The impact of obesity on chronic oedema/lymphoedema of the leg - an international multicenter cross-sectional study (LIMPRINT).

BACKGROUND/OBJECTIVES: Obesity and chronic oedema/lymphoedema are two distinct but related conditions, rarely investigated together. The aim was to study the impact of increased weight on chronic oedema and related factors. SUBJECTS/METHODS: A cross-sectional study, 38 centers, nine countries. Patients with clinically confirmed chronic oedema/lymphoedema of the leg were included. Weight category was estimated as: normal weight (BMI 20-30), class I-II obesity (BMI 30-40), or class III obesity (BMI > 40). Factors were tested for an association with increased weight, using a multivariable model. RESULTS: A total of 7397 patients were included; 43% with normal weight, 36% class I-II obesity and 21% class III obesity. Increased weight was associated with more advanced stages of chronic oedema (ISL stage III; the most advanced form); affecting 14% in normal weight, 18% class I-II obesity and 39% class III obesity (p < 0.001). Ten factors were independently associated with increased weight: diabetes (OR 2.4), secondary lymphoedema (OR 2.7), cellulitis/erysipelas within 12 months (OR 1.2), bilateral lymphoedema (OR 3.6), compression therapy (OR 2.1), increased swelling duration (1-2 years OR 1.3, 2-5 years OR 2.5, 5-10 years OR 3.6, >10 years OR 3.5) decreased mobility (walking with aid OR 1.9, being chair bound OR 1.2) and age (reference<45 years; 45-64 years OR 1.5, 75-84 years OR 0.6, 85+ years OR 0.2). Increased weight was associated with a lower presentation of peripheral arterial disease (OR 0.7) and poorer chronic oedema control (OR 0.8). Patients with obesity had lower function, appearance and more severe symptoms (LYMQOL) and lower quality of life (EuroQol). CONCLUSIONS: Obesity negatively impacts chronic oedema, leading to more advanced stages. Achieving good control of swelling with compression is more difficult in these patients. Increased awareness of chronic oedema/lymphoedema as a complication of obesity is important for early detection and for developing effective strategies to prevent and manage them.

Type 2 diabetes mellitus in patients with ischemic stroke - A nationwide study.

AIMS: Type 2 diabetes (T2D) is a risk factor for ischemic stroke (IS) and associated with an adverse prognosis. Both stroke and diabetes care has evolved substantially during the last decade. This study aimed to determine the prevalence of T2D among IS patients along with time trends in the risk profile, use of glucose-lowering medications, quality-of-care and clinical outcomes, including stroke severity; length-of-stay; mortality, readmission and recurrent stroke in a large national cohort. METHODS: Registry-based cohort study including all IS events in Denmark from 2004 to 2020. IS with co-morbid T2D were compared to IS without diabetes while adjusting for age, sex, stroke severity, co-morbidity and socio-economic factors. RESULTS: The study included 169,262 IS events; 24,479 with co-morbid T2D. The prevalence of T2D in IS increased from 12.0% (2004-2006) to 17.0% (2019-2020). The adjusted absolute 30-day mortality risk in IS with T2D decreased from 9.9% (2004-2006) to 7.8% (2019-2020). The corresponding adjusted risk ratios (aRR) were 1.22 95% confidence interval (1.09-1.37) and 1.29 (1.11-1.50), respectively. The aRR of 365-day mortality was in 2004-2006: 1.20 (1.12-1.29) and in 2019-2020: 1.34 (1.22-1.47). The 30- and 365-day readmissions rates were also consistently higher in IS with T2D. CONCLUSIONS: The prevalence of T2D in IS increased over time. The 30- and 365-day mortality rates decreased over the time-period but were consistently higher in IS with co-morbid T2D. Readmissions were also higher in IS with T2D. This highlights an urgent need for strategies to further improve the prognosis in IS patients with co-morbid T2D.

Glucagonlike peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors in ischemic strokes with diabetes 2.

