The GLP-1-mediated gut-kidney cross talk in humans: mechanistic insight.

Incretin-based therapy is an antidiabetic and antiobesity approach mimicking glucagon-like peptide-1 (GLP-1) with additional end-organ protection. This review solely focuses on randomized, controlled mechanistic human studies, investigating the renal effects of GLP-1. There is no consensus about the localization of GLP-1 receptors (GLP-1Rs) in human kidneys. Rodent and primate data suggest GLP-1R distribution in smooth muscle cells in the preglomerular vasculature. Native GLP-1 and GLP-1R agonists elicit renal effects. Independently of renal plasma flow and glomerular filtration rate, GLP-1 has a natriuretic effect but only during volume expansion. This is associated with high renal extraction of GLP-1, suppression of angiotensin II, and increased medullary as well as cortical perfusion. These observations may potentially indicate that impaired GLP-1 sensing could establish a connection between salt sensitivity and insulin resistance. It is concluded that a functional GLP-1 kidney axis exists in humans, which may play a role in renoprotection.

[15O]H2O myocardial perfusion positron emission tomography: Added value of relative stress perfusion deficit in the prediction of significant coronary artery stenosis in a mixedpopulation.

BACKGROUND: It remains unknown whether estimation of the relative stress perfusion deficit offers added value in the prediction of significant coronary artery stenosis in myocardial perfusion imaging with [15O]H2O positron emission tomography (PET) in a population with high prevalence of established cardiac disease. METHODS: During eight months, we consecutively included all patients undergoing [15O]H2O PET and subsequent invasive coronary angiography (ICA). Significant stenosis was defined from ICA as fractional flow reserve ≤.8 or coronary artery narrowing of ≥70%. We calculated absolute and relative total perfusion deficits (aTPD and rTPD, respectively) as semiquantitative measures of the extent and severity of reduced stress perfusion. A multivariate logistic regression analysis was performed to test the adjusted associations (odds ratio (OR) with 95% CI) with significant coronary artery stenosis. RESULTS: Of 800 patients undergoing [15O]H2O PET, 144 underwent ICA, where 142 patients had aTPD of ≥3% and 79 (55%) of these had at least one significant stenosis. In an adjusted analysis, rTPD (OR10% increase = 2.12 (1.44-3.12), P < .001), previous coronary artery bypass grafting (CABG) (OR = .11 (.03-.36), P < .001) and reduced left ventricular ejection fraction (LVEF) (OR = .25 (.08-.84), P = .02) were independently associated with significant stenosis, whereas the association with aTPD (OR10% increase = 1.14 (.98-1.32), P = .08) was modest. CONCLUSIONS: In the presence of an absolute perfusion deficit (aTPD of ≥3%), rTPD may improve the prediction of significant stenosis in a heterogeneous population of patients examined with [15O]H2O PET. Furthermore, previous CABG and reduced LVEF are associated with nonstenotic perfusion deficiencies, suggesting caution when interpreting myocardial perfusion imaging in such patients.

82Rb and [15O]H2O myocardial perfusion PET imaging: a prospective head to head comparison.

BACKGROUND: 82Rb PET and [15O]H2O PET are both validated tracers for myocardical perfusion imaging but have not previously been compared clinically. During our site's transition from 82Rb to [15O]H2O PET, we performed a head-to-head comparison in a mixed population with suspected ischemic heart disease. METHODS: A total of 37 patients referred for perfusion imaging due to suspicion of coronary stenosis were examined with both 82Rb and [15O]H2O PET on the same day in rest and during adenosine-induced stress. The exams were rated by two blinded readers as normal, regional ischemia, globally reduced myocardial perfusion, or myocardial scarring. For [15O]H2O PET, regional ischemia was defined as two neighboring segments with average stress perfusion ≤ 2.3 mL/(min·g). Further, we evaluated a total perfusion deficit (TPD) of ≥ 10% as a more conservative marker of ischemia. RESULTS: [15O]H2O PET identified more patients with regional ischemia: 17(46%) vs 9(24%), agreement: 59% corresponding to a Cohen's kappa of .31 [95%CI .08-.53], (P < .001). Using the more conservative TPD ≥ 10%, the agreement increased to 86% corresponding to a kappa of .62 [95%CI .33-.92], (P = .001). For the subgroup of patients with no known heart disease (n = 18), the agreement was 94%. Interrater agreement was 95% corresponding to a kappa of .89 [95%CI .74-1.00] (P < .001). CONCLUSIONS: In clinical transition from 82Rb to [15O]H2O PET, it is important to take into account the higher frequency of patients with regional ischemia detected by [15O]H2O PET.

