaluate differences in plasma cytokine levels longitudinally in pre-eclamptic and normotensive pregnancies. An increased inflammatory response has long been associated with pre-eclampsia, both early and late in the pre-eclamptic pregnancy. DESIGN: Blood samples were collected longitudinally during pregnancy from a cohort of 1 631 pregnant women. Thirty-two women with pre-eclampsia and 67 normotensive pregnant women were identified from the cohort. SETTING: A Danish regional hospital. SAMPLES: Samples were collected from the 18th week of pregnancy until delivery and divided into the following four gestational intervals: <25th week, 26th-29th week, 30th-35th week and >36th week. METHODS: Simultaneous measurement of all nine cytokines was done using a capture bead system. MAIN OUTCOME MEASURES: Plasma levels of interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-α, interferon-γ and granulocyte macrophage colony-stimulating factor during pre-eclamptic and normotensive pregnancies. RESULTS: Pre-eclampsia was associated with increased tumor necrosis factor-α between the 26th and 29th week (p=0.0421) and increased IL-6 after the 36th week (p=0.0044). The other cytokines measured were comparable in the two groups. CONCLUSIONS: This large prospective collection of blood samples was undertaken to determine inflammatory status during pre-eclamptic and normotensive pregnancies. Our results support a tendency towards increased inflammation in pre-eclampsia, but the measured cytokines are not eligible for prediction, monitoring or diagnosing pre-eclampsia.

Clinical presentation and outcomes of COVID-19 in older hospitalised patients assessed by the record-based multidimensional prognostic index, a cross-sectional study.

PURPOSE: Older people are the most frequently hospital admitted patients with COVID-19. We aimed to describe the clinical presentation of COVID-19 among frail and nonfrail older hospitalised patients and to evaluate the potential association between frailty and clinical course, decision of treatment level with outcomes change in functional capacity and survival. METHODS: We performed a multi-center, retrospective cross-sectional cohort study examining data on clinical presentation and frailty-related domains for hospitalised people aged 75 + years with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test. Frailty was assessed at admission using record-based MPI (rMPI) and Clinical Frailty Scale (CFS). Decision on treatment level about invasive ventilation and cardiopulmonary resuscitation (CPR), change in CFS-score from admission to discharge, changed need of home care, and in-hospital, 30-day and 90-day mortality were registered. RESULTS: 100 patients (median age 82 years (IQR 78-86), 56% female) with COVID-19 were included. 54 patients were assessed moderately or severely frail (rMPI-score = 2 or 3) and compared to non-frail (rMPI-score = 1). At admission, frail patients presented more frequently with confusion. At discharge, functional decline measured by change in CFS and increased home care was more prevalent among frail than the non-frail. Decisions about no invasive ventilation or CPR were more prevalent among frail older patients with COVID-19 than non-frail. Ninety-day mortality was 70% among frail patients versus 15% in non-frail. CONCLUSION: Frailty seems to be associated with confusion, more frequent decisions about treatment level, larger functional decline at discharge and a higher mortality rate among older patients with COVID-19.

SGLT2 Inhibition Does Not Affect Myocardial Fatty Acid Oxidation or Uptake, but Reduces Myocardial Glucose Uptake and Blood Flow in Individuals With Type 2 Diabetes: A Randomized Double-Blind, Placebo-Controlled Crossover Trial.

Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular morbidity and mortality in individuals with type 2 diabetes. Beneficial effects have been attributed to increased ketogenesis, reduced cardiac fatty acid oxidation, and diminished cardiac oxygen consumption. We therefore studied whether SGLT2 inhibition altered cardiac oxidative substrate consumption, efficiency, and perfusion. Thirteen individuals with type 2 diabetes were studied after 4 weeks' treatment with empagliflozin and placebo in a randomized, double-blind, placebo-controlled crossover study. Myocardial palmitate and glucose uptake were measured with 11C-palmitate and 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT). Oxygen consumption and myocardial external efficiency (MEE) were measured with 11C-acetate PET/CT. Resting and adenosine stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) were measured using 15O-H2O PET/CT. Empagliflozin did not affect myocardial free fatty acids (FFAs) uptake but reduced myocardial glucose uptake by 57% (P < 0.001). Empagliflozin did not change myocardial oxygen consumption or MEE. Empagliflozin reduced resting MBF by 13% (P < 0.01), but did not significantly affect stress MBF or MFR. In conclusion, SGLT2 inhibition did not affect myocardial FFA uptake, but channeled myocardial substrate utilization from glucose toward other sources and reduced resting MBF. However, the observed metabolic and hemodynamic changes were modest and most likely contribute only partially to the cardioprotective effect of SGLT2 inhibition.

Arterial stiffness and progression of cerebral white matter hyperintensities in patients with type 2 diabetes and matched controls: a 5-year cohort study.