BACKGROUND AND PURPOSE: Cardiovascular outcome trials demonstrate that glucagonlike peptide-1 receptor agonists (GLP-1RAs) reduce the risk of major adverse cardiovascular events in patients with type 2 diabetes (T2D), whereas dipeptidyl peptidase-4 inhibitors (DPP-4is) have not shown cardiovascular benefits. We compared acute ischemic stroke (AIS) with T2D treated with either a GLP-1RA or DPP-4i prior to the index stroke. METHODS: This national cohort study included AIS patients with T2D from 2017 to 2020 in Denmark who were users of a GLP-1RA or DPP-4i. To be categorized as a user, we required at least 12 months of exposure and no concurrent treatment with another newer glucose-lowering medication during the last 3 months prior to the index stroke. GLP-1RA users were compared to users of DPP-4i while adjusting for the calendar year of index stroke, age, sex, comorbidity, and socioeconomic factors. RESULTS: The study included 1567 AIS events with T2D; 593 were users of GLP-1RA and 974 of DPP-4i. The absolute risk of a very severe stroke was 2.4% (95% confidence interval [CI] = 1.2-3.7) in GLP-1RA users and 6.1% (95% CI = 4.6-7.7) in DPP-4i users. The corresponding adjusted risk ratio (aRR) of GLP-1RA versus DPP-4i was 0.49 (95% CI = 0.24-1.00). The aRRs of 30-day and 365-day mortality were 0.55 (95% CI = 0.32-0.94) and 0.72 (95% CI = 0.53-0.98), respectively. CONCLUSIONS: The risk of a very severe stroke as well as the 30-day and 365-day poststroke mortality rates were lower among the AIS patients with comorbid T2D receiving GLP-1RA prior to the index stroke compared to those receiving DPP-4i. Hence, GLP-1RA may improve stroke outcomes in comparison with DPP-4i.

Physician-led medication reviews in polypharmacy patients treated with at least 12 medications in a type 2 diabetes outpatient clinic: A randomised trial.

AIMS: Medication reviews can be used to promote appropriate pharmacotherapy and negate the harmful consequences of polypharmacy. This study aimed to evaluate the effect of physician-led medication reviews and increased cross-sectoral communication as a supplement to standard care in a type 2 diabetes outpatient clinic. METHODS: This pragmatic randomised clinical trial enrolled patients with type 2 diabetes treated with at least 12 medications. The subjects were randomised to either standard care (standard care consultation at the outpatient clinic) or standard care plus a medication review consultation and increased cross-sectoral communication. The primary outcome was the number of medications used after six months. Health-related quality of life was quantified using the EuroQoL 5-dimension 5-level (EQ5D-5 L) questionnaire. RESULTS: We recruited 50 participants with a median age of 72 (IQR 67-75) years. The mean number of medications per patient changed from 17.9 to 14.3 in the intervention group and 17.6 to 17.2 in the control group (rate ratio 0.81). The reasons for discontinuations were medication no longer indicated (60%), safety issues (20%), efficacy issues (15%) or patient preferences (5%). There was a significant difference in the change in health-related quality of life (EQ5D-5 L index score) in favour of the intervention (0.111, 95% CI 0.001 to 0.221). CONCLUSIONS: Physician-led medication reviews and increased cross-sectoral communication in patients with type 2 diabetes treated with at least 12 medications reduced the number of medications used and improved health-related quality of life. Implementing and further investigating similar interventions as standard care seems reasonable.

Brain proteome profiling implicates the complement and coagulation cascade in multiple system atrophy brain pathology.

