Background: The need for an improved treatment for diabetic nephropathy is greatest in patients who do not adequately respond to angiotensin II receptor blockers (ARBs). This study investigated the effect of the novel dipeptidyl peptidase-4 inhibitor linagliptin alone and in combination with the ARB telmisartan on the progression of diabetic nephropathy in diabetic endothelial nitric oxide synthase (eNOS) knockout mice. Methods: Sixty male eNOS knockout C57BL/6J mice were divided into four groups after receiving intraperitoneal highdose streptozotocin: telmisartan (1 mg/kg), linagliptin (3 mg/kg), linagliptin + telmisartan (3 mg/kg + 1 mg/kg) and vehicle. Fourteen mice were used as non-diabetic controls. Results: After 12 weeks, urine and blood were obtained and blood pressure measured. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan alone reduced systolic blood pressure by 5.9 mmHg versus diabetic controls (111.2 ± 2.3 mmHg vs 117.1 ± 2.2 mmHg; mean ± SEM; P=0.071). Combined treatment significantly reduced albuminuria compared with diabetic controls (71.7 ± 15.3 µg/24 h vs 170.8 ± 34.2 µg/24 h; P=0.017), whereas the effects of single treatment with either telmisartan (97.8 ± 26.4 µg/24 h) or linagliptin (120.8 ± 37.7 µg/24 h) were not statistically significant. DPP-4 inhibition, alone and in combination, led to significantly lower plasma osteopontin levels compared with telmisartan alone. Histological analysis revealed reduced glomerulosclerosis after Linagliptin alone and in combination with telmisartan in comparison to non treated diabetic animals (p<0.01 and p<0.05). Kidney malonaldehyde immune-reactivity, a marker of oxidative stress, was significantly lower in animals treated with linagliptin. Conclusions: DPP-4 inhibition on top of ARB treatment significantly reduced urinary albumin excretion and oxidative stress in diabetic eNOS knockout mice. Linagliptin on top of an angiotensin II receptor blocker may offer a new therapeutic approach for patients with diabetic nephropathy.

Plasma retinol-binding protein 4 (RBP4) may be a new adipokine linked to obesity-induced insulin resistance and type 2 diabetes. The impact of diabetic nephropathy on plasma RBP4 levels, however, is not known. We tested the hypothesis that microalbuminuria is associated with elevated plasma concentrations of RBP4 in type 2 diabetic subjects. Retinol, its binding protein and transthyretin (TTR) were measured in the plasma and urine of 62 type 2 diabetic subjects, 26 of whom had microalbuminuria. The results were compared to 35 healthy control subjects. Despite no differences in plasma retinol, concentrations of the RBP4 were significantly elevated in plasma of diabetic patients and significantly higher in those with microalbuminuria. The higher plasma levels of the binding protein in subjects with microalbuminuria were accompanied by both significantly elevated plasma TTR and increased urinary levels of RBP4. There were no correlations of plasma-binding protein levels and parameters of insulin resistance. Our study suggests that plasma RBP4 levels in type 2 diabetic patients are affected by incipient nephropathy. Therefore, further studies evaluating RBP4 as a regulator of systemic insulin resistance and type 2 diabetes will need to take renal function into consideration.

To gain a more comprehensive knowledge on whether, besides the well-known piperine, other compounds are responsible for the pungent and tingling oral impression imparted by black pepper, an ethanol extract prepared from black pepper (Piper nigrum L.) was screened for its key sensory-active nonvolatiles by application of taste dilution analysis (TDA). Purification of the compounds perceived with the highest sensory impact, followed by LC-MS and 1D/2D NMR experiments as well as synthesis, led to the structure determination of 25 key pungent and tingling phytochemicals, among which the eight amides 1-(octadeca-2E,4E,13Z-trienyl)piperidine, 1-(octadeca-2E,4E,13Z-trienyl)pyrrolidine, (2E,4E,13Z)-N-isobutyl-octadeca-2,4,13-trienamide, 1-(octadeca-2E,4E,12Z-trienoyl)-pyrrolidine, 1-(eicosa-2E,4E,15Z-trienyl)piperidine, 1-(eicosa-2E,4E,15Z-trienyl)pyrrolidine, (2E,4E,15Z)-N-isobutyl-eicosa-2,4,15-trienamide, and 1-(eicosa-2E,4E,14Z-trienoyl)-pyrrolidine were not yet reported in literature. Sensory studies by means of a modified half-tongue test revealed recognition thresholds ranging from 3.0 to 1150.2 nmol/cm² for pungency and from 520.6 to 2162.1 nmol/cm² for the tingling orosensation depending on their chemical structure.

