Institute Of Recherches Cliniques Of Montreal Montreal

Montréal, Canada

Institute Of Recherches Cliniques Of Montreal Montreal

Montréal, Canada
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Haidar A.,McGill University | Messier V.,Institute Of Recherches Cliniques Of Montreal Montreal | Legault L.,McGill University | Ladouceur M.,University of Montréal | Rabasa-Lhoret R.,University of Montréal
Diabetes, Obesity and Metabolism | Year: 2017

Aims: To assess whether the dual-hormone (insulin and glucagon) artificial pancreas reduces hypoglycaemia compared to the single-hormone (insulin alone) artificial pancreas in outpatient settings during the day and night. Material and methods: In a randomized, three-way, crossover trial we compared the dual-hormone artificial pancreas, the single-hormone artificial pancreas and sensor-augmented pump therapy (control) in 23 adults with type 1 diabetes. Each intervention was applied from 8 AM Day 1 to 8 PM Day 3 (60hours) in outpatient free-living conditions. The primary outcome was time spent with sensor glucose levels below 4.0mmol/L. A P value of less than .017 was regarded as significant. Results: The median difference between the dual-hormone system and the single-hormone system was -2.3% (P=.072) for time spent below 4.0mmol/L, -1.3% (P=.017) for time below 3.5mmol/L, and -0.7% (P=.031) for time below 3.3mmol/L. Both systems reduced (P<.017) hypoglycaemia below 4.0, 3.5 and 3.3mmol/L compared to control therapy, but reductions were larger with the dual-hormone system than with the single-hormone system (medians -4.0% vs -3.4% for 4.0mmol/L; -2.7% vs -2.2% for 3.5mmol/L; and -2.2% vs -1.2% for 3.3mmol/L). There were 34 hypoglycaemic events (<3.0mmol/L for 20minutes) with control therapy, 14 with the single-hormone system and 6 with the dual-hormone system. These differences in hypoglycaemia were observed while mean glucose level was low and comparable in all interventions (P=NS). Conclusions: The dual-hormone artificial pancreas had the lowest risk of hypoglycaemia, but the differences were not statistically significant. Larger studies are needed. © 2017 John Wiley & Sons Ltd.

Al Khalifah R.A.,King Khalid University | Suppere C.,Institute Of Recherches Cliniques Of Montreal Montreal | Haidar A.,McGill University | Rabasa-Lhoret R.,McGill University | Legault L.,McGill University
Diabetic Medicine | Year: 2016

Aim: To determine the impact of physical fitness level on hypoglycaemia risk during exercise in people with Type 1 diabetes. Methods: A total of 44 patients [34 adults (aged 22-70 years) and 10 adolescents (aged 12-18 years)] with Type 1 diabetes, treated with insulin pump therapy, underwent a standardized exercise session. Cardiorespiratory fitness (maximum oxygen uptake) was measured and classified, based on established norms for age and sex, into either poor (< 25th percentile) or good fitness level (> 25th percentile). Plasma glucose levels were measured every 10 min, each patient performed physical activity at 60% maximum oxygen uptake either on a treadmill for 1 h or on a bicycle for 30 min. Frequency of hypoglycaemia (plasma glucose < 4 mmol/l) and decline in plasma glucose levels during exercise were assessed. Results: In all, 23 patients had a good exercise fitness level. Hypoglycaemic events occurred in 17/23 patients (74.0%) in the good fitness level group compared with 8/21 patients (38.0%) in the poor fitness level group (P = 0.02). Both groups had similar pre-exercise plasma glucose levels. The plasma glucose values during exercise in the good fitness level group compared with the poor fitness level group were: plasma glucose nadir 3.9 ± 1.6 vs 5.5 ± 2.4 mmol/l (P = 0.01) and plasma glucose change -4.6 ± 3.4 vs. -2.1 ± 3.1 mmol/l (P = 0.01). The correlation between the plasma glucose nadir and maximum oxygen uptake was r = -0.38 (P = 0.01). Conclusions: Patients with good fitness level seem to be more prone to hypoglycaemia during exercise. This could be the result of better insulin sensitivity and the fact that they tend to exercise at greater work thresholds. These results are a step toward a better understanding of the association between physical fitness and exercise-induced hypoglycaemia. © 2016 Diabetes UK.

