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1.
Expert Rev Endocrinol Metab ; 15(2): 95-114, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32368944

RESUMO

Introduction: Lipodystrophy is a heterogeneous group of rare diseases characterized by various degrees of fat loss which leads to serious morbidity due to metabolic abnormalities associated with insulin resistance and subtype-specific clinical features associated with underlying molecular etiology.Areas covered: This article aims to help physicians address challenges in diagnosing and managing lipodystrophy. We systematically reviewed the literature on PubMed and Google Scholar databases to summarize the current knowledge in lipodystrophy management.Expert opinion: Adipose tissue is a highly active endocrine organ that regulates metabolic homeostasis in the human body through a comprehensive communication network with other organ systems such as the central nervous system, liver, digestive system, and the immune system. The adipose tissue is capable of producing and secreting numerous factors with important endocrine functions such as leptin that regulates energy homeostasis. Recent developments in the field have helped to solve some of the mysteries behind lipodystrophy that allowed us to get a better understanding of adipocyte function and differentiation. From a clinical standpoint, physicians who suspect lipodystrophy should distinguish the disease from several others that may present with similar clinical features. It is also important for physicians to carefully interpret clinical features, laboratory, and imaging results before moving to more sophisticated tests and making decisions about therapy.

2.
Food Chem ; 327: 127045, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32464460

RESUMO

In this study, the inhibitory potentials of food originated 34 phenolic acids, and flavonoid compounds were screened against acetylcholinesterase, butyrylcholinesterase, urease, and tyrosinase enzymes. All compounds included in this study exhibited high antioxidant activity with an ignorable cytotoxic activity. In general, they also showed poor anti-urease and anti-tyrosinase activities. Compounds in aglycone form (quercetin, myricetin, chrysin, and luteolin) showed strong anticholinesterase activities. No relation was observed between the tested bioactivities except from the case that aglycone compounds exhibited a strong positive relationship between antioxidant activities and anticholinesterase activity. Interestingly, there was a relation between the molecular weights of aglycone compounds and their anticholinesterase activities. The study showed that flavonoids with molecular mass of 250-320 g/mol have high potential of anticholinesterase activities and are valuable for future experiments on animals and humans. Potential inhibitory effects of these molecules on target proteins were investigated using docking and molecular dynamics calculations.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32213649

RESUMO

Summary: A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients. Learning points: A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years. Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed. The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin. Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite. Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.

4.
Saudi Med J ; 41(1): 38-45, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31915793

RESUMO

OBJECTIVES: To examine the changes in nitric oxide (NO), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and L-arginine levels in schizophrenia during acute psychotic exacerbation and in bipolar disorder during mania and to compare those changes to healthy controls. METHODS: Thirty schizophrenia patients with acute psychotic exacerbation and 30 bipolar disorder patients with mania, who attended the Psychiatry Department,  Erenköy Hospital for Mental and Nervous Diseases, Istanbul, Turkey, in 2010. Thirty healthy controls were included. The diagnosis was made using the Structured Clinical Interview for Axis I Disorders (SCID-I) interviews. Patients' demographic data were recorded, and NO, SDMA, L-arginine, and ADMA levels were studied. RESULTS: Nitric oxide levels in schizophrenia patients were significantly lower than the control group. Nitric oxide levels in the bipolar group were lower than the control group but the difference was not statistically significant. The levels of SDMA, ADMA, and L-arginine were found to be significantly higher in schizophrenia and bipolar disorder patients than the control group. The disease duration was slightly negatively correlated with NO levels in bipolar patients. In schizophrenia patients, the disease severity was slightly positively correlated with NO levels. CONCLUSION: Significant changes in NO, SDMA, ADMA, and L-arginine levels in schizophrenia and bipolar disorder patients suggest that NO and inhibitors of NO might be implicated in the neurobiology of schizophrenia and bipolar disorder.

