ABSTRACT
OBJECTIVES: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for the treatment of children 6-17 years of age with functional constipation (FC). This study evaluated the dose-response, safety, and efficacy of 4 weeks of linaclotide compared with placebo in children 2-5 years of age with FC. METHODS: In this phase 2, randomized, double-blind, placebo-controlled, multidose study, 35 children with FC (based on Rome III criteria) were randomized 3:1 to receive linaclotide (18, 36, or 72 µg, for groups 1, 2, and 3, respectively) and 5:1 to receive linaclotide 9, 18, 36, or 72 µg (group 4), or matching placebo. Key endpoints were the changes from baseline in overall spontaneous bowel movement (SBM) frequency (SBMs/week), stool consistency, and straining, as well as the proportion of days with fecal incontinence during the study intervention period. Adverse events (AEs) were recorded. RESULTS: Of the randomized patients, 34 (97.1%) completed the treatment period and 33 (94.3%) completed the posttreatment period. Mean change from baseline over the treatment period for three of the four key efficacy endpoints showed greater improvement in the linaclotide 72 µg group versus placebo. A dose-response trend was seen for stool consistency in patients receiving linaclotide. Four patients randomized to linaclotide experienced treatment-emergent AEs, one of which was treatment-related (mild diarrhea). All AEs were mild or moderate and none were severe. CONCLUSIONS: Linaclotide was well tolerated in this pediatric population and an efficacy trend was seen with linaclotide 72 µg versus placebo.
ABSTRACT
OBJECTIVES: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for the treatment of children 6-17 years old with functional constipation. This study evaluated the safety and efficacy of various linaclotide doses in children 7-17 years old with irritable bowel syndrome with constipation (IBS-C). METHODS: In this 4-week, randomized, double-blind, placebo-controlled, parallel-group, Phase 2 study, children with IBS-C were randomized to once-daily placebo or linaclotide (Dose A: 18 or 36 µg, B: 36 or 72 µg, and C: 72 µg or 145 µg, or 290 µg); those aged 7-11 years in a 1:1:1:1 allocation based on weight (18 to <35 kg:18 µg, 36 µg, or 72 µg; or ≥35 kg: 36 µg, 72 µg, or 145 µg), and those aged 12-17 years in a 1:1:1:1:1 allocation (the higher option of Doses A-C or 290 µg). The primary efficacy endpoint was a change from baseline in 4-week overall spontaneous bowel movement (SBM) frequency rate over the treatment period. Adverse events and clinical laboratory measures were also assessed. RESULTS: Efficacy, safety, and tolerability were assessed in 101 patients. In the intent-to-treat population, numerical improvement was observed in overall SBM frequency rate with increasing linaclotide doses (A: 1.62, B: 1.52, and C: 2.30, 290 µg: 3.26) compared with placebo. The most reported treatment-emergent adverse events were diarrhea and pain, with most cases being mild and none being severe. CONCLUSIONS: Linaclotide was tolerated well in this pediatric population, showing numerical improvement in SBM frequency compared with placebo.
Subject(s)
Irritable Bowel Syndrome , Peptides , Child , Humans , Adolescent , Irritable Bowel Syndrome/complications , Irritable Bowel Syndrome/drug therapy , Treatment Outcome , Constipation/drug therapy , Abdominal Pain/drug therapy , Abdominal Pain/etiology , Double-Blind MethodABSTRACT
OBJECTIVES: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for treatment of children 6-17 years old with functional constipation (FC). This study evaluated the safety and efficacy of several linaclotide doses in children 6-17 years old with FC. METHODS: In this multicenter, randomized, double-blind, placebo-controlled phase 2 study, 173 children with FC (based on Rome III criteria) were randomized to once-daily linaclotide (A: 9 or 18 µg, B: 18 or 36 µg, or C: 36 or 72 µg) or placebo in a 1:1:1:1 ratio for 6- to 11-year-olds (dosage determined by weight: 18 to <35 or ≥35 kg) and linaclotide (18, 36, 72, or 145 µg) or placebo in a 1:1:1:1:1 ratio for 12- to 17-year-olds. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency throughout the 4-week treatment period. Adverse events (AE), clinical laboratory values, and electrocardiograms were monitored. RESULTS: Efficacy and safety were assessed in 173 patients (52.0% aged 6-11 years; 48.0% aged 12-17 years); 162 (93.6%) completed the treatment period. A numerical improvement in mean SBM frequency was observed with increasing linaclotide doses (1.90 in 6- to 11-year-olds [36 or 72 µg] and 2.86 in 12- to 17-year-olds [72 µg]). The most reported treatment-emergent AE was diarrhea, with most cases being mild; none were severe. CONCLUSIONS: Linaclotide was well tolerated in this pediatric population, with a trend toward efficacy in the higher doses, warranting further evaluation.
