piperidines and Diabetic-Nephropathies

The dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of blood glucose-lowering therapy with proven efficacy, tolerability and safety. Four of the five commercially available DPP-4 inhibitors are subject to significant renal clearance, and pharmacokinetic studies in people with renal impairment have led to lower recommended doses based on creatinine clearance in order to prevent drug accumulation. Data from these pharmacokinetic studies and from supratherapeutic doses in healthy individuals and people with uncomplicated diabetes during development suggest, however, that there is a wide therapeutic margin. This should protect against toxicity if people with renal impairment are inadvertently prescribed higher doses than recommended. Doses appropriate to renal function are associated with reductions in HbA1c that are equivalent to those observed in people with type 2 diabetes who do not have renal impairment. Recent large-scale cardiovascular safety trials of saxagliptin and alogliptin have identified heart failure as a potential concern and renal impairment may increase the risk of this complication. Although the incidence of pancreatitis does not appear to be significantly increased by DPP-4 inhibitor therapy, renal impairment is also an independent risk factor. Additional data from other ongoing DPP-4 inhibitor cardiovascular safety trials should provide a more precise assessment of the risks of these uncommon complications, including in people with renal impairment.

Topics: Adamantane; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Glycated Hemoglobin; Humans; Piperidines; Renal Insufficiency; Risk Factors; Treatment Outcome; Uracil

Chronic kidney disease (CKD) is a common complication of diabetes mellitus and the most common cause of end-stage renal disease (ESRD). As the worldwide prevalence of diabetes continues to increase, the number of patients with CKD will also increase. Therefore, it is essential that physicians know how to safely and effectively manage diabetes in the setting of CKD. Adequate glycaemic control in patients with diabetes is important to prevent ESRD and other complications and to decrease mortality. However, many glucose-lowering agents need to be dose-adjusted or should not be used in the setting of stage 3 CKD or higher (defined as an estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m(2)), particularly in patients with stage 5 CKD (eGFR <15 ml/min/1.73 m(2)) and in those receiving dialysis. Insulin therapy is appropriate for patients undergoing dialysis; however, several orally administered glucose-lowering agents can also be used safely in these patients. In this Review, we provide an overview of the use of noninsulin glucose-lowering agents in the dialysis population.

Topics: Adamantane; Biguanides; Diabetic Nephropathies; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Glucagon-Like Peptides; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Linagliptin; Meglumine; Metformin; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Renal Dialysis; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome; Triazoles; Uracil; Vildagliptin

To explore the effects of systematic diet education combined with multidisciplinary nursing on nutritional status and calcium and phosphorus metabolism in patients with diabetic kidney disease (DKD) in uremic phase after treatment with alogliptin.. A total of 90 DKD patients with uremia admitted to our hospital from January 2020 to January 2021 were selected as the research objects. The subjects were divided into combined group and routine group by random number table method. All patients received alogliptin medication. The combination group received systematic dietary education combined with multidisciplinary nursing after the medication, and the conventional group received conventional intervention. Serum albumin, blood calcium, and other indexes were detected between both groups after intervention.. After intervention, compared with the conventional group, all nutritional indexes of the combined group were obviously higher, levels of serum phosphorus and calcium-phosphorus product of the combined group were obviously lower (. With conspicuous intervention effect, systematic diet education combined with multidisciplinary nursing is a reliable method that can improve the nutritional status and levels of calcium and phosphorus metabolism, enhance treatment compliance, and reduce anxiety. Further research will help to provide a better solution for patients. This trial is registered with ChiCTR2200057011.

Topics: Calcium; Diabetes Mellitus; Diabetic Nephropathies; Diet; Female; Humans; Male; Nutritional Status; Phosphorus; Piperidines; Uracil

Imarikiren is a novel, potent, and selective direct renin inhibitor that has shown high oral availability during clinical development for the treatment of diabetic nephropathy. We evaluated the efficacy and safety of imarikiren in patients with type 2 diabetes mellitus and microalbuminuria.. This was a randomized, multicenter, placebo-controlled, double-blind, phase 2, dose-finding trial. A total of 415 patients were randomized to imarikiren 5, 20, 40, or 80 mg; placebo; or candesartan cilexetil 8 mg treatment for 12 weeks. The primary end point was change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment analyzed using analysis of covariance and a fixed sequence testing procedure. Secondary efficacy end points included urine albumin-to-creatinine ratio at each assessment point and remission and progression rates. Exploratory efficacy end points included eGFR and sitting BP before dosing.. Imarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria.