Biomarkers of inflammation and endothelial dysfunction as predictors of pulse pressure and incident hypertension in type 1 diabetes: a 20 year life-course study in an inception cohort.

AIMS/HYPOTHESIS: Vascular inflammation and endothelial dysfunction are thought to contribute to arterial stiffening and hypertension. This study aims to test this hypothesis with longitudinal data in the context of type 1 diabetes. METHODS: We investigated, in an inception cohort of 277 individuals with type 1 diabetes, the course, tracking and temporal inter-relationships of BP, specifically pulse pressure (a marker of arterial stiffening) and hypertension, and the following biomarkers of systemic and vascular inflammation/endothelial dysfunction: C-reactive protein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cellular adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin). These biomarkers and other risk factors were measured at baseline and repeatedly up to 20 years after the onset of type 1 diabetes. Data were analysed with generalised estimating equations including adjustments for age, sex, smoking status, BMI, HbA1c, serum creatinine, total cholesterol, urinary AER, insulin treatment dose and mean arterial pressure. RESULTS: Increases were noted in all biomarkers except sE-selectin, which decreased over time. Levels differed from baseline at 2-4 years and preceded the increase in pulse pressure, which occurred at 8-10 years after the onset of type 1 diabetes. Higher levels of sICAM-1 and sVCAM-1, but not CRP or sE-selectin, at baseline and throughout the 20 year follow-up, were significantly associated with higher (changes in) pulse pressure at subsequent time points. Higher levels of sVCAM-1 at baseline and during follow-up were also significantly associated with the prevalence (OR 3.60 [95% CI 1.36, 9.53] and OR 2.28 [1.03, 5.25], respectively) and incidence (OR 2.89 [1.08, 7.75] and OR 3.06 [1.01, 9.26], respectively) of hypertension. We also investigated the longitudinal associations between BP or hypertension as determinants of subsequent (changes in) levels of CRP, sICAM-1, sVCAM-1 and sE-selectin, but did not find evidence to support a reverse causality hypothesis. CONCLUSIONS/INTERPRETATION: These findings support the involvement of vascular endothelial dysfunction and inflammation in the development of premature arterial stiffening and hypertension in type 1 diabetes.

Intravenous saline administration in patients with severe acquired brain injury and orthostatic intolerance for tilt-table mobilization.

PRIMARY OBJECTIVE: This study aimed to investigate the effect of intravenous saline administration on orthostatic hypotension (OH) during head up tilt (HUT) and the change in the renin-angiotensin-aldosterone system before and after HUT in patients with severe acquired brain injury (ABI). RESEARCH DESIGN: The study is designed as an observational study. METHODS AND PROCEDURES: Fourteen patients with ABI, low level of consciousness and OH were monitored before, during and after HUT with non-invasive beat-to-beat blood pressure measurement, and transcranial Doppler determination of middle cerebral artery blood flow velocity. Blood samples were collected before and after two HUT sessions separated by 1 hour and saline was administered in between. MAIN OUTCOMES AND RESULTS: Patients' ability to stand upright did not change after saline administration due to OH. The patients showed signs of reduced cerebral autoregulation at both HUT sessions. The patients had a significant lower level of renin and angiotensin II but not aldosterone. CONCLUSIONS: Patients with severe ABI and OH demonstrate no improvement in standing time with reduced plasma renin and angiotensin II after two HUT sessions and 1 hour fluid administration. Research focusing on the ability to retain fluid after bed rest is warranted.

