glucagon-like-peptide-1 and Kidney-Diseases

The increasing number of newer type 2 diabetes therapies has allowed providers an increased armamentarium for the optimal management of patients with diabetes. In fact, these newer agents have unique benefits in the management of type 2 diabetes. However, they are also associated with certain adverse effects. This review article aims to describe the notable adverse effects of these newer antidiabetic therapies including the glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and the sodium-glucose cotransporter 2 inhibitors. The adverse effects reviewed herein include pancreatitis, medullary thyroid carcinoma, heart failure, gastrointestinal disturbances, renal impairment, and genitourinary infections. More clinical data are necessary to solidify the association of some of these adverse effects with the newer diabetes agents. However, it is important for health care practitioners to be well informed and prepared to properly monitor patients for these adverse effects.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug-Related Side Effects and Adverse Reactions; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Kidney Diseases; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Established therapies for type-2 diabetes effectively reduce blood glucose, but are often associated with adverse effects that pose risks to patient's health or diminish adherence to treatment. Weight gain, hypoglycaemia and gastrointestinal symptoms are commonly reported and some agents may not be safe for use in patients with renal impairment or elevated cardiovascular risk. New treatments based on the action of the endogenous human hormone glucagon-like peptide-1 (GLP-1), including exenatide and liraglutide, are available. These therapies provide a novel pharmacological approach to glycaemic control via multiple mechanisms of action, and accordingly exhibit different safety and tolerability profiles than conventional treatments. GLP-1 receptor agonists stimulate insulin release only in the presence of elevated blood glucose and are therefore associated with a fairly low risk of hypoglycaemia. Gastrointestinal symptoms are common but transient, and there appears to be little potential for interaction with other drugs. GLP-1 receptor agonists are associated with weight loss rather than weight gain. As protein-based therapies, these agents have the potential to induce antibody formation, but the impact on efficacy and safety is minor. GLP-1 receptor agonists thus offer a new and potentially useful option for clinicians concerned about some of the common adverse effects of type-2 diabetes therapies.

Topics: Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Drug Interactions; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Diseases; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Kidney Diseases; Pancreatitis; Receptors, Glucagon; Sulfonylurea Compounds; Thiazolidinediones; Thyroid Diseases

The therapeutic benefits of the incretin hormone, glucagon-like peptide 1 (GLP1), for people with type 2 diabetes and/or obesity, are now firmly established. The evidence-base arising from head-to-head comparative effectiveness studies in people with type 2 diabetes, as well as the recommendations by professional guidelines suggest that GLP1 receptor agonists should replace more traditional treatment options such as sulfonylureas and dipeptidyl-peptidase 4 (DPP4) inhibitors. Furthermore, their benefits in reducing cardiovascular events in people with type 2 diabetes beyond improvements in glycaemic control has led to numerous clinical trials seeking to translate this benefit beyond type 2 diabetes. Following early trial results their therapeutic benefit is currently being tested in other conditions including fatty liver disease, kidney disease, and Alzheimer's disease.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Kidney Diseases

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Kidney Diseases; Practice Guidelines as Topic; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors

High dietary fructose consumption has been linked to the development of renal fibrosis. Dulaglutide is a long acting glucagon like peptide-1 (GLP-1) analog, showing some renoprotective properties; however its action on renal fibrosis remains uncertain. We investigated the effect of dulaglutide on fructose-induced renal fibrosis in comparison to pirfenidone, as well-established anti-fibrotic drug, and the contribution of epithelial-mesenchymal transition (EMT) process and its upstream signaling.. Six week-old male Wistar albino rats received 10%w/v fructose solution in drinking water for 24 weeks and co-treated with either pirfenidone (100 mg/kg/day, orally) or dulaglutide (0.2 mg/kg/week, s.c) for the last four weeks. Lipid profile, glucose homeostasis, kidney functions were assessed. Kidneys were harvested for biochemical and histological analyses.. High dietary fructose consumption for 24 weeks induced insulin resistance, dyslipidemia and renal dysfunction that were ameliorated by dulaglutide and pirfenidone to lesser extent. Histological examination revealed histological lesions and interstitial fibrosis in renal sections of high fructose-fed rats, which were reversed by dulaglutide or pirfenidone treatment. Both drugs modulated the EMT-related proteins by increasing the epithelial marker, E-cadherin, while suppressing the mesenchymal markers, vimentin and alpha-smooth muscle actin (α-SMA) in renal tissue. Moreover, both drugs attenuated fructose-induced upregulation of GSK-3β/TGF-β1/Smad3 signaling.. These findings suggest that dulaglutide can emerge as a promising therapeutic agent for fructose-induced renal fibrosis. These results add mechanistic insights into the anti-fibrotic action of dulaglutide through suppressing EMT and the upstream GSK-3β/TGF-β1/Smad3 signaling.