BACKGROUND: Multiple system atrophy (MSA) is a rare, progressive, neurodegenerative disorder presenting glia pathology. Still, disease etiology and pathophysiology are unknown, but neuro-inflammation and vascular disruption may be contributing factors to the disease progression. Here, we performed an ex vivo deep proteome profiling of the prefrontal cortex of MSA patients to reveal disease-relevant molecular neuropathological processes. Observations were validated in plasma and cerebrospinal fluid (CSF) of novel cross-sectional patient cohorts. METHODS: Brains from 45 MSA patients and 30 normal controls (CTRLs) were included. Brain samples were homogenized and trypsinized for peptide formation and analyzed by high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS). Results were supplemented by western blotting, immuno-capture, tissue clearing and 3D imaging, immunohistochemistry and immunofluorescence. Subsequent measurements of glial fibrillary acid protein (GFAP) and neuro-filament light chain (NFL) levels were performed by immunoblotting in plasma of 20 MSA patients and 20 CTRLs. Finally, we performed a proteome profiling of 144 CSF samples from MSA and CTRLs, as well as other parkinsonian disorders. Data were analyzed using relevant parametric and non-parametric two-sample tests or linear regression tests followed by post hoc tests corrected for multiple testing. Additionally, high-throughput bioinformatic analyses were applied. RESULTS: We quantified more than 4,000 proteins across samples and identified 49 differentially expressed proteins with significantly different abundances in MSA patients compared with CTRLs. Pathway analyses showed enrichment of processes related to fibrinolysis and complement cascade activation. Increased fibrinogen subunit ß (FGB) protein levels were further verified, and we identified an enriched recognition of FGB by IgGs as well as intra-parenchymal accumulation around blood vessels. We corroborated blood-brain barrier leakage by a significant increase in GFAP and NFL plasma levels in MSA patients that correlated to disease severity and/or duration. Proteome profiling of CSF samples acquired during the disease course, confirmed increased total fibrinogen levels and immune-related components in the soluble fraction of MSA patients. This was also true for the other atypical parkinsonian disorders, dementia with Lewy bodies and progressive supra-nuclear palsy, but not for Parkinson's disease patients. CONCLUSION: Our results implicate activation of the fibrinolytic cascade and immune system in the brain as contributing factors in MSA associated with a more severe disease course.

Effect of Influenza Vaccination on Risk of Coronavirus Disease 2019: A Prospective Cohort Study of 46†000 Healthcare Workers.

BACKGROUND: The purpose of this study was to assess whether influenza vaccination has an impact on the risk of coronavirus disease 2019 (COVID-19). METHODS: A cohort of 46 112 healthcare workers were tested for antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and filled in a survey on COVID-19 symptoms, hospitalization, and influenza vaccination. RESULTS: The risk ratio of hospitalization due to SARS-CoV-2 for influenza vaccinated compared with unvaccinated participants was 1.00 for the seasonal vaccination in 2019/2020 (confidence interval, .56-1.78, P = 1.00). Likewise, no clinical effect of influenza vaccination on development of antibodies against SARS-CoV-2 was found. CONCLUSIONS: The present findings indicate that influenza vaccination does not affect the risk of SARS-CoV-2 infection or COVID-19.

On measurements of glucagon secretion in healthy, obese, and Roux-en-Y gastric bypass operated individuals using sandwich ELISA.

Glucagon is a key regulator of metabolism and is used in the diagnostic of neuroendocrine tumors. Accurate measurement of glucagon requires both extreme sensitivity and specificity since several peptides are derived from the same proglucagon precursor encoding part of the glucagon sequence and given that glucagon circulates in picomolar concentrations. A sandwich ELISA was recently developed and extensively evaluated; however, this method may not be accurate when measuring glucagon in patients with an enhanced production of proglucagon-derived peptides as seen after Roux-en-Y gastric bypass (RYGB). To overcome this, a modified version of the ELISA was developed. In this study, we evaluate an unmodified and a modified version of the ELISA in healthy individuals, individuals with obesity, and finally in two cohorts of patients following RYGB surgery using different nutrient stimuli to assess glucagon dynamics. Finally, in vitro spike-in recoveries using native glucagon and proglucagon-derived peptides were performed in buffer and in plasma. Our data support that both versions of the ELISA accurately capture endogenous and exogenous glucagon in healthy individuals and in individuals with obesity. However, the unmodified version of the assay may overestimate glucagon levels in patients following RYGB in line with minimal but consistent cross-reactivity to oxyntomodulin and glicentin that both are 50-fold increased after RYGB. Importantly, we did not find any changes between the two protocols at fasted conditions and therefore diagnostics of glucagonomas is not affected by the choice of assay procedure nor the surgical history of the patient (RYGB).

In Alzheimer's disease, amyloid beta accumulation is a protective mechanism that ultimately fails.