5.
Nord J Psychiatry ; 74(5): 340-345, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31900022

RESUMO

Purpose: Higher homocysteine (HHcy) levels have been detected in bipolar disorder (BD) patients, and BD patients show circadian rhythm disorders even during remission. Here, we determined the homocysteine (Hcy) levels and chronotype of patients with BD during remission and investigated whether this was related to the clinical course of the disease. Materials and methods: In total, 80 BD outpatients were included. Clinical evaluation was conducted using the Hamilton Depression Rating Scale (HDRS), Young Mania Rating Scale (YMRS), Pittsburgh Sleep Quality Index (PSQI) and the Morningness-Eveningness Questionnaire (MEQ). Hcy, folic acid, vitamin B12 levels and protein consumption the day before clinical evaluation were measured.Results and conclusions: HHcy was found in 11 patients (8.8%), most of whom were males (n = 8, 72.7%). During the course of BD, patients with HHcy had significantly more mixed episodes than patients without HHcy (p = .007, z = -2696). In addition, patients with HHcy had significantly lower MEQ scores than patients without HHcy (p = .04, t = 2018). There was no significant difference in chronotype between patients with and without HHcy. The HHcy group had significantly lower levels of vitamin B12 (p = .003, t = 2870). There were no statistically significant differences in daily protein intake and folic acid levels between HHcy and non-HHcy groups. Our study showed a significant relationship between the number of mixed episodes and HHcy. In terms of potential confounds, patients who abused alcohol were excluded, but alcohol consumption was not evaluated. This result should be considered in BD and should be evaluated in larger samples of BD patients.

6.
Nord J Psychiatry ; 74(3): 194-200, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31724476

RESUMO

Background/aim: The olfactory bulbectomy (OBX) technic is a well-known animal model for depression. According to serotonin hypothesis of depression, one of the possible explanations to this mechanism is the destroying effect of OBX on raphe nuclei which especially include serotonergic neurons. In this study, we aimed to explore histopathological findings in raphe nuclei in OBX rats.Materials and methods: Forty-eight rats (8 control group, 10 sham group, and 30 as the study group) were used. No procedure was applied to the control group. Only frontal burr holes were performed at the level of olfactory bulbs (OBs) on the sham group. Mechanical OBX by compression was applied to 20 rats and the OBs of 10 rats were cauterized. Their OBs, olfactory cortices, raphe nuclei were extracted, tissue specimens were taken than examined by using histopathological methods including hematoxylin and eosin, S-100, and TUNEL staining. Physical dissector method was used to evaluate the number of living and apoptotic neurons in the raphe nuclei.Results: Prominent neuronal loss and morphological changes in the dorsal raphe nuclei were detected in study groups.Conclusion: Raphe nuclei degeneration, related alterations in neurotransmitter system activities and functional brain connectivity might be related to neurobiology of depression.

7.
J Clin Res Pediatr Endocrinol ; 12(1): 17-28, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-31434462

RESUMO

Lipodystrophy is a heterogeneous group of disorders characterized by lack of body fat in characteristic patterns, which can be genetic or acquired. Lipodystrophy is associated with insulin resistance that can develop in childhood and adolescence, and usually leads to severe metabolic complications. Diabetes mellitus, hypertriglyceridemia, and hepatic steatosis ordinarily develop in these patients, and most girls suffer from menstrual abnormalities. Severe complications develop at a relatively young age, which include episodes of acute pancreatitis, renal failure, cirrhosis, and complex cardiovascular diseases, and all of these are associated with serious morbidity. Treatment of lipodystrophy consists of medical nutritional therapy, exercise, and the use of anti-hyperglycemic and lipid-lowering agents. New treatment modalities, such as metreleptin replacement, promise much in the treatment of metabolic abnormalities secondary to lipodystrophy. Current challenges in the management of lipodystrophy in children and adolescents include, but are not limited to: (1) establishing specialized centers with experience in providing care for lipodystrophy presenting in childhood and adolescence; (2) optimizing algorithms that can provide some guidance for the use of standard and novel therapies to ensure adequate metabolic control and to prevent complications; (3) educating patients and their parents about lipodystrophy management; (4) improving patient adherence to chronic therapies; (5) reducing barriers to access to novel treatments; and (5) improving the quality of life of these patients and their families.

