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 inhibitorcontaining regimens in HIV infection are unclear. Insulin resistance has been implicated as a major factor, but the affected tissues have not been identified. Furthermore, ␤-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 ␤-cell function. We evaluated ␤-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. ␤-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 ϳ50% (P < 0.003). Postabsorptive glucose production was appropriately suppressed for the prevailing hyperinsulinemia, whereas glucose clearance was reduced (P < 0.001). ␤-Cell function decreased by ϳ50% (P ‫؍‬ 0.002), as assessed by HOMA, and firstphase insulin release decreased by ϳ25%, 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 ␤-cell to compensate. Diabetes 52: 918 -925, 2003 U se of protease inhibitors has remarkably improved long-term survival after HIV infection (1,2). However, up to 60% of HIV-infected patients treated with these agents develop either impaired glucose tolerance (IGT) or type 2 diabetes (3-6), and it now appears to be well established that regimens including protease inhibitors are associated with insulin resistance (2,5,7,8). Noor et al. (9,10) have shown that acute and 4-week protease inhibitor exposure of normal volunteers reduces glucose disposal during euglycemichyperinsulinemic clamp experiments. Moreover, in vitro studies have demonstrated that protease inhibitors reduce insulin-stimulated glucose uptake in adipocytes and skeletal muscle (11,12).Knowledge of the mechanisms responsible for deterioration in glucose tolerance during protease inhibitorcontaining regimens is still incomplete. It is unclear whether protease inhibitors adversely affect pancreatic ␤-cell function (4,8) and what effec...

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

“…Metabolic side-effects may occur in up to 60% of HAART-treated patients, depending on host factors (presence of "traditional" risk factors for Type 2 diabetes) and on the specific agents used in the cocktail [3,4]. Further clinical and pharmacological studies have identified the HIV protease inhibitors as a class of agents that may independently contribute to the development of peripheral insulin resistance [5], as well as to impaired pancreatic beta cell function [6]. Yet adipose tissue alterations appear to lie at the centre of this metabolic syndrome, since it is frequently associated with adipose tissue redistribution, i.e.…”

“…lipodystrophy of subcutaneous "peripheral" adipose tissue, but an increase in abdominal adipose mass (central adiposity) [5,7,8]. Furthermore, impaired glucose tolerance and dyslipidaemia frequently occur, with elevated circulating levels of non-esterified fatty acids signifying abnormal regulation of adipocyte lipid metabolism [6]. Thus, a striking clinical similarity exists between common forms of the insulin resistance syndrome and this newly identified drug-induced metabolic syndrome.…”

Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic β-cells

“…glucose is a very sensitive index of b-cell function compared with the insulin response to non-glucose secretagogues (45). The aetiology of the islet b-cell dysfunction in HIV-lipodystrophy is not known, but a hypothesis focusing on a deleterious effect of HAART on b-cell function has been discussed (7,46). A defect in the incretin signalling may also explain the b-cell dysfunction (47).…”

“…The major phenotypic trait of HIV-associated lipodystrophy syndrome (HALS) is loss of extremity fat including facial and gluteal regions and fat gain in the trunk region (2). Metabolically, the syndrome is characterized by insulin resistance (3,4), impaired glucose tolerance (5,6) and hepatic insulin resistance (7). Also, fat metabolism is disturbed with reports on increased lipolysis (8), increased fat deposition in the liver (9) and muscle tissue (10,11), increased expression of tumour necrosis factor-a in fat tissue and decreased plasma levels of adiponectin (12).…”

Insulin resistance induced by antiretroviral drugs: Current understanding of molecular mechanisms

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