sirolimus and Metabolic-Syndrome

NAFLD can occur after liver transplantation (LT), as recurrence or de novo hepatic steatosis (HS). We aimed to evaluate the literature on prevalence, risk factors, and prognosis of post-LT HS. Systematic review with meta-analysis through a search on: PUBMED, Scopus, and Web-of-Science, from inception until the September 30, 2021. Forty studies were included, representing 6979 patients. The post-LT HS prevalence was 39.76% (95% CI, 34.06-45.46), with a rising kinetics (11.06% increase per decade, p =0.04), and a geographical distribution (15.10% more prevalent in American continent compared with Europe and Asia). Recurrent HS was up to 5-fold more likely than de novo HS [OR: 5.38 (2.69-10.76)]. Metabolic disturbances were stronger risk factors in the post-LT recipient [obesity: OR: 4.62 (3.07-6.96); metabolic syndrome: OR: 3.26 (2.03-5.25)] as compared with pre-LT recipients, with the exception of diabetes mellitus, which doubled the risk at any set [pre-LT diabetes mellitus: OR: 2.06 (1.58-2.68); post-LT diabetes mellitus: OR: 2.12 (1.73-2.59)]. Donor factors were not the relevant risk factors for post-LT HS and the only immunosuppressive drug associated with increased risk was sirolimus [OR: 1.68 (1.07-2.64)]. The prevalence of post-LT steatohepatitis was 28.82% (19.62-38.03) and the strongest risk factor was pre-LT NAFLD. Limited outcomes data suggest that post-LT HS did not increase the risk for liver cirrhosis or mortality in these studies. Two out of 5 patients submitted to LT will develop post-LT HS, being recurrent HS more common than de novo HS. Diabetes mellitus and post-LT metabolic syndrome are the strongest risk factors for HS and baseline NAFLD for steatohepatitis. All transplanted patients should be enrolled in lifestyle interventions to prevent post-LT metabolic syndrome, and sirolimus should be avoided in high-risk patients.

Topics: Diabetes Mellitus; Humans; Liver Transplantation; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Risk Factors; Sirolimus

The metabolic syndrome (MS) is an important risk factor for graft dysfunction and patient death after renal transplantation. The aim of this sub-analysis of the Symphony study was to assess the progression of the laboratory parameters associated with MS in the first year after transplantation.. Data collected from the Symphony study were used; 1645 patients were randomized to receive standard-dose cyclosporine (Stand-CsA), low-dose cyclosporine (Low-CsA), tacrolimus (Low-Tac) or sirolimus (Low-SRL), in addition to mycophenolate mofetil (MMF) and corticosteroids. Data were collected for levels and progression over the first year post-transplantation of systolic and diastolic blood pressure, uric acid, triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and fasting glucose levels by treatment arm.. The low-SRL group had significantly higher levels of triglycerides and LDL. The two CsA arms were associated with the highest uric acid levels at each time point. There were no significant differences in overall levels or changes in glucose or HDL. Patients in the standard-CsA arm had significantly higher diastolic blood pressure than those in the Low-SRL and Low-Tac arms. Systolic blood pressure was higher in the Low-CsA arm than in the Low-Tac arm. The use of antihypertensive and antidiabetic agents was similar between the treatment arms. In the Low-SRL arm, more patients were treated with lipid-lowering therapy. Mean daily steroid doses were the highest in the Low-SRL arm.. This sub-analysis demonstrates that there is a difference in metabolic parameters between immunosuppressive groups. CsA therapy was associated with the highest values of uric acid and systolic and diastolic blood pressure. Patients on SRL therapy had the worst lipaemic control. A possible effect of Tac on new-onset diabetes could not be excluded.