8.
Curr Diab Rep ; 19(12): 156, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31802258

RESUMO

PURPOSE OF REVIEW: We seek to characterize the impact of bariatric surgery on diabetes mellitus by recalling its history, examining the clinical data, exploring the putative mechanisms of action, and anticipating its future. RECENT FINDINGS: Results of clinical trials reveal that bariatric surgery induces remission of diabetes in 33-90% of individuals at 1-year post-treatment versus 0-39% of medically managed. Remission rates decrease over time but remain higher in surgically treated individuals. Investigations have revealed numerous actions of surgery including effects on intestinal physiology, neuronal signaling, incretin hormone secretion, bile acid metabolism, and microbiome changes. Bariatric surgery improves control of diabetes through both weight-dependent and weight-independent actions. These various mechanisms help explain the difference between individuals treated surgically vs. medically. They also explain differing effects of various bariatric surgery procedure types. Understanding how surgery affects diabetes will help optimize utilization of the therapy for both disease prevention and treatment.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31333877

RESUMO

Background: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare syndrome with unknown etiology. Metabolic abnormalities are not known to be part of the syndrome. We present one of the oldest cases reported in the literature, who developed severe metabolic abnormalities and hepatic disease suggesting that these features may be part of the syndrome. Case presentation: A 27-year-old woman, diagnosed with ROHHAD syndrome at age 15, who previously developed diabetes insipidus, growth hormone deficiency, hyperprolactinemia, and hypothyroidism in her first decade of life. This was followed by insulin resistance, NAFLD, liver fibrosis, and splenomegaly before age 14 years. Her regimen included a short course of growth hormone, and cyclic estrogen and progesterone. Her metabolic deterioration continued despite treatment with metformin. Interestingly, she had a favorable response to liraglutide therapy despite having a centrally mediated cause for her obesity. At age 26, a 1.6 cm lesion was found incidentally in her liver. Liver biopsy showed hepatocellular carcinoma which was successfully treated with radiofrequency ablation. Conclusion: Metabolic abnormalities, Insulin resistance and fatty liver disease are potentially part of the ROHHAD syndrome that may develop over time. GLP1 agonists were reasonably effective to treat insulin resistance and hyperphagia. Patients with ROHHAD may benefit from close follow up in regards to liver disease.

10.
J Clin Endocrinol Metab ; 104(11): 5120-5135, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31314093

RESUMO

CONTEXT: Limited natural history data are available in patients with non-HIV-related lipodystrophy syndromes who never received disease-specific therapies, making interpretation of benefits of therapies in lipodystrophy syndromes challenging. OBJECTIVE: We assessed the natural history of non-HIV-related generalized lipodystrophy (GL) and partial lipodystrophy (PL) in patients who have never received leptin or other lipodystrophy-specific therapies. DESIGN/SETTING/PATIENTS: We conducted an international chart review of 230 patients with confirmed GL or PL at five treatment centers who never received leptin or other lipodystrophy-specific therapies. Patients were observed from birth to loss to follow-up, death, or date of chart abstraction. OUTCOME MEASURES: Lifetime prevalence of diabetes/insulin resistance and select organ abnormalities, time to diabetes/insulin resistance, first organ abnormality, disease progression, and mortality were described. RESULTS: Diabetes/insulin resistance was identified in 58.3% of patients. Liver abnormalities were the most common organ abnormality (71.7%), followed by kidney (40.4%), heart (30.4%), and pancreatitis (13.0%). Kaplan-Meier estimates of mean (SE) time to first organ abnormality were 7.7 years (0.9) in GL and 16.1 years (1.5) in PL (P < 0.001). Mean time to diabetes/insulin resistance was 12.7 years (1.2) in GL and 19.1 years (1.7) in PL (P = 0.131). Mean time to disease progression was 7.6 years (0.8) and comparable between GL and PL subgroups (P = 0.393). Mean time to death was 51.2 years (3.5) in GL and 66.6 years (1.0) in PL (P < 0.001). CONCLUSIONS: This large-scale study provides comprehensive, long-term data across multiple countries on the natural history of non-HIV-related lipodystrophy.