Topics: Adult; Aged; Albuminuria; Benzimidazoles; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Japan; Male; Middle Aged; Morpholines; Piperidines; Protease Inhibitors; Renin; Time Factors; Treatment Outcome; Young Adult

Dipeptidyl peptidase-4 (DPP-4) inhibitor is a new class of anti-diabetic drug which exerts its glucose-lowering action by suppressing the degradation of a gut incretin hormone glucagon-like peptide-1 (GLP-1). To elucidate whether treatment with stronger DPP-4 inhibitor on top of angiotensin II type 1 receptor blocker (ARB) provides greater renal protective effects, we performed a crossover study with two DPP-4 inhibitors, sitagliptin and alogliptin, in twelve type 2 diabetic patients with incipient nephropathy taking ARBs. This study consisted of three treatment periods: sitagliptin 50 mg/day for 4 weeks (first period), alogliptin 25 mg/day for 4 weeks (second period), and sitagliptin 50 mg/day for 4 weeks (third period). Significant changes in body mass index, blood pressure, serum lipids, serum creatinine, estimated glomerular filtration rate, and HbA1c were not observed among the three treatment periods. Reduced urinary levels of albumin and an oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), increased urinary cAMP levels, and elevated plasma levels of stromal cell-derived factor-1α (SDF-1α) which is a physiological substrate of DPP-4 were observed after the switch from sitagliptin to a stronger DPP-4 inhibitor alogliptin. Given a large body of evidence indicating anti-oxidative action of cAMP and up-regulation of cellular cAMP production by SDF-1α, the present results suggest that more powerful DPP-4 inhibition on top of angiotensin II type 1 receptor blockade would offer additional protection against early-stage diabetic nephropathy beyond that attributed to glycemic control, via reduction of renal oxidative stress by SDF-1α-cAMP pathway activation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Chemokine CXCL12; Cross-Over Studies; Cyclic AMP; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Male; Middle Aged; Piperidines; Pyrazines; Receptor, Angiotensin, Type 1; Sitagliptin Phosphate; Triazoles; Up-Regulation; Uracil

To evaluate the influence of renal impairment on the safety and efficacy of repaglinide in type 2 diabetic patients.. This multinational, open-label study comprised a 6-week run-in period, continuing prestudy antidiabetic medication, followed by a titration period (1-4 weeks) and a 3-month maintenance period. Patients with normal renal function (n = 151) and various degrees of renal impairment (n = 130) were treated with repaglinide (maximal dose of 4 mg, three times daily). Safety and efficacy assessments were performed at baseline (end of run-in) and at the end of study treatment.. The type and severity of adverse events during repaglinide treatment were similar to the run-in period. The number of patients with adverse events was not significantly related to renal function during run-in or repaglinide treatment. Percentage of patients with hypoglycemic episodes increased significantly (P = 0.007) with increasing severity of renal impairment during run-in but not during repaglinide treatment (P = 0.074). Metabolic control (HbA(1c) and fasting blood glucose) with repaglinide was unchanged from that on previous antidiabetic medication. Final repaglinide dose tended to be lower for patients with severe and extreme renal impairment than for patients with less severe renal impairment or normal renal function (P = 0.032).. Repaglinide has a good safety and efficacy profile in type 2 diabetic patients complicated by renal impairment and is an appropriate treatment choice, even for individuals with more severe degrees of renal impairment.

Topics: Aged; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Piperidines; Severity of Illness Index