Topics: Adrenal Cortex Hormones; Adult; Blood Chemical Analysis; Blood Pressure Determination; Body Mass Index; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Metabolic Syndrome; Middle Aged; Monitoring, Physiologic; Mycophenolic Acid; Prognosis; Reference Values; Risk Assessment; Sirolimus; Tacrolimus; Transplantation Immunology

The purpose of the present study was to compare the efficacy and safety of paclitaxel-eluting stent (PES), sirolimus-eluting stent (SES), and zotarolimus-eluting stent (ZES) in primary percutaneous coronary intervention (PCI) for acute ST-segment elevation myocardial infarction (STEMI) with metabolic syndrome (MS).. Using data from Korea Acute Myocardial Infarction Registry (KAMIR; November 2005-December 2007), a total of 1,768 MS patients with STEMI who underwent primary PCI were enrolled: The PES group was 634, SES group, 906, and ZES group, 228. The primary endpoint was major adverse cardiac event (all-cause death, re-myocardial infarction, target lesion revascularization) during 12 months follow-up. At 12 months, the cumulative incidence of primary endpoint in the PES, SES, and ZES groups was 10.9%, 9.1%, and 11.0%, respectively (P=0.086). Incidence of death, recurrent myocardial infarction, or target lesion revascularization did not differ among the 3 groups. There were 7 episodes of acute (0.3% in PES group, 0.4% in SES group, and 0.4% in ZES group, respectively, P=0.773) and 18 episodes of cumulative stent thrombosis including late stent thrombosis (0.9% in PES group, 1.0% in SES group, and 1.3% in ZES group, respectively, P=0.448).. Implantation of SES, PES, and ZES in MS patients with STEMI undergoing primary PCI provided comparable clinical outcomes in patients enrolled in KAMIR.

Topics: Antineoplastic Agents, Phytogenic; Asian People; Disease-Free Survival; Drug-Eluting Stents; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Metabolic Syndrome; Middle Aged; Myocardial Infarction; Paclitaxel; Republic of Korea; Sirolimus; Survival Rate

Rapamycin treatment has positive and negative effects on progression of type 2 diabetes (T2D) in a recombinant inbred polygenic mouse model, male NONcNZO10/LtJ (NcZ10). Here, we show that combination treatment with metformin ameliorates negative effects of rapamycin while maintaining its benefits. From 12 to 30 weeks of age, NcZ10 males were fed a control diet or diets supplemented with rapamycin, metformin, or a combination of both. Rapamycin alone reduced weight gain, adiposity, HOMA-IR, and inflammation, and prevented hyperinsulinemia and pre-steatotic hepatic lipidosis, but exacerbated hyperglycemia, hypertriglyceridemia, and pancreatic islet degranulation. Metformin alone reduced hyperinsulinemia and circulating c-reactive protein, but exacerbated nephropathy. Combination treatment retained the benefits of both while preventing many of the deleterious effects. Importantly, the combination treatment reversed effects of rapamycin on markers of hepatic insulin resistance and normalized systemic insulin sensitivity in this inherently insulin-resistant model. In adipose tissue, rapamycin attenuated the expression of genes associated with adipose tissue expansion (Mest, Gpam), inflammation (Itgam, Itgax, Hmox1, Lbp), and cell senescence (Serpine1). In liver, the addition of metformin counteracted rapamycin-induced alterations of G6pc, Ppara, and Ldlr expressions that promote hyperglycemia and hypertriglyceridemia. Both rapamycin and metformin treatment reduced hepatic Fasn expression, potentially preventing lipidosis. These results delineate a state of "insulin signaling restriction" that withdraws endocrine support for further adipogenesis, progression of the metabolic syndrome, and the development of its comorbidities. Our results are relevant for the treatment of T2D, the optimization of current rapamycin-based treatments for posttransplant rejection and various cancers, and for the development of treatments for healthy aging.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fatty Liver; Hyperglycemia; Hyperinsulinism; Hypertriglyceridemia; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Metformin; Mice; Sirolimus