11.
J Hepatol ; 70(6): 1214-1221, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31000363

RESUMO

BACKGROUND & AIMS: Adult patients suffering from liver disease of unknown cause represent an understudied and underserved population. The use of whole-exome sequencing (WES) for the assessment of a broader spectrum of non-oncological diseases, among adults, remains poorly studied. We assessed the utility of WES in the diagnosis and management of adults with unexplained liver disease despite comprehensive evaluation by a hepatologist and with no history of alcohol overuse. METHODS: We performed WES and deep phenotyping of 19 unrelated adult patients with idiopathic liver disease recruited at a tertiary academic health care center in the US. RESULTS: Analysis of the exome in 19 cases identified 4 monogenic disorders in 5 unrelated adults. Patient 1 suffered for 18 years from devastating complications of undiagnosed type 3 familial partial lipodystrophy due to a deleterious heterozygous variant in PPARG. Molecular diagnosis enabled initiation of leptin replacement therapy with subsequent normalization of liver aminotransferases, amelioration of dyslipidemia, and decreases in daily insulin requirements. Patients 2 and 3 were diagnosed with MDR3 deficiency due to recessive mutations in ABCB4. Patient 4 with a prior diagnosis of non-alcoholic steatohepatitis was found to harbor a mitochondrial disorder due to a homozygous pathogenic variant in NDUFB3; this finding enabled initiation of disease preventive measures including supplementation with antioxidants. Patient 5 is a lean patient with hepatic steatosis of unknown etiology who was found to have a damaging heterozygous variant in APOB. CONCLUSIONS: Genomic analysis yielded an actionable diagnosis in a substantial number (∼25%) of selected adult patients with chronic liver disease of unknown etiology. This study supports the use of WES in the evaluation and management of adults with idiopathic liver disease in clinical practice. LAY SUMMARY: We performed whole-exome sequencing in 19 adult patients with unexplained liver disease after an unrevealing conventional work-up performed by a hepatologist. In 5 cases, genomic analysis led to a diagnosis and informed treatment and management of the disease. Therefore, we suggest using whole-exome sequencing in the evaluation and management of adults with unexplained liver disease.

12.
Clin Psychopharmacol Neurosci ; 17(2): 211-221, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-30905121

RESUMO

Objective: This study investigated changes in urotensin-II (U-II) and endocan levels which can be used as an early biological marker of endothelial injury in the episode and remission phases of bipolar affective disorder (BAD). Methods: We compared endocan and U-II levels, which has been shown to be closely associated with neurotransmitter systems in addition to continuity of endothelial structure and inflammatory response, in patients with BAD in remission for at least one year (n=42) and in patients still in manic or depressive episodes (n=16) with healthy controls (n=30). Results: Both endocan and U-II levels were significantly higher in the bipolar patients than in the controls. Endocan and U-II levels were also significantly correlated with one another (p =0.000, r=0.833). Both endocan (p =0.000) and U-II levels (p =0.000) were significantly higher in the bipolar attack group compared to the subjects in remission, and in the remission group compared to the controls. Conclusion: In this study we determined significantly higher endocan and U-II levels in BAD compared to the controls, while serum endocan and U-II levels of patients undergoing attacks were also significantly higher than those of the controls and also those of patients in remission.

13.
Artigo em Inglês | MEDLINE | ID: mdl-30923630

RESUMO

Background: Metreleptin, a recombinant methionyl -human -leptin, was approved to treat patients with generalized lipodystrophy (GL) in February 2014. However, leptin therapy has been associated with the development of lymphoma. We present a unique case of a patient with prior history of T cell lymphoma in remission, who was diagnosed with Acquired Generalized Lipodystrophy (AGL) during the following year after a clinical remission of her lymphoma without receiving leptin therapy. Case presentation: A 33-year-old woman with a diagnosis of stage IV subcutaneous panniculitis like T-cell lymphoma in 2011, underwent chemotherapy. Shortly after completion therapy, she had a relapse and required more chemotherapy with complete response, followed by allogenic stem cell transplant on June 28, 2012. Since that time, she has been on observation with no evidence of disease recurrence. Subsequent to the treatment, she was found to have high triglycerides, loss of fat tissue from her entire body and diagnosis of diabetes. Constellation of these findings led to the diagnosis of AGL in 2013. Her leptin level was low at 3.4 ng/mL (182 pmol/mL). She is currently not receiving any treatment with Metreleptin for her AGL. Conclusions: Causal association between exogenous leptin therapy and T-cell lymphoma still remains unclear. We hereby present a case of a young woman who was diagnosed with AGL after going into remission from T-cell lymphoma and who has never been treated with Metreleptin. Steroid therapy and chemotherapy might have masked the diagnosis of AGL in this patient. We believe that patients can develop these 2 conditions independent of each other.

