Effect of inhibition of angiotensin converting enzyme and/or neutral endopeptidase on vascular and neural complications in high fat fed/low dose streptozotocin-diabetic rats

Abstract

Treating high fat fed/low dose streptozotocin-diabetic rats; model of type 2 diabetes, with ilepatril (vasopeptidase inhibitor, blocks neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE)) improved vascular and neural function. Next, studies were performed to determine the individual effect of inhibition of NEP and ACE on diabetes-induced vascular and neural dysfunction. High fat fed rats (8 weeks) were treated with 30 mg/kg streptozotocin (i.p.) and after 4 additional weeks, were treated for 12 weeks with ilepatril, enalapril (ACE inhibitor) or candoxatril (NEP inhibitor) followed by analysis of vascular and neural function. Glucose clearance was impaired in diabetic rats and was not improved with treatment although treatment with ilepatril or candoxatril partially improved insulin stimulated glucose uptake by isolated soleus muscle. Diabetes caused slowing of motor and sensory nerve conduction, thermal hypoalgesia, reduction in intraepidermal nerve fiber (IENF) profiles and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide (CGRP) in epineurial arterioles of the sciatic nerve. Inhibition of NEP improved nerve conduction velocity and inhibition of NEP or ACE improved thermal sensitivity and protected IENF density. Ilepatril and candoxatril treatment of diabetic rats was efficacious in improving vascular responsiveness to acetylcholine in epineurial arterioles; whereas all three treatments improved vascular response to CGRP. These studies suggest that inhibition of NEP and ACE activity is an effective approach for treatment of type 2 diabetes neural and vascular complications.

Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice

“…Ceramides are released as products of complex sphingolipid hydrolysis or synthetized from sphingoid base (Sph or dhSph) and LCFa-CoA at the level of sarcoplasmic reticulum (45). The rise in circulating FFA and elevated muscle ceramide levels was observed previously in soleus and red gastrocnemius skeletal muscle of streptozotocin-diabetic rats (8,16) and in muscle-specific insulin receptor knockout mice and streptozotocin-treated mice (23). De novo sphingolipid synthesis depends on the supply of LCFa-CoA for both the sphingosine backbone formation by SPT and subsequent sphingosine acylation to yield ceramide.…”

Diabetic neuropathy: clinical manifestations and current treatments

“…The renin-angiotensin system (RAS), which controls blood pressure, is upregulated in obesity, and may also contribute to development of type 2 diabetes (in part through promotion of IR and pro-inflammatory cytokine secretion from adipose tissue) 99 . Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve diabetic neuropathy in animal studies 100, 101 , but the mechanism is unclear. Microvascular dysfunction in the nerve and decreased endoneurial perfusion are also thought to contribute to neuropathy 102 .…”

GLP-1-derived nonapeptide GLP-1(28–36)amide represses hepatic gluconeogenic gene expression and improves pyruvate tolerance in high-fat diet-fed mice

“…When the NEP 24.11 inhibitor candoxatril was administered in pigs undergoing GLP-1 infusion, glucose tolerance improved, likely through the improvement of GLP-1 pharmacokinetics (33). NEP 24.11 inhibition also led to improved vascular and neural complications in HFD-induced and streptozotocin-induced diabetic rats (9,10,30). These observations collectively suggest that the prevention of NEP 24.11-mediated GLP-1 degradation confers benefits to glucose homeostasis, which is conceptually in contradiction to the notion that GLP-1(28 -36)a exerts beneficial effects in glucose metabolism.…”