Enrolling in Studies
The Lipodystrophy research team, led by Abhimanyu Garg, M.D., is recruiting volunteers to participate in further studies pertaining to lipodystrophy. If you have been diagnosed with lipodystrophy or believe that you may have lipodystrophy, you and your family can be an important part of this research. Affected and unaffected family members are necessary to identify the genetic basis and cellular mechanisms responsible for different varieties of lipodystrophies.
If after reading the descriptions below, you are interested in participating in a research study, please email Claudia Quittner.
Physical and Metabolic Abnormalities in Lipodystrophy
The purpose of this ongoing study is to identify defective genes responsible for the body fat loss and metabolic abnormalities in various types of genetic lipodystrophies. We are also trying to identify underlying mechanisms (autoimmune and others) for fat loss in patients with the acquired lipodystrophies. You are invited to participate in this research because you or your family members have selective loss of body fat (generalized, partial or localized) called lipodystrophy.
In order to participate in this study you will undergo some screening tests. You will be asked questions about your health and health history. You will have blood tests for cholesterol, triglyceride, lipid, and hormone analysis. Oral glucose tolerance test (OGTT) will be done in order to measure your blood sugar level. You will also have to undergo anthropometric measurements which include height, weight, and percent of body fat measurements.
Novel Therapies for Metabolic Complications of Lipodystrophies
The management of diabetes, insulin resistance, hypertriglyceridemia, and fatty liver, which are frequently seen in patients with lipodystrophies, present a therapeutic challenge. The purpose of this study is to determine the efficacy and safety of three therapeutic interventions on above mentioned problems in lipodystrophic patients.
The interventions are:
- Extremely low-fat diet in patients with generalized lipodystrophy
- Leptin replacement therapy in patients with familial partial lipodystrophy
These interventions are designed to improve or resolve the fatty liver, hypertriglyceridemia, and insulin resistance or diabetes seen in these patients.
Obeticholic Acid for Hepatic Steatosis in Lipodystrophy
Lipodystrophies are rare disorders characterized by selective loss of adipose tissue. Hepatic steatosis is a common problem in these patients and in some it progresses to cirrhosis. Despite aggressive management of diabetes and hyperlipidemia, hepatic steatosis and its complications present a therapeutic challenge in many patients. There is no established therapy for nonalcoholic steatosis. Recombinant leptin therapy has been reported to reduce liver size and hepatic steatosis in hypoleptinemic patients with generalized lipodystrophies but has not been approved for partial lipodystrophy patients.
Recent insight into the role of farnesoid X receptor (FXR), in regulating hepatic triglyceride homeostasis offers new treatment options for hepatic steatosis. Primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA) are endogenous natural ligands for FXR but have weak activity compared to the synthetic ligand, obeticholic acid (OCA), which is 100 times more potent than CDCA. In various mouse models and recently in patients with nonalcoholic fatty liver disease, OCA has been shown to improve hepatic steatosis. Furthermore, OCA improved insulin sensitivity and lowered serum alanine aminotransferase and gamma glutamyl transferase levels in a recent study of patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Therefore, we propose to investigate the efficacy and safety of obeticholic acid in reducing hepatic steatosis in patients with familial partial lipodystrophy of the Dunnigan variety (FPLD).
Thus, this Phase II, randomized, double- blind, cross-over, placebo-controlled study is designed to investigate the efficacy and safety of obeticholic acid therapy in reducing hepatic triglyceride deposition in 20 FPLD patients with hepatic steatosis. OCA/placebo will be administered in a dose of 25 mg/day for four months each. The primary end point variable will be hepatic triglyceride concentration as determined by 1H magnetic resonance spectroscopy. Our results may lead to development of a novel therapeutic intervention for hepatic steatosis in patients with lipodystrophies.
Obesity remains a major health problem in US and causes metabolic complications such as diabetes, dyslipidemia and insulin resistance. Similar complications also occur in patients with familial lipodystrophies characterized by partial (familial partial lipodystrophy, FPL) or almost complete (congenital generalized lipodystrophy, CGL) lack of body fat. In the last few years, several genes for CGL (AGPAT2, BSCL2, CAV1 and PTRF); FPL (LMNA, PPARG, AKT2, CIDEC and PLIN1); mandibuloacral dysplasia (MAD; LMNA and ZMPSTE24); autoinflammatory (PSMB8); SHORT syndrome (short stature, hyperextensibility/hernias, ocular depression, Rieger anomaly and teething delay; PIK3R1); and MDP (mandibular hypoplasia, deafness and progeroid features) syndrome (POLD1) associated lipodystrophies have been identified. However, affected subjects from approximately 200 pedigrees with CGL, MAD and especially FPL lack mutations in these genes suggesting additional loci.
Furthermore, the genetic basis of many extremely rare varieties of lipodystrophies associated with SHORT and neonatal progeroid syndromes remains unknown. Thus, the first aim of this proposal is to identify additional gene(s) involved in adipocyte biology, development and differentiation that cause lipodystrophies and to determine their function in adipocyte biology. We will use state-of-the-art whole exome sequencing to identify the molecular defects in these families. The second aim is to ascertain relationships between molecular defects in lipodystrophy genes with metabolic derangements using well-phenotyped probands, families, and populations.
These studies will unravel molecular mechanisms involved in causation of lipodystrophy, and insulin resistance and its associated morbidities. This new knowledge may provide targets for developing novel drugs for treating diabetes, dyslipidemias and hepatic steatosis.