Shalaby K.H.,McGill University | Al Heialy S.,McGill University | Tsuchiya K.,McGill University | Farahnak S.,McGill University | And 5 more authors.
Immunology | Year: 2017

The Toll-like receptor (TLR) adaptor proteins myeloid differentiating factor 88 (MyD88) and Toll, interleukin-1 receptor and resistance protein (TIR) domain-containing adaptor inducing interferon-β (TRIF) comprise the two principal limbs of the TLR signalling network. We studied the role of these adaptors in the TLR4-dependent inhibition of allergic airway disease and induction of CD4+ ICOS+ T cells by nasal application of Protollin™, a mucosal adjuvant composed of TLR2 and TLR4 agonists. Wild-type (WT), Trif-/- or Myd88-/- mice were sensitized to birch pollen extract (BPEx), then received intranasal Protollin followed by consecutive BPEx challenges. Protollin's protection against allergic airway disease was TRIF-dependent and MyD88-independent. TRIF deficiency diminished the CD4+ ICOS+ T-cell subsets in the lymph nodes draining the nasal mucosa, as well as their recruitment to the lungs. Overall, TRIF deficiency reduced the proportion of cervical lymph node and lung CD4+ ICOS+ Foxp3- cells, in particular. Adoptive transfer of cervical lymph node cells supported a role for Protollin-induced CD4+ ICOS+ cells in the TRIF-dependent inhibition of airway hyper-responsiveness. Hence, our data demonstrate that stimulation of the TLR4-TRIF pathway can protect against the development of allergic airway disease and that a TRIF-dependent adjuvant effect on CD4+ ICOS+ T-cell responses may be a contributing mechanism. © 2017 John Wiley & Sons Ltd.

PubMed | Institute Of Recherches Cliniques Of Montreal Montreal, Pfizers Cardiovascular and Metabolic Diseases Research Unit Cambridge and Laval University
Type: Journal Article | Journal: Pharmacology research & perspectives | Year: 2014

We hypothesized that peptide hormone sequences that stimulate and internalize G protein-coupled receptors (GPCRs) could be prolonged with a functional protein cargo. To verify this, we have selected two widely different pairs of peptide hormones and GPCRs that nevertheless share agonist-induced arrestin-mediated internalization. For the parathyroid hormone (PTH) PTH1 receptor (PTH1R) and the bradykinin (BK) B2 receptor (B2R), we have designed fusion proteins of the agonists PTH1-34 and maximakinin (MK, a BK homologue) with the enhanced green fluorescent protein (EGFP), thus producing candidate high molecular weight ligands. According to docking models of each hormone to its receptor, EGFP was fused either at the N-terminus (MK) or C-terminus (PTH1-34) of the ligand; the last construction is also secretable due to inclusion of the preproinsulin signal peptide and has been produced as a conditioned medium. EGFP-MK has been produced as a lysate of transfected cells. Using an enzyme-linked immunosorbent assay (ELISA) for GFP, average concentrations of 1.5 and 1670 nmol/L, respectively, of ligand were found in these preparations. The functional properties and potential of these analogs for imaging receptor-expressing cells were examined. Microscopic and cytofluorometric evidence of specific binding and internalization of both fusion proteins was obtained using recipient HEK 293a cells that expressed the cognate recombinant receptor. Endosomal colocalization studies were conducted (Rab5, Rab7, -arrestin1). Evidence of agonist signaling was obtained (expression of c-Fos, cyclic AMP responsive element (CRE) reporter gene for PTH1-34-EGFP). The constructs PTH1-34-EGFP and EGFP-MK represent bona fide agonists that support the feasibility of transporting protein cargoes inside cells using GPCRs.

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