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  • 1
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    Online Resource
    LMNA Mutations, Skeletal Muscle Lipid Metabolism, and Insulin Resistance
    The Endocrine Society ; 2010
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 95, No. 4 ( 2010-04-01), p. 1634-1643
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 95, No. 4 ( 2010-04-01), p. 1634-1643
    Abstract: Context: Type 2 familial partial lipodystrophy (FPLD) is an autosomal-dominant lamin A/C-related disease associated with exercise intolerance, muscular pain, and insulin resistance. The symptoms may all be explained by defective metabolism; however, metabolism at the tissue level has not been investigated. Objective: We hypothesized that in FPLD, insulin resistance and impaired aerobic exercise capacity are explained by a common underlying mechanism, presumably a muscular metabolic defect. Patients and Methods: Carbohydrate and lipid metabolism was studied on 10 FPLD patients, one patient with limb-girdle muscular dystrophy (LGMD1B, a different lamin A/C disease), and 10 healthy control subjects before and during an oral glucose tolerance test by indirect calorimetry and im microdialysis. Muscle biopsies were taken for in vitro studies. Results: We observed marked increased skeletal muscle fatty acid β-oxidation rate in vitro and in vivo, even after glucose ingestion in FPLD patients. However, fatty acid oxidation was largely incomplete and accompanied by increased ketogenesis. The lipid oxidation abnormality was associated with impaired glucose disposition through reduction in glucose oxidation, rather than decreased cellular glucose uptake. A microarray showed down-regulation of complex I respiratory chain, glycolysis, and nuclear transport genes. Although not overtly insulin resistant, the LGMD1B patient showed similar metabolic derangements as the FPLD patients. Conclusions: Our study suggests imbalance between lipid oxidation and oxidative glucose metabolism in FPLD and LGMD1B patients. The observation suggests an intrinsic defect in skeletal muscle metabolism due to lamin A/C dysfunction. The metabolic FPLD phenotype likely results from this intrinsic defect combined with lipodystrophic “lipid pressure” due to decreased adipose tissue lipid storage capacity.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2009-1293
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2010
    detail.hit.zdb_id: 2026217-6
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  • 2
    Online Resource
    Online Resource
    Dyslipemia in Familial Partial Lipodystrophy Caused by an R482W Mutation in the LMNA Gene
    The Endocrine Society ; 2001
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 5 ( 2001-05-01), p. 2289-2295
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 86, No. 5 ( 2001-05-01), p. 2289-2295
    Abstract: Lipatrophic diabetes, also referred to as familial partial lipodystrophy, is a rare disease that is metabolically characterized by hypertriglyceridemia and insulin resistance. Affected patients typically present with regional loss of body fat and muscular hypertrophic appearance. Variable symptoms may comprise pancreatitis and/or eruptive xanthomas due to severe hypertriglyceridemia, acanthosis nigricans, polycystic ovaria, and carpal tunnel syndrome. Mutations within the LMNA gene on chromosome 1q21.2 were recently reported to result in the phenotype of familial partial lipodystrophy. The genetic trait is autosomal dominant. We identified a family with partial lipodystrophy carrying the R482W (Arg482Trp) missense mutation within LMNA. Here we present the lipoprotein characteristics in this family in detail. Clinically, the loss of sc fat and muscular hypertrophy especially of the lower extremities started as early as in childhood. Acanthosis and severe hypertriglyceridemia developed later in life, followed by diabetes. The characterization of the lipoprotein subfractions revealed that affected children present with hyperlipidemia. The presence and severity of hyperlipidemia seem to be influenced by age, apolipoprotein E genotype, and the coexistence of diabetes mellitus. In conclusion, dyslipemia is an early and prominent feature in the presented lipodystrophic family carrying the R482W mutation within LMNA.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jcem.86.5.7500
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2001
    detail.hit.zdb_id: 2026217-6
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  • 3
    Online Resource
    Online Resource
    Delayed Low Density Lipoprotein (LDL) Catabolism Despite a Functional Intact LDL-Apolipoprotein B Particle and LDL-Receptor in a Subject with Clinical Homozygous Familial Hypercholesterolemia
    The Endocrine Society ; 1998
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 6 ( 1998-06-01), p. 2167-2174
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 83, No. 6 ( 1998-06-01), p. 2167-2174