Long-time use of pharmacological immunosuppressive agents frequently leads to metabolic disorders. Most studies have focused on islet toxicity leading to posttransplantation diabetes mellitus. In contrast, the link between intestinal dysbiosis and immunosuppressive drug-induced metabolic disorders remains unclear.. We established a mouse model of metabolic abnormality via sirolimus treatment. Fecal microbiota was examined using 16S rRNA gene MiSeq sequencing. Intestinal barrier function was assessed using fluorescein isothiocyanate-dextran assay and mucus immunostaining. Systemic inflammation was determined using a multiplexed fluorescent bead-based immunoassay.. Sirolimus induced dyslipidemia and glucose intolerance in mice in a dose-dependent manner. Interestingly, the clinical-mimicking dose of sirolimus altered the intestinal microbiota community, which was characterized by the enrichment of Proteobacteria, depletion of Akkermansia, and potential function shifts to those involved in lipid metabolism and the immune system. In addition, the clinical-mimicking dose of sirolimus reduced the thickness of the intestinal mucosal layer, increased the intestinal permeability, and enriched the circulating pro-inflammatory factors, including interleukin (IL)-12, IL-6, monocyte chemotactic protein 1, granulocyte-macrophage colony stimulating factor, and IL-1β. Our results showed a close association between intestinal dysbiosis, intestinal barrier failure, systemic inflammation, and metabolic disorders. Furthermore, we demonstrated that oral intervention in the gut microbiota by Lactobacillus rhamnosus HN001 protected against intestinal dysbiosis, especially by depleting the lipopolysaccharide-producing Proteobacteria, and attenuated the sirolimus-induced systemic inflammation, dyslipidemia, and insulin resistance.. Our study demonstrated a potentially causative role of intestinal dysbiosis in sirolimus-induced metabolic disorders, which will provide a novel therapeutic target for transplant recipients.

Topics: Animals; Bacteria; Cytokines; Disease Models, Animal; Dysbiosis; Dyslipidemias; Feces; Gastrointestinal Microbiome; Inflammation Mediators; Insulin Resistance; Intestinal Mucosa; Lacticaseibacillus rhamnosus; Male; Metabolic Syndrome; Mice, Inbred C57BL; Probiotics; Sirolimus

Rapamycin, an inhibitor of the serine/threonine protein kinase mTOR, is an immunosuppressant used to treat renal transplant recipients, but it can cause endothelial and mitochondrial dysfunction. Metformin is used for the treatment of type 2 diabetes and was reported to exert therapeutic effects against rheumatoid arthritis and obesity by improving mitochondrial dysfunction via the activation of fibroblast growth factor 21. We investigated the therapeutic effects of rapamycin-metformin combination therapy in obese mice with collagen-induced arthritis (CIA).. Mouse embryonic fibroblasts were treated with rapamycin, metformin, or rapamycin-metformin, and their respiratory level and mitochondrial gene expression were assayed. Mice were fed a high-fat diet, immunized with type II collagen, and subsequently treated with rapamycin-metformin daily for 10 weeks.. Rapamycin-treated cells exhibited dysfunction of mitochondrial respiration and decreased mitochondrial gene expression compared with rapamycin-metformin-treated cells. Moreover, rapamycin-metformin reduced the clinical arthritis score and the extent of histological inflammation and improved the metabolic profile in obese mice with CIA. Rapamycin-metformin enhanced the balance between T helper 17 and regulatory T cells in vitro and in vivo.. These results suggest that rapamycin-metformin is a potential therapeutic option for autoimmune arthritis.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Drug Therapy, Combination; Hypoglycemic Agents; Immunosuppressive Agents; Metabolic Syndrome; Metformin; Mice; Mitochondria; Obesity; Sirolimus

