Glucosamine is a popular over-the-counter nutritional supplement that many people use for the treatment of osteoarthritis. Intravenous administration of glucosamine to animals or humans causes significant metabolic insulin resistance and vascular endothelial dysfunction. Moreover, experiments with various cell lines have implicated elevated glucosamine levels in the development of insulin resistance. However, there are no published studies examining the potential effects of oral glucosamine administration to modulate insulin sensitivity or capillary recruitment in humans. This is a significant concern because insulin resistance and vascular dysfunction contribute importantly to major public health problems including diabetes, obesity, hypertension, and cardiovascular diseases. Normal healthy volunteers and obese insulin resistant subjects will be enrolled in a randomized double-blind, placebo-controlled, crossover study to evaluate the effects of oral glucosamine to modulate insulin sensitivity and insulin-stimulated capillary recruitment. The reference standard hyperinsulinemic isoglycemic glucose clamp technique will be used to assess insulin sensitivity before treatment, after placebo or oral glucosamine (500 mg p.o. TID for 6 weeks), and after completion of the crossover. In addition, insulin-stimulated capillary recruitment will be measured at the same time as the glucose clamp studies by using the ultrasound microbubble contrast technique to assess blood flow in the brachial artery and capillary recruitment in forearm skeletal muscle in response to hyperinsulinemia. Finally, plasma glucosamine levels will be measured just prior to each glucose clamp study using an HPLC method. The results of this study will determine if oral glucosamine administration causes significant insulin resistance and impairment in insulin-stimulated capillary recruitment in healthy volunteers or worsens insulin resistance and capillary recruitment in obese subjects. In addition, our study will provide important information about how plasma glucosamine levels change with commonly used oral doses of glucosamine.

• INCLUSION CRITERIA:

HEALTHY VOLUNTEERS:

Males or females in good general health with no significant underlying illnesses, on no medication, between the ages of 21-65 years of age with HbA1C less than 6.5, fasting blood glucose less than 100 mg/dl, blood pressure less than 130/85, and BMI between 20-26 kg/m(2). Subjects should have never smoked tobacco or not smoked within the previous 2 years.

OBESE SUBJECTS:

Males or females in good general health with no significant underlying illnesses, on no medication, between the ages of 21-65 years of age with HbA1C less than 6.5, fasting blood glucose less than 110 mg/dl, blood pressure less than 130/85, and BMI between 30-40 kg/m(2).

EXCLUSION CRITERIA:

Subjects will be excluded if they have diabetes, hypertension, pregnancy, liver disease, pulmonary disease, renal insufficiency, coronary heart disease, heart failure, peripheral vascular disease, coagulopathy, actively smoking within last two years, in treatment for any form of cancer, positive tests for HIV, hepatitis B or C, or take systemic corticosteroids.

Subjects will also be excluded if they have an allergy to shellfish since glucosamine is derived from shellfish. Subjects will be excluded if they have taken glucosamine within the last three months. Subjects with allergies to blood products or eggs or known hypersensitivity to albumin will also be excluded from participating because of potential adverse effects from microbubble contrast agent. Subjects will be excluded from this study because children do not typically take glucosamine or have osteoarthritis.