Vascular and Neural Complications in Type 2 Diabetic Rats: Improvement by Sacubitril/Valsartan Greater Than Valsartan Alone

Abstract

Previously, we had shown that a vasopeptidase inhibitor drug containing ACE and neprilysin inhibitors was an effective treatment for diabetic vascular and neural complications. However, side effects prevented further development. This led to the development of sacubitril/valsartan, a drug containing angiotensin II receptor blocker and neprilysin inhibitor that we hypothesized would be an effective treatment for diabetic peripheral neuropathy. Using early and late intervention protocols (4 and 12 weeks posthyperglycemia, respectively), type 2 diabetic rats were treated with valsartan or sacubitril/valsartan for 12 weeks followed by an extensive evaluation of vascular and neural end points. The results demonstrated efficacy of sacubitril/valsartan in improving vascular and neural function was superior to valsartan alone. In the early intervention protocol, sacubitril/valsartan treatment was found to slow progression of these deficits and, with late intervention treatment, was found to stimulate restoration of vascular reactivity, motor and sensory nerve conduction velocities, and sensitivity/regeneration of sensory nerves of the skin and cornea in a rat model of type 2 diabetes. These preclinical studies suggest that sacubitril/valsartan may be an effective treatment for diabetic peripheral neuropathy, but additional studies will be needed to investigate these effects further.

Insulin Treatment Attenuates Small Nerve Fiber Damage in Rat Model of Type 2 Diabetes

“…Furthermore, this lack of pretreatment tests makes it difficult to completely determine if treatment slowed progression or reversed the nerve damages observed. Because slowing of MNCV was not observed in this study, there might be a difference in the neuropathic phenotype between the animals of the present study and the animals used in other studies [10,11,16]. This is further supported by the different effects of long-term diabetes on thermal induced pain (hypoalgesia vs. hyperalgesia) between the present study (Figures 4(a) and 4(b)) and other studies [10,11,16].…”

“…In this study, diabetes did not cause large nerve fiber damage when assessed by MNCV (Figure 4(d)). That 16 weeks of untreated diabetes was not enough to cause a decline in MNCV was surprising because decreased MNCV has been observed in other studies of similar length using similar rat models of T2D [10,11,16]. Increased sorbitol and decreased myo-inositol content in the sciatic nerve have The response variables (a) thermal induced pain and (b) intraepidermal nerve fiber density (IENFD) were evaluated in an analysis of covariance using stepwise backwards reduction leaving only significant covariates with group as class variable and HbA 1c %, sciatic nerve sorbitol content, triglyceride (TG), and total cholesterol (TC) as covariates to investigate the influence of the covariates on nerve damage.…”

“…In this study, diabetes did not cause large nerve fiber damage when assessed by MNCV ( Figure 4(d) ). That 16 weeks of untreated diabetes was not enough to cause a decline in MNCV was surprising because decreased MNCV has been observed in other studies of similar length using similar rat models of T2D [ 10 , 11 , 16 ]. Increased sorbitol and decreased myo -inositol content in the sciatic nerve have been associated with decreased MNCV in experimental type 1 diabetes [ 17 ].…”

“…Because slowing of MNCV was not observed in this study, there might be a difference in the neuropathic phenotype between the animals of the present study and the animals used in other studies [10,11,16]. This is further supported by the different effects of long-term diabetes on thermal induced pain (hypoalgesia vs. hyperalgesia) between the present study (Figures 4(a) and 4(b)) and other studies [10,11,16]. Vendor-derived differences in rats are a described phenomenon in other studies in respect to different behavioral, metabolic, and pain-related parameters [45][46][47] and might explain the different observations.…”

“…Four weeks after diabetes induction, the streptozotocin-treated diet-induced obese (STZ-DIO) animals were allocated using minimization [ 14 ] based on body weight, body fat percentage, and HbA 1c % to three treatment groups (STZ-DIO high-insulin, STZ-DIO low-insulin, and STZ-DIO vehicle) receiving either insulin-releasing or vehicle implants (LinShin Canada Inc., Linplant, Ontario, Canada). A 12-week treatment period was chosen not only because it would gain a stable treatment condition but also because this would result in 16 weeks of hyperglycemia which has resulted in substantial nerve damage in other studies using the same model [ 10 , 11 , 16 ]. Nonfasted morning blood glucose and body weight were monitored weekly during the whole treatment period.…”