Richard E. Ostlund Jr., M.D.

DEPARTMENT OF Internal Medicine
Keywords: lipids, metabolism, cholesterol, physiology, insulin, clinical research, inositol, diabetes

We have two main research thrusts: the study of human cholesterol metabolism using stable isotopic tracers and D-chiro-inositol and insulin action. Despite tens of thousands of published studies of plasma cholesterol concentration, very little is known about whole body cholesterol physiology. More than 90 percent of the cholesterol burden is located in tissues and is not directly accessible to plasma measurement. This laboratory has developed cholesterol tracer molecules heavily labeled with carbon-13 and deuterium to assess whole body cholesterol kinetics. These tracers are detected at very low levels by gas chromatography/mass spectrometry and isotope ratio mass spectrometry. Current research initiatives are directed toward the following studies:
1) Cholesterol absorption is not quantitative; only about 50 percent of a given load is retained. The important factors regulating percent and absolute cholesterol absorption rate are being sought in normal and hyperlipidemic subjects.
2) The rate of excretion of cholesterol from the body is thought to be reflected in HDL cholesterol concentration, but this hypothesis has never been tested. Transport of labeled cholesterol from red blood cells to tissues and its excretion from the body is being used to develop a new mathematical model of cholesterol metabolism. Quantitative abnormalities of whole body cholesterol metabolism are being related to atherosclerosis and metabolic illnesses such as diabetes mellitus.

Insulin has many post-receptor effects which are still poorly understood. Many adult diabetics and non-diabetics with adverse cardiovascular risk factors have elevated levels of plasma insulin and are resistant to some but not all of its actions. The result is that some metabolic pathways have excessive insulin effects whereas others are deficient, causing a syndrome of both insulin deficiency and insulin toxicity. This work is directed toward understanding the molecular mechanisms of insulin action on lipid metabolism and relating them to common abnormalities of diabetic patients. Almost all of the inositol in nature is myo-inositol. However, several preparations of phosphoglycan molecules that appear to mediate insulin action as second messengers contain D-chiro-inositol, an epimer of myo-inositol that was unknown in mammals until recently. This laboratory has shown that diabetic subjects excrete 5 to 40 times as much D-chiro-inositol in the urine as normal subjects and that the rate of excretion depends critically on the degree of diabetic control. Plasma D-chiro-inositol levels are influenced by insulin treatment and are a strong predictor of hypertriglyceridemia, the most common lipid abnormality in diabetic patients. D-chiro-inositol can be obtained from the diet in the form of pinitol, a methyl inositol found in legumes. Feeding diabetic patients D-chiro-inositol from soy results in reductions in plasma insulin levels. The effects on diabetic and hyperlipidemic subjects are being studied. The exact structure of the chiro-inositol-containing molecules thought to be responsible for these effects has not been reported. Negative ion gas chromatography/mass spectrometry and insulin bioassays can be used to prepare candidate biochemical fractions. Electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry are being employed to determine a structure for the intact mediator molecules.