To evaluate the long-term effectiveness and safety of repaglinide, a novel prandial glucose regulator, in comparison with glipizide in the treatment of patients with Type 2 diabetes.. Diet or tablet-treated patients with Type 2 diabetes (n = 256; age 40-75 years, body mass index (BMI) 20-35 kg/m2, HbA1c 4.2-12.8%), without signs of severe microvascular or macrovascular complications, were included in this double-blind, multicentre, parallel-group comparative trial. Patients were randomized at a 2:1 ratio to repaglinide, 1-4 mg at mealtimes, or glipizide, 5-15 mg daily.. Changes in fasting blood glucose (FBG) and HbA1c during the 12 months of treatment showed a significant difference in favour of repaglinide. In oral hypoglycaemic agents (OHA)-naive patients, HbA1c decreased in the repaglinide and glipizide groups by 1.5% and 0.3%, respectively (P < 0.05 between groups). Fasting blood glucose decreased in the repaglinide group by 2.4 mmol/l and increased in the glipizide group by 1.0 mmol/l (P < 0.05 between groups). In the study population as a whole, repaglinide was able to maintain glycaemic control (HbA1c level) during the 1-year study period, whereas control deteriorated significantly with glipizide. Change in HbA1c from baseline was significantly better with repaglinide than with glipizide after 12 months (P < 0.05). In addition, FBG deteriorated significantly in the glipizide group compared with the repaglinide group (P < 0.05). No patients in either group experienced a major hypoglycaemic event; the number of patients experiencing minor hypoglycaemia was similar in the repaglinide and glipizide groups (15% and 19%, respectively).. Repaglinide, given as a prandial glucose regulator, is shown to be an effective and safe treatment of patients with Type 2 diabetes, and is better than glipizide in controlling HbA1c and FBG levels, overall, and in OHA-naive patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Carbamates; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Double-Blind Method; Fasting; Female; Glipizide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Piperidines

We investigated the role of arginine vasopressin (AVP) in the development of diabetic nephropathy and the effect of specific vasopressin V1 receptor antagonist of 1-(1-[4-(3-acetylaminopropoxy)-benzoyl]-4-piperidyl)-3, 4-dihydro-2(1H)-quinolinone (CAS 131631-89-5, OPC-21268) on albuminuria in patients with non-insulin dependent diabetes mellitus. Basal levels of AVP in diabetic patients showing microalbuminuria were significantly high compared to diabetics without any complications, suggesting that in those patients abnormally high amounts of AVP seem to be secreted. Three-week treatment with OPC-21268 demonstrated that albuminuria significantly decreased without affecting renal function. Increased secretion of AVP may induce proliferation of renal mesangial cells and modify blood flows in the glomerular capillaries. The present data suggest that OPC-21268 may be useful for preventing the development of diabetic nephropathy, although its long-term effects should be examined. In conclusion, AVP may play a crucial role in the pathophysiology of diabetic nephropathy and that OPC-21268 seems to prevent further progression of nephropathy in non-insulin dependent diabetes mellitus.

Topics: Albuminuria; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Blood Glucose; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Heart Rate; Humans; Male; Middle Aged; Piperidines; Quinolones; Saline Solution, Hypertonic

Autophagy-mediated lipotoxicity plays a critical role in the progression of diabetic nephropathy (DN), but the precise mechanism is not fully understood. Whether lipophagy, a selective type of autophagy participates in renal ectopic lipid deposition (ELD) and lipotoxicity in the kidney of DN is unknown. Here, decreased lipophagy, increased ELD and lipotoxcity were observed in tubular cells of patients with DN, which were accompanied with reduced expression of AdipoR1 and p-AMPK. Similar results were found in db/db mice, these changes were reversed by AdipoRon, an adiponectin receptor activator that promotes autophagy. Additionally, a significantly decreased level of lipophagy was observed in HK-2 cells, a human proximal tubular cell line treated with high glucose, which was consistent with increased lipid deposition, apoptosis and fibrosis, while were partially alleviated by AdipoRon. However, these effects were abolished by pretreatment with ULK1 inhibitor SBI-0206965, autophagy inhibitor chloroquine and enhanced by AMPK activator AICAR. These data suggested by the first time that autophagy-mediated lipophagy deficiency plays a critical role in the ELD and lipid-related renal injury of DN.

Topics: Adult; AMP-Activated Protein Kinases; Animals; Apoptosis; Autophagosomes; Autophagy; Autophagy-Related Protein-1 Homolog; Cell Line; Diabetic Nephropathies; Enzyme Activators; Female; Fibrosis; Gene Ontology; Glucose; Humans; Intracellular Signaling Peptides and Proteins; Kidney Tubules; Lipid Droplets; Lipid Metabolism; Male; Mice, Inbred C57BL; Microtubule-Associated Proteins; Middle Aged; Oxidative Stress; Phosphorylation; Piperidines; rab7 GTP-Binding Proteins; Receptors, Adiponectin

Topics: Adenine; Aged; Diabetic Nephropathies; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Renal Dialysis; Renal Elimination; Treatment Outcome

Topics: Animals; Diabetic Nephropathies; Disease Models, Animal; Endoplasmic Reticulum Stress; Humans; Male; Mice; Piperidines

