Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The goal of antidiabetes therapy is to reduce glycosylated hemoglobin (HbA(1c)) levels to prevent or minimize the microvascular complications associated with this disease, such as retinopathy, nephropathy, and neuropathy. Glycemic control, defined by the American Diabetes Association (ADA) as HbA(1c) <7.0%, is often difficult to achieve despite current treatments, including oral antidiabetes agents, such as biguanides (metformin), sulfonylureas, thiazolidinediones, dipeptidyl peptidase-IV (DPP-IV) inhibitors, meglitinides, and alpha-glucosidase inhibitors, as well as injectable agents, such as glucagon-like peptide-1 (GLP-1) analogues and insulin. In addition, antidiabetes treatments often become less effective over time as insulin resistance increases and pancreatic beta-cell function deteriorates. The latest ADA guidelines also recommend a range of interventions to control the multiple coexisting conditions associated with this chronic, progressive disease, including dyslipidemia and hypertension. This review highlights the new antidiabetes drug classes, which include incretin mimetics, cannabinoid receptor type 1 antagonists, and bile acid sequestrants, and compares these agents to established treatments with regard to efficacy and tolerability. The more recently developed antidiabetes drugs have been shown in clinical trials to produce glucose-lowering effects similar to those of established antidiabetes agents. Many of the new antidiabetes agents can be safely combined with established therapies to further improve glycemic control. In addition, the new agents may provide additional significant cardiometabolic benefits, including improving the lipid profile, lowering blood pressure, and reducing body weight. These new treatments may have the potential to greatly improve the management of type 2 diabetes.
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PMID:More choices than ever before: emerging therapies for type 2 diabetes. 1853 25

Prolyl oligopeptidase (POP) is a serine protease that cleaves small peptides at the carboxyl side of an internal proline residue. Substance P, arginine-vasopressin, thyroliberin and gonadoliberin are proposed physiological substrates of this protease. POP has been implicated in a variety of brain processes, including learning, memory, and mood regulation, as well as in pathologies such as neurodegeneration, hypertension, and psychiatric disorders. Although POP has been considered to be a soluble cytoplasmic peptidase, significant levels of activity have been detected in membranes and in extracellular fluids such as serum, cerebrospinal fluid, seminal fluid, and urine, suggesting the existence of noncytoplasmic forms. Furthermore, a closely associated membrane prolyl endopeptidase (PE) activity has been previously detected in synaptosomes and shown to be different from the cytoplasmic POP activity. Here we isolated, purified and characterized this membrane-bound PE, herein referred to as mPOP. Although, when attached to membranes, mPOP presents certain features that distinguish it from the classical POP, our results indicate that this protein has the same amino acid sequence as POP except for the possible addition of a hydrophobic membrane anchor. The kinetic properties of detergent-soluble mPOP are fully comparable to those of POP; however, when attached to the membranes in its natural conformation, mPOP is significantly less active and, moreover, it migrates anomalously in SDS/PAGE. Our results are the first to show that membrane-bound and cytoplasmic POP are encoded by variants of the same gene.
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PMID:Characterization of membrane-bound prolyl endopeptidase from brain. 1865 87