14.
Endocrine ; 64(3): 500-511, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30805888

RESUMO

PURPOSE: To evaluate the effects of metreleptin in patients with partial lipodystrophy (PL). METHODS: Patients aged ≥ 6 months with PL, circulating leptin < 12.0 ng/mL, and diabetes mellitus, insulin resistance, or hypertriglyceridemia received metreleptin doses (once or twice daily) titrated to a mean of 0.124 mg/kg/day. Changes from baseline to month 12 in glycated hemoglobin (HbA1c) and fasting serum triglycerides (TGs; co-primary endpoints), fasting plasma glucose (FPG), and liver volume were evaluated. Additional assessments included the proportions of patients achieving target decreases in HbA1c or fasting TGs at month 12, long-term treatment effects, and treatment-emergent adverse events (TEAEs). RESULTS: Significant (p < 0.05) reductions in HbA1c (-0.6%), fasting TGs (-20.8%), FPG (-1.2 mmol/L), and liver volume (-13.4%) were observed in the overall PL population at month 12. In a subgroup of patients with baseline HbA1c ≥ 6.5% or TGs ≥ 5.65 mmol/L, significant (p < 0.05) reductions were seen in HbA1c (-0.9%), fasting TGs (-37.4%), FPG (-1.9 mmol/L), and liver volume (-12.4%). In this subgroup, 67.9% of patients had a ≥ 1% decrease in HbA1c or ≥ 30% decrease in fasting TGs, and 42.9% had a ≥ 2% decrease in HbA1c or ≥ 40% decrease in fasting TGs. Long-term treatment in this subgroup led to significant (p < 0.05) reductions at months 12, 24, and 36 in HbA1c, fasting TGs, and FPG. Metreleptin was well tolerated with no unexpected safety signals. The most common TEAEs were abdominal pain, hypoglycemia, and nausea. CONCLUSIONS: In patients with PL, treatment with metreleptin was well tolerated and resulted in improvements in glycemic control, hypertriglyceridemia, and liver volume.


Assuntos
Hipertrigliceridemia/tratamento farmacológico , Leptina/análogos & derivados , Lipodistrofia Parcial Familiar/tratamento farmacológico , Adolescente , Adulto , Glicemia , Criança , Feminino , Hemoglobina A Glicada , Humanos , Hipertrigliceridemia/sangue , Resistência à Insulina/fisiologia , Leptina/efeitos adversos , Leptina/sangue , Leptina/uso terapêutico , Lipodistrofia Parcial Familiar/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
15.
Biomed Chromatogr ; 33(4): e4468, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30549068

RESUMO

Olanzapine is an atypical antipsychotic drug from the thienobenzodiazepine family which displays efficacy in patients with schizophrenia and related psychoses. A novel LC/MS method was developed and validated for determination of olanzapine in schizophrenia patients' plasma. A liquid-liquid extraction procedure was carried out using 5 mL diethyl ether-diisopropyl ether mixture (1:1, v/v). Average recovery of the extraction procedure was 94.8%. Chromatographic separation was performed on reversed-phase C18 column (250 × 2.0 mm, 5 µm) using mixture of deionized water (trifluoro acetic acid 0.1%)-acetonitrile (20:80, v/v) as mobile phase at a flow rate of 1 mL/min. Irbesartan was used as internal standart and total run time was 2.5 min. Mass spectrometric analysis were carried out in selective-ion montoring mode, and detected olanzapine at m/z 313.1 and IS at m/z 429.4 in all forms of the ions. The calibration curve of olanzapine was linear in the range 2-300 ng/mL (r2 > 0.9993). The interday and intraday precisions (RSD) were <7.55%, and accuracy was >7.59% (n = 6). The proposed study was successfully validated with respect to the US Food and Drug Administration guidelines.


