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Adiponectin and urinary adiponectin excretions have been ascribed a function in glomerular physiology and seem to indicate vascular disease in diabetes. The aim of this study was to compare the urinary excretion of albumin and adiponectin as predictors for decline of renal function in patients with type 2 diabetes and early kidney disease. Over 141 patients were screened for renal function (estimated GFR, ml/min*1.73 m(2)), albumin excretion rate (AER, mg/24 h), total as well as high molecular weight (HMW) urinary adiponectin excretion (ng/mol u-creatinine). AER and adiponectin excretion were studied as predictors of renal function after 1 year. After 1 year, 36 patients were in the upper quartile of eGFR decline and defined as progressors (delta eGFR = - 12.3 ± 6.3) while the remaining 105 patients were defined as non-progressors (delta eGFR = 1.4 ± 6.0). At baseline, HMW-adiponectin excretion was positively correlated with HbA1c (p < 0.001) and negatively with eGFR (p < 0.001), but not with AER (p = 0.14). Progressors showed increased urinary HMW-adiponectin at baseline (158[IQR41/479] vs. 65[24/168] ng/mol; p < 0.01), while total adiponectin (182[101/1534] vs. 345[118/1361] ng/mol) and AER (48[23/109] vs. 46[25/108] mg/24 h) excretion showed no differences between the groups. Multivariate logistic regression showed that HMW-adiponectin excretion was an independent predictor of renal progression in all patients (OR 1.86 [95 % CI 1.34-2.59]; p < 0.01), especially in those (n = 45) with normal AER at baseline (OR 2.16 [95 % CI 1.1-4.56]; p < 0.05). Urinary HMW-adiponectin but not AER improved the prediction of progressors in ROC analysis (AUC 0.72 [95 % CI 0.63-0.81] vs. 0.80 [95 % CI 0.71-0.90], p < 0.05). In conclusion, urinary HMW-adiponectin excretion may identify diabetes patients at increased risk for progression of kidney disease.

Aims: To evaluate the efficacy/safety of dipeptidyl peptidase-4 inhibitor, linagliptin, in subjects with insufficiently controlled type 2 diabetes mellitus (T2DM), and factors influencing treatment response., Methods: Pooled analysis of data from 2258 subjects in three 24-week phase III, randomized, placebo-controlled, parallel-group studies, who received oral linagliptin (5 mg/day) or placebo as monotherapy, added-on to metformin, or added-on to metformin plus sulfonylurea was performed., Results: Among 388 subjects with HbA1c ≥9.0%, adjusted mean baseline HbA1c (9.4% both groups) declined to 8.3% in linagliptin group and 9.1% in placebo group at 24 weeks (P<.0001) and adjusted mean change from baseline was 1.2% (vs. 0.4%, placebo). Linagliptin significantly lowered fasting plasma glucose levels vs. placebo (1.6 mmol/l vs. 0.4 mmol/l); treatment difference, 1.1 mmol/l (95% CI, -1.7 to -0.5). Treatment and washout of previous oral antidiabetes drugs were the only factors to independently affect HbA1c change at week 24. Adverse event rates were similar for linagliptin (61.9%) and placebo (62.7%). Hypoglycemia was rare with linagliptin monotherapy/add-on to metformin (≤1%) and increased when linagliptin was added to metformin plus sulfonylurea (linagliptin, 17.9% vs. placebo, 8.3%)., Conclusions: Linagliptin was an effective, well-tolerated treatment in subjects with T2DM and insufficient glycemic control, both as monotherapy or added-on to metformin/metformin plus sulfonylurea., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Some patients with type 2 diabetes mellitus (T2DM) receiving monotherapy with a sulfonylurea (SU) are unable to meet recommended glycemic targets over the long term and require additional pharmacologic agents to maintain glycemic control. This study was designed to assess the utility of adjunctive therapy with the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in patients with T2DM inadequately controlled with SU monotherapy., Objective: To assess the efficacy and tolerability of linagliptin as add-on therapy in patients with inadequately controlled T2DM despite background therapy with an SU., Methods: In this Phase III, multicenter, randomized, double-blind, placebo-controlled trial, patients with inadequately controlled T2DM on SU monotherapy were randomly assigned to receive treatment with linagliptin 5 mg once daily (n = 161) or placebo (n = 84) for 18 weeks. The primary end point was the mean change in hemoglobin (Hb) A(1c) from baseline to week 18, evaluated using ANCOVA. Tolerability was assessed using laboratory analysis, spontaneous reporting, and physical examination and interview., Results: Mean baseline characteristics were similar in the linagliptin and placebo groups. Linagliptin treatment was associated with a placebo-corrected mean (95% CI) change in HbA(1c) from baseline (8.6%) to 18 weeks of -0.47% (-0.70 to -0.24; P < 0.0001). Patients in the linagliptin group were more likely compared with placebo to achieve the HbA(1c) target level of <7.0% after 18 weeks of treatment (15.2% vs 3.7%, respectively; odds ratio [OR] = 6.5; 95% CI, 1.7-24.8; P = 0.007). Similarly, patients in the linagliptin group were more likely to achieve an HbA(1c) reduction of ≥0.5% compared with those in the placebo group (57.6% vs 22.0%; OR = 5.1, 95% CI 2.7-9.6; P < 0.0001). The overall frequency of adverse events was similar between the linagliptin and placebo groups (42.2% vs 42.9%). The incidences of hypoglycemic events were not significantly different between the 2 groups (5.6% vs 4.8%), and none of the hypoglycemic episodes were assessed as severe by the investigator. The difference in the changes in mean body weight was not significant (+0.43 vs -0.01 kg; P = 0.12)., Conclusions: The addition of linagliptin to SU therapy for 18 weeks in these patients with T2DM was associated with statistically significant and clinically meaningful reductions in HbA(1c) compared with placebo. The overall tolerability of linagliptin was similar to that of placebo, with a low risk for hypoglycemia and no significant weight gain. These findings support the use of linagliptin as adjunctive therapy in patients with T2DM inadequately controlled on SU monotherapy. ClinicalTrials.gov identifier: NCT00819091., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Objective: Adipocyte fatty acid-binding protein (A-FABP) abundantly expressed in mature adipocytes and activated macrophages has dramatic effects on atherosclerosis in mice. Whether this pathophysiological role of A-FABP may also apply to atherosclerotic disease in humans is still unknown. This study investigated associations among serum A-FABP levels, cardiovascular risk factors, and long-term secondary cardiovascular disease (CVD) outcome in patients with coronary heart disease., Methods and Results: Serum A-FABP levels were measured in 1069 patients with prevalent coronary heart disease and a 10-year prospective follow-up was conducted (median, 119.5 [interquartile range, 74.1-120.6] months). During this period 204 patients (incidence, 24.0/1000 patient-years) experienced a secondary cardiovascular disease event (defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal cerebrovascular stroke). At baseline, circulating A-FABP was positively associated with a cluster of metabolic and inflammatory risk factors and independently predicted the presence of the metabolic syndrome (odds ratio per unit increase of natural log-transformed A-FABP, 2.95; 95% CI, 2.22-3.92, P<0.001). On long-term follow-up, subjects with high baseline A-FABP showed an increased risk for secondary cardiovascular disease events (hazard ratio per unit increase, 1.52; 95% CI, 1.18-1.95; P=0.001), which was attenuated after multivariable adjustment (hazard ratio 1.30; 95% CI, 0.98-1.73). In contrast, A-FABP remained significantly associated with cardiovascular death even after multivariable adjustment (hazard ratio, 1.75; 95% CI, 1.17-2.62, P=0.007)., Conclusions: Circulating A-FABP levels are associated with long-term prognosis in patients with coronary heart disease and may represent an important pathophysiological mediator of atherosclerosis, which may point to a new target of treatment options.