As it is controversial whether metabolic syndrome (MetS) affects cardiovascular outcomes in patients who underwent percutaneous coronary intervention (PCI), we investigated the impact of MetS on clinical outcomes in patients who underwent PCI with everolimus-eluting stents (EESs). Patients who underwent PCI with EESs from 2009 to 2013 were included in this single-center, prospective cohort study. A composite event consisted of repeat revascularization, nonfatal myocardial infarction, and cardiac death. Of 903 patients observed for 4.9 years (median 1.8 years), 570 were diagnosed with MetS. The MetS group displayed more severe coronary artery disease and underwent more extensive PCIs than did the non-MetS group. The overall composite event rate was not significantly different between the MetS and the non-MetS group (11.9% vs 13.2%, p = 0.572). Kaplan-Meier survival analysis showed no significant difference in the event-free survival of the composite event between the 2 groups (p = 0.700). A multivariable Cox regression analysis showed that MetS was not associated with the composite event, whereas total stent length, decreased renal function, diabetes, and the absence of abdominal obesity were associated with the composite event. Abdominal obesity was associated with decreased risk of the composite event, alleviating unfavorable clinical outcomes of patients with diabetes in the MetS group. In conclusion, MetS has no impact on the clinical outcomes of patients who underwent PCI with EESs, although the MetS group exhibited more severe coronary artery disease and underwent more extensive PCIs. The paradoxical association between obesity and favorable clinical outcomes may explain this result.

Topics: Antineoplastic Agents; Coronary Angiography; Coronary Restenosis; Disease-Free Survival; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Male; Metabolic Syndrome; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Postoperative Period; Prognosis; Prospective Studies; Republic of Korea; Risk Assessment; Risk Factors; Sirolimus; Survival Rate; Treatment Outcome

Despite common use of second-generation drug-eluting stents in treating patients with coronary artery disease, there is lack of data comparing these stents exclusively in patients with acute myocardial infarction (AMI), especially with metabolic syndrome (MetS), which is highly prevalent in AMI and potential to worsen clinical outcomes. The aim of this study was to compare clinical outcomes of everolimus-eluting stent (EES) and Resolute-zotarolimus-eluting stent (R-ZES) in AMI patients with MetS, in terms of stent-related and patient-related outcomes.. A total of 3942 AMI patients in the KAMIR (Korea Acute Myocardial Infarction Registry) were grouped according to the presence of MetS and stent type: EES (N=1582) and R-ZES (N=255) in MetS (1837). Target lesion failure (TLF) and patient-oriented composite events (POCE) at 1 year were evaluated.. In MetS patients, TLF (3.7% vs. 2.7%, p=0.592) and POCE (7.9% vs. 6.7%, p=0.764) were similar between EES and R-ZES. Also in Non-MetS patients, TLF (3.9% vs. 3.1%, p=0.307) and POCE (6.4% vs. 7.3%, p=0.866) were similar between 2 groups. TLF was similar between MetS and Non-MetS patients (3.6% vs. 3.8%), while POCEs (7.7% vs. 6.6%) were higher in MetS. Propensity-score matching analysis showed similar results between stent groups in MetS and Non-MetS. In multivariate analysis, left ventricular ejection fraction and symptom-to-door time were independent predictors of TLF and POCE in MetS patients with AMI.. In MetS patients with AMI, EES and R-ZES showed excellent performance and safety. However, patient-oriented composite events were relatively high, suggesting more efforts to improve them.

Topics: Coronary Angiography; Drug-Eluting Stents; Electrocardiography; Everolimus; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Propensity Score; Registries; Sirolimus; Time Factors; Treatment Outcome