Assuntos
Antipsicóticos/sangue , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Olanzapina/sangue , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/química , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapêutico , Monitoramento de Medicamentos/métodos , Estabilidade de Medicamentos , Feminino , Humanos , Limite de Detecção , Modelos Lineares , Masculino , Olanzapina/química , Olanzapina/farmacocinética , Olanzapina/uso terapêutico , Reprodutibilidade dos Testes
16.
Curr Diab Rep ; 18(12): 143, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30406415

RESUMO

PURPOSE OF REVIEW: This article focuses on recent progress in understanding the genetics of lipodystrophy syndromes, the pathophysiology of severe metabolic abnormalities caused by these syndromes, and causes of severe morbidity and a possible signal of increased mortality associated with lipodystrophy. An updated classification scheme is also presented. RECENT FINDINGS: Lipodystrophy encompasses a group of heterogeneous rare diseases characterized by generalized or partial lack of adipose tissue and associated metabolic abnormalities including altered lipid metabolism and insulin resistance. Recent advances in the field have led to the discovery of new genes associated with lipodystrophy and have also improved our understanding of adipose biology, including differentiation, lipid droplet assembly, and metabolism. Several registries have documented the natural history of the disease and the serious comorbidities that patients with lipodystrophy face. There is also evolving evidence for increased mortality rates associated with lipodystrophy. Lipodystrophy syndromes represent a challenging cluster of diseases that lead to severe insulin resistance, a myriad of metabolic abnormalities, and serious morbidity. The understanding of these syndromes is evolving in parallel with the identification of novel disease-causing mechanisms.


Assuntos
Predisposição Genética para Doença , Lipodistrofia/genética , Lipodistrofia/fisiopatologia , Adipocinas/metabolismo , Comorbidade , Humanos , Lipodistrofia/metabolismo , Lipodistrofia/mortalidade , Fenótipo , Prevalência
17.
Curr Diab Rep ; 18(12): 139, 2018 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-30370487

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to summarize the therapeutic approach for lipodystrophy syndromes with conventional treatment options and metreleptin therapy in detail and to point out the current investigational treatments in development. RECENT FINDINGS: The observation of leptin deficiency in patients with lipodystrophy and the potential of leptin replacement to rescue metabolic abnormalities in animal models of lipodystrophy were followed by the first clinical study of leptin therapy in patients with severe lipodystrophy. This and several other long-term studies demonstrated important benefits of recombinant human leptin (metreleptin) to treat metabolic abnormalities of lipodystrophy. These studies ultimately led to the recent FDA approval of metreleptin for the treatment of generalized lipodystrophy and EMA approval for both generalized and partial lipodystrophy. Additional research efforts in progress focus on novel treatment options, predominantly for patients with partial lipodystrophy. Current treatment of generalized lipodystrophy includes metreleptin replacement as an adjunct to diet and standard treatment approach for metabolic consequences of lipodystrophy. Beyond metreleptin, a number of different compounds and treatment modalities are being studied for the treatment of partial lipodystrophy.


Assuntos
Lipodistrofia/tratamento farmacológico , Animais , Dieta , Exercício Físico , Humanos , Leptina/efeitos adversos , Leptina/análogos & derivados , Leptina/metabolismo , Leptina/uso terapêutico
18.
Diabetes Care ; 41(10): 2255-2258, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30237235

RESUMO

OBJECTIVE: Lipodystrophy syndromes are a heterogeneous group of disorders associated with selective absence of fat. Currently, the diagnosis is established only clinically. RESEARCH DESIGN AND METHODS: We developed a new method from DXA scans called a "fat shadow," which is a color-coded representation highlighting only the fat tissue. We conducted a blinded retrospective validation study to assess its usefulness for the diagnosis of lipodystrophy syndromes. RESULTS: We evaluated the fat shadows from 16 patients (11 female and 5 male) with generalized lipodystrophy (GL), 57 (50 female and 7 male) with familial partial lipodystrophy (FPLD), 2 (1 female and 1 male) with acquired partial lipodystrophy, and 126 (90 female and 36 male) control subjects. FPLD was differentiated from control subjects with 85% sensitivity and 96% specificity (95% CIs 72-93 and 91-99, respectively). GL was differentiated from nonobese control subjects with 100% sensitivity and specificity (95% CIs 79-100 and 92-100, respectively). CONCLUSIONS: Fat shadows provided sufficient qualitative information to infer clinical phenotype and differentiate these patients from appropriate control subjects. We propose that this method could be used to support the diagnosis.


