Related Experiment Video
Updated: Sep 7, 2025
Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice
Published on: September 28, 2015
Insulinotropic Effects of Neprilysin and/or Angiotensin Receptor Inhibition in Mice
Nathalie Esser1,2,3, Christine Schmidt1, Breanne M Barrow1
1Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States.
Abstract:
Treatment of heart failure with the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan improved glycemic control in individuals with type 2 diabetes. The relative contribution of neprilysin inhibition versus angiotensin II receptor antagonism to this glycemic benefit remains unknown. Thus, we sought to determine the relative effects of the neprilysin inhibitor sacubitril versus the angiotensin II receptor blocker valsartan on beta-cell function and glucose homeostasis in a mouse model of reduced first-phase insulin secretion, and whether any beneficial effects are additive/synergistic when combined in sacubitril/valsartan. High fat-fed C57BL/6J mice treated with low-dose streptozotocin (or vehicle) were followed for eight weeks on high fat diet alone or supplemented with sacubitril, valsartan or sacubitril/valsartan. Body weight and fed glucose levels were assessed weekly. At the end of the treatment period, insulin release in response to intravenous glucose, insulin sensitivity, and beta-cell mass were determined. Sacubitril and valsartan, but not sacubitril/valsartan, lowered fasting and fed glucose levels and increased insulin release in diabetic mice. None of the drugs altered insulin sensitivity or beta-cell mass, but all reduced body weight gain. Effects of the drugs on insulin release were reproduced in angiotensin II-treated islets from lean C57BL/6J mice, suggesting the insulin response to each of the drugs is due to a direct effect on islets and mechanisms therein. In summary, sacubitril and valsartan each exert beneficial insulinotropic, glycemic and weight-reducing effects in obese and/or diabetic mice when administered alone; however, when combined, mechanisms within the islet contribute to their inability to enhance insulin release.
Insights
Sacubitril and valsartan individually improved glucose control and insulin release in diabetic mice. However, the combination drug sacubitril/valsartan did not enhance these benefits, suggesting islet mechanisms limit combined effects.
Area of Science:
- Endocrinology
- Pharmacology
- Metabolic Diseases
Background:
- The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan improves glycemic control in type 2 diabetes patients.
- The specific contributions of neprilysin inhibition (sacubitril) versus angiotensin II receptor blockade (valsartan) to this benefit are unclear.
- Understanding these individual effects is crucial for optimizing diabetes treatment strategies.
Purpose of the Study:
- To compare the effects of sacubitril and valsartan on beta-cell function and glucose homeostasis in a mouse model.
- To investigate if combining sacubitril and valsartan yields additive or synergistic glycemic benefits.
- To elucidate the direct impact of these drugs on pancreatic islets.
Main Methods:
- High fat-fed mice received streptozotocin to induce diabetes and were treated with sacubitril, valsartan, or sacubitril/valsartan for eight weeks.
- Weekly monitoring of body weight and glucose levels.
- Assessment of insulin release, insulin sensitivity, and beta-cell mass post-treatment; isolated islet studies were also performed.
Main Results:
- Both sacubitril and valsartan monotherapy reduced fasting and fed glucose levels and enhanced insulin release in diabetic mice.
- Sacubitril/valsartan combination did not show improved insulin release compared to monotherapy, despite similar weight reduction.
- Neither drug altered insulin sensitivity or beta-cell mass, but both reduced body weight gain; islet studies confirmed direct drug effects.
Conclusions:
- Sacubitril and valsartan individually provide beneficial effects on insulin secretion, glucose levels, and body weight in obese/diabetic mice.
- The combination of sacubitril/valsartan did not enhance insulinotropic effects, indicating potential limitations from islet-specific mechanisms.
- These findings highlight distinct roles for neprilysin inhibition and angiotensin receptor blockade in glucose metabolism.
More Related Videos
Related Concept Videos
01:30Antihypertensive Drugs: Angiotensin-Converting Enzyme Inhibitors
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
01:25Antihypertensive Drugs: Direct Renin Inhibitors
01:30Antihypertensive Drugs: Angiotensin II Receptor Blockers
01:27Transducer Mechanism: Enzyme-Linked Receptors
Major types that are helpful drug targets include:
01:17Antihypertensive Drugs: Action of β1 Blockers