title: Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens.
abstract: The mechanisms responsible for the deterioration in glucose tolerance associated with protease inhibitor-containing regimens in HIV infection are unclear. Insulin resistance has been implicated as a major factor, but the affected tissues have not been identified. Furthermore, beta-cell function has not been evaluated in detail. The present study was therefore undertaken to assess the effects of protease inhibitor-containing regimens on hepatic, muscle, and adipose tissue insulin sensitivity as well as pancreatic beta-cell function. We evaluated beta-cell function in addition to glucose production, glucose disposal, and free fatty acid (FFA) turnover using the hyperglycemic clamp technique in combination with isotopic measurements in 13 HIV-infected patients before and after 12 weeks of treatment and in 14 normal healthy volunteers. beta-Cell function and insulin sensitivity were also assessed by homeostasis model assessment (HOMA). Treatment increased fasting plasma glucose concentrations in all subjects (P < 0.001). Insulin sensitivity as assessed by HOMA and clamp experiments decreased by approximately 50% (P < 0.003). Postabsorptive glucose production was appropriately suppressed for the prevailing hyperinsulinemia, whereas glucose clearance was reduced (P < 0.001). beta-Cell function decreased by approximately 50% (P = 0.002), as assessed by HOMA, and first-phase insulin release decreased by approximately 25%, as assessed by clamp data (P = 0.002). Plasma FFA turnover and clearance both increased significantly (P < 0.001). No differences at baseline or in responses after treatment were observed between drug naïve patients who were started on a nucleoside reverse transcriptase inhibitor (NRTI) plus a protease inhibitor and patients who had been on long-term NRTI treatment and had a protease inhibitor added. The present study indicates that protease inhibitor-containing regimens impair glucose tolerance in HIV-infected patients by two mechanisms: 1) inducement of peripheral insulin resistance in skeletal muscle and adipose tissue and 2) impairment of the ability of the beta-cell to compensate.
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, New York, USA.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Woerle
authors.forename: Peter R
authors.initials: PR
authors.lastname: Mariuz
authors.forename: Christian
authors.initials: C
authors.lastname: Meyer
authors.forename: Richard C
authors.initials: RC
authors.lastname: Reichman
authors.forename: Emilia M
authors.initials: EM
authors.lastname: Popa
authors.forename: Jean M
authors.initials: JM
authors.lastname: Dostou
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Welle
authors.forename: John E
authors.initials: JE
authors.lastname: Gerich
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D001823:Body Composition; D001824:Body Constitution; D002096:C-Peptide / Q000097:blood; D018791:CD4 Lymphocyte Count; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005934:Glucagon / Q000097:blood; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000139:chemically induced*; D006442:Glycated Hemoglobin / Q000032:analysis; D005990:Glycerol / Q000097:blood; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000009:adverse effects*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000503:physiopathology; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects; D011384:Proinsulin / Q000097:blood; D019562:Viral Load
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D005230:Fatty Acids, Nonesterified; D005934:Glucagon; D006442:Glycated Hemoglobin; D005990:Glycerol; D017320:HIV Protease Inhibitors; D007328:Insulin; D008055:Lipids; D011384:Proinsulin