Disease relevance of Diabetes Mellitus, Lipoatrophic

• Mutations in the LMNA gene encoding A-type lamins cause several diseases, including Emery-Dreifuss muscular dystrophy and Dunnigan-type familial partial lipodystrophy (FPLD) [1].
• In this study, we examined lamin A/C processing in three laminopathies characterized by lipodystrophic phenotypes: Dunnigan type familial partial lipodystrophy, mandibuloacral dysplasia and atypical Werner's syndrome [2].
• Mutations in the region of human LMNA encoding the carboxyl-terminal tail Lamin A/C are associated with forms of muscular dystrophy and familial partial lipodystrophy (FPLD) [3].
• Mutations in different domains of the LMNA (lamin A/C) gene encoding nuclear envelope proteins lamin A and lamin C cause familial partial lipodystrophy (Dunnigan variety), dilated cardiomyopathy, and autosomal dominant forms of Emery-Dreifuss and limb-girdle muscular dystrophies [4].
• OBJECTIVE: The phenotypic expression of partial lipodystrophy is present in two familial syndromes: familial partial lipodystrophy type 1 (FPLD1), with fat loss from the extremities, and central obesity and FPLD type 2, with fat loss from the extremities, abdomen, and thorax [5].

High impact information on Diabetes Mellitus, Lipoatrophic

• Null mutations in BSCL2, which encodes the protein seipin, were previously shown to be associated with autosomal recessive Berardinelli-Seip congenital lipodystrophy (OMIM #269700) [6].
• The results indicate that IRS-1 and IRS-3 play important complementary roles in adipogenesis and establish the Irs1(-/-)/Irs3(-/-) double knockout mouse as a novel model of lipoatrophic diabetes [7].
• Anecdotal examples of apparent modulation of atherosclerosis severity by lifestyle changes were also seen in other monogenic metabolic problems, such as hepatic lipase deficiency and Dunnigan-type familial partial lipodystrophy [8].
• Therefore, troglitazone may have therapeutic benefit in lipoatrophic diabetes [9].
• Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy [1].

Chemical compound and disease context of Diabetes Mellitus, Lipoatrophic

• Recently, two missense mutations (N88S, S90L) in the Berardinelli-Seip congenital lipodystrophy gene have been identified in autosomal dominant distal hereditary motor neuropathy and Silver syndrome [10].
• Late-onset lipoatrophic diabetes. Phenotypic and genotypic familial studies and effect of treatment with metformin and lispro insulin analog [11].
• Improved glucose tolerance after effective lipid-lowering therapy with bezafibrate in a patient with lipoatrophic diabetes mellitus: a putative role for Randle's cycle in its pathogenesis [12]?
• Long-term treatment experience in a subject with Dunnigan-type familial partial lipodystrophy: efficacy of rosiglitazone [13].
• Thus a reduced peripheral clearance of triglyceride-rich lipoprotein could be an important determinant of lipoprotein abnormalities in lipoatrophic diabetes [14].

Biological context of Diabetes Mellitus, Lipoatrophic

• Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes [15].
• Recently, mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively [16].
• Dunnigan-type familial partial lipodystrophy (FPLD) is caused by mutations in LMNA, the gene that encodes nuclear lamins A and C. FPLD is characterized by peripheral fat loss, excess central adiposity, insulin resistance, and hyperlipidaemia, which are difficult to treat [13].

Anatomical context of Diabetes Mellitus, Lipoatrophic

• CONCLUSION: Troglitazone therapy improved metabolic control and increased body fat in patients with lipoatrophic diabetes [9].
• Two of these, Emery-Dreifuss muscular dystrophy (EDMD-AD) and a form of dilated cardiomyopathy (CMD1A), involve muscle defects, and the other, familial partial lipodystrophy (FPLD), involves loss of subcutaneous adipose tissue [17].
• A few specific mutations, however, cause a disease with remarkably different clinical features: FPLD, or familial partial lipodystrophy (Dunnigan-type), which mainly affects adipose tissue [18].
• The Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) gene encodes an integral membrane protein, called seipin, of unknown function localized to the endoplasmic reticulum of eukaryotic cells [19].
• Insulin binding and the action of insulin on several aspects of glucose metabolism have been investigated in cultured fibroblasts derived from a patient with congenital lipoatrophic diabetes and compared to cultures from 9 nondiabetic controls [20].

Gene context of Diabetes Mellitus, Lipoatrophic

• PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy [21].
• Mutations in the seipin and AGPAT2 genes clustering in consanguineous families with Berardinelli-Seip congenital lipodystrophy from two separate geographical regions of Brazil [22].
• RXRA is also a positional candidate gene for Berardinelli-Seip congenital lipodystrophy [23].
• These data support the hypothesis that reducing intracellular triglycerides in non-adipose tissues improves insulin sensitivity and suggest that further investigation of the role of PPARalpha agonists in the treatment of lipoatrophic diabetes is warranted [24].
• Molecular scanning of beta-3-adrenergic receptor gene in total congenital lipoatrophic diabetes mellitus [25].

References