fumarates and Diabetes-Mellitus

Aliskiren was shown to increase adverse events in patients with diabetes and concomitant renin-angiotensin blockade. We aim to investigate the efficacy and safety of aliskiren in patients with diabetes and increased cardiovascular risk or established cardiovascular disease.. MEDLINE and Embase were searched for prospective studies comparing addition of aliskiren to standard medical therapy in patients with diabetes and cardiovascular disease, or ⩾1 additional cardiovascular risk factor (hypertension, abnormal lipid profile, microalbuminuria/proteinuria, chronic kidney disease). Relative risk for efficacy (all-cause mortality, combined cardiovascular mortality and hospitalisation) and safety (hyperkalaemia, hypotension, renal impairment) outcomes was calculated.. Of 2151 studies identified in the search, seven studies enrolling 13,395 patients were included. Aliskiren had no effect on all-cause mortality (relative risk: 1.05, 95% confidence interval: 0.90 to 1.24, p = 0.53), or combined cardiovascular mortality or heart failure hospitalisation (relative risk: 1.07, 95% confidence interval: 0.81 to 1.40, p = 0.64). Patients receiving aliskiren had a greater risk of developing hyperkalaemia (relative risk: 1.32, 95% confidence interval: 1.14 to 1.53, p = 0.0003) and renal impairment (relative risk: 1.15, 95% confidence interval: 1.02 to 1.30, p = 0.03), but not hypotension.. Patients with diabetes and cardiovascular disease or cardiovascular risk do not benefit from the addition of aliskiren to standard medical therapy. Detrimental safety profile in pooled analysis supports current warnings.

Topics: Amides; Cardiovascular Agents; Cardiovascular Diseases; Chi-Square Distribution; Diabetes Mellitus; Fumarates; Humans; Odds Ratio; Renin-Angiotensin System; Risk Assessment; Risk Factors; Treatment Outcome

Non-diabetic glomerulonephritis is a frequent cause of end-stage renal disease. The use of renin-angiotensin-aldosterone system blockers is a fundamental therapeutic approach. However, converting enzyme inhibitors (ACE-is) and angiotensin receptor blockers do not always achieve the desired target of proteinuria. The induction of the prorenin and renin up-regulation is a possible explanation. Aliskiren is the first drug acting as direct inhibitor of plasmatic renin activity, also able to interfere with the prorenin and renin profibrotic escape. We aimed at reviewing the literature for the assessment of potential efficacy and safety of aliskiren in the treatment of non-diabetic glomerulonephritis. The data on this topic are limited; however, we concluded for a possible usefulness of aliskiren. The renal safety profile appears potentially acceptable in non-diabetic patients although extreme carefulness, particularly with respect to long-term renal and cardiovascular tolerability, is recommended.

Topics: Amides; Diabetes Mellitus; Fumarates; Glomerulonephritis; Humans; Kidney Failure, Chronic; Renin; Treatment Outcome

There is evidence that patients with moderate to severe psoriasis have an increased risk of conditions such as cardiovascular disease, obesity, diabetes mellitus, and metabolic syndrome. The precise mechanisms underlying the observed increase in cardiovascular disease in psoriasis remain to be defined but inflammatory pathways mutual to both conditions are probably involved. Suppression of systemic inflammation in psoriasis could help reduce cardiovascular inflammation but robust evidence is still lacking evidence is lacking. This article summarizes the current literature on cardiovascular and metabolic comorbidities in psoriasis, identifies research gaps, and suggests management strategies to reduce cardiovascular risk in patients with moderate to severe psoriasis.

Topics: Acitretin; Adipokines; Alcoholism; Antibodies, Monoclonal, Humanized; Cardiovascular Diseases; Comorbidity; Cyclosporine; Dermatologic Agents; Diabetes Mellitus; Fumarates; Humans; Immunosuppressive Agents; Inflammation; Metabolic Syndrome; Methotrexate; Obesity; Psoriasis; Risk Factors; Smoking; Tumor Necrosis Factor-alpha; Ustekinumab