Data from the Centers for Disease Control and Prevention indicate that the prevalence of diabetes is increasing steadily and is coupled with a rise in obesity. Studies such as the Nurses' Health Study show that even slight glucose abnormalities, namely insulin resistance, increase the risk of myocardial infarctions, strokes, other cardiovascular disease, and mortality. Insulin resistance was found to accelerate atherosclerosis, inflammation, the onset of diabetes, cardiovascular disease, obesity, hypertension, chronic kidney disease, and dyslipidemia. Adiponectin was found to have potent antiinflammatory and antiatherosclerotic effects. Similarly, studies indicate that peroxisome proliferators-activated receptor agonists have the potential to treat obesity, diabetes, and atherosclerosis. From a preventive standpoint, it was shown that intensive glucose control reduces long-term cardiovascular risk. This intensive control approach included the use of thiazolidinediones (TZDs; troglitazone, pioglitazone, and rosiglitazone), which were demonstrated to have vascular and nonglycemic effects beyond glucose-lowering. A drawback of using TZDs is peripheral fluid retention. The DREAM study showed that participants with impaired fasting glucose or impaired glucose tolerance who are free from cardiovascular disease benefited significantly from taking 8 mg rosiglitazone per day. The ADOPT study provided evidence that rosiglitazone is more efficient at controlling glycemic loss and maintaining low glycosylated hemoglobin levels than metformin and glyburide. Data from the CHICAGO study indicate that the progression of carotid artery intima-media thickness, a marker of atherosclerosis and a surrogate end point for cardiovascular disease, was slowed more with pioglitazone than glimepiride in a racially diverse population of men and women with diabetes mellitus type 2. Overall, investigators have shifted from a focus on hyperglycemia to a multifactorial approach to risk management in diabetes. This multifactorial approach includes intensive glycemic control, lifestyle intervention, and intensive management of comorbid (dyslipidemia, hypertension, early renal disease) conditions. The implementation of a regular, rigorous exercise and diet program greatly decreased insulin resistance and allowed far more patients to reach their glycosylated hemoglobin goals. Studies with atrovastatin show significant improvement in cardiovascular risk factors in patients with diabetes and hypertension. Short-term studies provide support for the administration of a combination of TZD + sulfonylureas in patients with diabetes mellitus type 2. Likewise, studies have shown that a combination of TZDs + metformin reduced the risk of myocardial infarction. Finally, dipeptidyl peptidase-IV inhibitors and glycolipoprotein-1 analogs show potential for helping prevent the deterioration of glucose metabolism in early diabetes mellitus type 2.
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PMID:Cardiovascular manifestations of insulin resistance. 1911 74

Intraglomerular renin-angiotensin system enzyme activities have been examined previously using glomerular lysates and immune-based assays. However, preparation of glomerular extracts compromises the integrity of their anatomic architecture. In addition, antibody-based assays focus on angiotensin (Ang) II detection, ignoring the generation of other Ang I-derived metabolites, some of which may cross-react with Ang II. Therefore, our aim was to examine the metabolism of Ang I in freshly isolated intact glomeruli using matrix-assisted laser desorption ionization time of flight mass spectrometry as an analytic method. Glomeruli from male Sprague-Dawley rats were isolated by sieving and incubated in Krebs buffer in the presence of 1 micromol/L of Ang I for 15 to 90 minutes, with or without various peptidase inhibitors. Peptide sequences were confirmed by matrix-assisted laser desorption ionization time of flight tandem mass spectrometry or linear-trap-quadrupole mass spectrometry. Peaks were quantified using customized valine-(13)C(.15)N-labeled peptides as standards. The most prominent peaks resulting from Ang I cleavage were 899 and 1181 m/z, corresponding with Ang (1-7) and Ang (2-10), respectively. Smaller peaks for Ang II, Ang (1-9), and Ang (3-10) also were detected. The disappearance of Ang I was significantly reduced during inhibition of aminopeptidase A or neprilysin. In contrast, captopril did not alter Ang I degradation. Furthermore, during simultaneous inhibition of aminopeptidase A and neprilysin, the disappearance of Ang I was markedly attenuated compared with all of the other conditions. These results suggest that there is prominent intraglomerular conversion of Ang I to Ang (2-10) and Ang (1-7), mediated by aminopeptidase A and neprilysin, respectively. Formation of these alternative Ang peptides may be critical to counterbalance the local actions of Ang II. Enhancement of these enzymatic activities may constitute potential therapeutic targets for Ang II-mediated glomerular diseases.
Hypertension 2009 May
PMID:Angiotensin I is largely converted to angiotensin (1-7) and angiotensin (2-10) by isolated rat glomeruli. 1928 51

