The insulin resistance syndrome is characterized by several risk factors for cardiovascular disease. Chronic chemical activation of AMP-activated protein kinase by the adenosine analog 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR) has been shown to augment insulin action, upregulate mitochondrial enzymes in skeletal muscles, and decrease the content of intraabdominal fat. Furthermore, acute AICAR exposure has been found to reduce sterol and fatty acid synthesis in rat hepatocytes incubated in vitro as well as suppress endogenous glucose production in rats under euglycemic clamp conditions. To investigate whether chronic AICAR administration, in addition to the beneficial effects on insulin sensitivity, is capable of improving other phenotypes associated with the insulin resistance syndrome, obese Zucker (fa/fa) rats (n ‫؍‬ 6) exhibiting insulin resistance, hyperlipidemia, and hypertension were subcutaneously injected with AICAR (0.5 mg/g body wt) daily for 7 weeks. Obese control rats were either pair-fed (PF) (n ‫؍‬ 6) or ad libitum-fed (AL) (n ‫؍‬ 6). Lean Zucker rats (fa/؊) (n ‫؍‬ 8) served as a reference group. AICAR administration significantly reduced plasma triglyceride levels (P < 0.01 for AICAR vs. AL, and P ‫؍‬ 0.05 for AICAR vs. PF) and free fatty acids (P < 0.01 for AICAR vs. AL, and P < 0.05 for AICAR vs. PF) and increased HDL cholesterol levels (P < 0.01 for AICAR vs. AL and PF). AICAR treatment also lowered systolic blood pressure by 14.6 ؎ 4.3 mmHg (P < 0.05), and AICAR-treated animals exhibited a tendency toward decreased intra-abdominal fat content. Furthermore, AICAR administration normalized the oral glucose tolerance test and decreased fasting concentrations of glucose and insulin close to the level of the lean animals. Finally, in line with previous findings, AICAR treatment was also found to enhance GLUT4 protein expression and to increase maximally insulin-stimulated glucose transport in primarily white fast-twitch muscles. Our data provide strong evidence that longterm administration of AICAR improves glucose tolerance, improves the lipid profile, and reduces systolic blood pressure in an insulin-resistant animal model. The present study gives additional support to the hypothesis that AMPK activation might be a potential future pharmacological strategy for treating the insulin resistance syndrome.

Recent studies have demonstrated that chronic administration of AICAR (5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside), an activator of the AMP-activated protein kinase, increases hexokinase activity and the contents of total GLUT4 and glycogen in rat skeletal muscles. To explore whether AICAR also affects insulinstimulated glucose transport and GLUT4 cell surface content, Wistar rats were subcutaneously injected with AICAR for 5 days in succession (1 mg/g body wt). Maximally insulin-stimulated (60 nmol/l) glucose uptake was markedly increased in epitrochlearis (EPI) muscle (average 63%, P < 0.001, n = 18-19) and in extensor digitorum longus muscle (average 26%, P < 0.001, n = 26-30). In contrast, administration of AICAR did not maximally influence insulin-stimulated glucose transport in soleus muscle. Studies of EPI muscle with the 4,4Ј-O-[2-[2-[2-[2-[2-[6-(biotinylamino)hexanoyl]amino]ethoxy]ethoxy] ethoxy]-4-(1-azi-2,2,2,-trifluoroethyl)benzoyl]amino-1,3-propanediyl]bis-D-mannose photolabeling techniqueshowed a concomitant increase (average 68%, P < 0.02) in cell surface GLUT4 content after insulin exposure in AICARinjected rats when compared with controls. In conclusion, 5 days of AICAR administration induces a pronounced fiber type-specific increase in insulin-stimulated glucose uptake and GLUT4 cell surface content in rat skeletal muscle with the greatest effect observed on white fast-twitch glycolytic muscles (EPI). These results are comparable with the effects of chronic exercise training, and it brings the AMP-activated protein kinase into focus as a new interesting target for future pharmacological intervention in insulin-resistant conditions. Diabetes 50:12-17, 2001 P hysical exercise augments insulin sensitivity in skeletal muscle of insulin-resistant animals (1-4) and can also improve insulin sensitivity in type 2 diabetic individuals (5,6). Exercise is therefore pivotal in the treatment of type 2 diabetes. Studies in skeletal muscle from type 2 diabetic and (7) insulin-resistant prediabetic individuals (8) have shown an increased fraction of white type 2b muscle fibers. This change toward fast-twitch fibers in skeletal muscle has further been demonstrated in hyperinsulinemic rats (9) and in fructose-fed rats (an animal model of insulin-resistance) (10). Because it is well established that fasttwitch fibers (in particular type 2b fibers) are less insulin sensitive (11,12), this change in muscle morphology might potentially play a role in the decreased insulin action seen in skeletal muscle of insulin-resistant individuals.Muscle fibers also seem to differ in their ability to increase insulin action as a response to physical exercise (1-3). The exercise intensity used during exercise programs appears to play an important role for the fiber types recruited during the work performed and thus for their capability to exhibit adaptive changes with respect to insulin action (3) and oxidative capacity (13). Several animal studies featuring treadmill-running programs have shown that predominantly fast-t...