    Abstract: We identified a 38-yr-old male patient with the clinical expression of homozygous familial hypercholesterolemia presenting as severe coronary artery disease, tendon and skin xanthomas, arcus lipoides, and joint pain. The genetic trait seems to be autosomal recessive. Interestingly, serum concentrations of cholesterol responded well to diet and statins. We had no evidence of an abnormal low density lipoprotein (LDL)-apolipoprotein B (apoB) particle, which was isolated from the patient using the U937 proliferation assay as a functional test of the LDL-binding capacity. The apoB 3500 and apoB 3531 defects were ruled out by PCR. In addition, we found no evidence for a defect within the LDL-receptor by skin fibroblast analysis, linkage analysis, single-strand conformational polymorphism and Southern blot screening across the entire LDL-receptor gene. The in vivo kinetics of radioiodinated LDL-apoB were evaluated in the proband and three normal controls, subsequently. The LDL-apoB isolated from the patient showed a normal catabolism, confirming an intact LDL particle. In contrast the fractional catabolic rate (d−1) of autologous LDL in the subject and the normal controls revealed a remarkable delayed catabolism of the patient’s LDL (0.15 vs. 0.33–0.43 d−1). In addition, the elevation of LDL-cholesterol in the patient resulted from an increased production rate with 22.8 mg/kg per day vs. 12.7–15.7 mg/kg per day. These data indicate that there is another catabolic defect beyond the apoB and LDL-receptor gene causing familial hypercholesterolemia.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jcem.83.6.4840
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 1998
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  • 4
    Online Resource
    Online Resource
    Peroxisome Proliferator-Activated Receptor-γ C190S Mutation Causes Partial Lipodystrophy
    The Endocrine Society ; 2007
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 6 ( 2007-06-01), p. 2248-2255
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 92, No. 6 ( 2007-06-01), p. 2248-2255
    Abstract: Context: Mutations in PPARG are associated with insulin resistance and familial partial lipodystrophy, a disease characterized by altered distribution of sc fat and symptoms of the metabolic syndrome. The encoded protein, peroxisome proliferator-activated receptor (PPAR)-γ, plays a pivotal role in regulating lipid and glucose metabolism, the differentiation of adipocytes, and other cellular regulatory processes. Objectives: The objective of the study was to detect a novel PPARG mutation in a kindred with partial lipodystrophy and analyze the functional characteristics of the mutant protein. Patients and Methods: In three subjects with partial lipodystrophy, one unaffected family member, and 124 unaffected subjects, PPARG was screened for mutations by direct sequencing. Body composition, laboratory abnormalities, and hepatic steatosis were assessed in each affected subject. Transcriptional activity was determined, and EMSA was performed to investigate DNA binding capacity of the mutant protein. Results: We identified a PPARG mutation, C190S, causing partial lipodystrophy with metabolic alterations in three affected family members. The mutation was absent in the unaffected family member and unaffected controls. The mutation is located within zinc-finger 2 of the DNA binding domain. C190S PPARγ has a significantly lower ability to activate a reporter gene than wild-type PPARγ in absence and presence of rosiglitazone. A dominant-negative effect was not observed. Compared with wild-type PPARγ, C190S PPARγ shows a reduced capacity to bind DNA. Conclusion: Mutation of a zinc-binding amino acid of PPARγ leads to an altered protein-DNA binding pattern, resulting in a partial loss of function, which in turn is associated with partial lipodystrophy.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2005-2624
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2007
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  • 5
    Online Resource
    Online Resource
    Functioning Thoracic Paraganglioma: Association with Von Hippel-Lindau Syndrome*
    The Endocrine Society ; 1997
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 10 ( 1997-10-01), p. 3356-3360
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 82, No. 10 ( 1997-10-01), p. 3356-3360
    Abstract: Functioning thoracic paraganglioma (pheochromocytoma) is unusual and therefore suggestive of a pathogenesis distinct from that of sporadic adrenal pheochromocytoma. To determine whether the pheochromocytoma-associated syndromes Von Hippel-Lindau disease (VHL) and multiple endocrine neoplasia type 2 (MEN 2) play a role in the development of thoracic functioning paragangliomas, germline DNA from five unselected patients with this rare tumor was analyzed for mutations in the genes that predispose to VHL and MEN 2. Genetic investigations and further clinical data revealed that three had VHL, with two different germline mutations of the vhl gene, but no individual was affected by MEN 2. Two of the three patients with VHL did not show any additional VHL-associated lesions. This result suggests that VHL should be considered in the differential diagnosis of thoracic pheochromocytoma, as such a diagnosis carries further important implications for the patient and family. Conversely, in patients suspected of a catecholamine-secreting tumor and known VHL, thoracic localization should be considered if an adrenal pheochromocytoma cannot be detected.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jcem.82.10.4050
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 1997
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