Showing papers by "Cees J. Tack published in 2006"

Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance.

Abstract: Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of Il18-/- mice resulted from accumulation of fat tissue based on increased food intake. Il18-/- mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia. Insulin resistance was secondary to obesity induced by increased food intake and occurred at the liver level as well as at the muscle and fat-tissue level. The molecular mechanisms responsible for the hepatic insulin resistance in the Il18-/- mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18-/- mice, resulting from defective phosphorylation of STAT3. Recombinant IL-18 (rIL-18) administered intracerebrally inhibited food intake. In addition, rIL-18 reversed hyperglycemia in Il18-/- mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity.

Improved insulin sensitivity by anti-TNFα antibody treatment in patients with rheumatic diseases

Abstract: Insulin resistance is a key factor in the pathogenesis of the metabolic syndrome and type 2 diabetes, but the underlying mechanisms remain poorly understood. Adipocytokines, including tumour necrosis factor α (TNFα), interleukin 6, leptin and adiponectin,1,2 are increasingly recognised as important regulators of both insulin sensitivity, as well as inflammation, and a dysregulation of their levels and/or functions has been shown in both obesity and rheumatoid arthritis.3 Further investigations have substantiated the important negative effects of TNFα on insulin-mediated glucose uptake and the development of insulin resistance.4 In this study, the influence of therapeutic TNFα blockade on insulin sensitivity was investigated in regularly treated patients with rheumatic diseases. A group of eight patients who were non-diabetic and having various chronic inflammatory disorders (table 1) were investigated in an open prospective …

Fluid Retention and Vascular Effects of Rosiglitazone in Obese, Insulin-Resistant, Nondiabetic Subjects

Abstract: OBJECTIVE —The use of thiazolidinedione (TZD) derivatives is associated with fluid retention, especially when combined with insulin. Because TZDs improve the metabolic effect of insulin, they may also reverse the blunted vascular response to insulin. We hypothesize that improvement of the action of insulin on vascular tone or permeability is the key mechanism of TZD-related fluid retention. RESEARCH DESIGN AND METHODS —In a randomized, double-blind, placebo-controlled, cross-over study in 18 obese, nondiabetic subjects with features of the metabolic syndrome, we investigated the effects of a 12-week treatment with 4 mg rosiglitazone twice a day on glucose disposal, hemodynamics (including forearm vasoconstrictor response to nitric oxide [NO]), synthase inhibition by N -monomethyl-l-arginine-acetate (l-NMMA), vascular permeability (transcapillary escape rate of albumin), and plasma volume during a hyperinsulinemic-euglycemic clamp (120 min, 120 mU/m 2 per min). RESULTS —As expected, rosiglitazone increased the glucose infusion rate during clamping. However, neither vascular permeability nor forearm blood flow response to hyperinsulinemia or l-NMMA was affected by rosiglitazone. Compared with placebo, rosiglitazone decreased diastolic blood pressure by 5 mmHg (95% CI 2.35–6.87, P = 0.0005) and increased plasma volume by 255 ml/1.73 m 2 (80–430, P = 0.007). Interestingly, the positive effect of rosiglitazone on glucose disposal correlated with change in foot volume ( R 2 = 0.53, P = 0.001). CONCLUSIONS —Rosiglitazone improved insulin sensitivity but had no effect on NO-dependent vasodilatation in the forearm or vascular permeability in obese, insulin-resistant, nondiabetic subjects. As such, TZD-related fluid retention was not caused by improvement of the vascular actions of insulin. Nonetheless, rosiglitazone-induced improvement in insulin sensitivity appears to be correlated to edema formation.

Thiazolidinedione derivatives in type 2 diabetes mellitus

Abstract: In Europe, the thiazolidinedione derivatives pioglitazone and rosiglitazone have been approved for the treatment of type 2 diabetes mellitus either as monotherapy for patients with intolerance or contraindications to metformin or in combination therapy. This class of drugs seems particularly suited for obese patients, but is currently not considered as a first choice for monotherapy. The efficacy with respect to blood glucose lowering is comparable with sulphonylurea (SU) derivatives and with metformin. Long-term data with respect to efficacy and side effects are still limited.