Patients with metabolic syndrome (MetS) are at increased risk of cardiovascular events. The long-term effectiveness of sirolimus-eluting stents (SES) in patients with MetS and in diabetic patients is not well defined.. 563 consecutive patients with 629 de novo coronary lesions (< 50 mm lesion length, reference diameter < 3.5 mm) successfully treated with SES were enrolled in the study and followed for 41 +/- 17 months. Bifurcation and left main lesions were excluded. Patients were categorized into three groups: 1) no MetS and no diabetes; 2) MetS and no diabetes; and 3) diabetes. MetS was defined as the presence of > or = 3 of the following criteria: obesity, hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol, elevated fasting glucose.. 284 patients (51%) with 318 lesions had neither MetS nor diabetes, 148 patients (26%) with 163 lesions had MetS without diabetes and 131 patients (23%) with 148 lesions had diabetes. Baseline angiographic parameters were comparable between the three groups. Clinically driven target lesion revascularization rates for controls, MetS and diabetics were 7.7%, 5.4% and 14.5%, respectively (p = 0.041). Mortality rates for the three groups were 4.2%, 10.1% and 15.3%, respectively (p = 0.042). There were also significant differences in stent thrombosis (ST) rates with 0.3% in controls, 0.6% in MetS and 6.1% in diabetics (p = 0.037). Annual mortality and ST rates for controls, patients with MetS and diabetic patients were 1.2%, 3.0% and 5.6% (p = 0.037) and 0.2%, 0.3% and 2.7% (p = 0.039), respectively. Late loss in-lesion was 0.19 +/- 0.59 mm in controls, 0.17 +/- 0.44 mm in patients with MetS/no diabetes and 0.46 +/- 0.81 mm in diabetics (p < 0.001).. During long-term follow up after implantation of SES in de novo coronary lesions, MetS without diabetes does not result in an increase in target lesion revascularization or ST rates compared with control patients. However, patients with MetS have a higher follow-up mortality rate compared to control patients.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Disease; Coronary Thrombosis; Diabetes Complications; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Incidence; Longitudinal Studies; Male; Metabolic Syndrome; Middle Aged; Prognosis; Sirolimus; Survival Rate; Treatment Outcome

Alcohol intake is one of the important lifestyle factors for the risk of insulin resistance and type 2 diabetes. Acetaldehyde, the major ethanol metabolite which is far more reactive than ethanol, has been postulated to participate in alcohol-induced tissue injury although its direct impact on insulin signaling is unclear. This study was designed to examine the effect of acetaldehyde on glucose uptake and insulin signaling in human dopaminergic SH-SY5Y cells. Akt, mammalian target of rapamycin (mTOR), ribosomal-S6 kinase (p70(S6K)), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and insulin receptor substrate (IRS)-2 were evaluated by Western blot analysis. Glucose uptake and apoptosis were measured using [(3)H]-2-deoxyglucose uptake and caspase-3 assay, respectively. Short-term exposure (12 h) of acetaldehyde (150 muM) facilitated glucose uptake in a rapamycin-dependent manner without affecting apoptosis, IRS-2 expression and insulin-stimulated glucose uptake in SH-SY5Y cells. Acetaldehyde suppressed basal and insulin-stimulated Akt phosphorylation without affecting total Akt expression. Acetaldehyde inhibited mTOR phosphorylation without affecting total mTOR and insulin-elicited response on mTOR phosphorylation. Rapamycin, which inhibits mTOR leading to inactivation of p70(S6K), did not affect acetaldehyde-induced inhibition on phosphorylation of Akt and mTOR. Interestingly, acetaldehyde enhanced p70(S6K) activation and depressed 4E-BP1 phosphorylation, the effect of which was blunted and exaggerated, respectively, by rapamycin. Collectively, these data suggested that acetaldehyde did not adversely affect glucose uptake despite inhibition of insulin signaling cascade at the levels of Akt and mTOR, possibly due to presence of certain mechanism(s) responsible for enhanced p70(S6K) phosphorylation.