Diabetic patients are at risk of macro- and micro-vascular complications, including diabetic nephropathy, and have difficulties in achieving blood pressure (BP) goals. Aliskiren, a direct renin inhibitor, inhibits the first step of the renin angiotensin aldosterone system. We aimed to systematically address the relevant evidence on the effects of aliskiren in diabetic individuals.. We considered randomized controlled trials (RCTs) evaluating aliskiren in diabetic patients. Information was recorded independently by 2 investigators. We were limited to trials published in English.. PubMed search retrieved 16 items. After excluding 12, we ended with 4 eligible studies with 1488 participants. Mean baseline BP levels were 143/82 mmHg and median follow up was 2 months. Aliskiren was compared against angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) or aliskiren plus ACE inhibitor/ARB in 2 studies and against placebo in the other 2. The most frequent indication for aliskiren therapy was diabetes plus hypertension and albuminuria. Aliskiren seems to be effective in reducing BP levels, albuminuria in diabetics, either as monotherapy (compared with placebo), or in addition to ACE inhibitors/ARB (compared with monotherapy), without any major safety considerations.. There are promising results on the effect of aliskiren in diabetic patients, but the available evidence is limited so far. This is a poorly investigated field with few RCTs and new studies focusing on "hard" outcomes are needed.

Topics: Albuminuria; Amides; Antihypertensive Agents; Blood Pressure; Diabetes Complications; Diabetes Mellitus; Fumarates; Humans; Randomized Controlled Trials as Topic; Renin

Aliskiren, a drug which inhibits the initial and rate-limiting step of the renin angiotensin aldosterone system (RAAS), recently approved for the treatment of hypertension, may become a reasonable therapeutic choice in a broad number of clinical conditions sharing an increased cardiovascular risk, where the inhibition of the RAAS has been shown to be beneficial.. The present review summarizes the pharmacokinetic and pharmacodynamic properties of aliskiren along with the clinical trials that took into account the effects of aliskiren on blood pressure control and on a number of renal and cardiovascular end points. The specific effects of aliskiren on different populations (e.g., elderly hypertensives, patients with diabetes and hypertension, patients with hypertension and renal impairment) are discussed.. The review discusses the most recent discoveries of the cardiovascular and renal effects of aliskiren, including a comprehensive discussion of the ongoing trials and of the areas of remaining uncertainty.. Aliskiren is a promising drug that may become a convenient choice in several clinical conditions. The full spectrum of the beneficial effects of aliskiren will be fully elucidated when the results of the large ongoing trials become available.

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus; Drug Evaluation; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Fumarates; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

Nowadays, social and economic burden related to cardiovascular and renal diseases still remains extremely high, although there has been a dramatic improvement of diagnostic options and therapeutic strategies reported in the last 30 years. The progressively higher attention towards integrated pharmacological strategies, which are able to interfere with different pathophysiological mechanisms, has certainly led to better control of cardiovascular and renal diseases. In view of the large involvement of the renin-angiotensin system (RAS) in the vast majority of pathophysiological mechanisms leading to the development and progression of cardiovascular and renal diseases, it can be easily understood why it has been long viewed as the 'ideal' target for the pharmacological treatment of several clinical conditions. Recently, besides the well known therapeutic approaches for RAS blockade, based on the use of ACE inhibitors, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) and aldosterone antagonists, both the scientific and medical community have focused their attention on a novel therapeutic option. In 2007, aliskiren, the first compound of a new drug class, the direct renin inhibitors (DRIs), has become available for clinical use, being a novel and innovative therapeutic option. Aliskiren is able to interfere with the enzymatic activity of renin by blocking the catalytic site of the molecule and inducing an 'upstream' RAS blockade. This leads to a modulation of the biological properties of renin, thus resulting in the missed cleavage of angiotensinogen to angiotensin I. Aliskiren has demonstrated antihypertensive efficacy comparable or even superior to that of other classes of antihypertensive drugs, both in monotherapy and in combination therapies. Its safety and tolerability are comparable with those of other antihypertensive drug classes and almost similar to placebo. In addition, it has been demonstrated to reduce progression of cardiac and renal organ damage in addition to ACE inhibitors or ARBs. An ambitious and large clinical trial programme specifically designed for this innovative antihypertensive drug will evaluate the efficacy of aliskiren in terms of reduced incidence of major cardiovascular and renal outcomes in patients with hypertension and cardiovascular disease, besides the use of optimal (standard) therapeutic strategies, including ACE inhibitors and ARBs.