BACKGROUND: Stroke is a serious complication in patients with type 2 diabetes (T2DM). Arterial stiffness may improve stroke prediction. We investigated the association between carotid-femoral pulse wave velocity [PWV] and the progression of cerebral white matter hyperintensities (WMH), a marker of stroke risk, in patients with T2DM and controls. METHODS: In a 5-year cohort study, data from 45 patients and 59 non-diabetic controls were available for analysis. At baseline, participants had a mean (± SD) age of 59 ± 10 years and patients had a median (range) diabetes duration of 1.8 (0.8-3.2) years. PWV was obtained by tonometry and WMH volume by an automated segmentation algorithm based on cerebral T2-FLAIR and T1 MRI (corrected by intracranial volume, cWMH). High PWV was defined above 8.94 m/s (corresponding to the reference of high PWV above 10 m/s using the standardized path length method). RESULTS: Patients with T2DM had a higher PWV than controls (8.8 ± 2.2 vs. 7.9 ± 1.4 m/s, p < 0.01). WMH progression were similar in the two groups (p = 0.5). One m/s increase in baseline PWV was associated with a 16% [95% CI 1-32%], p < 0.05) increase in cWMH volume at 5 years follow-up after adjustment for age, sex, diabetes, pulse pressure and smoking. High PWV was associated with cWMH progression in the combined cohort (p < 0.05). We found no interaction between diabetes and PWV on cWMH progression. CONCLUSIONS: PWV is associated with cWMH progression in patients with type 2 diabetes and non-diabetic controls. Our results indicate that arterial stiffness may be involved early in the pathophysiology leading to cerebrovascular diseases.

Frailty is associated with hospital readmission in geriatric patients: a prognostic study.

PURPOSE: Targeting health care interventions requires valid measurements when predicting unplanned hospital readmission. The Multidimensional Prognostic Index (MPI) based on Comprehensive Geriatric Assessment (CGA) enables the prediction of mortality and length of stay (LOS) in older hospitalized patients. Our aim was to validate if the MPI as a frailty tool could predict unplanned hospital readmission in geriatric patients. METHODS: This prognostic study was conducted in geriatric wards. The target population was 65 + -year-old patients hospitalized with acute illness. The MPI tool is derived from eight CGA domains by an interdisciplinary team: social aspects, number of drugs, activities of daily living (ADL), instrumental-ADL, cognitive status, severity of morbidity, risk of developing pressure sores, and nutritional status. Patients assessed were categorized into three groups: non-frail (MPI-1), moderate frail (MPI-2) or severe frail (MPI-3). Primary outcome was 30-day unplanned readmission and secondary LOS and 90-day mortality. RESULTS: In total 1467 patients were included from January 1, 2018, to October 1, 2019. Mean age was 84.2 years (± 7.4) and 59% were women. 15.7% were readmitted. Hazard ratio (HR) for readmission in the MPI-2 group (n = 635) was 2.57; 95% confidence interval (CI) 1.25-5.29 (p = 0.01), and 2.60; 95% CI 1.27-5.33 (p = 0.009) in the MPI-3 group (n = 711) compared to the MPI-1 group (n = 121). MPI was a predictor of LOS and mortality. CONCLUSION: Using the MPI tool to identify the frail and non-frail patients is applicable to predict unplanned hospital readmission in geriatric patients. The MPI is superior to the prognostic value of each single domain. MPI will be of great value to health professionals' decision-making.

A reliable and record-based frailty assessment method for older medical inpatients.

PURPOSE: The comprehensive geriatric assessment (CGA) including frailty assessment is considered the gold standard of assessment in geriatric patients. The Multidimensional Prognostic Index (MPI) is a CGA-based bedside assessment tool. Older medical inpatients' medical records comprehensively describe the MPI-featured components. Consequently, MPI-based frailty assessment may be accomplished retrospectively. We found no previous studies concerning record-based MPI. We studied the reproducibility and diagnostic accuracy of a record-based MPI. METHODS: The study was designed as a fully crossed, prospective, and cross-sectional study. A total of 50 inpatients aged ≥ 75 years were included from two medical wards. Record-based MPI was assessed by two independent raters in patients who required personal assistance on a daily basis or had a Charlson Comorbidity Index (CCI) ≥ 1. In the same patients, a bedside MPI rating was performed. Inter-rater and inter-method reproducibility and diagnostic accuracy measures were calculated. RESULTS: Evaluating the inter-rater reproducibility; the mean difference was -0.02 points [95% confidence interval (CI) - 0.06 to 0.01, p = 0.20]. Intraclass correlation coefficient (ICC) was 0.71. Evaluating inter-method reproducibility; the mean difference was -0.02 (95% CI - 0.04 to 0.01, p = 0.18); ICC = 0.83. Sensitivity was 100% and specificity 80%. The areas under the receiver operating curves (ROC) was 0.92 (95% CI 0.75-1.00) and 0.77 (95% CI 0.52-1.00). CONCLUSION: The record-based MPI rating method has an acceptable inter-rater reliability, good inter-method reliability, and high agreement as compared to the bedside-rated MPI. The diagnostic accuracy seems considerable. The record-based MPI seems useful in retrospective frailty assessment among older medical inpatients.