HYPOTHESIS AND PREDICTIONS: Here, we claim that amyloid beta (Aß) accumulation is a protective mechanism that ultimately fails. We predict that more Aß accumulates in regions with higher rates of glucose metabolism, reaching a maximum followed by progression of pathology. BACKGROUND: Aß accumulation is characteristic of Alzheimer's disease (AD) but the accumulation does not correlate with cognitive decline, unlike the rates of glucose metabolism. STRATEGY: We compared averaged and individual estimates of regional binding potentials of [11 C]Pittsburgh compound B to regionally averaged and individual values of metabolism of [18 F]fluorodeoxyglucose in brain regions of volunteers with AD. SIGNIFICANCE: The claim explains the cognitive decline in some patients at a significantly lower level of Aß deposition than in other patients, as well as the presence of cognitively healthy individuals with high Aß accumulation. With further support of the hypothesis, the significance of Aß accumulation in brains of patients with AD may require revision.

Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases.

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain's utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain's metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain's glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer's disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson's disease and cognitive benefits in patients with-or at risk of-Alzheimer's disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.

Experimental non-severe hypoglycaemia substantially impairs cognitive function in type 2 diabetes: a randomised crossover trial.

AIMS/HYPOTHESIS: Previous studies have demonstrated a relationship between cognitive impairment and hypoglycaemia (<3 mmol/l). This study hypothesised that non-severe insulin-induced hypoglycaemia reduces cognitive function in individuals with type 2 diabetes. METHODS: In this randomised crossover study, 25 participants with type 2 diabetes attended two experimental visits with hyperinsulinaemic glucose clamping: one hypoglycaemic clamp (plasma glucose 3.0 ± 0.2 mmol/l) and one euglycaemic clamp (plasma glucose 6.0 ± 0.2 mmol/l). Participants were eligible if their diabetes was treated with diet or glucose-lowering medications (except sulfonylureas or insulin), age was 35-70 years, BMI was 23-35 kg/m2 and HbA1c was below 75 mmol/mol (9%). Cognitive function was assessed with a neurocognitive test battery measuring verbal memory, executive function, sustained attention and psychomotor speed. From the examined cognitive domains, a global cognition score was constructed estimating global cognition. A measurement for psychomotor speed was selected as the primary outcome. Participants and people assessing the outcomes were blinded to group assignment. RESULTS: Cognitive performance was impaired during hypoglycaemia with a mean score in the primary outcome test, Symbol Digit Modalities Test measuring psychomotor speed, of 48.7 ± 9.8 (hypoglycaemia) vs 56.6 ± 12.0 (euglycaemia); i.e. a change of -7.9 points (95% CI -10.9, -4.9; p < 0.0001). In addition, hypoglycaemia reduced global cognitive score by -0.7 (95% CI -0.9, -0.6; p < 0.0001). A stable glucose plateau was achieved during both experimental visits. For the hypoglycaemic clamp, mean plasma glucose concentration (± SD) during neurocognitive testing was 3.1 (± 0.3) mmol/l. Age, sex, fasting C-peptide, counter-regulatory hormones and the severity of hypoglycaemic symptoms did not influence cognitive function. CONCLUSIONS/INTERPRETATION: Acute non-severe hypoglycaemia (mean plasma glucose 3.1 mmol/l) has a substantial negative impact on cognitive function in individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03014011. FUNDING: The study was supported in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp (MSD-MA-NORD-007-01). The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. Funding was also received from Skibsreder Per Henriksen, R. og hustrus Foundation, The Danish Alzheimer Foundation and Savværksejer Jeppe Juhl og hustrus Foundation.

Multiple Soluble Components of the Glycocalyx Are Increased in Patient Plasma After Ischemic Stroke.