Adiponectin is known to take part in the regulation of energy metabolism. AdipoRon, an orally-active synthetic adiponectin agonist, binds to both adiponectin receptors (AdipoR)1/R2 and ameliorates diabetic complications. Among the lipid metabolites, the ceramide subspecies of sphingolipids have been linked to features of lipotoxicity, including inflammation, cell death, and insulin resistance. We investigated the role of AdipoRon in the prevention and development of type 2 diabetic nephropathy.. AdipoRon (30 mg/kg) was mixed into the standard chow diet and provided to db/db mice (db + AdipoRon, n = 8) and age-matched male db/m mice (dm + AdipoRon, n = 8) from 17 weeks of age for 4 weeks. Control db/db (db cont, n = 8) and db/m mice (dm cont, n = 8) were fed a normal diet of mouse chow.. AdipoRon-fed db/db mice showed a decreased amount of albuminuria and lipid accumulation in the kidney with no significant changes in serum adiponectin, glucose, and body weight. Restoring expression of adiponectin receptor-1 and -2 in the renal cortex was observed in db/db mice with AdipoRon administration. Consistent up-regulation of phospho-Thr. AdipoRon may prevent lipotoxicity in the kidney particularly in both GECs and podocytes through an improvement in lipid metabolism, as shown by the ratio of ceramide to sphingosines, and further contribute to prevent deterioration of renal function, independent of the systemic effects of adiponectin. The reduction in oxidative stress and apoptosis by AdipoRon provides protection against renal damage, thereby ameliorating endothelial dysfunction in type 2 diabetic nephropathy.

Topics: Adiponectin; Albuminuria; Animals; Apoptosis; Ceramides; Diabetic Nephropathies; Energy Metabolism; Kidney; Lipid Metabolism; Male; Mice; Oxidative Stress; Phosphorylation; Piperidines; Podocytes

Accumulating evidence has shown that macrophages play a vital role in development and pathogenesis of diabetic nephropathy (DN) by secreting inflammatory cytokines. Although Bruton's tyrosine kinases (Btk) is a biologically important molecule implicated in immune regulation, the role of Btk in high glucose (HG)-stimulated inflammatory response in macrophages and the mechanism involved need further investigation. In our study, we used bone marrow-derived macrophages (BMMs) to investigate the involvement of Btk on HG-induced inflammatory cytokines expression and to explore the underlying mechanisms. We found that high glucose induced phosphorylation of Btk, MAPKs and NF-κB, and the expression of downstream inflammation cytokines monocyte chemo-attractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β). Btk inhibitor (PCI-32765) not only down-regulated ERK1/2 phosphorylation and NF-κB activation, but also decreased the secretion of MCP-1, TNF-α and IL-1β in HG-treated BMMs. These results indicate that Btk plays an important role in HG-induced inflammatory cytokines expression and that PCI-32765 may be used as an immunoregulatory agent against hyperglycemia-induced inflammatory response in DN.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Anti-Inflammatory Agents; Bone Marrow Cells; Cells, Cultured; Cytokines; Diabetic Nephropathies; Extracellular Signal-Regulated MAP Kinases; Glucose; Humans; Immunomodulation; Inflammation Mediators; Macrophages; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Phosphorylation; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction

We have previously demonstrated that KMUP-1, a xanthine-based nitric oxide enhancer, attenuates diabetic glomerulosclerosis, while increasing renal endothelial nitric oxide synthase expression in rats. However, the anti‑fibrotic mechanisms of KMUP‑1 treatment in diabetic nephropathy in terms of cell biology and transforming growth factor-β1 (TGF‑β1) remain unclear. Therefore, the present study involved investigating the effects of KMUP‑1 on high glucose (HG) or TGF‑β1‑induced pro‑fibrotic proteins in mouse mesangial (MES13) cells, and the effects of KMUP‑1 on streptozotocin (STZ)‑induced diabetic rats. It was identified that KMUP‑1 (10 µM) attenuated HG (30 mM)‑induced cell hypertrophy while attenuating TGF‑β1 gene transcription and bioactivity in MES13 cells. In addition, KMUP‑1 attenuated TGF‑β1 (5 ng/ml)‑induced Smad2/3 phosphorylation while attenuating HG or TGF‑β1‑induced collagen IV and fibronectin protein expression. Furthermore, KMUP‑1 attenuated HG‑decreased Suv39h1 and H3K9me3 levels. Finally, KMUP‑1 attenuated diabetes-induced collagen IV and fibronectin protein expression in STZ‑diabetic rats at 8 weeks. In conclusion, KMUP‑1 attenuates HG and TGF‑β1‑induced pro‑fibrotic proteins in mesangial cells and attenuation of TGF‑β1‑induced signaling and attenuation of HG‑decreased Suv39h1 expression may be two of the anti-fibrotic mechanisms of KMUP‑1.

