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...

To characterize postprandial glucose disposal more completely, we used the tritiated water technique, a triple-isotope approach (intravenous [3-H3]glucose and [14C]bicarbonate and oral [6,6-2H2]glucose) and indirect calorimetry to assess splanchnic and peripheral glucose disposal, direct and indirect glucose storage, oxidative and nonoxidative glycolysis, and the glucose entering plasma via gluconeogenesis after ingestion of a meal in 11 normal volunteers. During a 6-h postprandial period, a total of ∼98 g of glucose were disposed of. This was more than the glucose contained in the meal (∼78 g) due to persistent endogenous glucose release (∼21 g): splanchnic tissues initially took up ∼23 g, and an additional ∼75 g were removed from the systemic circulation. Direct glucose storage accounted for ∼32 g and glycolysis for ∼66 g (oxidative ∼43 g and nonoxidative ∼23 g). About 11 g of glucose appeared in plasma as a result of gluconeogenesis. If these carbons were wholly from glucose undergoing glycolysis, only ∼12 g would be available for indirect pathway glycogen formation. Our results thus indicate that glycolysis is the main initial postprandial fate of glucose, accounting for ∼66% of overall disposal; oxidation and storage each account for ∼45%. The majority of glycogen is formed via the direct pathway (∼73%).

1During liver transplantation and after both meal ingestion and prolonged fasting, renal glucose release (RGR) increases while hepatic glucose release (HGR) decreases. These and other observations have led to the concept of hepatorenal reciprocity. According to this concept, reciprocal changes in hepatic and renal glucose release may occur to minimize deviations from normal glucose homeostasis. We further assessed this concept by testing the hypothesis that during counterregulation of hypoglycemia in patients with type 2 diabetes, who would be expected to have reduced HGR, RGR would be increased. Accordingly, we performed hypoglycemic hyperinsulinemic clamp experiments (ϳ3.1 mmol/l) in 12 type 2 diabetic and in 10 age-weight-matched nondiabetic volunteers and measured total endogenous glucose release (TEGR) and RGR using a combined isotopic net balance approach. HGR was calculated as the difference between TEGR and RGR since only these organs are capable of releasing glucose. We found that during comparable hypoglycemia and hyperinsulinemia, TEGR was reduced in type 2 diabetes (6.6 ؎ 0.6 vs. 10.2 ؎ 1.1 mol ⅐ kg ؊1 ⅐ min ؊1 in nondiabetic volunteers, P ‫؍‬ 0.01) due to reduced HGR (3.9 ؎ 0.5 vs. 8.6 ؎ 1.0 mol ⅐ kg ؊1 ⅐ min ؊1 in nondiabetic volunteers, P ‫؍‬ 0.0015). In contrast, RGR was increased approximately twofold in type 2 diabetes (3.3 ؎ 0.5 vs. 1.6 ؎ 0.3 mol ⅐ kg ؊1 ⅐ min ؊1 in nondiabetic volunteers, P ‫؍‬ 0.015). Plasma epinephrine, lactate, and free fatty acid concentrations, which would promote RGR, were also greater in type 2 diabetes (all P < 0.01). Our results provide further support for hepatorenal reciprocity and may explain at least in part the relatively low occurrence of severe hypoglycemia in type 2 diabetes compared with type 1 diabetes where both HGR and RGR counterregulatory responses are reduced.

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Pestivirus infections are important in the livestock industries, with infection occurring in cattle, sheep and pigs. The Pestivirus genus of the family Flaviviridae, includes four recognized species: bovine viral diarrhea virus 1 (BVDV-1), bovine viral diarrhea virus 2 (BVDV-2), border disease virus (BDV), and classical swine fever virus (CSFV). All pestivirus species can infect pigs, therefore accurate and specific pestivirus detection and differentiation is of great importance to assure control measures in swine populations. The aim of the study was the molecular detection of different pestiviruses in domestic and feral pigs. A total of 527 samples (92 pigs and 435 wild boars) were tested for pestiviruses detection using molecular assays. Eleven positive samples (6 wild boars and 5 domestic pigs) were identified using panpestivirus primers targeting the 5’- UTR region of the pestivirus RNA genome. Further all the positive samples were sequentially tested for detection of CSFV, BVDV-1 and BVDV-2 using specific primers. All RNAs were identified as positives for BVDV-1 and no amplification signals were obtained from BVDV-2 and CSFV. The current detection of BVDV-1 in clinical swine specimens highlights the important risk factor of swine population as reservoir and consequently carrier for BVDV.