The major areas of interest of Dr. Garg's laboratory include diet therapy of diabetes, insulin resistance disorders, diabetic dyslipidemias, and lipodystrophies. Current projects include researching metabolic and genetic basis of familial lipodystrophies, mechanisms of lipodystrophies in HIV-infected patients, and the development of diet therapies for diabetes.
Dr. Garg's research has focused on the problems of diabetes, insulin resistance, and disorders of adipose tissue. During his early years in the Center for Human Nutrition, he carried significant studies on dietary therapy of patients with diabetes and drug therapy of lipid disorders in patients with adult-onset (type 2) diabetes. His careful studies on the General Clinical Research Center at UT Southwestern showed that diabetes and its metabolic complications are better controlled with diets high in monounsaturated fatty acids than on low-fat, high-carbohydrate diets. His first major publication, which was carried out entirely at UT Southwestern, had a major impact on health professional who care for patients with diabetes.
Traditionally, emphasis in dietary therapy had been given to reducing the fat content of patients with diabetes. However, Dr. Garg showed that a better clinical result can be obtained if the diet is kept higher in fat, provided that the fat is in the form of unsaturated fatty acids, especially monounsaturated fatty acids. High-carbohydrate diets were found to worsen the high blood glucose which are characteristic of patients of diabetes, and they produce adverse effects on the blood lipids and lipoproteins. This study led the American Diabetes Association to reconsider its recommendations for dietary therapy in patients with type 2 diabetes. Subsequently Dr. Garg organized a multicenter dietary trial to reexamine the relative effects of monounsaturated fats and carbohydrates in patients with type 2 diabetes. This large study confirmed his first investigation and provided stronger evidence for avoidance of high-carbohydrate diets in patients with type 2 diabetes. Dr. Garg also carried out important investigations on the use of drugs to treat lipid disorders in patients with type 2 diabetes. He carried out the first systematic study on the effects of the new statin drugs on cholesterol levels in these patients. He found that statins are highly effective in treatment of elevated cholesterol in patients with diabetes. Previously it had been thought that the major lipid problem in these patients was an elevation in blood triglyceride.
However, Dr. Garg's finding changed the focus from triglyceride to cholesterol. His important study anticipated the results of future major clinical trials with statins. These trials confirm that statins reduce the risk for coronary heart disease in patients with diabetes. In fact, there is a growing view that most patients with type 2 diabetes should receive statin therapy to reduce their risk for coronary heart disease, which is the number one killer in these patients.
Dr. Garg also published important papers on the effects of other drugs — nicotinic acid, gemfibrozil, and cholestyramine —in patients with diabetes. These studies also have been influential in the defining the range of indications and contraindications for use of lipid-lowering drugs in patients with type 2 diabetes. In the past decade the focus of Dr. Garg's research has turned to the problem of insulin resistance and adipose tissue disorders. Insulin resistance appears to be the underlying cause of type 2 diabetes. When resistance to the actions of insulin are so impaired that the amount of insulin secreted by beta-cells of the pancreas is insufficient to overcome the block in insulin action, the blood glucose becomes elevated. In addition, many patients develop the metabolic syndrome.
Perhaps the major cause of insulin resistance is overloading of tissues with fat. The excess fat in tissues in some way interferes with the actions of insulin. There is growing evidence that fat accumulates in the body's tissues when it can't be stored properly in the body's fat tissue (adipose tissue). Dr. Garg thus has focused his research on the hypothesis of abnormalities in adipose tissue are a major cause of insulin resistance. He showed that increasing obesity, even in young adults, is associated with increasing insulin resistance. He also participated in studies that found that fat in the trunk is more likely to produce insulin resistance than is fat in the lower body. In particular, excess fat beneath the skin subcutaneous fat) is particularly implicated in the development of insulin resistance. This subcutaneous abdominal fat appears to be even more important for causing insulin resistance than fat located within the abdomen (visceral fat).