cRetinoids are vitamin A (retinol) derivatives and complex regulators of adipogenesis by activating specific nuclear receptors, including the retinoic acid receptor (RAR) and retinoid X receptor (RXR). Circulating retinol-binding protein 4 (RBP4) and its membrane receptor STRA6 coordinate cellular retinol uptake. It is unknown whether retinol levels and the activity of RAR and RXR in adipocyte precursors are linked via RBP4/STRA6. Here, we show that STRA6 is expressed in precursor cells and, dictated by the apo-and holo-RBP4 isoforms, mediates bidirectional retinol transport that controls RAR␣ activity and subsequent adipocyte differentiation. Mobilization of retinoid stores in mice by inducing RBP4 secretion from the liver activated RAR␣ signaling in the precursor cell containing the stromal-vascular fraction of adipose tissue. Retinol-loaded holo-RBP4 blocked adipocyte differentiation of cultured precursors by activating RAR␣. Remarkably, retinol-free apo-RBP4 triggered retinol efflux that reduced cellular retinoids, RAR␣ activity, and target gene expression and enhanced adipogenesis synergistically with ectopic STRA6. Thus, STRA6 in adipocyte precursor cells links nuclear RAR␣ activity to the circulating RBP4 isoforms, whose ratio in obese mice was shifted toward limiting the adipogenic potential of their precursors. This novel cross talk identifies a retinoldependent metabolic function of RBP4 that may have important implications for the treatment of obesity.

OBJECTIVE-It has been suggested that retinol-binding protein 4 (RBP4) links adiposity, insulin resistance, and type 2 diabetes. However, circulating RBP4 levels are also affected by kidney function. Therefore, the aim of this study was to test whether RBP4 serum levels are primarily associated with kidney function or type 2 diabetes.RESEARCH DESIGN AND METHODS-RBP4 serum concentration was determined by enzyme-linked immunosorbent assay in 126 nondiabetic and 104 type 2 diabetic subjects. The study population was divided according to estimated glomerular filtration rate (eGFR) into the following groups: eGFR Ͼ90 ml/min per 1.73 m 2 (n ϭ 53), 60 -90 ml/min per 1.73 m 2 (n ϭ 90), 30 -60 ml/min per 1.73 m 2 (n ϭ 38), and Ͻ30 ml/min per 1.73 m 2 (n ϭ 49). Each group was subdivided into nondiabetic and type 2 diabetic subjects.RESULTS-RBP4 serum concentration was elevated (2.65 vs. 2.01 mol/l; P Ͻ 0.001) and eGFR was reduced (56 vs. 74 ml/min per 1.73 m 2 ; P Ͻ 0.001) in type 2 diabetic vs. nondiabetic subjects, respectively. By stratifying for eGFR, no more differences in RBP4 serum concentration were detectable between type 2 diabetic and nondiabetic subjects. A linear regression analysis revealed an influence of eGFR (r ϭ Ϫ0.477; P Ͻ 0.001) but not A1C (r ϭ 0.093; P ϭ 0.185) on RBP4 serum concentration.CONCLUSIONS-Existing human data showing elevated RBP4 levels in type 2 diabetic patients may be the result of moderate renal insufficiency rather than support for the suggestion that RBP4 links obesity to type 2 diabetes. Diabetes 57:3323-3326, 2008 R etinol-binding protein 4 (RBP4) is a small visceral protein (ϳ21 kDa), mainly synthesized in the liver and catabolized in the kidneys after glomerular filtration (1). To prevent the renal loss of RBP4 before delivering its ligand retinol to the target tissues, RBP4 is complexed by transthyretin, a homotetrameric protein with a molecular weight of ϳ55 kDa, formerly known as prealbumin (2). RBP4 was recently discussed as a new adipokine that is possibly linked to insulin resistance and type 2 diabetes (3-5). Although it is known that RBP4 serum levels are elevated in states of impaired kidney function (1,6 -8) (which is a common feature of diabetes, metabolic syndrome, and obesity [9,10]), parameters of kidney function have not been reported in most of the studies concerning RBP4 and insulin resistance and/or diabetes (3-5). Therefore, the aim of this study was to determine whether RBP4 serum concentration is associated with kidney function rather than type 2 diabetes. RESEARCH DESIGN AND METHODSSerum samples of 230 age-matched subjects (131 male, including 59 with type 2 diabetes, and 99 female, including 45 with type 2 diabetes) were collected by the Department of Endocrinology, Diabetes and Nutrition and the Department of Nephrology-both of Charité -Universitä tsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany-and by the Department of Clinical Nutrition of the German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany. The study protocol was approved by ...