Background and Purpose- The GLX (glycocalyx) is a protein/polysaccharide meshwork at the cellular surface. Consisting largely of glycosaminoglycans and proteoglycans, the GLX can shed in response to stress. In this study, we assay 11 components of the GLX in plasma from patients with ischemic stroke from a longitudinal cohort. Methods- Plasma samples from healthy individuals (N=8), and patients with ischemic stroke day ≥3, day 7, and day 90 (N=9-14) were immunoassayed for diverse components of the GLX. Results- Median stroke severity was mild (National Institutes of Health Stroke Scale 2.0 (range, 0-6) at day ≤3). Three (keratan-chondroitin-heparan-sulfate) of 4 glycosaminoglycans and CD44 (proteoglycan) were increased at day 7 and returned to baseline at day 90. Proteoglycan syndecan (Syn)-3 increased and Syn-2 levels decreased, significantly. Conclusions- Individual GLX components are often assayed as stand-alone biomarkers for endothelial health. This study suggests a full assessment of GLX components is more indicative of the endothelial health of an individual and represents a complex GLX signature that may be valuable as a composite biomarker of disease.

Growth hormone signaling and action in obese versus lean human subjects.

Growth hormone (GH) levels are blunted in obesity, but it is not known whether this relates to altered GH sensitivity and whether this influences the metabolic adaptation to fasting. Therefore, we investigated the effect of obesity on GH signal transduction and fasting-induced changes in GH action. Nine obese (BMI 35.7 kg/m2) and nine lean (BMI 21.5 kg/m2) men were studied in a randomized crossover design with 1) an intravenous GH bolus, 2) an intravenous saline bolus, and 3) 72 h of fasting. Insulin sensitivity (hyperinsulinemic, euglycemic clamp) and substrate metabolism (glucose tracer and indirect calorimetry) were measured in studies 1 and 2. In vivo GH signaling was assessed in muscle and fat biopsies. GH pharmacokinetics did not differ between obese and lean subjects, but endogenous GH levels were reduced in obesity. GH signaling (STAT5b phosphorylation and CISH mRNA transcription), and GH action (induction of lipolysis and peripheral insulin resistance) were similar in the two groups, but a GH-induced insulin antagonistic effect on endogenous glucose production only occurred in the obese. Fasting-induced IGF-I reduction was completely abrogated in obese subjects despite a comparable relative increase in GH levels (ΔIGF-I: lean, -66 ± 10 vs. obese, 27 ± 16 µg/l; P < 0.01; ΔGH: lean, 647 ± 280 vs. obese, 544 ± 220%; P = 0.76]. We conclude that 1) GH signaling is normal in obesity, 2) in the obese state, the preservation of IGF-I with fasting and the augmented GH-induced central insulin resistance indicate increased hepatic GH sensitivity, 3) blunted GH levels in obesity may protect against insulin resistance without compromising IGF-I status.

Hypercortisolism in Newly Diagnosed Type 2 Diabetes: A Prospective Study of 384 Newly Diagnosed Patients.

Cross-sectional studies in small and selected populations report a high prevalence of hypercortisolism in patients with type 2 diabetes (T2D), which could have therapeutic implications, if confirmed. We therefore estimated the prevalence of hypercortisolism in a large and unselected cohort of recently diagnosed T2D patients. Consecutive patients with recently diagnosed T2D first underwent an overnight dexamethasone (1 mg) suppression test (OD). Patients not suppressing serum cortisol ≤50 nmol/l proceeded with a 48-h low dose dexamethasone suppression test (LDDST) and 24-h urinary free cortisol collection (UFC). Patients with elevated cortisol levels according to LDDST and/or UFC underwent imaging guided by plasma ACTH levels, and assessment of bone mineral density. A total of 384 T2D patients (232male/152 females) with a mean age of 60±10 years were included. Eighty-five (22%) patients suppressed incompletely to OD of whom 20 (5%) failed to suppress after LDDST and/or had elevated UFC (=hypercortisolism). Patients with hypercortisolism did not differ as regards age, BMI, HbA1c, T-score or blood pressure, but a higher proportion of them received antihypertensive treatment (100% vs. 64%, p=0.001). Imaging revealed adrenal adenoma(s) in 9 cases and a pituitary macroadenoma in 1 case. We found a 5% prevalence of hypercortisolism in unselected, recently diagnosed T2D, which was not associated with a persuasive cushingoid phenotype. The clinical implications are therefore uncertain.

Effects of hypoglycaemia on working memory and regional cerebral blood flow in type 1 diabetes: a randomised, crossover trial.