Subject(s)
Constipation , Guanylyl Cyclase C Agonists , Peptides , Humans , Constipation/drug therapy , Child , Adolescent , Double-Blind Method , Female , Male , Peptides/therapeutic use , Peptides/administration & dosage , Peptides/adverse effects , Treatment Outcome , Guanylyl Cyclase C Agonists/therapeutic use , Guanylyl Cyclase C Agonists/administration & dosage , Defecation/drug effects , Dose-Response Relationship, Drug , Gastrointestinal Agents/therapeutic use , Gastrointestinal Agents/administration & dosageABSTRACT
BACKGROUND: Cenicriviroc (CVC) is a novel, orally administered antagonist of chemokine receptor types 2/5 that has demonstrated antifibrotic activity in a phase 2b study of patients with NASH. This phase 2, open-label, rollover study investigated the long-term safety and tolerability of CVC in patients with NASH and stage 0-4 liver fibrosis. METHODS: Eligible patients who completed the phase 2 CENTAUR study or reached a predefined endpoint in the phase 3 AURORA study were rolled over and received open-label CVC 150 mg once daily. Safety assessments were conducted at the start of the study, and patients were seen in the clinic every 3 months until the study sponsor terminated CVC development. Safety endpoints included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, adverse event severity, and clinical laboratory assessments. RESULTS: A total of 167 patients were enrolled, with a median treatment duration of 33.6 months. Before study termination, 36 patients (21.6%) prematurely discontinued the study. Treatment-related TEAEs were reported in 28 patients (16.8%). The most common treatment-related TEAEs were 4 cases of diarrhea (2.4%) and 2 cases each (1.2%) of abdominal pain, nausea, alanine aminotransferase increased, aspartate aminotransferase increased, hypertriglyceridemia, myalgia, pruritus, and rash. The majority of these treatment-related events were mild in intensity, and none were life-threatening. There were no clinically meaningful changes in hepatic function, chemistry, or liver parameters from baseline to the end of the study. CONCLUSIONS: In this rollover study, CVC 150 mg once daily was well tolerated in patients with NASH and stage 0-4 liver fibrosis. No new safety signals were reported, and these data further support the safety and tolerability of CVC.