The effect of liraglutide on renal function: A randomized clinical trial.

AIMS: Among patients with type 2 diabetes and albuminuria, cardiorenal morbidity and mortality are high despite multifactorial treatment. Short-term reduction in albuminuria is considered suggestive of long-term renoprotective effects. We evaluated the renal effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide on top of multifactorial care, including renin-angiotensin-system (RAS)-inhibition. MATERIALS AND METHODS: Randomized, double-blind, placebo-controlled, cross-over trial including patients with type 2 diabetes and persistent albuminuria (urinary albumin-to-creatinine ratio >30 mg/g) and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 . Patients received liraglutide (1.8 mg/d) and matched placebo for 12 weeks in a random order. The primary endpoint was change in 24-h urinary albumin excretion rate (UAER). RESULTS: A total of 32 patients were randomized and 27 completed the study. After placebo treatment, geometric mean (IQR) UAER was 199 (81-531) mg/24-h, mean (SD) measured GFR (mGFR) 75 (36) mL/min/1.73 m2 , 24-h blood pressure 145/80 (15/8) mm Hg and HbA1c 61 (11) mmol/mol. Liraglutide reduced HbA1c by 8 (95% CI: 5; 11) mmol/mol (P < .001) and weight by 1.8 (95% CI: 0.2; 3.4) kg (P = .032) compared to placebo. Furthermore, liraglutide reduced UAER by 32 (95% CI: 7; 50)% ( P = .017) compared with placebo. The change in mGFR was -5 (95% CI: -11; 2) mL/min/1.73 m2 ( P = .15), and change in 24-h systolic blood pressure was -5 (95% CI: -10; 0) mm Hg ( P = .07). In multivariate regression models, change in UAER was associated with change in 24-h systolic blood pressure ( P = .025) but not with change in HbA1c, weight or mGFR ( P ≥ .14), overall model R 2 = .39. CONCLUSIONS: Our placebo-controlled randomized trial suggests that liraglutide has renoprotective effects on top of multifactorial treatment, including RAS-inhibition, in patients with type 2 diabetes and albuminuria.

Determinants of vitamin D status in young adults: influence of lifestyle, sociodemographic and anthropometric factors.

BACKGROUND: Very few studies have investigated the determinants of circulating 25-hydroxyvitamin D (25[OH]D) in young adults (18-25 years old) using a set of variables that include lifestyle, sociodemographic, and anthropometric data. Our aim was to investigate the association between these variables and vitamin D status in a sample of untreated young adults. METHODS: A total of 738 young adults were enrolled in a (June cross-sectional study 2012 to May 2014) and were recruited from educational institutions in the Copenhagen area. For multivariate logistic regression subjects was categorized based on 25[OH]D in serum into; vitamin D sufficiency (S-25[OH]D > 50 nmol/L), vitamin D insufficiency (25 nmol/L ≤ S-25[OH]D ≤ 50 nmol/L), vitamin D deficiency (S-25[OH]D < 25 nmol/L). Information on lifestyle factors and education was obtained by self-reported questionnaires. RESULTS: 700 subjects with a valid measurement of S-25[OH]D and a completed questionnaire was analysed. 238 had vitamin D insufficiency, 135 had vitamin D deficiency of which 13 had severe vitamin D deficiency (S-25[OH]D < 12.5 nmol/L). The relative risk (RR) for vitamin D deficiency was highest for men 2.09 (1.52, 2.87); obese subjects 2.00 (1.27, 3.15); smokers 1.33 (1.02, 1.73); subjects who exercised 0-½ hours a week 1.88 (1.21, 2.94); and subjects who consumed fast food once a week 1.59 (1.05, 2.43). The relative risk was significantly lower for subjects who were studying for a Bachelor's degree (0.40 (0.23, 0.68). For vitamin D insufficiency, the highest RR was again for men 1.31 (1.06, 1.61); obese subjects 1.57 (1.17, 2.11); and subjects who exercised 0-½ hours a week 1.51 (1.11, 2.06). CONCLUSION: In this study of young adults, vitamin D deficiency was highly prevalent. Modifiable factors such as smoking, maintenance of normal BMI, and physical activity are all potential targets for interventional trials to determine the causal order; such knowledge would be useful in improving S-25[OH]D in young adults. The small group with severe vitamin D deficiency warrants increased attention.

