Elif Arioglu

AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34.

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.

Efficacy and Safety of Troglitazone in the Treatment of Lipodystrophy Syndromes

Obesity causes insulin resistance, a central feature in the pathogenesis of type 2 diabetes (1). Paradoxically, the absence of adipose tissue also causes insulin resistance and diabetes in humans (2, 3) and genetically engineered animal models (4-6). Lipoatrophy and lipodystrophy are features of a group of heterogeneous syndromes characterized by a paucity of fat, insulin resistance, and hypertriglyceridemia (7). If patients develop diabetes, the syndrome is referred to as lipoatrophic diabetes. The disease has several genetic forms, including face-sparing partial lipoatrophy (the Dunnigan syndrome or the KoberlingDunnigan syndrome, OMIM [Online Mendelian Inheritance in Man] 308980), an autosomal dominant form caused by mutations in the lamin A/C gene (8), and congenital generalized lipoatrophy (the SeipBerardinelli syndrome, OMIM 269700), an autosomal recessive form mapping to chromosome 9q34 in some pedigrees (9). These diseases are rare; reported estimated prevalences are less than 1 in 10 million (10), although our experience suggests that the actual prevalences may be somewhat higher. An association between lipoatrophy and autoimmune disease, such as juvenile dermatomyositis, has also been described (11), suggesting that autoimmune destruction of adipose tissue results in a form of lipoatrophy. Thiazolidinediones, a new class of antidiabetic drugs (12), are ligands for peroxisome proliferatoractivated receptor- (PPAR-), a nuclear receptor expressed predominantly in adipose tissue (13). Thiazolidinediones are believed to exert their primary actions in adipose tissue and to indirectly increase insulin sensitivity in other tissues (14). Because thiazolidinediones have been reported to both increase insulin sensitivity (15, 16) and promote adipocyte development (17), these drugs seemed ideally suited to treat lipoatrophic diabetes. Troglitazone, the first thiazolidinedione to be approved for therapeutic use in the United States, has been shown to improve glycemic control and ameliorate hypertriglyceridemia in patients with type 2 diabetes (18). However, the use of troglitazone is complicated by a rare form of severe, irreversible hepatotoxicity. Two additional thiazolidinediones, rosiglitazone and pioglitazone, were recently approved for use. These drugs are also effective in improving glycemic control in patients with type 2 diabetes (19). Although initial studies of rosiglitazone and pioglitazone suggested that they might not be toxic to the liver, recent reports have raised the possibility that rosiglitazone may rarely cause hepatotoxicity (19, 20). Because PPAR- ligands promote adipocyte differentiation in vitro (13), we hypothesized that troglitazone would promote adipocyte development in patients with various forms of lipoatrophy. This hypothesis implicitly assumes that some lipoatrophic patients possess pre-adipocytes that could be stimulated by troglitazone to complete adipocyte differentiation. In addition, we sought to determine whether troglitazone therapy would improve metabolic control in patients with various forms of lipoatrophy. In light of data suggesting that troglitazone exerts its primary effects on adipocytes, it was uncertain whether the drug would be effective in such patients. Methods Patients Potential study participants were referred by multiple physicians in the United States and Canada in response to advertisements placed in medical journals, notices on the Internet, or word-of-mouth. Some patients had been followed at the National Institutes of Health for varying periods of time (up to 20 years). Because of the rarity of the syndrome, it was not practical to conduct population-based recruitment. To be eligible for the study, patients had to have both insulin resistance and lipoatrophy. For our purposes, insulin resistance was defined as either a fasting plasma insulin level greater than 143 pmol/L or impaired response to intravenous insulin (0.15 U/kg). The latter criterion was defined as a decrease in plasma glucose of less than 50% in patients with fasting glucose levels of 11 mmol/L or less ( 200 mg/dL) or a decrease of 5.5 mmol/L or less (<100 mg/dL) in patients with fasting glucose levels greater than 11.1 mmol/L (>200 mg/dL). Of 33 patients screened for this study, 8 were excluded because serum aminotransferase concentrations were abnormal (range, 833 to 6666 nkat/L) and liver biopsies showed steatohepatitis with varying degrees of fibrosis. Five patients were excluded for various reasons, such as the inability to give informed consent or adhere to the study follow-up schedule. The remaining 20 patients were recruited into the study (Table). Table. Characteristics of the Study Patients Fat distribution was assessed by physical examination and magnetic resonance imaging (MRI). A region of the body was defined as affected if MRI showed a marked decrease in fat in that