AIMS/HYPOTHESIS: The aim of this randomised, crossover trial was to compare cognitive functioning and associated brain activation patterns during hypoglycaemia (plasma glucose [PG] just below 3.1 mmol/l) and euglycaemia in individuals with type 1 diabetes mellitus. METHODS: In this patient-blinded, crossover study, 26 participants with type 1 diabetes mellitus attended two randomised experimental visits: one hypoglycaemic clamp (PG 2.8 ± 0.2 mmol/l, approximate duration 55 min) and one euglycaemic clamp (PG 5.5 mmol/l ± 10%). PG levels were maintained by hyperinsulinaemic glucose clamping. Cognitive functioning was assessed during hypoglycaemia and euglycaemia conditions using a modified version of the digit symbol substitution test (mDSST) and control DSST (cDSST). Simultaneously, regional cerebral blood flow (rCBF) was measured in pre-specified brain regions by six H215O-positron emission tomographies (PET) per session. RESULTS: Working memory was impaired during hypoglycaemia as indicated by a statistically significantly lower mDSST score (estimated treatment difference [ETD] -0.63 [95% CI -1.13, -0.14], p = 0.014) and a statistically significantly longer response time (ETD 2.86 s [7%] [95% CI 0.67, 5.05], p = 0.013) compared with euglycaemia. During hypoglycaemia, mDSST task performance was associated with increased activity in the frontal lobe regions, superior parietal lobe and thalamus, and decreased activity in the temporal lobe regions (p < 0.05). Working memory activation (mDSST - cDSST) statistically significantly increased blood flow in the striatum during hypoglycaemia (ETD 0.0374% [95% CI 0.0157, 0.0590], p = 0.002). CONCLUSIONS/INTERPRETATION: During hypoglycaemia (mean PG 2.9 mmol/l), working memory performance was impaired. Altered performance was associated with significantly increased blood flow in the striatum, a part of the basal ganglia implicated in regulating motor functions, memory, language and emotion. TRIAL REGISTRATION: NCT01789593, clinicaltrials.gov FUNDING: This study was funded by Novo Nordisk.

Pathophysiology-based phenotyping in type 2 diabetes: A clinical classification tool.

BACKGROUND: Type 2 diabetes may be a more heterogeneous disease than previously thought. Better understanding of pathophysiological subphenotypes could lead to more individualized diabetes treatment. We examined the characteristics of different phenotypes among 5813 Danish patients with new clinically diagnosed type 2 diabetes. METHODS: We first identified all patients with rare subtypes of diabetes, latent autoimmune diabetes of adults (LADA), secondary diabetes, or glucocorticoid-associated diabetes. We then used the homeostatic assessment model to subphenotype all remaining patients into insulinopenic (high insulin sensitivity and low beta cell function), classical (low insulin sensitivity and low beta cell function), or hyperinsulinemic (low insulin sensitivity and high beta cell function) type 2 diabetes. RESULTS: Among 5813 patients diagnosed with incident type 2 diabetes in the community clinical setting, 0.4% had rare subtypes of diabetes, 2.8% had LADA, 0.7% had secondary diabetes, 2.4% had glucocorticoid-associated diabetes, and 93.7% had WHO-defined type 2 diabetes. In the latter group, 9.7% had insulinopenic, 63.1% had classical, and 27.2% had hyperinsulinemic type 2 diabetes. Classical patients were obese (median waist 105 cm), and 20.5% had cardiovascular disease (CVD) at diagnosis, while insulinopenic patients were fairly lean (waist 92 cm) and 17.5% had CVD (P = 0.14 vs classical diabetes). Hyperinsulinemic patients were severely obese (waist 112 cm), and 25.5% had CVD (P < 0.0001 vs classical diabetes). CONCLUSIONS: Patients clinically diagnosed with type 2 diabetes are a heterogeneous group. In the future, targeted treatment based on pathophysiological characteristics rather than the current "one size fits all" approach may improve patient prognosis.

Capillary dysfunction is associated with symptom severity and neurodegeneration in Alzheimer's disease.