Physical exercise associated with improved BMD independently of sex and vitamin D levels in young adults.

PURPOSE: Young men and women accrue the majority of their bone mass in their teens and twenties, where their bone mass peaks (PBM), yet little is known about the roles of physical exercise, vitamin D levels and bone mineral density (BMD) near PBM. METHODS: To comparatively examine the effect of physical exercise and two vitamin D levels (insufficient s-25[OH]D <50 nmol/L and sufficient s-25[OH]D >80 nmol/L) on the BMD measured at the femoral neck, total hip (bilaterally) and the lumbar spine (L2-L4) in male and female participants approaching PBM. RESULTS: The insufficient s-25[OH]D group, median age 21.6 (19.8-22.8) years, and BMI 24.2 ± 5.0 kg/m(2) had BMD 0.10 (0.03, 0.17) g/cm(2) (p = 0.008) lower at all DXA-scan sites compared to the sufficient s-25[OH]D group, median age 19.5 (19.0-22.3) years, and BMI of 22.6 ± 1.8 kg/m(2). Exercise was positively associated with the BMD at all DXA-scan sites (p trend = 0.0001) and with equal benefit; there was no interaction between exercise and the DXA-scan site (p = 0.09). The male participants did not have a systematically higher BMD than the female participants for all scan sites; only for hips total and femoral neck bilaterally, while it was equal at the lumbar spine. CONCLUSION: The BMD in young healthy adults is associated with physical exercise, independent of sex and s-25[OH]D status. A sufficient s-25[OH]D status was systematically associated with a higher BMD for all levels of exercise. For both sexes and vitamin D levels exercise was equally positively associated with BMD.

Improved prognosis of diabetic nephropathy in type 1 diabetes.

The natural history of diabetic nephropathy offered an average survival of only 5-7 years. During the past decades, multiple changes in therapy and lifestyle have occurred. The prognosis of diabetic nephropathy after implementing stricter control of blood pressure (including increased use of long-term renin-angiotensin system inhibition), lipids, and glycemia, along with less smoking and other lifestyle and treatment advancements, is inadequately analyzed. To clarify this, we studied 497 patients with type 1 diabetes and diabetic nephropathy at the Steno Diabetes Center and compared them with previous data, obtained using identical criteria at our hospital. The glomerular filtration rate, measured yearly by 51Cr-EDTA plasma clearance, was a mean of 71 ml/min per 1.73 m2 at baseline. The mean glomerular filtration rate decline was significantly reduced by 19% (95% confidence interval 5-34) from previously 4.0 to 3.3 ml/min per 1.73 m2/year. During a median follow-up of 9.1 years, 29% of participants doubled their plasma creatinine or developed end-stage renal disease. Mortality risk was similar to our prior study (hazard ratio 1.05 (0.76-1.43). However, after age adjustment, as both diabetes and nephropathy onset occurred later in life, mortality was reduced by 30%. Risk factors for decline in glomerular filtration rate, death, and other renal end points were generally in agreement with prior studies. Thus, with current treatment of nephropathy in type 1 diabetes, the prognosis and loss of renal function has improved along with better control of modifiable risk factors.

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.

Sertraline treatment influences [18F]FE-PE2I PET imaging for Parkinsonism.

