Insulin Action in the Hypothalamus Increases Second-Phase Insulin Secretion in Humans.

BACKGROUND: Animal studies and initial correlative data in humans indicate that insulin action in the brain may affect pancreatic insulin secretion. An important brain region for this process is the hypothalamus, an area that can develop insulin resistance. METHODS: Fifteen young, healthy men (27 ± 3 years) with a wide BMI spectrum (20-30 kg/m2) underwent 2 hyperglycemic clamps (target blood glucose: 10 mmol/L). In this double-blind study, subjects received 160 U of insulin or placebo as a nasal spray on 2 days in randomized order. On another day, insulin sensitivity of the hypothalamus was determined by functional magnetic resonance imaging. RESULTS: Glucose levels were comparable on both study days. In the whole group, C-peptide levels were not significantly different between conditions. Though, there was a significant interaction between insulin sensitivity of the hypothalamus × nasal spray × time on C-peptide levels (p = 10-6). The group was therefore divided according to median hypothalamic insulin sensitivity. C-peptide concentrations were higher after intranasal insulin compared to placebo spray in the group with a strong hypothalamic insulin response (p < 0.0001, ß = 6.00 ± 1.24) and lower in the brain insulin-resistant group (p = 0.005, ß = -2.68 ± 0.95). Neither somatostatin nor glucagon kinetics was altered by the nasal spray. CONCLUSIONS: In participants with high hypothalamic insulin sensitivity, insulin action in the brain enhanced second-phase insulin secretion from pancreatic beta cells. This reaction could, for example, contribute to late postprandial glucose regulation by suppressing hepatic glucose production by portal venous insulin.

Combined choline and DHA supplementation: a randomized controlled trial.

OBJECTIVE: Choline and docosahexaenoic acid (DHA) are essential nutrients for preterm infant development. They are metabolically linked via phosphatidylcholine (PC), a constitutive plasma membrane lipid and the major transport form of DHA in plasma. Plasma choline and DHA-PC concentrations rapidly decline after preterm birth. To improve preterm infant nutrition, we evaluated combined compared to exclusive choline and DHA supplementation, and standard feeding. DESIGN: Randomized partially blinded single-center trial. SETTING: Neonatal tertiary referral center in Tübingen, Germany. PATIENTS: 24 inborn preterm infants < 32 week postmenstrual age. INTERVENTIONS: Standard nutrition (control) or, additionally, enteral choline (30 mg/kg/day), DHA (60 mg/kg/day), or both for 10 days. Single enteral administration of 3.6 mg/kg [methyl-D9-] choline chloride as a tracer at 7.5 days. MAIN OUTCOME MEASURES: Primary outcome variable was plasma choline following 7 days of supplementation. Deuterated and unlabeled choline metabolites, DHA-PC, and other PC species were secondary outcome variables. RESULTS: Choline supplementation increased plasma choline to near-fetal concentrations [35.4 (32.8-41.7) µmol/L vs. 17.8 (16.1-22.4) µmol/L, p < 0.01] and decreased D9-choline enrichment of PC. Single DHA treatment decreased DHA in PC relative to total lipid [66 (60-68)% vs. 78 (74-80)%; p < 0.01], which was prevented by choline. DHA alone increased DHA-PC only by 35 (26-45)%, but combined treatment by 63 (49-74)% (p < 0.001). D9-choline enrichment showed preferential synthesis of PC containing linoleic acid. PC synthesis via phosphatidylethanolamine methylation resulted in preferential synthesis of DHA-containing D3-PC, which was increased by choline supplementation. CONCLUSIONS: 30 mg/kg/day additional choline supplementation increases plasma choline to near-fetal concentrations, dilutes the D9-choline tracer via increased precursor concentrations and improves DHA homeostasis in preterm infants. TRIAL REGISTRATION: clinicaltrials.gov. Identifier: NCT02509728.

Safety of intranasal human insulin: A review.

AIMS: To conduct a review in order to assess the safety of intranasal human insulin in clinical studies as well as the temporal stability of nasal insulin sprays. MATERIAL AND METHODS: An electronic search was performed using MEDLINE. We selected original research on intranasal human insulin without further additives in humans. The studies included could be of any design as long as they used human intranasal insulin as their study product. All outcomes and adverse side effects were extracted. RESULTS: A total of 38 studies in 1092 individuals receiving acute human intranasal insulin treatment and 18 studies in 832 individuals receiving human intranasal insulin treatment lasting between 21 days and 9.7 years were identified. No cases of symptomatic hypoglycaemia or severe adverse events (AEs) were reported. Transient local side effects in the nasal area were frequently experienced after intranasal insulin and placebo spray, while other AEs were less commonly reported. There were no reports of participants being excluded as a result of AEs. No instances of temporal stability of nasal insulin were reported in the literature. Tests on insulin that had been repacked into spray flasks showed that it had a chemical stability of up to 57 days. CONCLUSIONS: Our retrospective review of published studies on intranasal insulin did not reveal any safety concerns; however, there were insufficient data to ensure the long-term safety of this method of chronic insulin administration. Improved insulin preparations that cause less nasal irritation would be desirable for future treatment.