Assuntos
Absorciometria de Fóton , Tecido Adiposo/diagnóstico por imagem , Lipodistrofia/diagnóstico por imagem , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Síndrome , Adulto Jovem
19.
Obes Surg ; 28(11): 3415-3423, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29909517

RESUMO

BACKGROUND: Sleeve gastrectomy (LSG) is now the predominant bariatric surgery performed, yet there is limited long-term data comparing important outcomes between LSG and Roux-en-Y gastric bypass (RYGB). This study compares weight loss and impact on comorbidities of the two procedures. METHODS: We retrospectively evaluated weight, blood pressure, hemoglobin A1c, cholesterol, and medication use for hypertension, diabetes, and hyperlipidemia at 1-4 years post-operatively in 380 patients who underwent RYGB and 334 patients who underwent LSG at the University of Michigan from January 2008 to November 2013. Follow-up rates from 714 patients initially were 657 (92%), 556 (78%), 507 (71%), and 498 (70%) at 1-4 years post-operatively. RESULTS: Baseline characteristics were similar except for higher weight and BMI in LSG. There was greater weight loss with RYGB vs. LSG at all points. Hemoglobin A1c and total cholesterol improved more in RYGB vs. LSG at 4 years. There was greater remission of hypertension and discontinuation of all medications for hypertension and diabetes with RYGB at 4 years. CONCLUSIONS: Weight loss, reduction in medications for hypertension and diabetes, improvements in markers of diabetes and hyperlipidemia, and remission rates of hypertension were superior with RYGB vs. LSG 4 years post-operatively. Choice of bariatric procedures should be tailored to surgical risk, comorbidities, and weight loss goals.


Assuntos
Gastrectomia , Derivação Gástrica , Obesidade Mórbida , Perda de Peso/fisiologia , Pressão Sanguínea/fisiologia , Peso Corporal/fisiologia , Comorbidade , Gastrectomia/efeitos adversos , Gastrectomia/estatística & dados numéricos , Derivação Gástrica/efeitos adversos , Derivação Gástrica/estatística & dados numéricos , Humanos , Obesidade Mórbida/epidemiologia , Obesidade Mórbida/fisiopatologia , Obesidade Mórbida/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
20.
Clin Endocrinol (Oxf) ; 89(1): 65-75, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29722904

RESUMO

OBJECTIVES: Lipodystrophy syndromes are a group of heterogeneous disorders characterized by adipose tissue loss. Proteinuria is a remarkable finding in previous reports. STUDY DESIGN: In this multicentre study, prospective follow-up data were collected from 103 subjects with non-HIV-associated lipodystrophy registered in the Turkish Lipodystrophy Study Group database to study renal complications in treatment naïve patients with lipodystrophy. METHODS: Main outcome measures included ascertainment of chronic kidney disease (CKD) by studying the level of proteinuria and the estimated glomerular filtration rate (eGFR). Kidney volume was measured. Percutaneous renal biopsies were performed in 9 patients. RESULTS: Seventeen of 37 patients with generalized and 29 of 66 patients with partial lipodystrophy had CKD characterized by proteinuria, of those 12 progressed to renal failure subsequently. The onset of renal complications was significantly earlier in patients with generalized lipodystrophy. Patients with CKD were older and more insulin resistant and had worse metabolic control. Increased kidney volume was associated with poor metabolic control and suppressed leptin levels. Renal biopsies revealed thickening of glomerular basal membranes, mesangial matrix abnormalities, podocyte injury, focal segmental sclerosis, ischaemic changes and tubular abnormalities at various levels. Lipid vacuoles were visualized in electron microscopy images. CONCLUSIONS: CKD is conspicuously frequent in patients with lipodystrophy which has an early onset. Renal involvement appears multifactorial. While poorly controlled diabetes caused by severe insulin resistance may drive the disease in some cases, inherent underlying genetic defects may also lead to cell autonomous mechanisms contributory to the pathogenesis of kidney disease.


Assuntos
Nefropatias/etiologia , Lipodistrofia/complicações , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Lactente , Resistência à Insulina/fisiologia , Rim/patologia , Nefropatias/fisiopatologia , Lipodistrofia/fisiopatologia , Lipodistrofia Parcial Familiar/complicações , Lipodistrofia Parcial Familiar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
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