UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

Who studies metabolic regulation these days - the flow of metabolites through competing pathways in complex networks, the anabolic and catabolic processes that determine tissue composition, adaptations to stresses and how their failure leads to disease? Not most Biochemistry or Molecular Biology Departments. It is our belief that the study of physiologic chemistry (metabolic regulation) in the broadest sense can be seized by metabolism, endocrinology and nutrition researchers interested in making fundamental contributions to biochemistry and medicine.

Toward this end, our laboratory has focused on measuring metabolic processes not previously accessible to study in vivo , particularly in humans. Our goal is to answer questions concerning regulation of molecular fluxes through complex pathways in living systems and, ultimately, to apply the techniques in humans in the setting of disease and therapeutics. Much effort is spent on methods development. For example, we have developed a stable isotope-mass spectrometric method that resolves the fundamental problem in measuring polymerization biosynthesis – the endogenous synthesis of biomolecules such as fatty acids, cholesterol, glucose and proteins. This technique is called mass isotopomer distribution analysis (MIDA). It has been used to ask basic questions in metabolic physiology (e.g.,do humans convert excess carbohydrate calories to fat? where does blood glucose come from during normal fasting? is this different in diabetes?). We also have developed a very accurate and non-toxic method for measuring rates of cell proliferation (mitogenesis), by labeling the deoxyribose moiety of DNA with heavy water. Many questions have been answered by use of this technique: for example, how rapidly are new cells made in pancreatic islets in insulin-resistant states or in the brain (hippocampus) in response to trophic factors? What is the effect of HIV infection on turnover of T-lymphocytes? Does the rate of tumor cell proliferation in CLL predict clinical aggressiveness of disease? Other techniques of central interest in metabolic disorders have also been developed in our laboratory—e.g., an assay of insulin resistance and pancreatic compensation, a direct measurement of reverse cholesterol transport and a measure of mitochondrial biogenesis in response to exercise.

Accordingly, our group is involved in a number of projects. These include studies of obesity/diabetes and dyslipidemias; protein metabolism and body composition, neurobiology, oncology and immunology. Translation of new kinetic techniques to humans to investigate processes responsible for health and disease is the unifying theme.

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