Effect of probiotics on vaginal health in pregnancy. EFFPRO, a randomized controlled trial.

BACKGROUND: Preterm delivery is a leading cause of neonatal morbidity and death. It often results from chorioamnionitis, which is a complication of bacterial vaginosis. Probiotics are effective in the treatment of bacterial vaginosis in women who were not pregnant; studies in pregnant woman are missing. OBJECTIVE: The purpose of this study was to evaluate whether an oral probiotic food supplement supports the maintenance or restoration of a normal vaginal microbiota during pregnancy. STUDY DESIGN: We conducted a randomized, placebo-controlled, triple-blind, parallel group trial. Oral Lactobacillus rhamnosus GR-1and L reuteri RC-14 (109 colony-forming units) or placebo were administered for 8 weeks to women with <12 completed weeks of pregnancy. Participants were enrolled at Tuebingen University Hospital and 10 recruiting gynecologic practices. Vaginal swabs were taken before and after intervention and analyzed according to the Nugent scoring system. Telephone interviews were performed before and after intervention and after delivery. Primary outcome was the proportion of swabs with normal Nugent score (<4) after intervention, compared by Fisher's exact test in an intention-to-treat analysis. RESULTS: Three hundred twenty pregnant women were enrolled. Vaginal swabs were analyzed from 290 women before and 271 women after intervention. The proportion of normal vaginal microbiota decreased from 82.6 to 77.8% in the treatment group and from 79.1 to 74.3% in the placebo group, with no significant difference across groups after intervention (P=.297). CONCLUSION: Oral probiotics may be suitable for implementation in antenatal care but, as administered here, had no effect on vaginal health during mid gestation. Other application routes or probiotic preparations may be more effective in supporting vaginal microbiota during pregnancy.

Corneal Penetration of Low-Dose Atropine Eye Drops.

Major studies demonstrating the inhibition of myopia in children and juveniles by low-dose atropine eye drops provide little information on the manufacturing process and the exact composition of the atropine dilutions. However, corneal penetration might significantly vary depending on preservatives, such as benzalkonium chloride (BAC), and the atropine concentration. Since there is a trade-off between side effects, stability, and optimal effects of atropine on myopia, it is important to gain better knowledge about intraocular atropine concentrations. We performed an ex vivo study to determine corneal penetration for different formulations. Atropine drops (0.01%) of different formulations were obtained from pharmacies and applied to the cornea of freshly enucleated pig eyes. After 10 min, a sample of aqueous humor was taken and atropine concentrations were determined after liquid-liquid extraction followed by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The variability that originated from variations in applied drop size exceeded the differences between preserved and preservative-free formulations. The atropine concentration in the anterior chamber measured after 10 min was only 3.8 × 10-8 of its concentration in the applied eye drops, corresponding to 502.4 pM. Obviously, the preservative did not facilitate corneal penetration, at least ex vivo. In the aqueous humor of children's eyes, similar concentrations, including higher variability, may be expected in the lower therapeutic window of pharmacodynamic action.

Choline Supplementation in Cystic Fibrosis-The Metabolic and Clinical Impact.

BACKGROUND: Choline is essential for the synthesis of liver phosphatidylcholine (PC), parenchymal maintenance, bile formation, and lipoprotein assembly to secrete triglycerides. In choline deficiency, the liver accretes choline/PC at the expense of lung tissue, thereby impairing pulmonary PC homoeostasis. In cystic fibrosis (CF), exocrine pancreas insufficiency results in impaired cleavage of bile PC and subsequent fecal choline loss. In these patients, the plasma choline concentration is low and correlates with lung function. We therefore investigated the effect of choline supplementation on plasma choline/PC concentration and metabolism, lung function, and liver fat. METHODS: 10 adult male CF patients were recruited (11/2014⁻1/2016), and orally supplemented with 3 × 1 g choline chloride for 84 (84⁻91) days. Pre-/post-supplementation, patients were spiked with 3.6 mg/kg [methyl-D9]choline chloride to assess choline/PC metabolism. Mass spectrometry, spirometry, and hepatic nuclear resonance spectrometry served for analysis. RESULTS: Supplementation increased plasma choline from 4.8 (4.1⁻6.2) µmol/L to 10.5 (8.5⁻15.5) µmol/L at d84 (p < 0.01). Whereas plasma PC concentration remained unchanged, D9-labeled PC was decreased (12.2 [10.5⁻18.3] µmol/L vs. 17.7 [15.5⁻22.4] µmol/L, p < 0.01), indicating D9-tracer dilution due to higher choline pools. Supplementation increased Forced Expiratory Volume in 1 second percent of predicted (ppFEV1) from 70.0 (50.9⁻74.8)% to 78.3 (60.1⁻83.9)% (p < 0.05), and decreased liver fat from 1.58 (0.37⁻8.82)% to 0.84 (0.56⁻1.17)% (p < 0.01). Plasma choline returned to baseline concentration within 60 h. CONCLUSIONS: Choline supplementation normalized plasma choline concentration and increased choline-containing PC precursor pools in adult CF patients. Improved lung function and decreased liver fat suggest that in CF correcting choline deficiency is clinically important. Choline supplementation of CF patients should be further investigated in randomized, placebo-controlled trials.

