Diabetes mellitus as a modulator of functional impairment and decline in Alzheimer's disease. The Real.FR cohort.

AIMS: To determine whether diabetes mellitus influences functional status in patients with Alzheimer's disease. METHODS: We studied 608 community-dwelling patients with Alzheimer's disease from a prospective multicenter cohort. Diabetes was assessed at baseline. Functional status was assessed twice yearly with the Activities of Daily Living scale. Each patient had a baseline functional disability if their Activities of Daily Living score was < 6. Progression of functional disability was defined by a decreased Activities of Daily Living score over 4 years of follow-up visits. RESULTS: At baseline, diabetes was present in 63 participants (10.4%) and, compared with those without diabetes, was associated with functional impairment [age- and sex-adjusted OR = 2.73 (95% CI 1.41-5.28)]. After controlling for confounders, the association remained significant [OR = 2.04 (95% CI 1.02-4.11)]. Follow-up demonstrated a significant interaction between duration of Alzheimer's disease and diabetes, which was associated with progression of functional impairment in patients who had been diagnosed with Alzheimer's disease for less than 1 year [age- and sex-adjusted hazard ratio = 1.52 (95% CI 1.01-2.30), P = 0.048], but not in those who had been diagnosed with Alzheimer's disease for more than 1 year [age- and sex-adjusted hazard ratio = 0.78 (95% CI 0.47-1.28), P = 0.32]. Abnormal one-leg balance, polymedication and obesity seem to be important factors explaining the association between diabetes and functional status. CONCLUSIONS: At baseline, the presence of diabetes significantly increases the risk of functional disability in patients with Alzheimer's disease; our longitudinal data confirm that in patients with a recent diagnosis of Alzheimer's disease (but not in those who have had Alzheimer's disease for longer than 1 year), diabetes continues to worsen functional status.

The effects of phorbol 12,13-diacetate on responses of guinea-pig isolated trachea to methylxanthines, isoprenaline and ryanodine.

1. Using guinea-pig isolated trachea, we have studied how phorbol 12,13-diacetate (PDA) modulates mechanical responses of the tissue to methylxanthines, isoprenaline and ryanodine. 2. Caffeine (10 microM-5 mM), theophylline (10 microM-5 mM) and isoprenaline (1 nM-1 microM), each inhibited the spontaneous tone of the trachea. Pretreatment with PDA (0.1-10 microM) converted relaxant responses to high concentrations of the methylxanthines into contractions. PDA produced no equivalent effect against isoprenaline. Pretreatment with verapamil (1 or 10 microM), nifedipine (0.1 microM) or incubation with Ca(2+)-free, EGTA (0.1 mM)-containing physiological salt solution (PSS) suppressed the contraction produced by caffeine or theophylline in PDA (5 microM)-treated tissues. 3. The ability of PDA (5 microM) to convert caffeine-induced relaxation into caffeine-induced contraction was retained in tissues pretreated with a combination of atropine (1 microM) and mepyramine (1 microM) and in tissues denuded of the airway epithelium. 4. Caffeine (10 microM-5 mM), theophylline (10 microM-5 mM) and isoprenaline (1 nM-1 microM), each relaxed trachea contracted with histamine (0.1 mM). The relaxation induced by caffeine, theophylline and isoprenaline was markedly reduced in the presence of PDA (5 microM) and the responses to high concentrations of caffeine and theophylline, but not those to isoprenaline, were reversed to contractions. Verapamil (10 microM) prevented the effects of PDA against caffeine- or theophylline-induced relaxation. 5. PDA (1 microM) enhanced the tracheal spasm produced by caffeine (10 mM) and theophylline (10 mM) in indomethacin (2.8 microM)-treated trachea maintained at 20 degrees C. This enhancement was reduced in the presence of verapamil (10 microM). 6. Tested in trachea bathed by K+-rich (40 mM), Ca2+-free PSS, CaCl2 (0.1-20 mM) caused concentration-dependent spasm. PDA (1-5 MicroM) did not significantly modify the shape or position of the log concentration-effect curve for CaCl2. In contrast, verapamil (1 and 10 MicroM) antagonized CaCl2.7. Tested in trachea bathed by indomethacin (2.8 MicroM)-containing PSS, ryanodine (1-100 MicroM) caused concentration-dependent spasm. PDA (5 MicroM) potentiated ryanodine. Verapamil (10 MicroM) inhibited ryanodine in inducing spasm and suppressed the ability of PDA to potentiate ryanodine.8. It is concluded that, in guinea-pig isolated trachea, PDA augments the spasmogenic activity of the methylxanthines and ryanodine. This effect of PDA does not result from PDA-induced suppression of spontaneous tone, from increased cellular entry of Ca2+ through L-type channels or from sensitization of the intracellular contractile machinery to activator Ca2+. The evidence suggests, instead, that PDA facilitates methylxanthine- or ryanodine-induced release of Ca2+ from the intracellular store.