Topics: Amides; Animals; Antihypertensive Agents; Diabetes Mellitus; Diffusion of Innovation; Drug Design; Fumarates; Heart Diseases; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System; Translational Research, Biomedical

Diabetes mellitus is an independent risk factor for cardiovascular disease (CVD) and current opinion holds that hyperglycemia directly damages smaller blood vessels, resulting in microvascular complications of nephropathy, retinopathy, and neuropathy. In a patient with diabetes, hypertension compounds and greatly increases the risk of microvascular complications, and thus the risk of end-stage kidney disease, vision loss, and nontraumatic limb amputations. Hypertension and hyperglycemia directly damage the microvasculature, leading to small vessel dysfunction that manifests as the clinical disease states of diabetic retinopathy and nephropathy. Early recognition and treatment of both hyperglycemia and hypertension may prevent vision loss and chronic kidney disease, the devastating outcomes of these microvascular complications. One of the pathogenic mechanisms for microvascular dysfunction is upregulation of the angiotensin II type 1 receptor, the most physiologically common receptor for the vasoconstrictor properties of angiotensin II. In patients with diabetic retinopathy and nephropathy, tight control of blood pressure (BP) (< 130/80 mm Hg) delays the progression of retinopathy and nephropathy in addition to reducing cardiovascular morbidity and mortality. Aggressive treatment with 2 or more antihypertensive agents, selected from different drug classes, is often needed to reach the optimal BP target level. A PubMed search was conducted to identify randomized controlled trials that evaluated hypertension control and microvascular outcomes in patients with diabetes. Several clinical trials have yielded promising data with renin-angiotensin-aldosterone system (RAAS) inhibitors (the direct renin inhibitor aliskiren, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers). Attainment of BP control with RAAS inhibitors reduces the risk for CVD, nephropathy, and retinopathy. In addition, RAAS inhibitors have demonstrated renoprotective effectiveness independent of the BP reduction achieved. This review will examine the results of clinical trials in the context of BP control, diabetes, and the microvascular complications of retinopathy and nephropathy.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetes Mellitus; Diabetic Nephropathies; Diabetic Retinopathy; Disease Progression; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Microvessels

Cardiovascular (CV) and renal complications associated with diabetes can be attenuated with antihypertensives that work on the renin-angiotensin-aldosterone system (RAAS),particularly angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and possibly direct renin inhibitors (DRIs). Cardioprotective and renoprotective benefits are independent of the blood pressure-lowering effect of the RAAS inhibitor. Given more complete RAAS blockade, evidence has suggested that the use of ACE inhibitor/ARB combination therapy may provide greater target organ protection. However, recent data have challenged this assumption. Although advances have been made in reducing diabetic nephropathy progression through use of ACE inhibitors and ARBs, improvement in organ protection is needed because diabetes remains the leading cause of end-stage renal disease. Despite the use of these agents in patients with CV disease and diabetes, CV adverse events remain high, suggesting the need for improved outcomes. Newer agents such as DRIs may have the potential to offer similar target organ protection. The first DRI, aliskiren, administered alone or in combination with other RAAS inhibitors, has been shown to confer renoprotective and cardioprotective benefits in human and animal studies that have measured surrogate endpoints. An ongoing outcomes study (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints [ALTITUDE]), which is assessing renal and CV morbidity and mortality, will further define whether aliskiren provides additional benefits beyond RAAS inhibition and lowering of blood pressure.

Topics: Amides; Cardiovascular Diseases; Diabetes Mellitus; Fumarates; Humans; Renin; Renin-Angiotensin System