Subject(s)
Imidazoles , Non-alcoholic Fatty Liver Disease , Sulfoxides , Humans , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/drug therapy , Treatment Outcome , Liver Cirrhosis/complications , Liver Cirrhosis/drug therapyABSTRACT
BACKGROUND: Linaclotide, a guanylate cyclase C agonist, has been approved in the USA for the treatment of chronic idiopathic constipation and irritable bowel syndrome with predominant constipation in adults. We aimed to assess the efficacy and safety of linaclotide in paediatric patients aged 6-17 years with functional constipation. METHODS: This randomised, double-blind, placebo-controlled, multicentre, phase 3 study was done at 64 clinic or hospital sites in seven countries (USA, Canada, Israel, Italy, the Netherlands, Ukraine, and Estonia). Patients aged 6-17 years who met modified Rome III criteria for functional constipation were randomly assigned (1:1), with a block size of four and stratified by age (6-11 years and 12-17 years), to receive either oral linaclotide 72 µg or placebo once daily for 12 weeks. Participants, investigators, and data assessors were masked to assignment. The primary efficacy endpoint was change from baseline (CFB) in the 12-week frequency rate of spontaneous bowel movements (SBMs; occurring in the absence of rescue medication on the calendar day of or before the bowel movement) per week and the secondary efficacy endpoint was CFB in stool consistency over the 12-week treatment period; efficacy and safety were analysed in all patients in the randomised population who received at least one dose of study intervention (modified intention-to-treat population and safety population, respectively). The study is registered with ClinicalTrials.gov, NCT04026113, and the functional constipation part of the study is complete. FINDINGS: Between Oct 1, 2019, and March 21, 2022, 330 patients were enrolled and randomly assigned to linaclotide (n=166) or placebo (n=164). Two patients in the linaclotide group did not receive any treatment; thus, efficacy and safety endpoints were assessed in 328 patients (164 patients in each group). 293 (89%) patients completed the 12-week treatment period (148 in the linaclotide group and 145 in the placebo group). 181 (55%) of 328 patients were female and 147 (45%) were male. At baseline, the mean frequency rate for SBMs was 1·28 SBMs per week (SD 0·87) for placebo and 1·16 SBMs per week (0·83) for linaclotide, increasing to 2·29 SBMs per week (1·99) for placebo and 3·41 SBMs per week (2·76) for linaclotide during intervention. Compared with placebo (least-squares mean [LSM] CFB 1·05 SBMs per week [SE 0·19]), patients treated with linaclotide showed significant improvement in SBM frequency (LSM CFB 2·22 SBMs per week [0·19]; LSM CFB difference 1·17 SBMs per week [95% CI 0·65-1·69]; p<0·0001). Linaclotide also significantly improved stool consistency over placebo (LSM CFB 1·11 [SE 0·08] vs 0·69 [0·08]; LSM CFB difference 0·42 [95% CI 0·21-0·64]; p=0·0001). The most reported treatment-emergent adverse event (TEAE) by patients treated with linaclotide was diarrhoea (seven [4%] of 164 vs three [2%] of 164 patients in the placebo group) and by patients treated with placebo was COVID-19 (five [3%] vs four [2%] in the linaclotide group). The most frequent treatment-related TEAE was diarrhoea (linaclotide: six [4%] patients; placebo: two [1%] patients). One serious adverse event of special interest (treatment-related severe diarrhoea resulting in dehydration and hospitalisation) occurred in a female patient aged 17 years in the linaclotide group; this case resolved without sequelae after administration of intravenous fluids. No deaths occurred during the study. INTERPRETATION: Linaclotide is an efficacious and well tolerated treatment for functional constipation in paediatric patients and has subsequently been approved by the US Food and Drug Administration for this indication. FUNDING: AbbVie and Ironwood Pharmaceuticals.