Topics: Actins; Animals; Cadherins; Drinking Water; Epithelial-Mesenchymal Transition; Fibrosis; Fructose; Glucagon-Like Peptide 1; Glucose; Glycogen Synthase Kinase 3 beta; Kidney Diseases; Lipids; Male; Rats; Rats, Wistar; Signal Transduction; Transforming Growth Factor beta1; Vimentin

Increased mortality due to type 2 diabetes mellitus (T2DM) has been associated with renal and/or cardiovascular dysfunction. Dipeptidyl dipeptidase-4 inhibitors (iDPP-4s) may exert cardioprotective effects through their pleiotropic actions via glucagon-like peptide 1-dependent mechanisms. In this study, the pharmacological profile of a new iDPP-4 (LASSBio-2124) was investigated in rats with cardiac and renal dysfunction induced by T2DM.. T2DM was induced in rats by 2 weeks of a high-fat diet followed by intravenous injection of streptozotocin. Metabolic disturbance and cardiac, vascular, and renal dysfunction were analyzed in the experimental groups.. Sitagliptin and LASSBio-2124 administration after T2DM induction reduced elevated glucose levels to 319.8 ± 13.2 and 279.7 ± 17.8 mg/dL, respectively (p < 0.05). LASSBio-2124 also lowered the cholesterol and triglyceride levels from 76.8 ± 8.0 to 42.7 ± 3.2 mg/dL and from 229.7 ± 25.4 to 100.7 ± 17.1 mg/dL, in diabetic rats. Sitagliptin and LASSBio-2124 reversed the reduction of the plasma insulin level. LASSBio-2124 recovered the increased urinary flow in diabetic animals and reduced 24-h proteinuria from 23.7 ± 1.5 to 13.3 ± 2.8 mg (p < 0.05). It also reduced systolic and diastolic left-ventricular dysfunction in hearts from diabetic rats.. The effects of LASSBio-2124 were superior to those of sitagliptin in the cardiovascular systems of T2DM rats. This new prototype showed promise for the avoidance of comorbidities in a T2DM experimental model, and thus may constitute an innovative therapeutic agent for the treatment of these conditions in the clinical field in future.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart; Kidney Diseases; Male; Rats; Rats, Wistar; Sitagliptin Phosphate; Streptozocin; Ventricular Dysfunction, Left

To investigate the role of glucagon-like peptide-1 analog (GLP-1) in high-fat diet-induced obesity-related glomerulopathy (ORG). Male C57BL/6 mice fed a high-fat diet for 12 wk were treated with GLP-1 (200 μg/kg) or 0.9% saline for 4 wk. Fasting blood glucose and insulin and the expression of podocin, nephrin, phosphoinositide 3-kinase (PI3K), glucose transporter type (Glut4), and microtubule-associated protein 1A/1B-light chain 3 (LC3) were assayed. Glomerular morphology and podocyte foot structure were evaluated by periodic acid-Schiff staining and electron microscopy. Podocytes were treated with 150 nM GLP-1 and incubated with 400 μM palmitic acid (PA) for 12 h. The effect on autophagy was assessed by podocyte-specific Glut4 siRNA. Insulin resistance and autophagy were assayed by immunofluorescence and Western blotting. The high-fat diet resulted in weight gain, ectopic glomerular lipid accumulation, increased insulin resistance, and fusion of podophyte foot processes. The decreased translocation of Glut4 to the plasma membrane and excess autophagy seen in mice fed a high-fat diet and in PA-treated cultured podocytes were attenuated by GLP-1. Podocyte-specific Glut4 siRNA promoted autophagy, and rapamycin-enhanced autophagy worsened the podocyte injury caused by PA. Excess autophagy in podocytes was induced by inhibition of Glut4 translocation to the plasma membrane and was involved in the pathology of ORG. GLP-1 restored insulin sensitivity and ameliorated renal injury by decreasing the level of autophagy.

