Xenin-25 delays gastric emptying and reduces postprandial glucose levels in humans with and without type 2 diabetes.

Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine cells. In animals, Xen regulates gastrointestinal function and glucose homeostasis, typically by initiating neural relays. However, little is known about Xen action in humans. This study determines whether exogenously administered Xen modulates gastric emptying and/or insulin secretion rates (ISRs) following meal ingestion. Fasted subjects with normal (NGT) or impaired (IGT) glucose tolerance and Type 2 diabetes mellitus (T2DM; n = 10-14 per group) ingested a liquid mixed meal plus acetaminophen (ACM; to assess gastric emptying) at time zero. On separate occasions, a primed-constant intravenous infusion of vehicle or Xen at 4 (Lo-Xen) or 12 (Hi-Xen) pmol · kg(-1) · min(-1) was administered from zero until 300 min. Some subjects with NGT received 30- and 90-min Hi-Xen infusions. Plasma ACM, glucose, insulin, C-peptide, glucagon, Xen, GIP, and glucagon-like peptide-1 (GLP-1) levels were measured and ISRs calculated. Areas under the curves were compared for treatment effects. Infusion with Hi-Xen, but not Lo-Xen, similarly delayed gastric emptying and reduced postprandial glucose levels in all groups. Infusions for 90 or 300 min, but not 30 min, were equally effective. Hi-Xen reduced plasma GLP-1, but not GIP, levels without altering the insulin secretory response to glucose. Intense staining for Xen receptors was detected on PGP9.5-positive nerve fibers in the longitudinal muscle of the human stomach. Thus Xen reduces gastric emptying in humans with and without T2DM, probably via a neural relay. Moreover, endogenous GLP-1 may not be a major enhancer of insulin secretion in healthy humans under physiological conditions.

A retrospective analysis of the clinical effectiveness of subcutaneously tunneled femoral vein cannulations at the bedside: A low risk central venous access approach in the neonatal intensive care unit.

OBJECTIVE: The purpose of this retrospective analysis was to evaluate the clinical efficacy and safety of ultrasound (US)-guided, subcutaneously tunneled, femoral inserted central catheters (ST-FICCs) in the neonatal intensive care unit (NICU). METHODS: Following clinical success with ST-FICCs in adults, we expanded this practice to the neonatal population. In an 18-month retrospective cohort analysis (2018-2020) of 82 neonates, we evaluated the clinical outcome for procedural success, completion of therapy, and incidence of early and late complications for insertion of US-guided ST-FICCs in the NICU. RESULTS: Placement of ST-FICCs were successful in 100% of neonates (n = 82/82) with 94% to the right (n = 77/82) and 6% to the left common femoral veins (n = 5/82). Gestational age ranged 23-39 weeks with median age of 29 weeks. Birthweight ranged from 450 g to >2000 g. Weight at insertion ranged 570 to 3345 g and day of life 1 to 137, with median at day 5. Ultrasound guided femoral vein puncture was recorded on 74 patients, first attempt 63/74 (85%), second attempt 8/74 (11%) and third attempt 3/74 (4%). Catheter french used: 1.9Fr (n = 80/82), 2.6Fr (n = 1/82), and 3-Fr (n = 1/82). Catheter lengths were 8 to 20 cm, average 12cm. Catheter termination confirmed with posterior/anterior and lateral abdominal radiographs with inferior vena cava (IVC) (n = 33/82), IVC/right atrial junction (n = 31/82), or right atrium (n = 18/82). Atrial placements were retracted; no cases of malposition to the lumbar/renal/hepatic veins (n = 0/82). 1528 catheter days ranging 5 to 72 days (average 18). No insertion-related or post-insertion complications. All patients completed prescribed therapy with one catheter. CONCLUSION: Bedside placement of an ST-FICC is a safe route for central venous access in the NICU, preserving upper extremity vasculature, eliminates risks associated with sedation, fluoroscopy, tunneled and non-tunneled supra-diaphragmatic central venous insertion.

Comparative Effects of Coenzyme Q10 or n-3 Polyunsaturated Fatty Acid Supplementation on Retinal Angiogenesis in a Rat Model of Oxygen-Induced Retinopathy.