Sympathetic nervous system function in HIV-associated adipose redistribution syndrome.

Abstract: It was recently suggested that HIV-associated adipose redistribution syndrome (HARS) results from an autonomic dysbalance. We investigated the local and global sympathetic nervous system function of patients with HIV-1 infection and HARS. Interstitial noradrenaline concentrations in skeletal muscle and subcutaneous adipose tissue were increased in the absence of changes in global sympathetic nerve activity, consistent with locally increased sympathetic activity. This could promote localized lipolysis in subcutaneous adipose tissue and contribute to the development of HARS.

Transport within the Interstitial Space, Rather Than Membrane Permeability, Determines Norepinephrine Recovery in Microdialysis

Abstract: Microdialysis is a sampling method that permits measurement of hormones, drugs, and other lower molecular weight compounds present in interstitial fluid. We developed a straightforward mathematical model that predicts a linear relationship between the reciprocal dialysate concentration of the analyte from the interstitium and perfusion rate, permitting estimation of the interstitial concentration by extrapolation to zero perfusion rate. Conversely, linearity between the reciprocal dialysate concentration of internal standard added to the perfusion medium (retrodialysis), and the reciprocal perfusion rate, is predicted. In nine healthy volunteers, interstitial norepinephrine (NE) was estimated by NE measurements in microdialysates obtained from skeletal muscle and adipose subcutaneous tissue, using sodium salicylate (Sal) in the perfusion buffer as internal standard, at perfusion rates of 2 and 5 mul/min. Comparison with microdialysis in vitro by immersing the probe in a large volume of buffer containing NE showed that the in vivo (retro)recovery of NE and Sal is almost exclusively determined by transport of NE through the interstitial space toward and Sal from the membrane and that membrane permeability itself plays a negligible role. This was supported by the observation that applying lower body negative pressure, a measure that is unlikely to affect membrane permeability, resulted in a significant (p < 0.05) decrease of Sal retrorecovery from muscle interstitium. This validated new model significantly adds insight into the factors determining recovery of substances from the interstitium in microdialysis and provides a simpler alternative to previous approaches for estimation of interstitial concentrations.

Forearm vasoconstrictor response in uncomplicated type 1 diabetes mellitus.

Abstract: BACKGROUND: According to the 'haemodynamic hypothesis', increased tissue perfusion predisposes to microangiopathy in diabetic patients We hypothesized that the typical haemodynamic changes underlying the increased tissue perfusion can be explained by a decreased sympathetic nerve activity caused by chronic hyperglycaemia In this study we investigated sympathetic activity in patients with uncomplicated type 1 diabetes mellitus (DM) MATERIALS AND METHODS: In 15 DM patients (DM duration 63 +/- 38 year; HbA1c 79 +/- 13%) and 16 age- and sex-matched healthy volunteers (Control), sympathetic nervous system activity was measured at rest (baseline) and during sympathoneural stimulation (lower body negative pressure (LBNP)) by means of interstitial and plasma noradrenaline (NA) sampling and power spectral analysis Muscle sympathetic nerve activity (MSNA) was measured before (baseline) and during a cold pressure test Forearm blood flow was measured during forearm vascular alpha- and beta-adrenergic receptor blockade RESULTS: At baseline, forearm vascular resistance (FVR), plasma NA concentrations, MSNA and heart rate variability were similar in both groups LBNP-induced vasoconstriction was significantly attenuated in the DM group compared with the Control group (DeltaFVR: 12 +/- 4 vs 19 +/- 3 arbitrary units, P < 005) The responses of plasma NA and heart rate variability did not differ CONCLUSIONS: Baseline FVR and sympathetic nerve activity are normal in patients with uncomplicated type 1 diabetes However, the forearm vasoconstrictor response to sympathetic stimulation is attenuated, which cannot be attributed to an impaired sympathetic responsiveness