Topics: Animals; Cell Line; Collagen Type IV; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fibronectins; Fibrosis; Glucose; Histones; Mesangial Cells; Methyltransferases; Mice; Piperidines; Signal Transduction; Smad2 Protein; Smad3 Protein; Streptozocin; Transforming Growth Factor beta1; Xanthines

The molecular signaling mechanisms between glomerular cell types during initiation/progression of diabetic kidney disease (DKD) remain poorly understood. We compared the early transcriptome profile between DKD-resistant C57BL/6J and DKD-susceptible DBA/2J (D2) glomeruli and demonstrated a significant downregulation of essential mitochondrial genes in glomeruli from diabetic D2 mice, but not in C57BL/6J, with comparable hyperglycemia. Diabetic D2 mice manifested increased mitochondrial DNA lesions (8-oxoguanine) exclusively localized to glomerular endothelial cells after 3 weeks of diabetes, and these accumulated over time in addition to increased urine secretion of 8-oxo-deoxyguanosine. Detailed assessment of glomerular capillaries from diabetic D2 mice demonstrated early signs of endothelial injury and loss of fenestrae. Glomerular endothelial mitochondrial dysfunction was associated with increased glomerular endothelin-1 receptor type A (Ednra) expression and increased circulating endothelin-1 (Edn1). Selective Ednra blockade or mitochondrial-targeted reactive oxygen species scavenging prevented mitochondrial oxidative stress of endothelial cells and ameliorated diabetes-induced endothelial injury, podocyte loss, albuminuria, and glomerulosclerosis. In human DKD, increased urine 8-oxo-deoxyguanosine was associated with rapid DKD progression, and biopsies from patients with DKD showed increased mitochondrial DNA damage associated with glomerular endothelial EDNRA expression. Our studies show that DKD susceptibility was linked to mitochondrial dysfunction, mediated largely by Edn1-Ednra in glomerular endothelial cells representing an early event in DKD progression, and suggest that cross talk between glomerular endothelial injury and podocytes leads to defects and depletion, albuminuria, and glomerulosclerosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Albuminuria; Animals; Antioxidants; Chromatography, High Pressure Liquid; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Susceptibility; DNA, Mitochondrial; Endothelin-1; Endothelium; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Kidney Glomerulus; Male; Mesangial Cells; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Organophosphorus Compounds; Oxygen Consumption; Piperidines; Podocytes; Real-Time Polymerase Chain Reaction; Receptor, Endothelin A; Signal Transduction; Young Adult

Hyperglycemia leads to elevation of oxidative stress and proinflammatory cytokines which are the main causes of diabetic nephropathy (DN). NLRP3 inflammasome and thioredoxin-interacting protein (TXNIP) are recently assumed to participate in the development of DN. We aimed to investigate the effects of Cepharanthine (CEP), Piperine (Pip) and their combination in streptozotocin (STZ)-induced DN focusing on their role to modulate NLRP3 and TXNIP induced inflammation.. Diabetic rats were treated with intraperitoneal (i.p.) injection of CEP (10mg/kg/day), Pip (30mg/kg/day) or their combination for 8weeks. Nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) were assessed by ELISA technique. TXNIP and NLRP3 genes expressions were evaluated by real time-PCR.. Diabetic rats showed significant increase in renal TXNIP and NLRP3 expression. CEP, Pip or their combination significantly decreased TXNIP and NLRP3 expression in diabetic kidneys. Hyperglycemia induced NF-κB activation leading to increased IL-1β and TNF-α levels. CEP, Pip or their combination showed significant inhibition of NF-κB together with decreased IL-1β and TNF-α levels in diabetic rats. Also, diabetic rats showed significant decrease in creatinine clearance and increase in blood glucose, serum creatinine, blood urea nitrogen, malondialdehyde, proteinuria, and kidney weight to body Weight ratio. All of these changes were reversed by CEP, Pip or their combination.. The antioxidant and anti-inflammatory effects of CEP and Pip which were accompanied by inhibition of NF-κB and NLRP3 activation might be helpful mechanisms to halt the progression of DN.

Topics: Alkaloids; Animals; Benzodioxoles; Benzylisoquinolines; Diabetic Nephropathies; Inflammasomes; Male; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley

Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2α), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2α) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2α), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.