Topics: Animals; Autophagy; Blood Glucose; Cell Line; Cytoprotection; Diet, High-Fat; Disease Models, Animal; Glucagon-Like Peptide 1; Glucose Transporter Type 4; Insulin; Insulin Resistance; Kidney Diseases; Male; Mice, Inbred C57BL; Obesity; Palmitic Acid; Podocytes; Protein Transport; Signal Transduction; Sirolimus

Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs in patients with type 2 diabetes. In our previous study, we showed that glucagon-like peptide-1 (GLP-1) receptor agonist has reno-protective effects through anti-inflammatory action. The mechanism of action of DPP-4 inhibitor is different from that of GLP-1 receptor agonists. It is not obvious whether DPP-4 inhibitor prevents the exacerbation of diabetic nephropathy through anti-inflammatory effects besides lowering blood glucose or not. The purpose of this study is to clarify the reno-protective effects of DPP-4 inhibitor through anti-inflammatory actions in the early diabetic nephropathy.. Five-week-old male Sprague-Dawley (SD) rats were divided into three groups; non-diabetes, diabetes and diabetes treated with DPP-4 inhibitor (PKF275-055; 3 mg/kg/day). PKF275-055 was administered orally for 8 weeks.. PKF275-055 increased the serum active GLP-1 concentration and the production of urinary cyclic AMP. PKF275-055 decreased urinary albumin excretion and ameliorated histological change of diabetic nephropathy. Macrophage infiltration was inhibited, and inflammatory molecules were down-regulated by PKF275-055 in the glomeruli. In addition, nuclear factor-κB (NF-κB) activity was suppressed in the kidney.. These results indicate that DPP-4 inhibitor, PKF275-055, have reno-protective effects through anti-inflammatory action in the early stage of diabetic nephropathy. The endogenous biological active GLP-1 might be beneficial on diabetic nephropathy besides lowering blood glucose.

Topics: Adamantane; Animals; Anti-Inflammatory Agents; Cyclic AMP; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Glucagon-Like Peptide 1; Kidney Diseases; Kidney Glomerulus; Male; Nitriles; Protective Agents; Pyrrolidines; Rats; Rats, Sprague-Dawley

Obesity-related glomerulopathy is characterized initially by glomerular hyperfiltration with hypertrophy and then development of proteinuria. Putative mechanisms include endothelial dysfunction and filtration barrier injury due to oxidant stress and immune activation. There has been recent interest in targeting dipeptidyl peptidase 4 (DPP4) enzyme due to increasing role in non-enzymatic cellular processes.. The Zucker obese (ZO) rat (aged 8 weeks) fed a normal chow or diet containing the DPP4 inhibitor linagliptin for 8 weeks (83 mg/kg rat chow) was utilized.. Compared to lean controls, there were increases in plasma DPP4 activity along with proteinuria in ZO rats. ZO rats further displayed increases in glomerular size and podocyte foot process effacement. These findings occurred in parallel with decreased endothelial stromal-derived factor-1α (SDF-1α), increased oxidant markers, and tyrosine phosphorylation of nephrin and serine phosphorylation of the mammalian target of rapamycin (mTOR). DPP4 inhibition improved proteinuria along with filtration barrier remodeling, circulating and kidney tissue DPP4 activity, increased active glucagon like peptide-1 (GLP-1) as well as SDF-1α, and improved oxidant markers and the podocyte-specific protein nephrin.. These data support a role for DPP4 in glomerular filtration function and targeting DPP4 with inhibition improves oxidant stress-related glomerulopathy and associated proteinuria.

Topics: Animals; Dipeptidyl-Peptidase IV Inhibitors; Glomerular Filtration Barrier; Glucagon-Like Peptide 1; Hypoglycemic Agents; Kidney Diseases; Kidney Glomerulus; Male; Obesity; Oxidative Stress; Podocytes; Rats; Rats, Zucker

The wide ubiquity of GLP-1 receptors in the body has stimulated the search for different extrapancreatic actions of GLP-1 and its receptor agonists. Thus, severe cardioprotective effects directed on myocardial ischaemia and dysfunction as well as diverse antiaterogenic actions have been reported. Also, native and GLP-1 receptor agonists have demonstrated significant beneficial effects on liver steatosis and fibrosis and on neuronal protection in experimental models of Alzheimer, and Parkinson's disease as well as on cerebral ischaemia. Recent evidences suggest that these drugs may also be useful for prevention and treatment of diabetic retinopathy, nephropathy and peripheral neuropathy. Good results have also been reported in psoriasis. Despite we still need confirmation that these promising effects can be applied to clinical practice, they offer new interesting perspectives for treatment of type 2 diabetes associated complications and give to GLP-1 receptor agonists an even more integral position in diabetes therapy.

