Diabetic nephropathy (DN) is a major cause of end-stage renal disease and affects a large number of individuals with diabetes. However, the development of specific treatments for DN has not yet been identified. Hence, this review is concisely designed to understand the molecular pathways leading to DN in order to develop suitable therapeutic strategies. Extensive literature search have been carried in regard with the pathogenesis and pathophysiology of DN, drug targets and updates on clinical trials, the consequences associated with DN and the potential biomarkers for diagnosis and prediction of DN are discussed in this review. DN is characterised by microalbuminuria and macroalbuminuria, and morphological changes such as glomerular thickening, interstitial fibrosis, formation of nodular glomerulosclerosis and decreased endothelial cell fenestration. Besides, the involvement of renin-angiotensin-aldosterone system, inflammation and genetic factors are the key pathways in the progression of DN. In regard with drug development drugs targeted to epidermal growth factor, inflammatory cytokines, ACTH receptor and TGFβ1 receptors are in pipeline for clinical trials whereas, several drugs have also failed in phase III and phase IV of clinical trials due to lack of efficacy and severe adverse effect. The research on DN is limited with respect to its pathogenesis and drug development. Thus, a more detailed understanding of the pathogenesis of DN is very essential to progress in the drug development process.
Matched MeSH terms: Dipeptidyl-Peptidase IV Inhibitors/pharmacology
Camel milk proteins are an important substrate for bioactive peptides generation. This study investigates in-vitro antidiabetic effect (via inhibition of α-amylase (AA), α-glucosidase (AG) and dipeptidyl peptidase IV (DPP-IV)) of bovine (BC) and camel casein (CC) hydrolysates. Further, effect of simulated gastrointestinal digestion (SGID) on inhibitory potential of generated hydrolysates was also explored. Both BC and CC hydrolysates displayed potent inhibitory properties against AA (IC50 value- 0.58 & 0.59 mg/mL), AG (IC50 value- 1.04 & 0.59 mg/mL) and DPP-IV (IC50 value- 0.62 & 0.66 mg/mL), respectively. Among different peptides identified in BC and CC hydrolysates, it was observed that FLWPEYGAL was predicted to be most potent inhibitory peptide against AA. While LPTGWLM, MFE and GPAHCLL as most active inhibitor of AG and HLPGRG, QNVLPLH and PLMLP were predicted to be active against DPP-IV. Overall, BC and CC hydrolysates can be proposed to be used in different food formulations as functional antidiabetic agents.
Matched MeSH terms: Dipeptidyl-Peptidase IV Inhibitors/pharmacology
Dipeptidyl peptidase 4 (DPP-4) is a serine protease enzyme expressed widely in many tissues, including the cardiovascular system. The incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from the small intestine into the vasculature during a meal, and these incretins have a potential to release insulin from pancreatic beta cells of islets of Langerhans, affording a glucose-lowering action. However, both incretins are hurriedly degraded by the DPP-4. Inhibitors of DPP-4, therefore, enhance the bioavailability of GLP-1 and GIP, and thus have been approved for better glycemic management in patients afflicted with type 2 diabetes mellitus (T2DM). Five different DPP-4 inhibitors, often called as 'gliptins', namely sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin have been approved hitherto for clinical use. These drugs are used along with diet and exercise to lower blood sugar in diabetic subjects. T2DM is intricately related with an increased risk of cardiovascular disease. Growing body of evidence suggests that gliptins, in addition to their persuasive anti-diabetic action, have a beneficial pleiotropic action on the heart and vessels. In view of the fact of cardiovascular disease susceptibility of patients afflicted with T2DM, gliptins might offer additional therapeutic benefits in treating diabetic cardiovascular complications. Exploring further the cardiovascular pleiotropic potentials of gliptins might open a panorama in impeccably employing these agents for the dual management of T2DM and T2DM-associated perilous cardiovascular complications. This review will shed lights on the newly identified beneficial pleiotropic actions of gliptins on the cardiovascular system.
Matched MeSH terms: Dipeptidyl-Peptidase IV Inhibitors/pharmacology
The molecular basis of the anti-diabetic properties of camel milk reported in many studies and the exact active agent are still elusive. Recent studies have reported effects of camel whey proteins (CWP) and their hydrolysates (CWPH) on the activities of dipeptidyl peptidase IV (DPP-IV) and the human insulin receptor (hIR). In this study, CWPH were generated, screened for DPP-IV binding in silico and inhibitory activity in vitro, and processed for peptide identification. Furthermore, pharmacological action of intact CWP and their selected hydrolysates on hIR activity and signaling and on glucose uptake were investigated in cell lines. Results showed inhibition of DPP-IV by CWP and CWPH and their positive action on hIR activation and glucose uptake. Interestingly, the combination of CWP or CWPH with insulin revealed a positive allosteric modulation of hIR that was drastically reduced by the competitive hIR antagonist. Our data reveal for the first time the profiling and pharmacological actions of CWP and their derived peptides fractions on hIR and their pathways involved in glucose homeostasis. This sheds more light on the anti-diabetic properties of camel milk by providing the molecular basis for the potential use of camel milk in the management of diabetes.
Matched MeSH terms: Dipeptidyl-Peptidase IV Inhibitors/pharmacology
The inhibition of α-glucosidase and DPP enzymes capable of effectively reducing blood glucose level in the management of type 2 diabetes. The purpose of the present study is to evaluate the inhibitory potential of α-glucosidase and DPP (IV) activity including with the 2-NBDG uptake assay and insulin secretion activities through in vitro studies. The selected of active compounds obtained from the screening of compounds by LC-MS were docked with the targeted enzyme that involved in the mechanism of T2DM. From the results, root extracts displayed a better promising outcome in α-glucosidase (IC50 2.72 ± 0.32) as compared with the fruit extracts (IC50 3.87 ± 0.32). Besides, root extracts also displayed a better activity in the inhibition of DPP (IV), enhance insulin secretion and glucose uptake activity. Molecular docking results revealing that phlorizin binds strongly with α-glucosidase, DPP (IV) and Insulin receptor (IR) enzymes with achieving the lowest binding energy value. The present work suggests several of the compounds have the potential that contribute towards inhibiting α-glucosidase and DPP (IV) and thus effective in lowering post-prandial hyperglycaemia.
Matched MeSH terms: Dipeptidyl-Peptidase IV Inhibitors/pharmacology*