Topics: Albuminuria; Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Progression; Female; Glomerular Mesangium; Hypercholesterolemia; Hypertriglyceridemia; Hypertrophy; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Kidney; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Piperidines; PPAR alpha; Propionates

The endocannabinoid system is important in the pathogenesis of obesity-related metabolic disorders. However, the effect of inhibiting the endocannabinoid system in type 2 diabetic nephropathy is unclear. Therefore, we examined the effect of the cannabinoid (CB)1 receptor antagonist, SR141716, on insulin resistance and diabetic nephropathy in db/db mice. Six-week-old db/db mice were treated with the CB1-specific antagonist SR141716 (10 mg/kg · d) for 3 months. Treatment with SR141716 significantly improved insulin resistance and lipid abnormalities. Concomitantly, CB1 antagonism improved cardiac functional and morphological abnormality, hepatic steatosis, and phenotypic changes of adipocytes into small differentiated forms, associated with increased adiponectin expression and decreased lipid hydroperoxide levels. CB1 receptor was overexpressed in diabetic kidneys, especially in podocytes. Treatment with the SR141716 markedly decreased urinary albumin excretion and mesangial expansion and suppressed profibrotic and proinflammatory cytokine synthesis. Furthermore, SR141716 improved renal lipid metabolism and decreased urinary 8-isoprostane levels, renal lipid hydroperoxide content, and renal lipid content. In cultured podocytes, high-glucose stimulation increased CB1 receptor expression, and SR141716 treatment abolished high-glucose-induced up-regulation of collagen and plasminogen activator inhibitor-1 synthesis. Additionally, knockdown of CB1 receptor expression by stealth small interfering RNA abolished high-glucose-induced sterol-regulatory element-binding protein-1 expression in podocytes. These findings suggest that CB1 blockade improves insulin resistance and protect against renal injury through both metabolic and antifibrotic effects in type 2 diabetic nephropathy. Targeting CB1 blockade could therefore provide a new therapeutic target to prevent type 2 diabetic nephropathy.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Gene Expression Regulation; Glucose; Insulin Resistance; Lipid Metabolism; Lipids; Male; Mice; Mice, Inbred C57BL; Piperidines; Podocytes; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; RNA Interference; RNA, Small Interfering

In this paper we analyse the discrepancies that exist in the widespread prescription of metformin in patients with type 2 diabetes and the lack of guidelines concerning its prescription in the different stages of renal failure. This cross-sectional study includes 304 patients with type 2 diabetes treated with oral antidiabetic drugs (ADOs) and a glomerular filtration rate (estimated GFR) <60ml/min/1.73m2. Patients were attended in consecutive visits to primary health centres or in hospital departments of endocrinology or nephrology during 2010. We studied the frequency of metformin and other ADO prescriptions according to renal function and the department in which the patient was treated. The ADO most frequently prescribed was metformin (54.9%), followed by repaglinide (47.7%), DPP4 inhibitors (28.6%), and sulfonylureas (18.4%). However, in nephrology departments, repaglinide was more frequently prescribed than metformin (P<.001), whereas in primary health centres, the prescription of DPP4 inhibitors increased. In patients with an estimated GFR of 15-29ml/min/1.73m2, metformin (13.3%) and sulfonylureas were the least prescribed, whereas metformin was much more frequently prescribed (70.0%) when estimated GFR was 45-59ml/min/1.73m2 (P<.001). In contrast, patients with an estimated GFR of 15-29ml/min/1.73m2 were mainly prescribed repaglinide (76.7%), as opposed to patients with an estimated GFR of 45-59ml/min/1.73m2 (38.9%) (P<.001). Substantial evidence suggests that the recommendations for the use of ADO should be modified. This would lead to safely prescribing ADO in patients with an estimated GFR<60ml/min/1.73m2, and more importantly in medical practice, according to the law.

