Stimulation of insulin secretion by short-term glucagon receptor (GCGR) activation is well characterized; however, the effect of long-term GCGR activation on b-cell function is not known, but of interest, since hyperglucagonemia occurs early during development of type 2 diabetes. Therefore, we examined whether chronic GCGR activation affects insulin secretion in glucose intolerant mice. To induce chronic GCGR activation, high-fat diet fed mice were continuously (2 weeks) infused with the stable glucagon analog ZP-GA-1 and challenged with oral glucose and intravenous glucoseGglucagon-like peptide 1 (GLP1). Islets were isolated to evaluate the insulin secretory response to glucoseGGLP1 and their pancreas were collected for immunohistochemical analysis. Two weeks of ZP-GA-1 infusion reduced insulin secretion both after oral and intravenous glucose challenges in vivo and in isolated islets. These inhibitory effects were corrected for by GLP1. Also, we observed increased b-cell area and islet size. We conclude that induction of chronic ZP-GA-1 levels in glucose intolerant mice markedly reduces insulin secretion, and thus, we suggest that chronic activation of the GCGR may contribute to the failure of b-cell function during development of type 2 diabetes.
Endogenous peptide hormones, such as glucagon used for treatment of severe hypoglycemia events in patients with diabetes, are commonly unstable in aqueous solution making development of ready-to-use injection solutions a challenge. Analogs of endogenous peptide hormones can be designed to increase the stability of the molecules. Another approach to enable easy administration of unstable peptides is to formulate them in non-aqueous formulations, such as DMSO (dimethyl sulfoxide). The current study was conducted to compare the PK/PD of glucagon following SC administration in rats when formulated in DMSO or an aqueous formulation (Phosphate buffered solution (PBS)). The PD data were compared to data generated for the stable glucagon analog dasiglucagon in rats. Four to six male Sprague-Dawley rats received 3 nmol/kg of glucagon in DMSO or in a PBS formulation or dasiglucagon at 2 nmol/kg in a PBS formulation. Blood samples for bioanalysis (glucagon groups only) and blood glucose measurement were taken at pre-dose (0) and 15, 30, 45, 60, 75, 90, 105 and 120 min post dose. Glucagon in PBS demonstrated a faster absorption, a higher Cmax (98.3 versus 39.9 pmol/L) and faster Tmax (15 versus 45 minutes) compared to glucagon in DMSO. The increase in blood glucose was similar for glucagon and dasiglucagon in PBS and faster compared to glucagon in DMSO. Disclosure C. Wenander: Employee; Self; Zealand Pharma A/S. A.H. Valeur: Employee; Self; Zealand Pharma A/S. M. Elander: Employee; Self; Zealand Pharma A/S.
Background Chronic mitral regurgitation (MR) leads to progressive left atrial (LA) dilation. Its relative contribution to 3-dimensional (3D) LA structural and functional remodelling and the impact of concomitant clinical and hemodynamic factors, has been less explored. Aims To assess 3D LA size and mechanics, as well as mean LA pressure estimated from the pulmonary vein flow, in relation to chronic MR severity. Methods In the prospective 3D-PRIME (3D Echocardiography and Cardiovascular Prognosis in Mitral Regurgitation) study, 46 patients with chronic MR (69±13 years, body mass index (BMI) 26.2±4.3kg/m2, 50% women, 26% with atrial fibrillation, 30% with severe MR) recruited at one heart valve center were investigated with 2D and 3D transthoracic and transesophageal echocardiography. MR severity was quantified by the regurgitant volume (RV) and MR classified as organic, atrial functional or ventricular functional, as by current recommendations. LA size was measured by 3D maximum volume (LAV) indexed for body surface area (LAVI), LA mechanics by 3D peak relative increase in longitudinal volume in the reservoir phase (Sr), and mitral size by 3D annulus area and total leaflet area. Pulmonary vein Doppler flow profile was recorded in both right and left upper veins, and mean LA pressure was estimated from the average pulmonary vein systolic/diastolic velocity time integral ratio. Results Average mitral RV was 38±26ml, LAVI 53ml/m2, and Sr 17±11%. Increased mitral RV correlated with higher LAV and mean LA pressure (Figure 1), larger mitral annulus area (r=0.42) and total leaflet area (r=0.38) (all p<0.01), but not with Sr. In backward stepwise multivariate linear regression analyses, increased LAVI was independently predicted by larger mitral RV, higher age and atrial fibrillation (R2=0.62), higher mean LAP by larger mitral RV, body mass index and atrial fibrillation (R2=0.55), while lower Sr was associated with higher age and atrial fibrillation (R2=0.62) (all p<0.001). Patients with atrial functional MR (30% of the total group) had the largest LAVs and lowest Sr despite slightly lower mitral RV (Figure 2). Conclusion Chronic MR is associated with progressive increase in LA volume, mean LA pressure, and mitral annulus and total leaflet area. While MR is accompanied by low 3D LA longitudinal deformation, impaired LA mechanics is multifactorial and related closely to age and history of atrial arrythmias. FUNDunding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Haukeland University Hospital Figure 1 Figure 2
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