BACKGROUND: The dopamine transporter (DaT) PET ligand [18F]FE-PE2I is used to aid the diagnosis of Parkinson's disease. After encountering four patients with a history of daily sertraline use, who all showed atypical findings on [18F]FE-PE2I PET, we suspected that the selective serotonin reuptake inhibitor (SSRI), sertraline, might interfere with the results and lead to globally reduced striatal [18F]FE-PE2I binding due to sertraline's high affinity for DaT. METHODS: We rescanned the four patients with [18F]FE-PE2I PET after a 5-day sertraline pause. Sertraline plasma concentration was estimated based on body weight and dose, and specific binding ratios (SBR) in caudate nucleus, known to be more preserved in Parkinson's, were used to estimate the effect on tracer binding. Comparison was made to a patient with [18F]FE-PE2I PET before and after a 7-day Modafinil pause. RESULTS: We found a significant effect of sertraline on caudate nucleus SBR (p = 0.029). The effect showed a linear dose-dependent relationship that corresponds to a reduction in SBR by 0.32 or 0.44 for a 75 kg male or a 65 kg female, respectively, taking a daily dose of 50 mg sertraline. CONCLUSION: Sertraline is one of the most commonly used antidepressants and in contrast to other SSRI's, sertraline show high affinity for DaT. We recommend that sertraline treatment is taken into account when patients are undergoing [18F]FE-PE2I PET especially in patients showing apparent globally reduced PE2I binding. If tolerable, pausing of the sertraline treatment should be considered, especially for doses above 50 mg/day.

Age- and sex-specific changes in visceral fat mass throughout the life-span.

OBJECTIVE: Visceral fat mass (VFM) is a risk factor for cardiovascular diseases, type 2 diabetes mellitus, and malignancy; however, normative data are limited. The aim of this study was to provide reference data for VFM from a large, apparently healthy Caucasian adult population. METHODS: Volunteers aged 20 to 93 years from the Copenhagen City Heart Study had a standardized whole-body dual-energy x-ray absorptiometry scan performed using the iDXA (GE Lunar). Total and regional fat mass was measured. VFM was quantified using the CoreScan application. RESULTS: A total of 1277 participants were included (708 women, mean [SD], age: 56 [19] years, height: 1.66 [0.07] m, BMI: 24.64 [4.31] kg/m2 ; and 569 men, age: 57 [18] years, height: 1.80 [0.07] m, BMI: 25.99 [3.86] kg/m2 ). Increased VFM was positively correlated with age in both sexes. Men had significantly higher VFM in mass (g) after normalization to body size (m2 ) and total fat mass (p < 0.001). VFM increased more in women with high values of the android/gynoid ratio. CONCLUSIONS: Normative data of VFM from a large, healthy Danish cohort aged 20 to 93 years are presented. VFM increased with age in both sexes, but men had significantly higher VFM compared with women with the same BMI, body fat percentage, and fat mass index.

Irbesartan treatment does not influence plasma levels of the advanced glycation end products N(epsilon)(1-carboxymethyl)lysine and N(epsilon)(1-carboxyethyl)lysine in patients with type 2 diabetes and microalbuminuria. A randomized controlled trial.

BACKGROUND: In vitro and animal experiments have shown inhibiting effects of angiotensin receptor blockers (ARBs) on the formation of advanced glycation end products (AGEs), which are known to be involved in the development of cardiovascular complications in diabetes. However, sufficient human data to confirm such beneficial effects of ARBs on AGEs are lacking. Therefore, we investigated the effects of irbesartan treatment on plasma levels of the AGEs N(ε)(1-carboxymethyl)lysine (CML) and N(ε)(1-carboxyethyl)lysine (CEL) in hypertensive patients with type 2 diabetes and microalbuminuria. METHODS: We analysed data from a multicentre, double-blind, parallel, randomized controlled trial in patients with type 2 diabetes and microalbuminuria, the primary goal of which was to examine the renoprotective effects of irbesartan treatment (150 or 300 mg daily). Secondary end points included plasma CML and CEL in the treatment arm receiving 300 mg irbesartan (n = 139) and in the placebo group (n = 125). Effects of treatment at 1- and 2-year follow-up were analysed by means of generalized estimating equations according to an intention-to-treat principle. RESULTS: Levels of CML and CEL did not differ between groups at baseline. No significant changes were observed in CML and CEL over time in either group and there was no effect of treatment on CML and CEL at any time-point. Mean differences for the irbesartan versus placebo group over time were -0.96 µmol/mol lysine (95% confidence interval: -3.43 to 1.51) for CML and -0.10 µmol/mol lysine (-0.76 to 0.56) for CEL. CONCLUSIONS: Long-term irbesartan treatment does not influence plasma levels of the AGE CML and CEL in patients with type 2 diabetes and microalbuminuria.