High circulating fetuin-A has recently been linked to risk of primary cardiovascular disease (CVD). The clinical importance of fetuin-A in patients at markedly increased cardiovascular risk, however, has not been fully elucidated. We studied the association between serum fetuin-A and future cardiovascular outcome in patients with prevalent coronary heart disease (CHD). Fetuin-A levels were measured in 1,049 patients with CHD. Associations with traditional cardiovascular risk factors and with secondary CVD events during 6 years of follow-up (median 73.4 months, interquartile range 57.4 to 74.3) were analyzed. Serum fetuin-A levels were significantly increased in patients with prevalent hypertriglyceridemia (0.71 vs 0.69 g/L, p = 0.013). No association with baseline metabolic syndrome was found (odds ratio 0.95 for highest vs lowest fetuin-A quintile, 95% confidence interval 0.59 to 1.53, p = 0.82). In Cox proportional hazards analyses, serum fetuin-A levels were not significantly associated with secondary CVD events (hazard ratio 0.67 for highest vs lowest fetuin-A quintile, 95% confidence interval 0.37 to 1.21, p = 0.18). In conclusion, fetuin-A is significantly associated hypertriglyceridemia but not with other traditional cardiovascular risk factors or metabolic syndrome in patients with manifest CHD. Measurement of serum fetuin-A levels may not emerge as a valuable tool for evaluating future CVD risk in patients aggressively treated for advanced atherosclerosis.

Little is known about the mechanisms converting psychosocial stress into cellular dysfunction. Various genes, up-regulated in atherosclerosis but also by psychosocial stress, are controlled by the transcription factor nuclear factor kappaB (NF-kappaB). Therefore, NF-kappaB is a good candidate to convert psychosocial stress into cellular activation. Volunteers were subjected to a brief laboratory stress test and NF-kappaB activity was determined in peripheral blood mononuclear cells (PBMC), as a window into the body and because PBMC play a role in diseases such as atherosclerosis. In 17 of 19 volunteers, NF-kappaB was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min. To model this response, mice transgenic for a strictly NF-kappaB-controlled beta-globin transgene were stressed by immobilization. Immobilization resulted in increased beta-globin expression, which could be reduced in the presence of the alpha1-adrenergic inhibitor prazosin. To define the role of adrenergic stimulation in the up-regulation of NF-kappaB, THP-1 cells were induced with physiological amounts of catecholamines for 10 min. Only noradrenaline resulted in a dose- and time-dependent induction of NF-kappaB and NF-kappaB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated phosphophatidylinositol 3-kinase, Ras/Raf, and mitogen-activated protein kinase activation. Induction was reduced by alpha(1)- and beta-adrenergic inhibitors. Thus, noradrenaline-dependent adrenergic stimulation results in activation of NF-kappaB in vitro and in vivo. Activation of NF-kappaB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response.