Neonatal intermittent hypoxia (IH) or apnea afflicts 70% to 90% of all preterm infants <28 weeks gestation, and is associated with severe retinopathy of prematurity (ROP). We tested the hypotheses that coenzyme Q10 (CoQ10) or omega-3 polyunsaturated fatty acids (n-3 PUFAs) supplementation during neonatal IH reduces the severity of oxygen-induced retinopathy (OIR). Newborn rats were exposed to two IH paradigms: (1) 50% O2 with brief hypoxia (12% O2); or (2) 21% O2 with brief hypoxia, until postnatal day 14 (P14), during which they received daily oral CoQ10 in olive oil, n-3 PUFAs in fish oil, or olive oil only and compared to room air (RA) treated groups. Pups were examined at P14, or placed in RA until P21. Retinal angiogenesis, histopathology, and morphometry were determined. Both IH paradigms produced severe OIR, but these were worsened with 50/12% O2 IH. CoQ10 and n-3 PUFAs reduced the severity of OIR, as well as ocular growth factors in both IH paradigms, but CoQ10 was more effective in 50/12% O2 IH. Supplementation with either CoQ10 or n-3 PUFAs targeting IH-induced retinal injury is individually effective for ameliorating specific characteristics consistent with ROP. Given the complexity of ROP, further studies are needed to determine whether combined CoQ10 and n-3 PUFAs supplementation would optimize their efficacy and result in a better outcome.

Co-Enzyme Q10 and n-3 Polyunsaturated Fatty Acid Supplementation Reverse Intermittent Hypoxia-Induced Growth Restriction and Improved Antioxidant Profiles in Neonatal Rats.

Neonatal intermittent hypoxia (IH) increases the risk for many morbidities in extremely low birth weight/gestational age (ELBW/ELGA) neonates with compromised antioxidant systems and poor growth. We hypothesized that supplementation with coenzyme Q10 (CoQ10, ubiquinol) or n-3 polyunsaturated fatty acids (PUFAs) during neonatal IH improves antioxidant profiles and somatic growth in neonatal rats. Newborn rats were exposed to two IH paradigms at birth (P0): (1) 50% O2 with brief hypoxic episodes (12% O2); or (2) room air (RA) with brief hypoxia, until P14 during which they received daily oral CoQ10 in olive oil, n-3 PUFAs in fish oil, or olive oil only from P0 to P14. Pups were studied at P14 or placed in RA until P21 for recovery from IH (IHR). Body weight and length; organ weights; and serum antioxidants and growth factors were determined at P14 and P21. Neonatal IH resulted in sustained reductions in somatic growth, an effect that was reversed with n-3 PUFAs. Improved growth was associated with higher serum growth factors. CoQ10 decreased superoxide dismutase (SOD) and glutathione, but increased catalase, suggesting reduced oxidative stress. Further studies are needed to determine the synergistic effects of CoQ10 and n-3 PUFA co-administration for the prevention of IH-induced oxidative stress and postnatal growth deficits.

Hormonal Responses to Cholinergic Input Are Different in Humans with and without Type 2 Diabetes Mellitus.

UNLABELLED: Peripheral muscarinic acetylcholine receptors regulate insulin and glucagon release in rodents but their importance for similar roles in humans is unclear. Bethanechol, an acetylcholine analogue that does not cross the blood-brain barrier, was used to examine the role of peripheral muscarinic signaling on glucose homeostasis in humans with normal glucose tolerance (NGT; n = 10), impaired glucose tolerance (IGT; n = 11), and type 2 diabetes mellitus (T2DM; n = 9). Subjects received four liquid meal tolerance tests, each with a different dose of oral bethanechol (0, 50, 100, or 150 mg) given 60 min before a meal containing acetaminophen. Plasma pancreatic polypeptide (PP), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucose, glucagon, C-peptide, and acetaminophen concentrations were measured. Insulin secretion rates (ISRs) were calculated from C-peptide levels. Acetaminophen and PP concentrations were surrogate markers for gastric emptying and cholinergic input to islets. The 150 mg dose of bethanechol increased the PP response 2-fold only in the IGT group, amplified GLP-1 release in the IGT and T2DM groups, and augmented the GIP response only in the NGT group. However, bethanechol did not alter ISRs or plasma glucose, glucagon, or acetaminophen concentrations in any group. Prior studies showed infusion of xenin-25, an intestinal peptide, delays gastric emptying and reduces GLP-1 release but not ISRs when normalized to plasma glucose levels. Analysis of archived plasma samples from this study showed xenin-25 amplified postprandial PP responses ~4-fold in subjects with NGT, IGT, and T2DM. Thus, increasing postprandial cholinergic input to islets augments insulin secretion in mice but not humans. TRIAL REGISTRATION: ClinicalTrials.gov NCT01434901.