Topics: Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Cardiotonic Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Disease Models, Animal; Endothelium, Vascular; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin Resistance; Kidney Diseases; Lipid Metabolism; Liver Diseases; Multicenter Studies as Topic; Nervous System Diseases; Neuroprotective Agents; Organ Specificity; Receptors, Glucagon; Recombinant Proteins

Activation of glucagon-like peptide-1 (GLP-1) receptors improves insulin sensitivity and induces vasodilatation and diuresis. AC3174 is a peptide analogue with pharmacologic properties similar to the GLP-1 receptor agonist, exenatide. Hypothetically, chronic AC3174 treatment could attenuate salt-induced hypertension, cardiac morbidity, insulin resistance, and renal dysfunction in Dahl salt-sensitive (DSS) rats.. DSS rats were fed low salt (LS, 0.3% NaCl) or high salt (HS, 8% NaCl) diets. HS rats were treated with vehicle, AC3174 (1.7 pmol/kg/min), or GLP-1 (25 pmol/kg/min) for 4 weeks via subcutaneous infusion. Other HS rats received captopril (150 mg/kg/day) or AC3174 plus captopril.. HS rat survival was improved by all treatments except GLP-1. Systolic blood pressure (SBP) was lower in LS rats and in GLP-1, AC3174, captopril, or AC3174 plus captopril HS rats than in vehicle HS rats (p < 0.05). AC3174 plus captopril attenuated the deleterious effects of high salt on posterior wall thickness, LV mass, and the ratio of LV mass to body weight (P < or = 0.05). In contrast, GLP-1 had no effect on these cardiovascular parameters. All treatments reduced LV wall stress. GLP-1, AC3174, captopril, or AC3174 plus captopril normalized fasting insulin and HOMA-IR (P < or = 0.05). AC3174, captopril, or AC3174 plus captopril improved renal function (P < or = 0.05). Renal morphology in HS rats was associated with extensive sclerosis. Monotherapy with AC3174, captopril, or GLP-1 attenuated renal damage. However, AC3174 plus captopril produced the most effective improvement.. Thus, AC3174 had antihypertensive, cardioprotective, insulin-sensitizing, and renoprotective effects in the DSS hypertensive rat model. Furthermore, AC3174 improved animal survival, an effect not observed with GLP-1.

Topics: Animals; Antihypertensive Agents; Blood Glucose; Captopril; Cardiotonic Agents; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Hyperglycemia; Hypertension, Renal; Hypoglycemic Agents; Insulin Resistance; Kidney Diseases; Male; Peptides; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Venoms

Dahl salt-sensitive (Dahl S) rats exhibit many phenotypic traits associated with salt-sensitive hypertension in man. Specifically, they are salt-sensitive, insulin-resistant and hyperlipidemic. They also develop endothelial dysfunction, cardiac injury and glomerulosclerosis. Insulin resistance is linked to hypertension, renal and cardiac damage and endothelial dysfunction. Thus, an agent that has diuretic action and can improve insulin resistance, like recombinant glucagon-like peptide-1(7-36)amide (rGLP-1), may have an antihypertensive effect.. To determine whether chronic administration of rGLP-1 attenuates the development of hypertension, endothelial dysfunction and/or hypertension-induced renal and cardiac end organ damage in Dahl S rats.. Mean arterial pressure (MAP) and urinary excretion of protein and albumin were measured in Dahl S rats before and after they were fed a 8% NaCl diet and infused with rGLP-1 (1 micro g/kg per min, i.v.) or vehicle for 14 days. At the end of the study, the degree of renal and cardiac injury was histologically assessed and endothelium-dependent relaxing function was studied using aortic rings. In other rats, the effects of rGLP-1 on sodium and water balance and plasma glucose and insulin levels for the first 3 days following a step change in sodium intake from a 0.1% NaCl diet to 7.5 mEq/day were determined.. rGLP-1 significantly attenuated the development of hypertension in Dahl S rats (136 +/- 7 versus 174 +/- 6 mmHg). This was associated with reduction in proteinuria (46 +/- 7 versus 128 +/- 15 mg/day) and albuminuria (46 +/- 7 versus 86 +/- 18 mg/day) and improvement of endothelial function and renal and cardiac damage. rGLP-1 markedly increased urine flow and sodium excretion for the first 3 days following elevation in sodium intake. It had no significant effects on plasma glucose and insulin concentrations.. rGLP-1 has antihypertensive and cardiac and renoprotective effects in Dahl S rats fed a high salt diet. The antihypertensive effect of rGLP-1 in Dahl S rats is due mainly to its diuretic and natriuretic effects, rather than an effect to improve insulin-resistance.

Topics: Animals; Antihypertensive Agents; Aorta; Blood Glucose; Diuresis; Endothelium, Vascular; Glucagon; Glucagon-Like Peptide 1; Heart Diseases; Hypertension; Insulin; Kidney Diseases; Male; Natriuresis; Peptide Fragments; Protein Precursors; Rats; Rats, Inbred Dahl; Sodium; Sodium Chloride, Dietary; Water-Electrolyte Balance