The influence of the maxillary sinuses in acoustic rhinometry (AR) has not been evaluated, and this is the aim of the present study. We examined six subjects with AR and magnetic resonance imaging (MRI) after nasal decongestion to compare the area-distance relationships determined by the two methods. From the MRI data we obtained copies of the nasal cavities with and without maxillary sinuses, which were made in plastic by a stereolithographic method. AR curves from models without maxillary sinuses differed from AR curves with sinuses included but were in agreement with MRI curves without inclusion of sinuses. A similar difference in AR was seen in two subjects before and after the nasal cavities were flushed with saline to fill up the maxillary sinuses. The measured volume in the first 50 mm of the nasal cavity models was unaffected by the sinuses, but the volume in the first 70 mm corresponding to the length of the nasal cavity septum was increased slightly but significantly (from 10.8 to 11.3 cm3; P = 0.05). The presence of maxillary sinuses increased the volume of the epipharynx (70-100 mm from the nostril) from 12.2 to 21.3 cm3 (P < 0.01), and this increase was not due to the influence from the contralateral nasal cavity. We conclude that the maxillary sinuses may significantly contribute to the acoustically determined areas in the posterior part of the nasal cavity and the epipharynx, especially during decongestion, and may explain a part of the difference between area-distance curves obtained by AR and MRI, whereas contribution from the contralateral nasal cavity does not.

The aim of this study was to assess the cytokine response after nasal exposure to organic dusts.In a double blinded, crossover study five garbage workers with occupational airway symptoms and five healthy garbage workers were intranasally exposed to endotoxin (lipopolysaccharide LPS), b-1,3-D-glucan (GLU), Aspergillus sp., compost or the saline dilute for 15 min. Nasal cavity volume and nasal lavage (NAL) were performed at baseline and 3, 6, 11 h postexposure. NAL was analysed with differential cell counts, cysteinyl-leukotrienes, tumour necrosis factor a, interleukin (IL)-1b, IL-6 and IL-8. A whole blood assay on cytokine-release was performed with LPS and GLU.NAL cytokines neutrophils, lymphocytes and albumin increased significantly at 6 h after LPS exposure. GLU induced an increase in albumin and a slight increase in IL1b 6±11 h post exposure. In the WBA a significant increase in all cytokines after exposure to LPS as well as GLU was found. Significantly more cells were seen in NAL of the control group 6 h post LPS exposure.In conclusion lipopolysaccharide is the most potent inducer of inflammation in the nasal mucosa whereas compost and b-1,3-D-glucan only induce minor changes. This reaction to lipopolysaccharide is attenuated in workers with occupational airway symptoms. In whole blood assay, however, b-1,3-D-glucan also induces cytokine release, indicating a different protective effect of the nasal mucosa towards lipopolysaccharide and b-1,3-D-glucan. Eur Respir J 2000; 16: 140±145.

Abstract. Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study. Metformin 0.5 g trice daily or placebo were given for 4 weeks. At the end of each period fasting and day-time postprandial values of plasma glucose, insulin, C-peptide and lactate were determined, and in vivo insulin action was assessed using the euglycemic clamp in combination with [3-3H]glucose tracer technique. Metformin treatment significantly reduced mean day-time plasma glucose levels (10.2 ± 1.2 vs 11.4 ± 1.2 mmol/l, P< 0.01) without enhancing mean day-time plasma insulin (43 ± 4 vs 50 ± 7 mU/l, NS) or C-peptide levels (1.26 ± 0.12 vs 1.38 ± 0.18 nmol/l, NS). Fasting plasma lactate was unchanged (1.57 ± 0.16 vs 1.44 ± 0.11 mmol/l, NS), whereas mean day-time plasma lactate concentrations were slightly increased (1.78 ± 0.11 vs 1.38 ± 0.11 mmol/l, P< 0.01). The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization (370 ± 38 vs 313 ± 33 mg · m−2 · min−1, P< 0.01), whereas insulin-mediated suppression of hepatic glucose production was unchanged. Also basal glucose clearance was improved (61.0 ± 5.8 vs 50.6 ± 2.8 ml · n−2 · min−1,, P< 0.05), whereas basal hepatic glucose production was unchanged (81 ± 6 vs 77 ± 4 mg · m−2 · min−1, NS). Conclusions: 1) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion. 2) The improved glycemic control during metformin treatment was associated with an enhanced insulin-mediated glucose utilization, presumably in skeletal muscle, whereas no effect could be demonstrated on hepatic glucose production.