We tested the hypothesis that chronic treatment with the direct renin inhibitor aliskiren improves vascular function in resistance and conduit arteries of type two diabetic and hypertensive patients.. Sixteen patients with mild essential hypertension and with a previous diagnosis of noninsulin-dependent diabetes mellitus were included in the study. Patients were then randomized to aliskiren (150 mg once daily, n = 9), or ramipril (5 mg once daily, n = 7). Each patient underwent a biopsy of the subcutaneous tissue and small arteries were dissected and mounted on a pressurized micromyograph to evaluate endothelium dependent vasorelaxation in response to acetylcholine ± N omega-nitro-L-arginine methyl ester hydrochloride in vessels precontracted with norepinephrine. Endothelial function has been quantified also in large conduit arteries by flow-mediated dilation.. A similar office blood pressure-lowering effect was observed with the two drugs, although changes in DBP were not statistically significant in the ramipril group. Aliskiren significantly improved endothelium-dependent relaxation in subcutaneous resistance arteries, as well as increased flow-mediated dilation in conduit arteries, whereas the effects induced by ramipril did not reach statistical significance. Only aliskiren significantly increased the expression of p1177-endothelial nitric oxide synthase in the endothelium. Both aliskiren and ramipril had a negligible effect on markers of oxidative stress.. Aliskiren restored endothelial function and induced a more prompt peripheral vasodilation in hypertensive and diabetic patients possibly through the increased production of nitric oxide via the enhanced expression and function of the active phosphorylated form of endothelial nitric oxide synthase.

Topics: Amides; Blood Pressure; Diabetes Mellitus; Endothelium, Vascular; Fumarates; Humans; Hypertension; Nitric Oxide; Renin; Vasodilation

Because of concerns about the safety of aliskiren in patients with diabetes, study treatment was stopped prematurely in the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE). We examined outcomes and treatment effect in these patients compared with those without diabetes.. ATMOSPHERE included 7016 patients with heart failure and a reduced ejection fraction (HFrEF) randomly assigned to enalapril plus aliskiren, aliskiren alone, or enalapril. At baseline, 1944 (27.7%) patients had diabetes. Median follow-up was shorter in patients with diabetes compared with those without (24 months vs. 46 months). Among patients with diabetes, the primary endpoint of cardiovascular death or hospitalization for heart failure occurred in 216 patients (33.1%) in the enalapril group (reference), 172 (27.4%) in the aliskiren group [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67-1.00; P = 0.053], and 196 (29.5%) in the combination group (HR 0.86, 95% CI 0.71-1.04; P = 0.13). The effects of the treatments studied did not differ significantly compared with patients without diabetes. In patients with diabetes, aliskiren monotherapy was associated with a lower risk of symptomatic hypotension compared to enalapril [42 (6.7%) vs. 65 (10.0%); P = 0.04], whereas other adverse events were generally balanced between the three groups.. In patients with HFrEF and diabetes, there was no signal of harm and a trend towards benefit when direct renin inhibition monotherapy was compared with an angiotensin-converting enzyme inhibitor, whereas combined aliskiren and enalapril treatment led to more adverse events with no improvement in outcomes. Treatment effects did not differ in patients with diabetes compared with those without. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cause of Death; Diabetes Mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Enalapril; Europe; Female; Follow-Up Studies; Fumarates; Heart Failure; Humans; Male; Middle Aged; Prospective Studies; Stroke Volume; Survival Rate

To: (i) describe the baseline characteristics of patients in ATMOSPHERE and the changes in the planned analysis of ATMOSPHERE resulting from the mandated discontinuation of study treatment in patients with diabetes; (ii) compare the baseline characteristics of patients in ATMOSPHERE with those in the Prospective comparison of Angiotensin Receptor neprilysin inhibitors with Angiotensin converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF); and (iii) compare the characteristics of patients with and without diabetes at baseline in ATMOSPHERE.. A total of 7063 patients were randomized into ATMOSPHERE April 2009-April 2014 at 755 sites in 43 countries. Their average age was 63 years and 78% were men. ATMOSPHERE patients were generally similar to those in PARADIGM-HF although fewer had diabetes, renal dysfunction, and were treated with a mineralocorticoid receptor antagonist. In ATMOSPHERE, patients with diabetes differed in numerous ways from those without. Patients with diabetes were older and had worse heart failure status but a similar left ventricular ejection fraction (mean 28%); they had a higher body mass index and more co-morbidity, especially hypertension and coronary heart disease. Mean estimated glomerular filtration rate was slightly lower in those with diabetes compared with those without.. ATMOSPHERE will determine whether patients with HF and reduced ejection fraction (particularly those without diabetes) benefit from the addition of a direct renin inhibitor to standard background therapy, including an angiotensin-converting enzyme inhibitor, beta-blocker, and a mineralocorticoid receptor antagonist. ATMOSPHERE will also determine whether aliskiren alone is superior to, or at least non-inferior to, enalapril.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Diabetes Mellitus; Drug Therapy, Combination; Enalapril; Female; Fumarates; Heart Failure; Humans; Male; Middle Aged; Renin; Stroke Volume; Ventricular Dysfunction, Left