Serum uric acid as a new player in the development of diabetic nephropathy.

The pathogenesis of diabetic nephropathy is complex and still not fully elucidated. Uric acid has been associated with renal disease, even though hyperuricemia may be a marker of or by itself be responsible for microvascular disease in diabetes. In animal models, elevated level of uric acid can lead to arteriolopathy of preglomerular vessels, impaired autoregulation, glomerular hypertension, as well as endothelial dysfunction. Kidney damage in hyperuricemic rats is not dependent on blood pressure, and instead involves the renin-angiotensin system. In patients with diabetes, serum uric acid early in the course of diabetes is significantly, and independent of confounders, associated with later development of persistent macroalbuminuria. Therefore, uric acid may be a novel and important player in the pathogenesis of microvascular complications in diabetes. A dose-response relationship between serum uric acid and early decline in renal function has recently been demonstrated in patients with type-1 diabetes. Randomized controlled trials on drugs that lower uric acid need to be conducted to evaluate the causal relationship between serum uric acid and development and progression of diabetic kidney disease; in addition, large scale long-term treatment trials need to be performed, as they are still lacking.

Associations between inflammatory markers, body composition, and physical function: the Copenhagen Sarcopenia Study.

BACKGROUND: Chronic low-grade inflammation has been suggested as one of the key elements in the development of sarcopenia, but in contrast to disease-related loss of muscle mass, the role of chronic low-grade inflammation in age-related (primary) sarcopenia is still not clear. The aim of this study was to investigate low-grade inflammation in relation to age and the potential association between inflammatory biomarkers and body composition, muscle strength and physical performance in a healthy Danish cohort. METHODS: There were 1160 generally healthy men and women (range: 22-93 years) included. Appendicular lean mass (ALM) and visceral fat normalized to height (kg/m2 ) was assessed by dual-energy X-ray absorptiometry (iDXA, GE Lunar). Muscle strength and physical performance were evaluated by handgrip strength (HGS), 30 s sit-to-stand performance, and maximal gait speed (GS). Systemic levels of TNF-α, IL-6, IL-1ß, IL-4, IL-13, and IFN-γ were measured using multiplex bead-based immunoassays (Bio-Rad). hsCRP was assessed using latex particle-enhanced immunoturbidimetric assays (Roche Diagnostics). RESULTS: With age, ALM/h2 , HGS, sit-to-stand performance and GS decreased, whereas visceral fat/h2 increased in both men and women (P < 0.05). Systemic levels of hsCRP, TNF-α, IL-4, and IFN-γ increased with age in men and women (P < 0.05), while IL-1ß increased in women only (P < 0.01). Higher levels of hsCRP were associated with lower ALM/h2 in elderly (≥65 years) men and women (P < 0.001). Higher levels of hsCRP were associated with lower handgrip strength in elderly women (P < 0.05) whereas higher levels of hsCRP was not associated with lower HGS in elderly men (P = 0.056). Higher levels of hsCRP were associated with lower GS (P < 0.05), whereas IFN-γ was positively associated with GS in elderly women (P < 0.05), but not elderly men. Visceral fat index was positively associated with hsCRP in elderly men and women (P < 0.001). Compared with elderly with normal HGS, elderly men and women with low HGS displayed higher levels of TNF-α and hsCRP (P < 0.05). CONCLUSIONS: With age, systemic levels of hsCRP, TNF-α, IL-4, and IFN-γ increased, with hsCRP and TNF-α being especially elevated in more physically frail elderly supporting the association between low-grade systemic inflammation and poor physical function. In contrast, only high levels of hsCRP were weakly associated with low muscle mass and positively associated with visceral fat and low physical function, suggesting that chronic low-grade inflammation is not the main driver of age-related loss of muscle mass as previously suggested.