The structure-function relationships of aspartic peptidases (APs) (EC 3.4.23.X) have been extensively investigated, yet much remains to be elucidated regarding the various molecular mechanisms of these enzymes. Over the past years, APs have received considerable interest for food applications (e.g. cheese, fermented foods) and as potential targets for pharmaceutical intervention in human diseases including hypertension, cancer, Alzheimer's disease, AIDS (acquired immune deficiency syndrome), and malaria. A deeper understanding of the structure and function of APs, therefore, will have a direct impact on the design of peptidase inhibitors developed to treat such diseases. Most APs are synthesized as zymogens which contain an N-terminal prosegment (PS) domain that is removed at acidic pH by proteolytic cleavage resulting in the active enzyme. While the nature of the AP PS function is not entirely understood, the PS can be important in processes such as the initiation of correct folding, protein stability, blockage of the active site, pH-dependence of activation, and intracellular sorting of the zymogen. This review summarizes the current knowledge of AP PS function (especially within the A1 family), with particular emphasis on protein folding, cellular sorting, and inhibition.
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PMID:Multifunctional aspartic peptidase prosegments. 1949 Oct 47

Dipeptidyl peptidase-IV (DPP-IV) inhibitors decrease degradation of the incretins. DPP-IV inhibitors also decrease degradation of peptides, such as substance P, that may be involved in the pathogenesis of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. This study tested the hypothesis that DPP-IV inhibition affects risk of clinical angioedema, by comparing the incidence of angioedema in patients treated with the DPP-IV inhibitor vildagliptin versus those treated with comparator in Phase III randomized clinical trials. Prospectively defined angioedema-related events were adjudicated in a blinded fashion by an internal medicine adjudication committee and expert reviewer. Concurrent ACE inhibitor or angiotensin receptor blocker exposure was ascertained from case report forms. Study drug exposure was ascertained from unblinded data from phase III studies. Odds ratios and 95% confidence intervals comparing angioedema risk in vildagliptin-treated and comparator-treated patients were calculated for the overall population and for patients taking ACE inhibitors or angiotensin receptor blockers, using both an analysis of pooled data and a meta-analysis (Peto method). Overall, there was no association between vildagliptin use and angioedema. Among individuals taking an ACE inhibitor, however, vildagliptin use was associated with an increased risk of angioedema (14 confirmed cases among 2754 vildagliptin users versus 1 case among 1819 comparator users: odds ratio 4.57 [95% confidence interval 1.57 to 13.28]) in the meta-analysis. Vildagliptin use may be associated with increased risk of angioedema among patients taking ACE inhibitors, although absolute risk is small. Physicians confronted with angioedema in a patient taking an ACE inhibitor and DPP-IV inhibitor should consider this possible drug-drug interaction.
Hypertension 2009 Sep
PMID:Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema. 1958 3

Type 2 diabetes mellitus (T2DM) is a chronic, progressive disorder that affects more than 230 million people worldwide and is expected to affect 366 million by 2030. Both the prevalence of T2DM and the cost of its long term complications has driven the focus and emphasis on treatments aimed at reducing hyperglycemia and controlling hypertension and dyslipidemia. In the last 5 years new glucose lowering drugs acting on novel pathways have been developed, licensed and launched. These drugs include the glucagon-like peptide (GLP-1) agonists, exenatide, and dipeptidyl peptidase (DPP-IV) inhibitors such as sitagliptin and saxagliptin. This review describes current approaches to T2DM treatment, focusing on newer agents which tend to be associated with less hypoglycemia and possible weight loss, and addresses the potential roles of novel oral pharmacologic agents in the late-stages of development that might provide new options for the management of this disease.
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PMID:Pharmacotherapy of hyperglycemia. 1974 38