Subject(s)
Constipation , Peptides , Adult , Humans , Male , Female , Child , Treatment Outcome , Constipation/drug therapy , Constipation/chemically induced , Peptides/adverse effects , Diarrhea/chemically induced , Double-Blind MethodABSTRACT
BACKGROUND AND AIMS: Cenicriviroc (CVC) is a novel, orally administered, chemokine receptor type 2 and 5 antagonist that showed antifibrotic potential in preclinical and phase IIb studies of nonalcoholic steatohepatitis (NASH). Herein, we report efficacy and safety results from the phase III study. METHODS: The AURORA (A Study for the Efficacy and Safety of CVC for the Treatment of Liver Fibrosis in Adults With NASH) study was a phase III, randomized, double-blind, placebo-controlled, 2-part study of patients with NASH and stage 2/3 liver fibrosis. Adults, 18-75 years of age, were randomized to CVC 150 mg or placebo once daily for 12 months (part 1) or 60 months (part 2). Liver biopsies were performed at screening, month 12, and early study discontinuation or termination. The primary efficacy endpoint was the proportion of patients with fibrosis improvement ≥1 stage without worsening of steatohepatitis at month 12 relative to screening. Adverse events were assessed throughout the study. RESULTS: A total of 1778 patients were randomized and discontinued (part 1: n = 1293; part 2: n = 485). In part 1, at month 12, a similar proportion of patients receiving CVC or placebo achieved the primary endpoint (22.3% vs 25.5%; odds ratio, 0.84; 95% confidence interval, 0.63-1.10; P = .21) and complete resolution of steatohepatitis without worsening of fibrosis (23.0% vs 27.2%; P = .21). The safety profile was generally comparable across treatment groups. CONCLUSIONS: This study did not demonstrate the efficacy of CVC for treating liver fibrosis assessed by histology in adults with NASH; however, CVC was safe and well tolerated in patients with NASH and liver fibrosis. (ClinicalTrials.gov, Number: NCT03028740).
Subject(s)
Non-alcoholic Fatty Liver Disease , Adult , Humans , Child , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/pathology , Liver Cirrhosis/complications , Liver Cirrhosis/drug therapy , Liver Cirrhosis/pathology , Imidazoles , Fibrosis , Double-Blind Method , Liver/pathology , Treatment OutcomeABSTRACT
BACKGROUND AND AIMS: With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for NASH. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies. APPROACH AND RESULTS: Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 µg (TXR 140 ), CVC 150 mg (CVC), TXR 140 µg + CVC 150 mg (TXR 140 + CVC), or TXR 90 µg + CVC 150 mg (TXR 90 + CVC) for 48 weeks. The primary and secondary end points were safety and histological improvement, respectively. Rates of adverse events (AEs) were similar across treatment groups. Pruritus was the most frequently experienced AE, with highest incidence in the TXR 140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: -21%, TXR 140 ; -16%, TXR 140 + CVC; -13%, TXR 90 + CVC; and +17%, CVC). Reductions in body weight observed at week 24 (mean changes from baseline: TXR 140 , -2.5 kg; TXR 140 + CVC, -1.7 kg; TXR 90 + CVC, -1.0 kg; and CVC, -0.1 kg) were sustained to week 48. At least 1-point improvement in fibrosis stage/steatohepatitis resolution without worsening of fibrosis was observed in 32.3%/25.8%, 31.6%/15.8%, 29.7%/13.5%, and 32.5%/22.5% of patients in the TXR 140 , CVC, TXR 140 + CVC, and TXR 90 + CVC groups, respectively. CONCLUSIONS: The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological end points compared with monotherapy.
Subject(s)
Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/complications , Double-Blind Method , Treatment Outcome , Fibrosis , Body WeightABSTRACT
Type 2 diabetes mellitus is not just a risk factor but a progression factor for a plethora of multi-organ complications, including the liver and the vascular system. The profibrogenic-inflammatory liver disease nonalcoholic steatohepatitis affects patient's mortality and overall cardiovascular and liver-related complications. There is an evident overlap between these diseases; therefore, there are important implications for endocrinologists, cardiologists, and hepatologists when treating these patients. In addition, as newly approved nonalcoholic steatohepatitis pharmacotherapy is expected to be available early this year, clinicians need to be able to identify patients with type 2 diabetes mellitus that are at risk of advanced liver fibrosis to establish adequate and efficient management plans to limit or avoid cardiovascular or liver-related complications. In this review, we summarize the current knowledge in the nonalcoholic steatohepatitis field with potential value for clinicians focusing on the implications of the overlap between type 2 diabetes mellitus, cardiovascular disease, and nonalcoholic steatohepatitis, the available diagnostic tools for risk stratification, management pathways, and nonalcoholic steatohepatitis pharmacotherapy, including antidiabetic and cardiovascular drugs that may be beneficial or detrimental to their patients.