The Oral Bioavailability of 8-Prenylnaringenin from Hops (Humulus Lupulus L.) in Healthy Women and Men is Significantly Higher than that of its Positional Isomer 6-Prenylnaringenin in a Randomized Crossover Trial.

SCOPE: Prenylated chalcones and flavonoids from hop (Humulus lupulus L.), such as 6-prenylnaringenin (6-PN) and 8-prenylnaringenin (8-PN), are investigated for their health beneficial and anticancer activities. We, thus, compare the oral bioavailability and safety of 6-PN and 8-PN in healthy young women and men, and investigated their effects on peripheral blood mononuclear cells (PBMC). METHODS AND RESULTS: A double-blind, placebo-controlled, crossover trial is conducted with 16 healthy volunteers (eight women, eight men) given a single oral dose of 500 mg 6-PN, 8-PN, or placebo in random order. Maximum total concentrations of 6-PN and 8-PN in plasma (Cmax ; 543 and 2834 nmol L-1 ) and their respective area under the plasma concentration-time curve (AUC; 3635 and 15801 nmol L-1 × h) are significantly (5.2- and 4.3-fold) higher for 8-PN than for 6-PN (p Ë‚ 0.05). PBMC for ex vivo experiments are isolated from blood sampled before and 6 h after intake of 6-PN, 8-PN, or placebo. Despite the single-treatment regime and low blood concentrations, both 6-PN and 8-PN increase the survival of PBMC relative to control. CONCLUSION: 8-PN is significantly more bioavailable in healthy humans than its isomer 6-PN. Interestingly, 6-PN, despite being less bioavailable, is similarly effective as 8-PN in enhancing PBMC viability.

Tinnitus Patients with Comorbid Headaches: The Influence of Headache Type and Laterality on Tinnitus Characteristics.

BACKGROUND: Both clinical experience and clinical studies suggest a relationship between tinnitus and headache. Here, we aimed to investigate the influence of comorbid headache type and headache laterality on tinnitus characteristics. METHOD: The Tinnitus Research Initiative database was screened for patients of the Tinnitus Center of the University Regensburg who reported comorbid headaches. These patients were contacted to complete additional validated questionnaires. Based on these data, patients were categorized according to headache type and headache laterality, and their clinical characteristics were compared with tinnitus patients, who did not report comorbid headaches. RESULTS: Data from 193 patients with tinnitus and comorbid headaches were compared with those from 765 tinnitus patients without comorbid headaches. Tinnitus patients with comorbid headache have higher scores in tinnitus questionnaires, a lower quality of life and more frequently comorbidities such as painful sensation to loud sounds, vertigo, pain (neck, temporomandibular, and general), and depressive symptoms when compared with tinnitus patients without headaches. Both headache laterality and headache type interact with the degree of comorbidity with higher impairment in patients with left-sided and bilateral headaches as well as in patients with migraine or cluster headache. CONCLUSION: The observed increased impairment in tinnitus patients with comorbid headache can be explained as an additive effect of both disorders on health-related quality of life. The more frequent occurrence of further comorbidities suggests a generally increased amplification of sensory signals in a subset of tinnitus patients with comorbid headaches.

Tinnitus and Headache.

BACKGROUND: Tinnitus and headache are frequent disorders. Here, we aimed to investigate whether the occurrence of headache among tinnitus patients is purely coincidental or whether tinnitus and headache are pathophysiologically linked. We investigated a large sample of patients with tinnitus and headache to estimate prevalence rates of different headache forms, to determine the relationship between tinnitus laterality and headache laterality, and to explore the relationship between tinnitus and headache over time. METHOD: Patients who presented at a tertiary referral center because of tinnitus and reported comorbid headache were asked to complete validated questionnaires to determine the prevalence of migraine and tension-type headache and to assess tinnitus severity. In addition, several questions about the relationship between headache and tinnitus were asked. RESULTS: Datasets of 193 patients with tinnitus and headache were analysed. 44.6% suffered from migraine, 13% from tension-type headache, and 5.7% from both. Headache laterality was significantly related to tinnitus laterality and in the majority of patients fluctuations in symptom severity of tinnitus and headache were interrelated. CONCLUSION: These findings suggest a significant relationship between tinnitus and headache laterality and symptom interaction over time and argue against a purely coincidental cooccurrence of tinnitus and headache. Both disorders may be linked by common pathophysiological mechanisms.