The Study of HIV Protease Inhibitors and Their Effects on Glucose Metabolism
Condition: Diabetes; HIV Infections; Insulin Resistance
MeSH terms: Insulin Resistance
Study type: Observational

Summary: 
      The purpose of this study is to determine the mechanisms by which HIV protease inhibitors
      contribute to the development of diabetes in HIV-infected patients. The investigators propose
      that some HIV protease inhibitors impair insulin secretion and increase the production of
      glucose by the liver.
    

Detailed description: 
      HIV protease inhibitors (PIs) have been associated with type 2 diabetes. To design future HIV
      drugs that have have the least adverse metabolic effects, it is necessary to identify the
      disorders of glucose metabolism with PI therapy. Previously PIs have been shown to acutely
      induce insulin resistance in the periphery. Preliminary data show that PIs also impair
      insulin secretion and increase hepatic glucose production in humans. These lesions are key
      contributors to the development of type 2 diabetes. Due to the difficulty in separating out
      factors related to HIV infection from the direct effect of PIs, an effective design is to
      study HIV-negative subjects to define the direct effects of PIs on the liver and pancreas on
      glucose metabolism:

      Specific Aim 1: To determine which PIs acutely inhibit insulin secretion in humans;
      randomized, double-blind, placebo-controlled trials will be performed on healthy normal
      volunteers given either a single dose of PI or placebo using the hyperglycemic clamp to
      assess insulin secretion in relation to insulin sensitivity.

      Specific Aim 2: To determine which PIs acutely increase hepatic glucose production,
      glycogenolysis, and gluconeogenesis; measurements will be assessed in the fasting and
      hyperinsulinemic states using stable isotope analysis techniques. Samples have already been
      collected from double-blind, placebo-controlled trials of the effects of a single dose of PI
      on insulin sensitivity during the euglycemic hyperinsulinemic clamp.

      Specific Aim 3: To determine the mechanism by which certain PIs increase hepatic glucose
      production; an infusion of somatostatin during the fasting state and hyperinsulinemic state
      will be used to suppress the effects of glucagon. Subjects will undergo a randomized,
      double-blind, placebo-controlled trial of a single dose of PI or placebo on insulin
      sensitivity using the euglycemic hyperinsulinemic clamp. Somatostatin, glucagon, and growth
      hormone will be infused before and during the clamp study. Hepatic glucose production,
      glycogenolysis, and gluconeogenesis will be assessed using stable isotope tracer techniques.
      Results will be compared to PIs acutely given in the absence of somatostatin, as stated in
      Specific Aim 2.

      Determination of the effects of PI therapy allows clinicians to identify patients who may be
      at particular risk for developing diabetes on certain PIs and treat them more effectively. In
      the future, drugs for the treatment of HIV can be developed that avoid these disorders of
      glucose metabolism.
    

Keywords: Amprenavir; Glucagon; HIV Protease inhibitors; Indinavir; Lopinavir; Ritonavir