Alterations of alveolar type II cells and intraalveolar surfactant after bronchoalveolar lavage and perfluorocarbon ventilation. An electron microscopical and stereological study in the rat lung.

BACKGROUND: Repeated bronchoalveolar lavage (BAL) has been used in animals to induce surfactant depletion and to study therapeutical interventions of subsequent respiratory insufficiency. Intratracheal administration of surface active agents such as perfluorocarbons (PFC) can prevent the alveolar collapse in surfactant depleted lungs. However, it is not known how BAL or subsequent PFC administration affect the intracellular and intraalveolar surfactant pool. METHODS: Male wistar rats were surfactant depleted by BAL and treated for 1 hour by conventional mechanical ventilation (Lavaged-Gas, n = 5) or partial liquid ventilation with PF 5080 (Lavaged-PF5080, n = 5). For control, 10 healthy animals with gas (Healthy-Gas, n = 5) or PF5080 filled lungs (Healthy-PF5080, n = 5) were studied. A design-based stereological approach was used for quantification of lung parenchyma and the intracellular and intraalveolar surfactant pool at the light and electron microscopic level. RESULTS: Compared to Healthy-lungs, Lavaged-animals had more type II cells with lamellar bodies in the process of secretion and freshly secreted lamellar body-like surfactant forms in the alveoli. The fraction of alveolar epithelial surface area covered with surfactant and total intraalveolar surfactant content were significantly smaller in Lavaged-animals. Compared with Gas-filled lungs, both PF5080-groups had a significantly higher total lung volume, but no other differences. CONCLUSION: After BAL-induced alveolar surfactant depletion the amount of intracellularly stored surfactant is about half as high as in healthy animals. In lavaged animals short time liquid ventilation with PF5080 did not alter intra- or extracellular surfactant content or subtype composition.

Reliability of the microdialysis pump CMA 107 under hyperbaric conditions.

OBJECTIVE: Microdialysis measurements of extracellular substances under hyperbaric conditions were manifold used in several investigations. However, to our knowledge there is no analysis, which verified the applicability of microdialysis pumps under hyperbaric conditions. Thus, a goal of this study was to investigate the reliability of the microdialysis pump (MDP) CMA 107 in a hyperbaric environment up to 2.4bar absolute pressure. METHODS: The CMA 107 with a perfusion rate of 2microL/min was stored in a decompression chamber. The ambient pressure was increased from 1 to 2.4bar absolute within 15min, maintained for 90min and then decreased to 1bar within 15min. The vials were changed every 15min, weighed before as well as after collecting the sample volume and the absolute recovery of glutamate, pyruvate, lactate, glucose and glycerol was determined. The same setup was performed under normobaric conditions. RESULTS: The pumping capacity was 1.7% greater than expected under normobaric conditions, 36.5% less than expected in the compression phase, 10.5% less than expected in the isopression phase and 26.3% greater than expected in the decompression phase under hyperbaric conditions. The absolute recoveries under hyperbaric conditions were affected during the isopression phase with a deviation from -6 to +20% compared to normobaric environments. CONCLUSION: The study demonstrated that an absolute ambient pressure up to 2.4bar did influence the pumping capacity and the reliability of the absolute recovery. These results need to be taken into consideration when interpreting microdialysis studies performed under hyperbaric conditions.

Quantification of the Contribution of GLP-1 to Mediating Insulinotropic Effects of DPP-4 Inhibition With Vildagliptin in Healthy Subjects and Patients With Type 2 Diabetes Using Exendin [9-39] as a GLP-1 Receptor Antagonist.

We quantified the contribution of GLP-1 as a mediator of the therapeutic effects of dipeptidyl peptidase 4 (DPP-4) inhibition (vildagliptin) by using the GLP-1 receptor antagonist exendin [9-39] in patients with type 2 diabetes and in healthy subjects. Thirty-two patients with type 2 diabetes and 29 age- and weight-matched healthy control subjects were treated in randomized order with 100 mg once daily vildagliptin or placebo for 10 days. Meal tests were performed (days 9 and 10) without and with a high-dose intravenous infusion of exendin [9-39]. The main end point was the ratio of the areas under the curve (AUCs) of integrated insulin secretion rates (total AUCISR) and glucose (total AUCglucose) over 4 h after the meal. Vildagliptin treatment more than doubled responses of intact GLP-1 and glucose-dependent insulinotropic polypeptide and lowered glucose responses without changing AUCISR/AUCglucose in healthy subjects. Vildagliptin significantly increased this ratio by 10.5% in patients with type 2 diabetes, and exendin [9-39] reduced it (both P < 0.0001). The percentage reduction in the AUCISR/AUCglucose ratio achieved with exendin [9-39] was significantly smaller after vildagliptin treatment than after placebo treatment (P = 0.026) and was equivalent to 47 ± 5% of the increments due to vildagliptin. Thus, other mediators appear to contribute significantly to the therapeutic effects of DPP-4 inhibition.

GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes.

OBJECTIVE: The incretin glucagon-like peptide 1 (GLP-1) exerts insulinotropic activity in type 2 diabetic patients, whereas glucose-dependent insulinotropic polypeptide (GIP) no longer does. We studied whether GIP can alter the insulinotropic or glucagonostatic activity of GLP-1 in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Twelve patients with type 2 diabetes (nine men and three women; 61 ± 10 years; BMI 30.0 ± 3.7 kg/m²; HbA(1c) 7.3 ± 1.5%) were studied. In randomized order, intravenous infusions of GLP-1(7-36)-amide (1.2 pmol · kg⁻¹ · min⁻¹), GIP (4 pmol · kg⁻¹ · min⁻¹), GLP-1 plus GIP, and placebo were administered over 360 min after an overnight fast (≥ 1 day wash-out period between experiments). Capillary blood glucose, plasma insulin, C-peptide, glucagon, GIP, GLP-1, and free fatty acids (FFA) were determined. RESULTS: Exogenous GLP-1 alone reduced glycemia from 10.3 to 5.1 ± 0.2 mmol/L. Insulin secretion was stimulated (insulin, C-peptide, P < 0.0001), and glucagon was suppressed (P = 0.009). With GIP alone, glucose was lowered slightly (P = 0.0021); insulin and C-peptide were stimulated to a lesser degree than with GLP-1 (P < 0.001). Adding GIP to GLP-1 did not further enhance the insulinotropic activity of GLP-1 (insulin, P = 0.90; C-peptide, P = 0.85). Rather, the suppression of glucagon elicited by GLP-1 was antagonized by the addition of GIP (P = 0.008). FFA were suppressed by GLP-1 (P < 0.0001) and hardly affected by GIP (P = 0.07). CONCLUSIONS: GIP is unable to further amplify the insulinotropic and glucose-lowering effects of GLP-1 in type 2 diabetes. Rather, the suppression of glucagon by GLP-1 is antagonized by GIP.

Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as "isoglycemic" intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes.

BACKGROUND AND AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors block the degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. The aim of the present study was to quantitatively assess the incretin effect after treatment with the DPP-4 inhibitor vildagliptin (V) or placebo (P) in patients with type 2 diabetes. MATERIALS AND METHODS: Twenty-one patients (three women, 18 men) with type 2 diabetes previously treated with metformin (mean age, 59 yr; body mass index, 28.6 kg/m(2); glycosylated hemoglobin, 7.3%) were studied in a two-period crossover design. They received 100 mg V once daily or P for 13 d in randomized order. The incretin effect was measured on d 12 (75-g oral glucose) and d 13 ("isoglycemic" iv glucose) based on insulin and C-peptide determinations and insulin secretion rates (ISR). RESULTS: V relative to P treatment significantly increased intact incretin concentrations after oral glucose and insulin secretory responses to both oral glucose and isoglycemic iv glucose (e.g. AUC(ISR oral), by 32.7%, P = 0.0006; AUC(ISR iv), by 33.1%, P = 0.01). The numerical incretin effect was not changed (IE(ISR), V vs. P, 35.7 ± 4.9 and 34.6 ± 4.0%, P = 0.80). CONCLUSIONS: DPP-4 inhibition augmented insulin secretory responses both after oral glucose and during isoglycemic iv glucose infusions, with no net change in the incretin effect. Thus, slight variations in basal incretin levels may be more important than previously thought. Or, DPP-4 inhibitor-induced change in the incretin-related environment of islets may persist overnight, augmenting insulin secretory responses to iv glucose as well. Alternatively, yet unidentified mediators of DPP-4 inhibition may have caused these effects.

[Treatment options of acral ulcers in MCTD]. / Therapie akraler Nekrosen bei MCTD: Kombination von Iloprost, hyperbarer Oxygenation und regionaler Sympathikolyse - ein Fallbericht.

In patients with systemic sclerosis or mixed connective tissue disease (MCTD) acral ulcers are considered as frequent manifestations that may lead to amputation and loss of function, respectively, as a result of secondary Raynaud's phenomenon. Thus it is necessary to take advantage of all available medical and supportive measures. Adjuvant treatments such as hyperbaric oxygenation and regional sympathetic block represent interdisciplinary treatment options to improve oxygenation of critical ischemia and analgesia and should be subject of further investigation.