These results indicate that improvement of NO release with a low dose but not with a high dose of L-arginine significantly attenuates the development of hypertension and the progression of renal insufficiency in rats with reduced renal mass. These protective effects may be mediated in part by the reduction of vascular and renal ET-1 production.
These findings indicate that the effect of losartan on ET-1 production in peripheral blood vessels may be mediated, in part, by the reduction of blood pressure. In contrast, the reduction of renal ET-1 production is mediated by tissue-specific effects of AT1 receptor blockade, and may contribute to the renal protective effects of losartan.
Aims: To investigate the effects of 24 weeks of treatment with liraglutide added to basal/bolus insulin on anthropometric and metabolic parameters in overweight participants with type 1 diabetes.Methods: In a double-blinded cross-over fashion, 15 participants were randomly assigned (1:1) to receive placebo (saline solution) or liraglutide for 24 weeks including a 1-month titration period from 0.6 to 1.2 to 1.8 mg, in addition to their insulin. The treatment was followed by a 1-month wash-out period. Participants were then assigned to the other treatment for another 24 weeks. Paired rank tests were used to compare the metabolic parameters.Results: There was no treatment effect on HbA1c nor on insulin dose. Heart rate was increased by about 8 beats per minute with liraglutide. There were significant reductions in metabolic measures: weight, body mass index, waist and hip circumferences, body fatness, computed tomography scan abdominal and mid-thigh measurements, systolic and diastolic blood pressures (all P ≤ .05). There was no increase in time spent in hypoglycaemia with liraglutide.Conclusions: The addition of liraglutide to basal/bolus insulin therapy for 24 weeks in overweight/obese individuals with type 1 diabetes improved the anthropometric and metabolic profiles without an increase in hypoglycaemia.Clinical Trials.gov No: NCT01787916.
| INTRODUCTIONThe prevalence of overweight and obesity in type 1 diabetes (T1D) has been recently reported to be 42% and 22.7% respectively. 1 These percentages may result from the overall trend observed in the general population, as well as from an anabolic effect of insulin treatment, or a higher caloric intake to prevent hypoglycaemia. 2,3 It has been demonstrated that the increased weight and adiposity resulted in adverse lipid and haemodynamic profiles and is associated with longterm complications. 4,5 Glucagon-like peptide-1 receptor agonists (GLP-1 RA) demonstrate benefits in blood glucose control but could potentially preserve β-cell function and improve diabetes-related co-morbidities, such as hypertension and obesity. 6-8 GLP-1 RA improves the glycaemic profile by inhibiting glucagon secretion, delaying gastric emptying, and mediating weight loss by reducing appetite and caloric intake. 9 Liraglutide, mostly used with type 2 diabetes (T2D), exhibits favorable effects on diabetes control by increasing insulin sensitivity as an extrahepatic action. 10 With a growing number of overweight and obese patients with T1D, we may wonder if these potential metabolic benefits could also be relevant in this population.Several trials have looked at the effect of adding liraglutide to insulin to treat T1D patients. Varanasi et al. 11,12 showed improvements in glycaemic control, and reductions in insulin doses and body weight in obese T1D individuals. A recent randomized, doubleblinded, placebo-controlled trial in T1D patients showed that liraglutide was associated with reductions in weight, hypoglycaemic events, and insulin doses. 13 The ADJUNCT ONE Trial showed reductions in HbA1c...
Elevated plasma and urinary endothelin-1 (ET-1) levels have been reported in patients with renal failure as well as in remnant kidney models of chronic renal failure. We investigated whether these changes are related to increased ET-1 production in cardiovascular and renal tissues of rats with reduced renal mass. In uremic rats, systolic blood pressure rose in parallel with the progression of renal insufficiency. At week 6, changes in systolic blood pressure were positively correlated with serum creatinine levels (r = 0.728, p < 0.01). Plasma immunoreactive ET-1 (ir-ET-1) concentration was similar in uremic rats and sham-operated controls. In contrast, urinary ir-ET-1 excretion was significantly greater in uremic rats and was correlated with the elevation of serum creatinine and proteinuria (r = 0.795, and 0.922, p < 0.01, respectively). Compared to the controls, ir-ET-1 concentration in the thoracic aorta, preglomerular arteries and glomeruli were 1.4-, 3.5- and 6.7-fold higher, respectively, in uremic rats (p < 0.01) than in the controls. However, ir-ET-1 concentration in the mesenteric arterial bed and the left ventricle remained similar in the 2 groups, whereas it was significantly lower in the renal papilla of uremic rats (p < 0.01). Thus, ET-1 production is unchanged or slightly increased in extrarenal cardiovascular tissues of rats with reduced renal mass. In contrast, ET-1 production is significantly augmented in preglomerular arteries and glomeruli, but reduced in the papilla, suggesting that increased urinary ir-ET-1 excretion in uremic rats reflects ET-1 overproduction in the former renal tissues. Elevated ET-1 production in blood vessels and glomeruli may thus play a key role in the aggravation of hypertension and the progression of renal insufficiency in this rat remnant kidney model of chronic renal failure.
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