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BACKGROUND AND PURPOSE: Transradial percutaneous coronary intervention (TR-PCI) has been increasingly popular over the last decade in the US. Previous studies have shown that same-day (SD) discharge after elective PCI is as safe as overnight (ON) observation. Our study was performed to assess the clinical and financial impact of early discharge in patients undergoing TR-PCI. METHODS: This is a single center registry of patients undergoing elective TR-PCI. Timing of discharge was determined by the treating physician. (Groups: Same Day Discharge -SD-; Overnight Stay -ON-). Demographic data, procedural characteristics and adverse outcomes were recorded. Outcomes included 30â¯day-MACE and procedure- related complications, as well as total operative costs in patients from both groups. Propensity score matching for patient demographics, coronary symptoms and procedure indicators was used to compare both groups. RESULTS: The entire cohort included 852 patients (429 in SD group and 423 in ON group) and the propensity score matched groups of 245 patients in the SD group and 245 patients in the ON group. The two groups had no significant baseline clinical differences, and had similar clinical outcomes. Specifically, no significant difference was noted in procedural complications (3.7% vs 2.5%, pâ¯=â¯0.43), re-hospitalization (4.1% vs 4.1%, pâ¯=â¯0.92), re-intervention (2.5% vs 2.1%, pâ¯=â¯0.77), myocardial infarction (0% vs 0.08%, pâ¯=â¯0.15), stroke (0% vs 0%, pâ¯=â¯1.0) and all-cause mortality (0% vs 0%, pâ¯=â¯1.0). SD Group patients had a significant lower procedure-related cost compared to overnight stay patients ($3,346.45 vs $4,681.99, pâ¯<â¯0.0001) and lower 30-day post procedure-associated cumulative costs/total operating costs ($4,493.22 vs $7,112.21, pâ¯<â¯0.0001). CONCLUSION: In elective patients undergoing low risk TR-PCI, same-day discharge seems to be a safe and feasible clinical practice, with significant potential savings to the US healthcare system.
Subject(s)
Cardiac Catheterization/methods , Catheterization, Peripheral/methods , Coronary Artery Disease/surgery , Length of Stay , Patient Discharge , Percutaneous Coronary Intervention/methods , Radial Artery , Aged , Cardiac Catheterization/adverse effects , Cardiac Catheterization/economics , Catheterization, Peripheral/adverse effects , Catheterization, Peripheral/economics , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/economics , Cost Savings , Cost-Benefit Analysis , Feasibility Studies , Female , Hospital Costs , Humans , Length of Stay/economics , Male , Middle Aged , Patient Discharge/economics , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/economics , Propensity Score , Punctures , Registries , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome , United StatesABSTRACT
Diabetes mellitus elicits cellular, epigenetic, and post-translational changes that directly or indirectly affect the biology of the vasculature and other metabolic systems resulting in the apparition of cardiovascular disease. In this review, we provide a current perspective on the most recent discoveries in this field, with particular focus on hyperglycemia- induced pathology in the cardiovascular system. We also provide perspective on the clinical importance of molecular targeting of cardiovascular and diabetes mellitus therapies to treat hyperglycemia, inflammation, thrombosis, dyslipidemia, atherosclerosis, and hypertension.