Beyond these studies, Dr. Garg has carved out a unique area of research is a group of conditions in which adipose tissue is the site of abnormality. These conditions induce particularly severe forms of insulin resistance. They are called lipodystrophy. The term lipodystrophy means selective loss of adipose tissue. Patients with lipodystrophy have a deficiency of adipose tissue, either in local regions or over the entire body. Dr. Garg has studied three forms of lipodystrophy:
- congenital generalized lipodystrophy
- familial partial lipodystrophy
- acquired lipodystrophy
Congenital generalized lipodystrophy is characterized by a loss of adipose tissue over the entire body. It is a genetic condition. Dr. Garg showed that these patients lose fat in all locations except where the fat plays a mechanical role, as in joints. He thus identified a new form of adipose tissue called mechanical adipose tissue that is different from subcutaneous or visceral adipose tissue. Patients with congenital generalized lipodystrophy develop diabetes at an early age and they have severe elevations of triglyceride in the blood. They also get a severe fatty liver. Dr. Garg found that the diabetes in these patients is made worse by a destruction of beta-cells of the pancreas by a substance called amyloid.
Recently, he had carried out extensive studies on families that carry the gene for congenital generalized lipodystrophy. In collaboration with molecular biologists he has identified the chromosome that carries the gene for this disorder. His studies to identify the gene itself are underway. When the gene for congenital generalized lipodystrophy is found, it may be possible to develop a drug to treat patients with the disorder. In addition, it may provide important clues to the cause of adipose abnormalities in general.
Familial partial lipodystrophy is characterized by a deficiency of fat in subcutaneous adipose tissue. They accumulate visceral fat which gives rise to insulin resistance and the metabolic syndrome. Dr. Garg has carried out extensive metabolic studies on patients with this disorder. Patients have been identified from many places throughout the United States. He has systematically studied the families that carry the gene for familial partial lipodystrophy, and in collaboration with molecular biologists, he identified the chromosome that carried the gene. Because of his extensive family studies, which allowed for chromosomal location, other molecular biologists have been able to identify the specific gene cause the disorder. The protein produced by this gene is called lamin A/C. The protein was already known, and in fact, defects in the lamin A/C gene also produce some forms of muscular dystrophy and heart disease called cardiomyopathy. Other defects in the gene cause lipodystrophy. Thanks to Dr. Garg's careful research, the genetic basis of this important disease has been uncovered. This work provides critical new insights into the role of adipose tissue in the causation of insulin resistance and the metabolic syndrome.
There are several forms of acquired lipodystrophy. Drugs for treatment of HIV cause one that has received considerable attention in recent year. These drugs are called protease inhibitors. They have a dramatic effect to kill the HIV virus causing AIDS; but unfortunately, they also can cause lipodystrophy. As a result, they are associated with insulin resistance, the metabolic syndrome and its consequences, diabetes and coronary heart disease. Dr. Garg has initiated a series of studies to better understand how the protease inhibitors work and how they cause lipodystrophy. The goal of this research is to learn how to prevent this unfortunate consequence of this powerful and important class of drugs that has proven to be so effective in prolonging the lives of patients with HIV.
Recently, our group identified the gene on the long arm of chromosome 9 (9q34), which when mutated causes CGL. This gene encodes for the enzyme AGPAT2 (1-acylglycerol-3-phosphate O-acyltransferase 2) that is responsible for the production of an important intermediate in the synthesis of triglycerides or fat. Mutations in this gene may cause CGL by inhibiting the fat synthesis and storage in adipocytes (fat cells). Mutations in another gene called BSCL2 (Berardinelli-Seip Congenital Lipodystrophy 2) also can cause CGL. BSCL2 encodes a protein, Seipin, whose function remains unknown. Therefore how BSCL2 mutations cause CGL remains to be elucidated.
We also recently reported heterozygous mutation of peroxisome proliferator-activated receptor-g (PPAR-g) gene (involved in the differentiation of body fat) in a patient who did not appear to have Dunnigan variety of lipodystrophy. This patient had diabetes mellitus and high levels of serum triglycerides and noted loss fat from the extremities and face at the age of 50. Thus PPAR-g gene mutation could be the molecular basis for one of the variety of familial partial lipodystrophy.