The Renal Extraction and the Natriuretic Action of GLP-1 in Humans Depend on Interaction With the GLP-1 Receptor.

PURPOSE: The natriuretic effect of glucagon-like peptide-1 (GLP-1) in humans is independent of changes in renal plasma flow (RPF) and glomerular filtration rate (GFR) but may involve suppression of angiotensin II (ANG II) and a significant (~45%) renal extraction of GLP-1. The current study was designed to investigate the consequences for the renal extraction and the natriuretic effect of blocking GLP-1 receptors with the specific GLP-1 receptor antagonist, Exendin 9-39 (Ex 9-39). METHODS: Under fixed sodium intake for 4 days before each study day, 6 healthy male participants were recruited from our recent study where GLP-1 or vehicle was infused (1). In the present new experiments, participants were examined during a 3-hour infusion of GLP-1 (1.5 pmol/kg/min) together with a 3.5-hour infusion of Ex 9-39 (900 pmol/kg/min). Timed urine collections were conducted throughout the experiments. Renal extraction of GLP-1 as well as RPF and GFR were measured via Fick's principle after catheterization of a renal vein. Arterial plasma renin, ANG II, and aldosterone concentrations were measured. RESULTS: Co-infusion of Ex 9-39 significantly reduced renal extraction of GLP-1 to ~25% compared with GLP-1 infusion alone (~45%). Urinary sodium excretions remained at baseline levels during co-infusion of Ex 9-39 as well as vehicle. By contrast, GLP-1 infusion alone resulted in a 2-fold increase in natriuresis. Ex 9-39 abolished the GLP-1-induced decrease in arterial ANG II concentrations. RPF and GFR remained unchanged during all experiments. CONCLUSIONS: Renal extraction of GLP-1 and its effect on natriuresis are both dependent on GLP-1 receptor activation in healthy humans.

Increased oral sodium chloride intake in humans amplifies selectively postprandial GLP-1 but not GIP, CCK, and gastrin in plasma.

Human studies have demonstrated that physiologically relevant changes in circulating glucagon-like peptide-1 (GLP-1) elicit a rapid increase in renal sodium excretion when combined with expansion of the extracellular fluid volume. Other studies support the involvement of various gastrointestinal hormones, e.g., gastrin and cholecystokinin (CCK) in a gut-kidney axis, responsible for a rapid-acting feed-forward natriuretic mechanism. This study was designed to investigate the hypothesis that the postprandial GLP-1 plasma concentration is sensitive to the sodium content in the meal. Under fixed sodium intake for 4 days prior to each experimental day, 10 lean healthy male participants were examined twice in random order after a 12-hr fasting period. Arterial blood samples were collected at 10-20-min intervals for 140 min after 75 grams of oral glucose + 6 grams of oral sodium chloride (NaCl) load versus 75 grams of glucose alone. Twenty-four-hour baseline urinary sodium excretions were similar between study days. Arterial GLP-1 levels increased during both oral glucose loads and were significantly higher at the 40-80 min period during glucose + NaCl compared to glucose alone. The postprandial arterial responses of CCK, gastrin, and glucose-dependent insulinotropic polypeptide as well as glucose, insulin, and C-peptide did not differ between the two study days. Arterial renin, aldosterone, and natriuretic peptides levels did not change within subjects or between study days. Angiotensin II levels were significantly lower at the time GLP-1 was higher (60-80 min) during glucose + NaCl. Sodium intake in addition to a glucose load selectively amplifies the postprandial GLP-1 plasma concentration. Thus, GLP-1 may be part of an acute feed-forward mechanism for natriuresis.

The Copenhagen Sarcopenia Study: lean mass, strength, power, and physical function in a Danish cohort aged 20-93 years.