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OBJECTIVES: Single-dose del Nido cardioplegia has been used in the pediatric population for many years. Only a small amount of data exists about its use in adult cardiac surgery. We sought to compare the outcomes of all patients undergoing coronary artery bypass, using our 4:1 blood cardioplegia versus single-dose 1:4 del Nido cardioplegia, at our institution. METHODS: Data were retrospectively reviewed from all patients during 2 consecutive years (2013-2014). We switched our cardioplegia protocol from 4:1 blood cardioplegia to exclusively 1:4 single-dose del Nido cardioplegia in early 2014. A total of 408 patients were evaluated. Two hundred and forty-nine consecutive patients underwent coronary artery bypass using blood cardioplegia and 159 using del Nido Cardioplegia. RESULTS: Cardiopulmonary bypass time, cross-clamp time, in-hospital mortality and length of stay were similar (p>0.05): 63 ± 23 vs. 65 ± 21 min, 50 ± 20 vs. 52 ± 20 min, 0.8% vs. 0.6% and 6.4 ± 3 vs. 5.8 ± 3 days, respectively. For secondary outcomes: patients requiring defibrillation was 105/249 (42%) vs. 13/159 (8%) (p<0.0001), blood transfusion was required in 96/249 (38%) vs. 48/159 (30%) (p<0.085), total volume administered was 1139mL vs. 813 mL per case (p<0.0001), hematocrit change was 11.6% vs. 10.9% (p<0.04) and the mean cost per dose was $157.54 vs $5.74. CONCLUSIONS: Single-dose del Nido cardioplegia is an effective and economic cardioplegia and can be used with good outcomes in coronary surgery. Most patients have spontaneous return of sinus rhythm and there is a trend towards decreased transfusion rate.
Subject(s)
Cardioplegic Solutions/therapeutic use , Coronary Artery Bypass/methods , Heart Arrest, Induced/methods , Adult , Aged , Blood Transfusion , Cardioplegic Solutions/administration & dosage , Coronary Artery Bypass/mortality , Female , Heart Arrest, Induced/mortality , Hospital Mortality , Humans , Male , Middle Aged , Retrospective StudiesABSTRACT
BACKGROUND: Long-term patency rates for percutaneous peripheral arterial interventions are suboptimal. Optical coherence tomography (OCT) guided atherectomy may yield superior patency by optimizing plaque removal while preserving the tunica media and adventitia. METHODS: The VISION study is a multicenter prospective study of patients with peripheral arterial disease undergoing OCT guided atherectomy with the Pantheris™ device. In 11 patients enrolled in a single center, we report procedural and clinical outcomes, at 30days and 6months. RESULTS: The mean age was 63±11years and 73% (n=8) were men. The target lesion was in the superficial femoral artery in 82% (n=9) of the patients. Mean stenosis severity was 87%±10% and mean lesion length was 39±31mm. Procedural success was observed in all patients with no device related complications. Mean post-atherectomy stenosis was 18%±15%. Almost all excised tissue consisted of intimal plaque (94%). At 30days, significant improvements in Rutherford class, VascuQoL scores and ABI were observed, 0.9±0.8 vs. 3.1±0.7 (p=0.01), 4.9±1.9 vs. 3.6±1.5 (p=0.03) and 1.04±0.19 vs. 0.80±0.19 (p<0.01) respectively. At 6months, there were significant improvements in Rutherford class (1.0±1.0 vs. 3.1±0.7, p=0.01) and ABI (0.93±0.19 versus 0.80±0.19, p=0.02) but not in VascuQoL scores (3.7±1.4 versus 3.6±1.5, p=0.48). Target lesion revascularization occurred in 18% (n=2) of the patients. CONCLUSION: OCT guided atherectomy resulted in high procedural success, no device related complications and encouraging results up to 6months. Histological analysis suggested little injury to the media and adventitia. Larger studies are needed to confirm the efficacy of this approach.