Topics: Acidosis, Lactic; Aged; Carbamates; Consensus Development Conferences as Topic; Contraindications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Management; Drug Utilization; Endocrinology; Female; Follow-Up Studies; Glomerular Filtration Rate; Hospital Departments; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Nephrology; Piperidines; Practice Guidelines as Topic; Primary Health Care; Professional Practice; Societies, Medical; Spain; Sulfonylurea Compounds

Cannabinoid receptor 1 (CB1) is localized in the central nervous system and in peripheral tissues involved in energy metabolism control. However, CB1 receptors are also expressed at low level within the glomeruli, and the aim of this study was to investigate their potential relevance in the pathogenesis of proteinuria in experimental type 1 diabetes.. Streptozotocin-induced diabetic mice were treated with N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,3-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), a selective CB1-receptor antagonist, at the dosage of 1 mg x kg(-1) x day(-1) via intraperitoneal injection for 14 weeks. Urinary albumin excretion was measured by enzyme-linked immunosorbent assay. CB1 receptor expression was studied by immunohistochemistry, immunoblotting, and real-time PCR. Expression of nephrin, podocin, synaptopodin, and zonula occludens-1 (ZO-1) was assessed by immunofluorescence and real-time PCR. Fibronectin, transforming growth factor-beta1 (TGF-beta1), and connective tissue growth factor (CTGF) mRNA levels were quantitated by real-time PCR.. In diabetic mice, the CB1 receptor was overexpressed within the glomeruli, predominantly by glomerular podocytes. Blockade of the CB1 receptor did not affect body weight, blood glucose, and blood pressure levels in either diabetic or control mice. Albuminuria was increased in diabetic mice compared with control animals and was significantly ameliorated by treatment with AM251. Furthermore, CB1 blockade completely prevented diabetes-induced downregulation of nephrin, podocin, and ZO-1. By contrast overexpression of fibronectin, TGF-beta1, and CTGF in renal cortex of diabetic mice was unaltered by AM251 administration.. In experimental type 1 diabetes, the CB1 receptor is overexpressed by glomerular podocytes, and blockade of the CB1 receptor ameliorates albuminuria possibly via prevention of nephrin, podocin, and ZO-1 loss.

Topics: Albuminuria; Animals; Connective Tissue Growth Factor; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fibronectins; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Phosphoproteins; Piperidines; Polymerase Chain Reaction; Pyrazoles; Receptor, Cannabinoid, CB1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta1; Zonula Occludens-1 Protein

Transforming growth factor-beta (TGF-beta) is known to promote the accumulation of extracellular matrix (ECM) and the development of diabetic nephropathy. Halofuginone, an analog of febrifugine, has been shown to block TGF-beta(1) signaling and subsequent type I collagen production. Here, the inhibitory effect of halofuginone on diabetic nephropathy was examined. Halofuginone suppressed Smad2 phosphorylation induced by TGF-beta(1) in cultured mesangial cells. In addition, the expression of TGF-beta type 2 receptor decreased by halofuginone. Halofuginone showed an inhibitory effect on type I collagen and fibronectin expression promoted by TGF-beta(1). An in vivo experiment using db/db mice confirmed the ability of halofuginone to suppress mesangial expansion and fibronectin overexpression in the kidneys. Moreover, an analysis of urinary 8-OHdG level and dihydroethidium fluorescence revealed that halofuginone reduced oxidative stress in the glomerulus of db/db mice. These data indicate that halofuginone prevents ECM deposition and decreases oxidative stress, thereby suppressing the progression of diabetic nephropathy.

Topics: Animals; Collagen Type I; Diabetic Nephropathies; Extracellular Matrix; Fibronectins; Mesangial Cells; Mice; Mice, Inbred Strains; Oxidative Stress; Piperidines; Quinazolinones; Rats; Smad2 Protein; Transforming Growth Factor beta

Visfatin is an adipocytokine that improves insulin resistance and has an antidiabetic effect. However, the role of visfatin in the kidney has not yet been reported. In this experiment, the synthesis and physiological action of visfatin in cultured mesangial cells (MCs) were studied to investigate the role of visfatin in diabetic nephropathy. Visfatin was found synthesized in MCs as well as adipocytes. Visfatin synthesis was markedly increased, not by angiotensin II, but by high glucose stimuli. In addition, visfatin treatment induced a rapid uptake of glucose, peaking at 20 min after visfatin treatment in a dose-dependent manner. A small inhibiting RNA against insulin receptor significantly blocked visfatin-mediated glucose uptake. Visfatin stimuli also enhanced intracellular NAD levels, and treatment with FK866, which is a specific inhibitor of nicotinamide phosphoribosyltransferase (Nampt), significantly inhibited visfatin-induced NAD synthesis and glucose uptake. Visfatin treatment increased glucose transporter-1 (GLUT-1) protein expression in isolated cellular membranes, and pretreatment with cytochalasin B completely inhibited visfatin-induced glucose uptake. Moreover, immunofluorescent microscopy showed the migration of cytosolic GLUT-1 into cellular membranes after visfatin treatment. In accordance with these results, the activation of protein kinase B was detected after visfatin treatment. Furthermore, visfatin treatment dramatically increased the synthesis of profibrotic molecules including transforming growth factor-beta1, plasminogen activator inhibitor-1, and type I collagen, and pretreatment with cytochalasin B completely inhibited visfatin-induced upregulation of profibrotic molecules. These results suggest that visfatin is produced in MCs, which are a novel target for visfatin, and play an important role in the pathogenesis of diabetic nephropathy.