The prevalence of allergic rhinitis has exhibited an upward trend, and diabetes is a common endocrine metabolic disorder. Treatment of allergic rhinitis complicated with diabetes has been marginally explored. This study aimed to observe the effect of rupatadine fumarate combined with acupoint application in the treatment of allergic rhinitis complicated with diabetes and its effect on serum IgE levels. Totally 80 patients with allergic rhinitis complicated with diabetes admitted to our hospital from December 2019 to December 2020 were recruited and assigned to receive either rupatadine fumarate (control group) or rupatadine fumarate plus acupoint application (research group). The clinical observation indexes of the two groups of patients before and after treatment were analyzed, and the clinical efficacy of the two groups was evaluated. Rupatadine fumarate plus acupoint application was associated with a significantly higher efficacy (23 cases of markedly effective, 14 cases of effective, and 3 cases of ineffective) versus rupatadine fumarate alone (14 cases of markedly effective, 16 cases of effective, and 10 cases of ineffective) (

Topics: Acupuncture Points; Cyproheptadine; Diabetes Mellitus; Fumarates; Humans; Immunoglobulin E; Rhinitis, Allergic; Rhinitis, Allergic, Seasonal

Necrobiosis lipoidica (NL) is a rare granulomatous disorder of unknown aetiology. Randomized controlled studies are not available due to it being an orphan disease.. We evaluated patients in 2 dermatological centres to cluster data about epidemiology, the therapeutic approaches for NL, and their efficacy.. Comorbidity and the efficacy of the applied treatment was assessed for 98 patients.. We identified 54% of patients with concomitant diabetes and 19% with thyroidal disorders. Topical steroids (85.7%) were predominantly used followed by calcineurin inhibitors (31%) and phototherapy (41.8%). Systemically, fumaric acid esters were more frequently applied (26.8%) than steroids (24.4%) and dapsone (24.4%). Steroids, compression therapy, calcineurin inhibitors, phototherapy, fumaric acid esters, and dapsone showed remarkable efficacy.. Therapeutic options were chosen individually in accordance with the severity of NL and presence of ulceration. Topical calcineurin inhibitors, systemic application of fumaric acid esters, and dapsone represent effective alternatives to the use of steroids.

Topics: Adolescent; Adult; Calcineurin Inhibitors; Cluster Analysis; Comorbidity; Dapsone; Diabetes Mellitus; Female; Fumarates; Humans; Male; Necrobiosis Lipoidica; Retrospective Studies; Steroids; Thyroid Diseases; Young Adult

In 2012, the European Medicines Agency reviewed the safety of dual renin-angiotensin system (RAS) blockade because of potentially increased risks for inter alia acute kidney injury (AKI). Since residents of nursing homes are particularly vulnerable to adverse drug outcomes, the aims of our study were to describe RAS-inhibiting drug use in German nursing home residents and examine the risk of AKI associated with dual RAS blockade.. Based on claims data, a nested case-control study within a cohort of RAS-inhibiting drug users was conducted. Using conditional logistic regression, confounder-adjusted odds ratios (aORs) and 95% confidence intervals (CI) were obtained for the risk of AKI associated with dual RAS blockade. Subgroup analyses were performed in patients with diabetes or chronic kidney disease and both comorbidities.. Of all 127,227 nursing home residents, the study cohort included 64,567 (50.7%) who were treated with at least one RAS-inhibiting drug. More than three quarters of the study population were female (77.1%). Mean age was 86.0 ± 6.8 years. Most residents were treated with angiotensin-converting enzyme inhibitors (77.8%), followed by angiotensin II receptor blockers (21.6%) and aliskiren (0.2%). Annual prevalence of dual RAS blockade declined from 9.6 (95% CI 7.8-11.8) in 2010 to 4.7 (95% CI 4.0-5.4) per 1,000 users in 2014. In the overall cohort, AKI was not significantly associated with dual RAS blockade (aOR 1.99; 0.77-5.17). However, significantly increased aORs were observed when considering patients with diabetes (3.47; 1.27-9.47), chronic kidney disease (4.74; 1.24-18.13) or both (11.17; 2.65-47.15).. Prescribing of drugs inhibiting the RAS is common in German nursing homes. Though the prevalence of dual RAS blockade declined, our study showed an increased risk of AKI in patients with diabetes and/or chronic kidney disease. Therefore, cautious use is warranted in these vulnerable patients.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Case-Control Studies; Cohort Studies; Diabetes Mellitus; Drug Prescriptions; Drug Therapy, Combination; Female; Fumarates; Germany; Humans; Male; Nursing Homes; Renal Insufficiency, Chronic; Renin-Angiotensin System; Risk Factors