Subject(s)
Atherectomy/methods , Femoral Artery/diagnostic imaging , Peripheral Arterial Disease/diagnostic imaging , Peripheral Arterial Disease/therapy , Tomography, Optical Coherence , Aged , Angiography , Atherectomy/adverse effects , Atherectomy/instrumentation , Constriction, Pathologic , Equipment Design , Female , Femoral Artery/physiopathology , Humans , Male , Middle Aged , Peripheral Arterial Disease/physiopathology , Plaque, Atherosclerotic , Predictive Value of Tests , Prospective Studies , Severity of Illness Index , Time Factors , Treatment Outcome , Vascular PatencyABSTRACT
Mutations in the protein alpha-synuclein (SNCA) have been linked to Parkinson's disease. We recently reported that non-mutated SNCA enhanced glucose uptake through the Gab1-PI3 kinase-Akt pathway and elucidated its effects on glucose regulation. Here, we examined the association of SNCA with insulin resistance (IR), a condition that is characterized by decreased tissue glucose uptake. Our observations include those from a population study as well as a SNCA-deficient mouse model, which had not previously been characterized in an IR scenario. In 1,152 patients, we found that serum SNCA levels were inversely correlated with IR indicators--body mass index, homeostatic model assessment for IR (HOMA-IR) and immunoreactive insulin (IRI)--and, to a lesser extent, with blood pressure and age. Additionally, SNCA-deficient mice displayed alterations in glucose and insulin responses during diet-induced IR. Moreover, during euglycemic clamp assessments, SNCA knock-out mice fed a high-fat diet (HFD) showed severe IR in adipose tissues and skeletal muscle. These findings provide new insights into IR and diabetes and point to SNCA as a potential candidate for further research.
Subject(s)
Insulin Resistance/physiology , Insulin/metabolism , alpha-Synuclein/blood , alpha-Synuclein/metabolism , Adipose Tissue/metabolism , Animals , Body Mass Index , Cross-Sectional Studies/methods , Diet, High-Fat , Dietary Fats/metabolism , Glucose/metabolism , Humans , Mice , Mice, Knockout , Muscle, Skeletal/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/physiologyABSTRACT
Insulin is the main glucoregulator that promotes the uptake of glucose by tissues and the subsequent utilization of glucose as an energy source. In this paper, we describe a novel glucoregulator, the alpha-synuclein (SNCA) protein, that has previously been linked to Parkinson's disease. Treatment with recombinant SNCA promotes glucose uptake in vitro in preadipocytes and in vivo in the adipose tissues and skeletal muscles of mice through the LPAR2/Gab1/PI3K/Akt pathway; these effects occur independently of the insulin receptor. This function of SNCA represents a new mechanistic insight that creates novel avenues of research with respect to the process of glucose regulation.
Subject(s)
Adipocytes/metabolism , Glucose/metabolism , Recombinant Proteins/pharmacology , Signal Transduction/physiology , alpha-Synuclein/metabolism , Adaptor Proteins, Signal Transducing , Adipocytes/physiology , Analysis of Variance , Animals , Calorimetry, Indirect , Cell Line , Humans , Immunoblotting , Immunoprecipitation , Mice , Phosphatidylinositol 3-Kinases/metabolism , Phosphoproteins/metabolism , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
The recent discovery of functional brown adipocytes in adult humans illuminates the potential of these cells in the treatment of obesity and its associated diseases. In rodents, brown adipocyte-like cells are known to be recruited in white adipose tissue (WAT) by cold exposure or ß-adrenergic stimulation, but the molecular machinery underlying this phenomenon is not fully understood. Here, we show that inducible brown adipogenesis is mediated by the microRNA miR-196a. We found that miR-196a suppresses the expression of the white-fat gene Hoxc8 post-transcriptionally during the brown adipogenesis of white fat progenitor cells. In mice, miR-196a is induced in the WAT-progenitor cells after cold exposure or ß-adrenergic stimulation. The fat-specific forced expression of miR-196a in mice induces the recruitment of brown adipocyte-like cells in WAT. The miR-196a transgenic mice exhibit enhanced energy expenditure and resistance to obesity, indicating the induced brown adipocyte-like cells are metabolically functional. Mechanistically, Hoxc8 targets and represses C/EBPß, a master switch of brown-fat gene program, in cooperation with histone deacetylase 3 (HDAC3) through the C/EBPß 3' regulatory sequence. Thus, miR-196a induces functional brown adipocytes in WAT through the suppression of Hoxc8, which functions as a gatekeeper of the inducible brown adipogenesis. The miR-196a-Hoxc8-C/EBPß signaling pathway may be a therapeutic target for inducing brown adipogenesis to combat obesity and type 2 diabetes.