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Kitt Falk Petersen,
Elif Arioglu Oral,
Sylvie Dufour,
Douglas Befroy,
Charlotte Ariyan,
Chunli Yu,
Gary W Cline,
Alex M DePaoli, Simeon I Taylor,
Phillip Gorden,
Gerald I Shulman
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ABSTRACT: Lipodystrophy is a rare disorder that is characterized by selective loss of subcutaneous and visceral fat and is associated with hypertriglyceridemia, hepatomegaly, and disordered glucose metabolism. It has recently been shown that chronic leptin treatment ameliorates these abnormalities. Here we show that chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients. This improvement in insulin action was associated with a marked reduction in hepatic and muscle triglyceride content. These data suggest that leptin may represent an important new therapy to reverse the severe hepatic and muscle insulin resistance and associated hepatic steatosis in patients with lipodystrophy.
Journal of Clinical Investigation 06/2002; 109(10):1345-50. · 15.39 Impact Factor
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ABSTRACT: Congenital generalized lipodystrophy is an autosomal recessive disorder characterized by marked paucity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes. We report several different mutations of the gene (AGPAT2) encoding 1-acylglycerol-3-phosphate O-acyltransferase 2 in 20 affected individuals from 11 pedigrees of diverse ethnicities showing linkage to chromosome 9q34. The AGPAT2 enzyme catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. AGPAT2 mRNA is highly expressed in adipose tissue. We conclude that mutations in AGPAT2 may cause congenital generalized lipodystrophy by inhibiting triacylglycerol synthesis and storage in adipocytes.
Nature Genetics 06/2002; 31(1):21-3. · 35.53 Impact Factor
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Medicine 04/2002; 81(2):87-100. · 4.35 Impact Factor
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Elif Arioglu Oral,
Vinaya Simha,
Elaine Ruiz,
Alexa Andewelt,
Ahalya Premkumar,
Peter Snell,
Anthony J Wagner,
Alex M DePaoli,
Marc L Reitman, Simeon I Taylor,
Phillip Gorden,
Abhimanyu Garg
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ABSTRACT: The adipocyte hormone leptin is important in regulating energy homeostasis. Since severe lipodystrophy is associated with leptin deficiency, insulin resistance, hypertriglyceridemia, and hepatic steatosis, we assessed whether leptin replacement would ameliorate this condition.
Nine female patients (age range, 15 to 42 years; eight with diabetes mellitus) who had lipodystrophy and serum leptin levels of less than 4 ng per milliliter (0.32 nmol per milliliter) received recombinant methionyl human leptin (recombinant leptin). Recombinant leptin was administered subcutaneously twice a day for four months at escalating doses to achieve low, intermediate, and high physiologic replacement levels of leptin.
During treatment with recombinant leptin, the serum leptin level increased from a mean (+/- SE) of 1.3 +/- 0.3 ng per milliliter to 11.1 +/- 2.5 ng per milliliter (0.1 +/- 0.02 to 0.9 +/- 0.2 nmol per milliliter). The absolute decrease in the glycosylated hemoglobin value was 1.9 percent (95 percent confidence interval, 1.1 to 2.7 percent; P=0.001) in the eight patients with diabetes. Four months of therapy decreased average triglyceride levels by 60 percent (95 percent confidence interval, 43 to 77 percent; P<0.001) and liver volume by an average of 28 percent (95 percent confidence interval, 20 to 36 percent; P=0.002) in all nine patients and led to the discontinuation of or a large reduction in antidiabetes therapy. Self-reported daily caloric intake and the measured resting metabolic rate also decreased significantly with therapy. Overall, recombinant leptin therapy was well tolerated.
Leptin-replacement therapy improved glycemic control and decreased triglyceride levels in patients with lipodystrophy and leptin deficiency. Leptin deficiency contributes to the insulin resistance and other metabolic abnormalities associated with severe lipodystrophy.
New England Journal of Medicine 02/2002; 346(8):570-8. · 53.30 Impact Factor
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ABSTRACT: The lipodystrophies are characterized by loss of body fat and metabolic disturbances, but the CNS is seldom affected.
An investigation of a family with partial lipodystrophy and neurologic abnormalities included lipid analysis, dual-energy x-ray absorbtiometry (DEXA) for adiposity, insulin resistance, karyotype and other genetic analyses, peroxisomal function, glycosylation pattern of transferrin and thyroglobulin, and muscle biopsy.
The propositus, a 28-year-old woman with congenital partial lipodystrophy and cataracts, presented with a spastic-ataxic gait and lower extremity paresthesiae at age 18. Laboratory investigation revealed a type V hyperlipidemia pattern, insulin resistance, and high alpha-tocopherol levels. A similar syndrome in other family members suggested an autosomal dominant pattern of inheritance.
The progressive neurologic degenerative condition associated with this autosomal dominant, partial lipodystrophy may be misdiagnosed as MS or spinocerebellar degeneration. Search for a few relevant candidate genes was unrevealing. A genome-wide search to determine the molecular etiology can be undertaken if other similar cases are identified.
Neurology 02/2002; 58(1):43-7. · 8.31 Impact Factor
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ABSTRACT: Mutations in the insulin receptor gene have been identified in patients with genetic forms of insulin resistance. These mutations provide insight into structure-function relationships of the insulin receptor, and also into the causes of insulin resistance in human disease.
Trends in Endocrinology and Metabolism 1(3):134-9. · 8.11 Impact Factor