region. Four patients had generalized lipoatrophy, defined as involvement of the following nine regions: face, neck, upper trunk, abdominal subcutaneous fat, visceral fat, and all four extremities. Two of these patients (U1 and P1) had near-total absence of fat throughout their bodies; the other two (A1 and A2) had a generalized decrease in fat but retained some fat in their visceral abdomen. Sixteen patients, including 7 patients with the Dunnigan syndrome, had partial lipoatrophy affecting five to eight fat depots. Six patients had accompanying autoimmune disease or results on three or more laboratory tests that suggested autoimmunity (for example, antinuclear antibody, rheumatoid factor, and elevated erythrocyte sedimentation rate); these patients therefore were presumed to have an autoimmune cause of their lipoatrophy. The cause of lipoatrophy appeared to be genetic in 10 patients; lipoatrophy appeared shortly after birth in 1 patient, and 9 patients had several affected relatives. Seven of these 9 patients had Dunnigan partial lipodystrophy (21) (Table); the 7 patients were members of three pedigrees. After completion of the study, the diagnosis of the Dunnigan syndrome was confirmed by identifying the R482Q mutation in the lamin A/C gene in all three pedigrees (22). In 4 patients, the cause of disease was unknown. Of the 20 study patients (Table), 14 had diabetes and 2 had impaired glucose tolerance according to the 1997 American Diabetes Association criteria (23). Most diabetic patients were receiving pharmacotherapy before study entry. Five patients were receiving insulin (0.5 to 2 U/kg of body weight per day) and 5 were receiving sulfonylureas; patients continued to receive these therapies during the study. Two patients were receiving metformin, but this therapy was discontinued 6 weeks before initiation of troglitazone treatment. Syndromes of lipoatrophy are associated with substantial comorbid conditions. Of the 8 patients with triglyceride levels greater than 4.5 mmol/L (400 mg/dL), 6 had a history of pancreatitis. Seventeen patients had acanthosis nigricans, a dermatologic condition associated with insulin resistance. Twelve of the 18 female participants had histories of irregular menses and polycystic ovaries as documented by ultrasonography; 6 of these women had hirsutism. Of the 6 remaining female participants, 4 were postmenopausal, 1 was perimenopausal, and 1 was prepubertal. Fatty liver is another important feature sometimes associated with lipoatrophy. To be included in the study, patients had to have normal biochemical function of the liver (Table). Nevertheless, results of ultrasonography in 12 patients suggested fatty infiltration of the liver. Lipoatrophic diabetes was associated with chronic complications of diabetes in some patients. Six patients had albuminuria, seven had diabetic polyneuropathy, and three had diabetic retinopathy (one of whom had proliferative retinopathy). One patient had three-vessel coronary artery disease. Design Patients were treated with troglitazone in an open-label prospective trial in which each patient was compared with his or her own baseline state. Because of the rarity of lipoatrophy syndromes and the variability of the clinical features, it was not feasible to use a randomized, placebo-controlled design. The study was approved by the institutional review board of the National Institute of Diabetes and Digestive and Kidney Diseases. Informed consent was obtained from the patient or his or her legal guardian. The decision to analyze the data after 6 months of therapy was made before the study was begun. Patients were evaluated as inpatients at the Clinical Center of the National Institutes of Health before treatment with troglitazone was initiated. They were admitted again after 6 weeks, 3 months, and 6 months of treatment. Before starting troglitazone therapy, diabetic patients were followed for at least 6 weeks while receiving stable doses of medication. Patients receiving insulin or sulfonylureas continued therapy with these drugs; however, metformin therapy was discontinued before troglitazone therapy was initiated. In diabetic patients, troglitazone therapy was started at a dosage of 200 mg/d and was increased to 400 to 600 mg/d over the course of 6 to 12 weeks, with the goal of optimizing glycemic control. The slow titration was chosen to minimize the risk for hypoglycemia. Doses of insulin or sulfonylureas were decreased if this was necessary to prevent hypoglycemia. Patients received stable doses of lipid-lowering medication for at least 6 weeks before starting troglitazone therapy. In nondiabetic adult participants, troglitazone was prescribed at a dosage of 400 mg/d. In one 6-year-old child weighing 15 to 18 kg, the dosage was 100 mg/d. Liver function tests and blood counts were performed every 3 to 4 weeks. Patients completed weekly questionnaires about their symptoms to identify potential side effects. Patients were instructed not to change their diet and exercise habits during this study. Information about dietary habits was collected by using