Peroxisome proliferator-activated receptor gamma (PPAR) agonism reduces the insulin-stimulated increase in circulating interleukin-6 in GH replaced GH-deficient adults.

CONTEXT: Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists modify cardiovascular risk factors and inflammatory markers in patients with type 2 diabetes. GH treatment in GH-deficient (GHD) patients may cause insulin resistance and exerts ambiguous effects on inflammatory markers. OBJECTIVE: To investigate circulating markers of inflammation and endothelial function in GH replaced GHD patients before and after 12 weeks administration of either pioglitazone 30 mg/day (N = 10) or placebo (N = 10) in a randomized double-blind parallel design. METHODS: Circulating levels of interleukins (ILs)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, high sensitivity C-reactive protein, vascular cell adhesion molecule-I, and osteoprotegerin (OPG) were measured in the basal state and after a 2.5 h hyperinsulinaemic euglycaemic clamp. RESULTS: Insulin sensitivity improved in the group receiving PPARgamma agonist (P = 0.03). Serum IL-6 levels increased by 114 +/- 31% (mean +/- SE) in the entire group (N = 20) following the hyperinsulinaemic euglycaemic clamp (P = 0.01) performed at study start. Twelve weeks of PPARgamma agonist treatment significantly abrogated this insulin-stimulated increment in IL-6 levels compared to placebo (P = 0.01). Furthermore PPARgamma agonist treatment significantly lowered basal IL-4 levels (P < 0.05). CONCLUSIONS: (i) IL-6 levels increase during a hyperinsulinaemic clamp in GH replaced patients (ii) This increase in IL-6 is abrogated by PPARgamma agonist treatment (iii) we hypothesize that PPARgamma agonist-induced improvement of insulin sensitivity may obviate a compensatory rise in IL-6.

Intensive insulin therapy protects the endothelium of critically ill patients.

The vascular endothelium controls vasomotor tone and microvascular flow and regulates trafficking of nutrients and biologically active molecules. When endothelial activation is excessive, compromised microcirculation and subsequent cellular hypoxia contribute to the risk of organ failure. We hypothesized that strict blood glucose control with insulin during critical illness protects the endothelium, mediating prevention of organ failure and death. In this preplanned subanalysis of a large, randomized controlled study, intensive insulin therapy lowered circulating levels of ICAM-1 and tended to reduce E-selectin levels in patients with prolonged critical illness, which reflects reduced endothelial activation. This effect was not brought about by altered levels of endothelial stimuli, such as cytokines or VEGF, or by upregulation of eNOS. In contrast, prevention of hyperglycemia by intensive insulin therapy suppressed iNOS gene expression in postmortem liver and skeletal muscle, possibly in part via reduced NF-kappaB activation, and lowered the elevated circulating NO levels in both survivors and nonsurvivors. These effects on the endothelium statistically explained a significant part of the improved patient outcome with intensive insulin therapy. In conclusion, maintaining normoglycemia with intensive insulin therapy during critical illness protects the endothelium, likely in part via inhibition of excessive iNOS-induced NO release, and thereby contributes to prevention of organ failure and death.

Effect of insulin therapy on coagulation and fibrinolysis in medical intensive care patients.

OBJECTIVE: Most intensive care deaths beyond the first few days of critical illness are attributable to nonresolving organ failure, either due to or coinciding with sepsis. One of the mechanisms that is thought to contribute to the pathogenesis of organ failure is microvascular thrombosis. Recently, we reported significant improved survival and prevention of organ failure with the use of intensive insulin therapy to maintain normoglycemia for at least several days. We hypothesize that intensive insulin therapy also prevents severe coagulation abnormalities thereby contributing to less organ failure and better survival. DESIGN: This was a preplanned subanalysis of a large randomized controlled study, conducted at a university hospital medical intensive care unit. The intervention was strict blood glucose control to normoglycemia with insulin. RESULTS: Mortality of intensive insulin-treated patients was lower than that of conventionally treated patients for all classes of upon-admission disseminated intravascular coagulation (DIC) scores, except for those patients with overt DIC scores of 6 or higher (for DIC < 5, p = 0.003; for DIC > or = 5, p = 0.4). There was no effect of insulin therapy on any of the fibrinolytic, coagulation, or inflammatory parameters tested. CONCLUSIONS: This negative observation does not support a key role for these systems in explaining the clinical benefit of intensive insulin therapy, although a short-lived effect within 5 days of treatment cannot be excluded.