INTRODUCTION: We examined whether cortical microvascular blood volume and hemodynamics in Alzheimer's disease (AD) are consistent with tissue hypoxia and whether they correlate with cognitive performance and the degree of cortical thinning. METHODS: Thirty-two AD patients underwent cognitive testing, structural magnetic resonance imaging (MRI), and perfusion MRI at baseline and after 6 months. We measured cortical thickness, microvascular cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and capillary transit time heterogeneity (CTH) and estimated tissue oxygen tension (PtO2). RESULTS: At baseline, poor cognitive performance and regional cortical thinning correlated with lower CBF and CBV, with higher MTT and CTH and with low PtO2 across the cortex. Cognitive decline over time was associated with increasing whole brain relative transit time heterogeneity (RTH = CTH/MTT). DISCUSSION: Our results confirm the importance of microvascular pathology in AD. Deteriorating microvascular hemodynamics may cause hypoxia, which is known to precipitate amyloid retention.

Rates of Community-based Antibiotic Prescriptions and Hospital-treated Infections in Individuals With and Without Type 2 Diabetes: A Danish Nationwide Cohort Study, 2004-2012.

BACKGROUND: The excess risk of antibiotic use and hospital-treated infections in patients with type 2 diabetes (T2D) compared with general population is poorly understood. METHODS: In a nationwide cohort of patients with incident T2D (n = 155 158) and an age-, gender-, and residence-matched comparison cohort (n = 774 017), we used Cox regression to compute rates and confounder-adjusted rate ratios (aRRs) of community-based antibiotic prescription redemption and hospital-treated infections during 2004-2012. RESULTS: The rates of community-based antibiotic prescriptions in the T2D and comparison cohorts were 364 vs 275 per 1000 person-years after a median follow-up of 1.1 years (aRR = 1.24; 95% confidence interval [CI], 1.23 to 1.25). The corresponding rates for hospital-treated infection were 58 vs 39 per 1000 person-years after a median follow-up of 2.8 years (aRR = 1.49; 95% CI, 1.47 to 1.52). The aRRs were increased particularly for urinary tract infections (UTIs, 1.41; 95% CI, 1.35 to 1.45), skin infections (1.50; 95% CI, 1.45 to 1.55), septicemia (1.60; 95% CI, 1.53 to 1.67), and tuberculosis (1.61; 95% CI, 1.25 to 2.06) and of community-based antibiotics prescribed for UTIs (1.31; 95% CI, 1.29 to 1.33), Staphylococcus aureus infections (1.32; 95% CI, 1.30 to 1.34), and mycobacterial infections (1.69; 95% CI, 1.36 to 2.09). The 1-year aRR declined from 1.89 (95% CI, 1.75 to 2.04) in 2004 to 1.59 (95% CI, 1.45 to 1.74) in 2011 for hospital-treated infection (trend P = .007) and from 1.31 (95% CI, 1.27 to 1.36) in 2004 to 1.26 (95% CI, 1.22 to 1.30) in 2011 for community-based antibiotic prescriptions (trend P = .006). CONCLUSIONS: Patients with T2D have rates of community-based antibiotic prescriptions and hospital-treated infections that are higher than for the general population.

Differential regulation of lipid and protein metabolism in obese vs. lean subjects before and after a 72-h fast.

Increased availability of lipids may conserve muscle protein during catabolic stress. Our study was designed to define 1) intracellular mechanisms leading to increased lipolysis and 2) whether this scenario is associated with decreased amino acid and urea fluxes, and decreased muscle amino acid release in obese subjects under basal and fasting conditions. We therefore studied nine lean and nine obese subjects twice, after 12 and 72 h of fasting, using measurements of mRNA and protein expression and phosphorylation of lipolytic and protein metabolic signaling molecules in fat and muscle together with whole body and forearm tracer techniques. Obese subjects displayed increased whole body lipolysis, decreased urea production rates, and decreased forearm muscle protein breakdown per 100 ml of forearm tissue, differences that persisted after 72 h of fasting. Lipolysis per fat mass unit was reduced in obese subjects and, correspondingly, adipose tissue hormone-sensitive lipase (HSL) phosphorylation and mRNA and protein levels of the adipose triglyceride lipase (ATGL) coactivator CGI58 were decreased. Fasting resulted in higher HSL phosphorylations and lower protein levels of the ATGL inhibitor G0S2. Muscle protein expressions of mammalian target of rapamycin (mTOR) and 4EBP1 were lower in obese subjects, and MuRf1 mRNA was higher with fasting in lean but not obese subjects. Phosphorylation and signaling of mTOR decreased with fasting in both groups, whereas ULK1 protein and mRNA levels increased. In summary, obese subjects exhibit increased lipolysis due to a large fat mass with blunted prolipolytic signaling, together with decreased urea and amino acid fluxes both in the basal and 72-h fasted state; this is compatible with preservation of muscle and whole body protein.