GABAA receptor dysfunction contributes to high blood pressure and exaggerated response to stress in Schlager genetically hypertensive mice.

OBJECTIVE: Schlager BPH/2J hypertensive mice have high blood pressure (BP) likely due to overactivity of the sympathetic nervous system regulated by neurons in amygdala-hypothalamic pathways. These areas are normally under tonic inhibition by GABA containing neurons that may be deficient in Schlager hypertensive mice as suggested by microarray analysis. In the present study, cardiovascular effects of chronic activation of GABAA receptors were examined in BPH/2J mice. METHODS: Male normotensive BPN/3J and hypertensive BPH/2J mice were administered diazepam in drinking water for 7 days. BP, heart rate and locomotor activity were recorded by telemetry. RESULTS: Diazepam (2.5 mg/kg) reduced BP of BPN/3J mice during the night-time by -7.1 ± 2.0 mmHg (P = 0.001) but had no effect in BPH/2J mice (+2 ± 2 mmHg) and no effect on heart rate or locomotor activity in either strain. Diazepam reduced the responses to restraint stress in BPN/3J mice by 20% (P = 0.01) and there was no association between Fos-immunoreactive neurons and neurons expressing GABAA receptors or neuropeptide Y in the medial amygdala and paraventricular nucleus of the hypothalamus. By contrast diazepam had no effect on the pressor response to stress in BPH/2J mice and ~50% of stress-activated neurons in these regions also expressed GABAA receptors and ~45% were neuropeptide Y-containing. CONCLUSION: These findings show that BPH/2J mice are resistant to the effects of diazepam and suggest that GABAA receptor dysfunction in BPH/2J mice may be contributing to the neurogenic hypertension by not suppressing arousal-induced sympathetic activation within amygdala and hypothalamic nuclei.

The combination of GIP plus xenin-25 indirectly increases pancreatic polypeptide release in humans with and without type 2 diabetes mellitus.

Xenin-25 (Xen) is a 25-amino acid neurotensin-related peptide that activates neurotensin receptor-1 (NTSR1). We previously showed that Xen increases the effect of glucose-dependent insulinotropic polypeptide (GIP) on insulin release 1) in hyperglycemic mice via a cholinergic relay in the periphery independent from the central nervous system and 2) in humans with normal or impaired glucose tolerance, but not type 2 diabetes mellitus (T2DM). Since this blunted response to Xen defines a novel defect in T2DM, it is important to understand how Xen regulates islet physiology. On separate visits, subjects received intravenous graded glucose infusions with vehicle, GIP, Xen, or GIP plus Xen. The pancreatic polypeptide response was used as an indirect measure of cholinergic input to islets. The graded glucose infusion itself had little effect on the pancreatic polypeptide response whereas administration of Xen equally increased the pancreatic polypeptide response in humans with normal glucose tolerance, impaired glucose tolerance, and T2DM. The pancreatic polypeptide response to Xen was similarly amplified by GIP in all 3 groups. Antibody staining of human pancreas showed that NTSR1 is not detectable on islet endocrine cells, sympathetic neurons, blood vessels, or endothelial cells but is expressed at high levels on PGP9.5-positive axons in the exocrine tissue and at low levels on ductal epithelial cells. PGP9.5 positive nerve fibers contacting beta cells in the islet periphery were also observed. Thus, a neural relay, potentially involving muscarinic acetylcholine receptors, indirectly increases the effects of Xen on pancreatic polypeptide release in humans.

Using pressure transducers for noninvasive detectection of heart and respiratory rates.

The purpose of this study is the exploration of a new noninvasive method for detecting heart and respiratory rates using pressure transducers and medical tubing placed on a person’s chest. This device is intended to replace the individual who manually and visually takes vital signs in an emergency mass casualty situation. Instead it would provide a light weight device that can be carried in to the field, applied rapidly, and has the potential to be networked in such a way that one medical person can monitor 5-6 casualties simultaneously, thus acting as a force multiplier. The first step in the project was the validation of using pressure transducers to detect the desired signals. After the initial validation, the first board mount rendition of the system was implemented on a printed circuit board. An experiment was designed and carried out using a coil of latex tubing placed on a medical test mannequin that is used for breathing simulations. The pressure transducer read the change in pressure in this tubing and data was collected for several different respiratory rates. The results of this experiment are definitive. Respiratory rate can be derived using signal processing of the raw signal output from the system.