Mutational and Haplotype Analyses of Families with Familial Partial Lipodystrophy (Dunnigan Variety) Reveal Recurrent Missense Mutations in the Globular C-Terminal Domain of Lamin A/C

Familial partial lipodystrophy (FPLD), Dunnigan variety, is an autosomal dominant disorder characterized by marked loss of subcutaneous adipose tissue from the extremities and trunk but by excess fat deposition in the head and neck. The disease is frequently associated with profound insulin resistance, dyslipidemia, and diabetes. We have localized a gene for FPLD to chromosome 1q21-q23, and it has recently been proposed that nuclear lamin A/C is altered in FPLD, on the basis of a novel missense mutation (R482Q) in five Canadian probands. This gene had previously been shown to be altered in autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD) and in dilated cardiomyopathy and conduction-system disease. We examined 15 families with FPLD for mutations in lamin A/C. Five families harbored the R482Q alteration that segregated with the disease phenotype. Seven families harbored an R482W alteration, and one family harbored a G465D alteration. All these mutations lie within exon 8 of the lamin A/C gene-an exon that has also been shown to harbor different missense mutations that are responsible for EDMD-AD. Mutations could not be detected in lamin A/C in one FPLD family in which there was linkage to chromosome 1q21-q23. One family with atypical FPLD harbored an R582H alteration in exon 11 of lamin A. This exon does not comprise part of the lamin C coding region. All mutations in FPLD affect the globular C-terminal domain of the lamin A/C protein. In contrast, mutations responsible for dilated cardiomyopathy and conduction-system disease are observed in the rod domain of the protein. The FPLD mutations R482Q and R482W occurred on different haplotypes, indicating that they are likely to have arisen more than once.

Syndromes associated with insulin resistance and acanthosis nigricans.

Insulin is the most important hormone in regulating fuel metabolism. If there is a defect in either insulin secretion or insulin action, this can cause major metabolic abnormalities / l / . For example, autoimmune destruction of the ß-cell leads to type 1 diabetes mellitus, a disease characterized by hyperglycemia and ketoacidosis. In contrast, type 2 diabetes mellitus is generally associated with two physiologic defects: insulin deficiency and insulin resistance 121. Although the molecular causes of the common forms of type 2 diabetes have not yet been elucidated, specific molecular defects have been identified in some patients with relatively uncommon variants of noninsulin-dependent diabetes mellitus e.g., maturity-onset diabetes of the young (MODY) and genetic syndromes associated with insulin resistant diabetes. This paper focuses on patients with insulin resistance due to mutations in the insulin receptor gene.

Lipoatrophy syndromes: when ‘too little fat’ is a clinical problem

Arioglu E, Rother KI, Reitman ML, Premkumar A, Taylor SI. Lipoatrophy syndromes: when ‘too little fat’ is a clinical problem. Pediatric Diabetes 2000: 1: 155–168.