Patients with type 2 diabetes, approximately 85% of whom are overweight or obese, often have an increased incidence of cardiovascular disease (CVD) risk factors such as hypertension and dyslipidemia. Both type 2 diabetes and obesity are independent risk factors for CVD. Unfortunately, many therapies aimed at maintaining and improving glucose control are associated with weight gain. Among the older antidiabetes agents, most, including the insulin secretagogues and sensitizers, can lead to weight gain, except for metformin, which is weight-neutral. Among the newer agents, the dipeptidyl peptidase-4 inhibitors generally are weight-neutral in addition to lowering glucose, while the glucagon-like peptide-1 receptor agonists lead to weight reduction. Patients with type 2 diabetes are at an increased risk for both diabetes- and CV-related outcomes, and weight reduction is an important component of diabetes management. Weight gain in patients with type 2 diabetes can contribute to patient frustration and may negatively impact their compliance to therapeutic regimens. The selection of antidiabetes agents that not only improve glucose control but reduce or have a neutral effect on weight with beneficial effects on lipids are ideal options for managing patients with type 2 diabetes.
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PMID:The impact of weight gain on motivation, compliance, and metabolic control in patients with type 2 diabetes mellitus. 1982 Feb 78

The current epidemics of excessive weight and type 2 diabetes mellitus (T2DM) cause significant morbidity and mortality. T2DM frequently coexists with excess weight as well as hypertension and dyslipidemia, placing a significant percentage of the population at an elevated risk of cardiovascular disease. Maintaining effective glycemic control is linked with a diminished risk of developing microvascular complications, and recent studies have shown it may also reduce overall macro vascular complications. Reduction of associated risk factors, including those related to excessive weight, high blood pressure, and dyslipidemia, are also necessary to meaningfully decrease cardiovascular risk. Agents that can improve glycemia with weight neutrality or weight loss could offer additional benefit to overweight patients with T2DM. Although the major pathophysiologic defects in T2DM are recognized to be beta-cell dysfunction and peripheral insulin resistance, derangements in the incretin system may contribute as well. Antidiabetes agents targeting this system include dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Both classes have been shown to significantly reduce hyperglycemia. GLP-1 receptor agonists also promote significant weight loss and have potentially beneficial effects on cardiovascular risk markers.
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PMID:Current antihyperglycemic treatment strategies for patients with type 2 diabetes mellitus. 1995 3

Diabetes mellitus is a common disease and contributes to a high degree of morbidity and mortality. Cardiovascular complications, including diabetic cardiomyopathy are major causes of morbidity and mortality in diabetic patients. Diabetic cardiomyopathy is a condition that affects the myocardium, primarily. It is not necessarily associated with ischemic heart disease, high blood pressure, valvular or congenital anomalies. The pathology of diabetic cardiomyopathy includes interstitial fibrosis, apoptosis of cardiomyocytes, abnormal energy utilization, small vessel disease and cardiac neuropathy. These pathologies are induced by hyperglycemia and oxidative stress. Biochemical as well as electrolyte changes, especially reduced calcium availability also occurs in the myocardium of diabetic patients. The abnormal structure and biochemistry of the myocardium result in functional problems such as diastolic and systolic dysfunctions, which may cause symptoms of dyspnea and inability to tolerate exercise. No single specific therapeutic agent can treat diabetic cardiomyopathy because once the disease is overt, the management may require a variety of approaches such as risk factors and lifestyle modification, glucose control (insulin, alpha glucosidase inhibitors, sulfonylureas, biguanides, meglitinides, thiazolidinediones and dipeptidyl peptidase 4 (DPP-4) inhibitors); hormones (IGF-1); ACE inhibitors (captopril, enalapril); angiotensin II receptor antagonists (losartan, olmesartan); beta adrenoreceptor antagonists (acebutolol, carvedilol); peptides (adrenomedullin); endothelin-1 receptor antagonists (bosentan, tezosentan); calcium channel blockers (amlodipine, verapamil); antioxidants (methalothionein, alpha tocopherol, alpha lipoic acid) and antihyperlipidemic drugs (simvastatin, fenofibrate, ezetimibe) to effectively treat patients with diabetic cardiomyopathy.
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PMID:Medicinal chemistry of drugs used in diabetic cardiomyopathy. 2001 35


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