Topics: Acrylamides; Adipocytes, White; Angiotensin II; Animals; Blotting, Western; Cell Survival; Cells, Cultured; Collagen Type I; Cytokines; Diabetic Nephropathies; Gene Expression; Glucose; Glucose Transporter Type 1; Mesangial Cells; Nicotinamide Mononucleotide; Nicotinamide Phosphoribosyltransferase; Phosphorylation; Piperidines; Plasminogen Activator Inhibitor 1; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Transforming Growth Factor beta1

Adenosine 2A receptor (A(2A)R) activation was recently shown to be renoprotective in diabetic nephropathy. A(2A)R are found in glomeruli and have been shown to associate with the podocyte cytoskeletal protein alpha-actinin-4, but the effect of their activation on podocyte structure and function is unknown. Podocyte injury was induced in C57BL/6 mice with puromycin aminonucleoside, and the selective A(2A)R agonist ATL313 was found to attenuate the resulting albuminuria and foot process fusion. The selective A(2A)R antagonist ZM241385 reversed the effects of ATL313. In vitro, A(2A)R mRNA and protein were expressed in a conditionally immortalized podocyte cell line, and A(2A)R-like immunoreactivity co-localized with the actin cytoskeleton. Treatment with ATL313 also blocked the increased podocyte permeability to albumin and disruption of the actin cytoskeleton that accompanied puromycin aminonucleoside-induced injury in vitro. ATL313 was ineffective, however, in the presence of the A(2A)R antagonist and in A(2A)R-deficient podocytes. It was concluded that A(2A)R activation reduces glomerular proteinuria, at least in part, by preserving the normal structure of podocyte foot processes, slit diaphragms, and actin cytoskeleton.

Topics: Adenosine A2 Receptor Agonists; Albuminuria; Animals; Diabetic Nephropathies; Mice; Mice, Inbred C57BL; Piperidines; Podocytes; Proteinuria; Purine Nucleosides; Receptors, Adenosine A2; Triazines; Triazoles

Gut transit using radiopaque markers was assessed in 5 healthy subjects and 24 diabetic patients. In the diabetics, various parameters including duration of the disease and diabetic complications, such as neuropathy, retinopathy and nephropathy, were determined, and the relationships between gut transit times and these complications were evaluated. The effect of cisapride on gut transit was studied in 10 diabetic patients. Large intestinal, descending colon, distal colon, and whole gut transit times were delayed in diabetics with autonomic neuropathy compared to controls and to diabetics without autonomic neuropathy (P less than 0.01). There was no difference in proximal colon transit times among them. An inverse correlation was observed between CVRR and the transit times for descending colon, distal colon, large intestine and whole gut. Large intestinal and whole-gut transit times were delayed in diabetics with retinopathy or with nephropathy compared to diabetics without those complications (P less than 0.01). In the diabetics, oral administration of 7.5 mg/day of cisapride for 2 weeks significantly accelerated descending colon transit (P less than 0.05) and partially accelerated distal colon, large intestinal and whole-gut transit. It is concluded that diabetics with autonomic neuropathy have delayed transits for the whole gut and that this finding is apparent to some extent in the distal colon but not in the proximal colon. Chronic oral administration of cisapride, a gastrointestinal prokinetic drug, was effective to improve these gastrointestinal motility disorders in diabetics with autonomic neuropathy.

Topics: Administration, Oral; Adult; Cisapride; Colon; Contrast Media; Diabetes Mellitus; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Gastrointestinal Motility; Humans; Intestine, Small; Male; Middle Aged; Piperidines; Serotonin Antagonists

Topics: Adult; Cisapride; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Evaluation; Gastrointestinal Motility; Humans; Infusions, Parenteral; Kidney Failure, Chronic; Male; Myenteric Plexus; Peritoneal Dialysis, Continuous Ambulatory; Piperidines; Stimulation, Chemical