Low positive predictive value of midnight salivary cortisol measurement to detect hypercortisolism in type 2 diabetes.

BACKGROUND: Hypercortisolism is prevalent in type 2 diabetes (T2D), but analytical and functional uncertainties prevail. Measurement of salivary cortisol is considered an expedient screening method for hypercortisolism, but its usefulness in the context of T2D is uncertain. AIM: To compare late-night salivary cortisol (LNSC) with the 1 mg overnight dexamethasone suppression test (DST), which was considered 'reference standard', in T2D. PATIENTS AND METHODS: A total of 382 unselected and recently diagnosed patients with T2D underwent assessment of LNSC and DST, and the test outcome was related to age, gender, body mass index (BMI) and haemoglobin A1c levels. We used the following cut-off values: LNSC ≤ 3·6 nmol/l and DST ≤ 50 nmol/l. RESULTS: The median (range) levels of LNSC and DST were 6·1 (0·3-46·2) nmol/l and 34 (11-547) nmol/l, respectively. Hypercortisolism was present in 86% based on LNSC values and 22% based on DST. LNSC, as compared to DST, had the following test characteristics: sensitivity: 85% (95% CI: 7-92%), specificity: 14% (95% CI: 10-19%), positive predictive value: 22% (95% CI: 17-27%), negative predictive value: 76% (95% CI: 63-87%), and overall accuracy: 30% (95% CI: 25-34%). LNSC and DST values were not associated with haemoglobin A1c, BMI and age in this cohort of patients with T2D. CONCLUSION: The LNSC is characterized by very low specificity and poor positive predictive value as compared to the DST, resulting in an overall low accuracy. Further methodological and clinical studies are needed to substantiate the relevance of cortisol status in T2D.

Association of parental history of type 2 diabetes with age, lifestyle, anthropometric factors, and clinical severity at type 2 diabetes diagnosis: results from the DD2 study.

BACKGROUND: We investigated whether parental history of type 2 diabetes mellitus (T2D) is associated with age, lifestyle, anthropometric factors, and clinical severity at the time of T2D diagnosis. METHODS: We conducted a cross-sectional study based on the Danish Centre for Strategic Research in Type 2 Diabetes cohort. We examined the prevalence ratios (PR) of demographic, lifestyle, anthropometric, and clinical factors according to parental history, using Poisson regression adjusting for age and gender. RESULTS: Of 2825 T2D patients, 34% (n = 964) had a parental history of T2D. Parental history was associated with younger age at diagnosis [adjusted (a)PR 1.66, 95% confidence interval: 1.19, 2.31) for age <40 years; aPR 1.36 (95% confidence interval: 1.24, 1.48) for ages 40-59 years] and with higher baseline fasting plasma glucose [≥7.5 mmol/L, aPR 1.47 (95% confidence interval: 1.20, 1.80)], and also tended to be associated with lower beta cell function. In contrast, patients both with and without a parental history had similar occurrence of central obesity [91% vs. 91%], weight gain ≥30 kg since age 20 [52% vs. 53%], and lack of regular physical activity [60% vs. 58%]. Presence of diabetes complications or comorbidities at T2D diagnosis was not associated with parental history. CONCLUSIONS: The lack of an association between parental history and adverse lifestyle factors indicates that T2D patients do not inherit a particular propensity for overeating or inactivity, whereas patients with a parental history may have more severe pancreatic beta cell dysfunction at diagnosis.