Novel Therapy for Glucose Intolerance in HIV Disease

This study will test the hypothesis that chromium picolinate improves insulin-stimulated glucose uptake by increasing the insulin receptor-mediated tyrosine phosphorylation of insulin receptor substrate-1, resulting in increased association with phosphatidylinositol 3-kinase.

Specific Aim 1 will assess quantitative improvements in insulin-mediated glucose disposal in a placebo-controlled clinical trial of chromium supplementation with 1000mpg (19.2 pmol) of chromium as chromium picolinate, overa two-month course of therapy. The investigators have shown that the insulin resistance (i.e. the inability of insulin to stimulate glucose uptake into peripheral tissues like muscle) in patients with HIV disease is associated with a defect in the insulin-signaling pathway leading from the insulin receptor, through phosphatidylinositol 3-kinase(PI 3-K, Figure 5). A similar defect in intracellular signaling has also been reported in patients with type 2 diabetes mellitus ):15-171. The cellular mechanism of improved insulin sensitivity with chromium supplementation will be determined in Specific Aim 2.

Specific Aim 2 will assess the effect of chromium supplementation on the insulin-stimulated activity of insulin receptor substrate-I-associated phosphatidylinositol 3-kinase in biopsies of muscle and fat tissue. This aim will also test the hypothesis that these physiological effects of chromium are mediated by alterations in the activity of insulin signaling. Understanding this mechanism may facilitate the design of even more effective strategies for improving insulin sensitivity.

Inclusion criteria

• Age > 18 years and a diagnosis of HIV+ andlor AlDS made by standard CDC criteria.

Exclusion criteria

• positive pregnancy test (all women must have a negative pregnancy test before beginning protocol);
• diagnosis of cancer;
• acute illness of any sort, however, patients may be enrolled once they are stable;
• hemoglobin less than 11.0 gldl or hemodynamically unstable;
• creatinine greater than or equal to 1.5 mgldl;
• liver dysfunction as evidenced by elevations in transaminases 2-fold higher than upper limit of normal;
• use of certain medications within the past month (e.g., glucocorticoids).
• untreated hypertension (systolic BP > 150 mmHG, diastolic BP>100 mmHG);
• patients with diabetes mellitus
• hypogonadism
• abnormal thyroid function (serum T'4 < 4 or > 12; TSH < 0.35 or > 5.5)
• hepatitis C infection (if patients have had prior therapy and are now stable with no evidence of active infection they will be included. This will depend upon documentation from primary care giver).
• CD4 counts below 300
• viral load greater than 35,000.

Exclusion criteria

(13) and (14) are added because the protocol requires that subjects be on a stable anti-retroviral regime for 3 months prior to study and 2 months on study. These criteria will make it less likely that anti-retroviral therapies will be switched in this subject population who are doing well.