Pharmacological modulation of the spasmogenic response to methylxanthines in guinea-pig trachea.

The spasmogenic activity of methylxanthines was evaluated in guinea-pig isolated trachea treated with indomethacin (2.8 microM) and cooled to 20 degrees C. The contraction elicited by caffeine or theophylline (10 mM) was reduced in the presence of ouabain (10 microM), amiloride (100 microM), staurosporine (1 microM), H-7 (50 microM), polymyxin B (500 microM), K(+)-free solution, low Na+ (25 mM) medium or Ca(2+)-free (EGTA 0.1 mM) solution but was unaltered in the presence of verapamil (10 microM) or vanadate (10-100 microM). These results suggest that tracheal spasm to methylxanthines predominantly involves Ca2+ release from intracellular stores with a minor component due to extracellular Ca2+ entry through verapamil-insensitive pathways. A Na+/Ca2+ exchange process and the activation of protein kinase C may be also involved.

Effects of dantrolene on the responses to methylxanthines in the isolated guinea-pig trachea.

The effect of dantrolene on the responses to methylxanthines (caffeine and theophylline) and a beta-adrenoceptor agonist (salbutamol) was studied in isolated guinea-pig trachea. Caffeine and theophylline (1 microM-10 mM) and salbutamol (1 nM-10 microM) produced concentration-dependent relaxation of spontaneous and stimulated (acetylcholine 1 mM) tone. Responses to high concentrations (10 mM) of caffeine and theophylline added to tracheal strips either unstimulated (spontaneous tone) or indomethacin (2.8 microM)-treated were reversed to contractions in the presence of dantrolene (3 microM-0.3 mM). This effect was not observed for salbutamol or when relaxant responses to the agonists were generated in pre-contracted (acetylcholine 1 mM) strips. Dantrolene inhibited concentration dependently the contraction evoked by caffeine (1 mM) in indomethacin (2.8 microM)-treated strips at 20 degrees C. This effect of dantrolene was attenuated in a low Ca2+ (0.8 mM) medium or when the bath temperature was lowered to 10 degrees C. Although an intracellular site of action cannot be excluded these results suggest that dantrolene mainly interferes with transmembrane Ca2+ movements in the guinea-pig trachea.

Effect of dantrolene sodium in isolated guinea-pig trachea.

The effect of dantrolene sodium (3 microM-0.3 mM) on the spontaneous tone and responses to various contractile agonists was studied in isolated guinea-pig trachea. Dantrolene produced a concentration-related inhibition of the spontaneous tracheal tone, reaching a value of 94.8 +/- 4.8% of the relaxation induced by caffeine 10 mM. Removal of the epithelium did not affect the dantrolene-induced relaxation. Dantrolene did not alter the concentration-response curve for KCl and produced only small displacements of the concentration-response curves for CaCl2, acetylcholine and histamine, without affecting their maximal effects. Dantrolene dose relatedly inhibited the contraction induced by caffeine (1 mM) in Krebs solution containing indomethacin (2.8 microM) at 20 degrees C. The spasm induced by caffeine in Ca2(+)-free Krebs solution (20 degrees C, indomethacin 2.8 microM) was slightly depressed by dantrolene. Dantrolene did not depress the Ca2+ (1 microM)-induced contraction in skinned trachea. These results suggest that besides a possible intracellular site of action, the mechanism of the inhibitory effect of dantrolene in guinea-pig trachea may be related to interference with Ca2+ entry through pathways not susceptible to calcium channel blockers.