BACKGROUND: Despite no international consensus on the diagnostic criteria for sarcopenia, low lean mass, muscle strength, and physical function are important risk factors for disability, frailty, and mortality in older individuals, as well as in a wide range of patients with muscle loss. Here, we provide a population-based reference material of total and regional lean body mass, muscle strength/power parameters, and physical function in a healthy cohort of Danish men and women across the lifespan. METHODS: Volunteers aged 20-93 years from the Copenhagen City Heart Study were invited to establish a Danish reference material (Copenhagen Sarcopenia Study) on lean mass characteristics [appendicular lean mass (ALM), iDXA, GE Lunar], muscle function [handgrip strength (HGS), Jamar dynamometer and leg extension power (LEP), Nottingham Power Rig], and physical function [30 s sit-to-stand test (STS), 10-m maximal and habitual gait speed (GS)]. RESULTS: A total of 1305 participants [729 women (age: 56.4 ± 18.9 years, height: 1.66 ± 0.01 m, body mass index: 24.6 ± 4.3 kg/m2 and 576 men, age: 57.0 ± 17.5 years, height: 1.80 ± 0.07 m, body mass index: 26.0 ± 3.9 kg/m2 ] completed all measurements and were included in the present analysis. Lean mass characteristics (TLM, ALM, and ALM/h2 ) decreased with increasing age in both men and women (P < 0.001). Men demonstrated larger absolute and relative total ALM and higher HGS and LEP compared with women at all age intervals (P < 0.001). HGS and LEP decreased progressively with age in both men and women (P < 0.01); 30 s STS performance, habitual GS, and maximal GS decreased at an accellerated rate of decline with increasing age in both men and women (P < 0.001). Habitual GS was reduced in men and women aged ≥70 years, while maximal GS was reduced from the age of ≥60 years compared with young adults (P < 0.001). Regardless of sex, 30 s STS was reduced from the age of ≥50 years compared with the young reference group (P < 0.001) CONCLUSIONS: While the power-based measurements (LEP and 30 s STS) started to decline already at age +50 years, less power-based parameters (GS and HGS) and lean mass characteristics (TLM, ALM, and ALM/h2 ) remained unaltered until after the age of +70 years. Notably, the cut-off thresholds derived in the present study differed from earlier reference data, which underlines the importance of obtaining updated and local reference materials.

Endothelial dysfunction and inflammation predict development of diabetic nephropathy in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study.

OBJECTIVE: To evaluate risk factors for progression from persistent microalbuminuria to diabetic nephropathy in the Irbesartan in Patients with Type 2 diabetes and Microalbuminuria (IRMA 2) study, including biomarkers of endothelial dysfunction, chronic low-grade inflammation, growth factors and advanced glycation end products (AGE peptides). METHODS: IRMA 2 was a 2-year multicentre, randomized, double-blind trial comparing irbesartan (150 and 300 mg once daily) versus placebo. The primary end-point was time to onset of diabetic nephropathy. Samples from a subgroup from the placebo and the 300 mg irbesartan treatment group were used in this post-hoc analysis (n = 269, 68 %). Nine biomarkers were analysed: high sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), fibrinogen, von Willebrand Factor (vWf), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin, transforming growth factor-beta (TGF-beta) and AGE peptides. Mean standard deviation scores (Z-scores) were used to combine biomarker information. RESULTS: In a Cox enter model with combined Z-scores for biomarkers of endothelial dysfunction (vWf, sVCAM-1, sICAM-1, sE-selectin) and for biomarkers of inflammation (hs-CRP, IL-6, fibrinogen), endothelial dysfunction (hazard ratio for a 28 % increase ( = 1 SD) in Z-score) 3.20 (1.56 to 6.56), p = 0.001) and UAER (HR for a 75 % increase ( = 1 SD) in UAER) 2.61 (1.30 to 5.23), p = 0.007) were found as independent predictors. Independently, IL-6 and vWf predicted the end-point. In addition, endothelial Z-score was associated with progression of albuminuria (p = 0.038). CONCLUSION: Endothelial dysfunction and possibly inflammation are novel predictors of progression to diabetic nephropathy in patients with type 2 diabetes and microalbuminuria independently of traditional risk factors. ClinicalTrials.gov ID: NCT00317915.