The purpose of the study is to analyze the impact of an intervention to disseminate safety alerts on the utilization of Aliskiren added to angiotensin converting enzyme inhibitor (ACEI) or an angiotensin-receptor blocker (ARB).. Quasi-experimental design (non-randomized intervention) comparing the utilization of Aliskiren + ACEI or ARB in a primary care area-intervention (PCA-I) with a primary care area-control (PCA-C) following a safety alert. All physicians were provided with a list of diabetic patients (DM) on Aliskiren + ACEI or ARB. Physicians in the PCA-I received also a non-DM patients list, a report with recommendations and information on the utilization of Aliskiren + ACEI or ARB in their area. Information was obtained from electronic medical records, period from May 2010 to December 2012. Interrupted time series analysis were used to assess the effect of the intervention on the number of patients on Aliskiren + ACEI or ARB.. The number of DM receiving Aliskiren + ACEI or ARB at the time of the alert (23 December 2011) was 106 in the PCA-I (91 non-DM) and 45 in the PCA-C (25 non-DM). After the alert, a decreased in the number of patients on Aliskiren + ACEI or ARB was noted at both PCAs, although the average of daily treatments ended was significantly higher in the PCA-I, both in the DM group (slope after alert: -0.81, 95%CI -0.91 to -0.71 vs. -0.30, 95%CI -0.37 to -0.22) as well as in the non-DM group (-0.56, 95%CI -0.67 to -0.45 vs. -0.10 95%CI -0.17 to -0.04).. The prescription of Aliskiren + ACEI or ARB decreased at both PCAs, albeit such decreased was more significant at the PCA-I. The intervention led to a more expeditious implementation of the safety alert recommendations. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetes Mellitus; Electronic Health Records; Fumarates; Humans; Interrupted Time Series Analysis; Practice Patterns, Physicians'; Primary Health Care

S-(2-succinyl)cysteine (2SC) is a chemical modification of proteins formed by a Michael addition reaction between the Krebs cycle intermediate, fumarate, and thiol groups in protein--a process known as succination of protein. Succination causes irreversible inactivation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in vitro. GAPDH was immunoprecipitated from muscle of diabetic rats, then analyzed by ultra-performance liquid chromatography-electrospray ionization-mass spectroscopy. Succination of GAPDH was increased in muscle of diabetic rats, and the extent of succination correlated strongly with the decrease in specific activity of the enzyme. We propose that 2SC is a biomarker of mitochondrial and oxidative stress in diabetes and that succination of GAPDH and other thiol proteins may provide the chemical link between glucotoxicity and the pathogenesis of diabetic complications.

Topics: Diabetes Complications; Diabetes Mellitus; Fumarates; Glucosephosphate Dehydrogenase; Humans; Kinetics; Peptide Fragments; Proteins; Reference Values; Succinates

Topics: Anesthesia; Animals; Blood Glucose; Carbon Isotopes; Chromatography, Gas; Citrates; Diabetes Mellitus; Diabetes Mellitus, Experimental; Fumarates; Glycosuria; Guinea Pigs; Hydroxybutyrates; Insulin Antibodies; Ketoglutaric Acids; Liver; Malates; Pyruvates; Rats; Starvation; Streptozocin; Succinates; Unconsciousness

Topics: Animals; Caprylates; Carbon Dioxide; Carnitine; Citrates; Citric Acid Cycle; Cyclic AMP; Depression, Chemical; Diabetes Mellitus; Diabetes Mellitus, Experimental; Fumarates; Glucagon; In Vitro Techniques; Insulin; Ketoglutaric Acids; Malates; Male; Mitochondria, Liver; Rats; Streptozocin; Succinates