Topics: Acetaldehyde; Adaptor Proteins, Signal Transducing; Alcohol-Induced Disorders, Nervous System; Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Diabetes Mellitus, Type 2; Dopamine; Glucose; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Metabolic Syndrome; Neurons; Phosphoproteins; Phosphorylation; Protein Kinases; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Patients with metabolic syndrome (MS) are at increased risk for cardiovascular events. Although the number of patients with MS requiring coronary revascularization is increasing rapidly, the impact of MS on clinical events and restenosis in patients who undergo stent placement is not well defined. Seven hundred thirty-four consecutive patients with 734 de novo coronary lesions (<50 mm lesion length, reference vessel diameter <3.5 mm) were enrolled in this study. Four hundred thirty-seven patients were treated with bare-metal stents, and 297 patients were treated with sirolimus-eluting stents. Patients with bifurcation lesions, left main lesions, and ST-segment-elevation myocardial infarctions were excluded from the study. Patients were categorized into 3 groups: those with (1) diabetes mellitus (DM), (2) MS without DM, and (3) no MS and no DM. MS was defined according to American Heart Association and National Heart, Lung, and Blood Institute criteria (the presence of > or =3 of the following criteria: obesity, hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol, and increased fasting glucose). Clinical follow-up was performed for > or =1 year (mean 27.5 +/- 18.1 months). One hundred sixty-four patients (22%) had DM, 180 patients (25%) had MS without DM, and 390 patients (53%) had no MS and no DM. Baseline clinical and angiographic parameters were comparable among the 3 groups, including lesion length and reference vessel diameter. In patients treated with bare-metal stents, the rates of major adverse cardiac events (MACEs) at 12 months were 14% in patients without DM or MS, 18% in those with MS but no DM, and 33% in those with DM (p = 0.046). In patients treated with sirolimus-eluting stents, the MACE rates were 3% in patients without DM or MS, 4% in those with MS, and 13% in those with DM (p = 0.034). DM (odds ratio 2.14, 95% confidence interval 1.48 to 3.07, p <0.001) and bare-metal stent (odds ratio 2.51, 95% confidence interval 1.49 to 4.22, p <0.001) implantation were independent predictors of MACEs during follow-up, whereas MS was not predictive. Similarly, MS was not a predictor of target lesion revascularization. In conclusion, patients with MS did not have an increased risk for target lesion revascularization or a greater MACE rate compared with control patients during a 12 month follow-up period after bare-metal or drug-eluting stent placement. In contrast, DM is associated with significantly increased event rates.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Disease; Coronary Restenosis; Diabetic Angiopathies; Female; Humans; Immunosuppressive Agents; Male; Metabolic Syndrome; Middle Aged; Retrospective Studies; Sirolimus; Stents

Patients with metabolic syndrome (MetS) are at increased risk of cardiovascular events. The impact of MetS on clinical events and restenosis after drug-eluting stent placement is not well defined.. Two hundred and seventy-four consecutive patients with 298 de-novo coronary lesions (<50 mm lesion length, reference diameter<3.5 mm) successfully treated with sirolimus-eluting stents (SES) were enrolled in the study. Bifurcation lesions, left main lesions and ST-segment elevation myocardial infarcts were excluded. Patients were categorized into three groups: (i) diabetes, (ii) MetS without diabetes, (iii) controls without MetS or diabetes. MetS was defined as presence of > or =3 of the following criteria: obesity, hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol, raised fasting glucose.. One hundred and twenty-one patients (44%) with 134 lesions had neither MetS nor diabetes, 84 patients (31%) with 89 lesions had MetS without diabetes and 69 patients (25%) with 75 lesions had diabetes. Baseline angiographic parameters were comparable between the three groups. Clinically driven target lesion revascularization rates and major adverse cardiac event rates at 12 months were 1, 1, 7% (P=0.039) and 3, 6 and 14% (P=0.032), respectively, for controls, patients with MetS/no diabetes and diabetic patients. Follow-up angiography at 6 months demonstrated late loss in lesion, which was 0.10+/-0.33 mm in the controls, 0.10+/-0.20 mm in patients with MetS/no diabetes and 0.36+/-0.66 mm in diabetic patients (P=0.009).. MetS without diabetes does not result in an increase in target lesion revascularization, major adverse cardiac event rates or angiographic late loss compared with control patients after implantation of SES in de-novo coronary lesions.

Topics: Aged; Coronary Angiography; Drug Delivery Systems; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Sirolimus; Stents