2. Academic Validation
  3. Cinaciguat in combination with insulin induces a favorable effect on implant osseointegration in type 2 diabetic rats

Cinaciguat in combination with insulin induces a favorable effect on implant osseointegration in type 2 diabetic rats

  • Biomed Pharmacother. 2019 Oct;118:109216. doi: 10.1016/j.biopha.2019.109216.
Tingting Jia 1,  Ya-Nan Wang 1,  Jiajia Zhang 1,  Xinyu Hao 2,  Dongjiao Zhang 3,  Xin Xu 4
Affiliations

Affiliations

  • 1 Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, Shandong Province, China; Department of Implantology, School of Stomatology, Shandong University, Jinan, Shandong Province, China.
  • 2 Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, Shandong Province, China; Department of Pediatric Dentistry, School of Stomatology, Shandong University, Jinan, Shandong Province, China.
  • 3 Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, Shandong Province, China; Department of Implantology, School of Stomatology, Shandong University, Jinan, Shandong Province, China. Electronic address: djzhang1109@163.com.
  • 4 Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, Shandong Province, China; Department of Implantology, School of Stomatology, Shandong University, Jinan, Shandong Province, China. Electronic address: xinxu@sdu.edu.cn.
PMID: 31319371 DOI: 10.1016/j.biopha.2019.109216
Abstract

The osseointegration process of implant is seriously impaired in type 2 diabetes mellitus (T2DM) that causes high failure rate, and insufficiency exists in current Insulin therapy, creating a demand for new bone-synergistic agent. Cinaciguat, a novel type of soluble Guanylate Cyclase (sGC) activator, plays a vital role in glucose metabolism, inflammation control and bone regeneration. We hypothesized that the combined application of cinaciguat and Insulin could reverse poor implant osseointegration in diabetes. To test this hypothesis, streptozotocin-induced diabetic rats were placed implants in the femur, and divided into five groups: control, T2DM, cinaciguat-treated T2DM (7 μg/kg), insulin-treated T2DM (12 IU/kg), cinaciguat plus Insulin combination-treated T2DM (7 μg/kg and 12 IU/kg respectively), according to different treatment received. The weight and glucose levels of rats were evaluated at fixed times, and plasma level of cyclic guanosine monophosphate (cGMP) was determined before euthanasia. Three months after therapy, the femurs were isolated for pull-out test, environmental scanning electron microscope observation, microscopic computerized tomography evaluation and various histology analysis. Results revealed that diabetic rats showed the highest blood glucose level and lowest cGMP content, which led to the worst structural damage and least osseointegration. Combined treatment could attenuate the diabetes induced hyperglycemia to be normal, restore the cGMP content, protein kinase G II (PKG II) expression, phosphodiesterase-5 (PDE5) activity and ameliorate the mechanical strength, the impaired bone microarchitecture and osseointegration to the highest level. Meanwhile, monotreatment (Insulin or cinaciguat) also showed restorative effect, but less. Our findings demonstrated that the cGMP/PKG II signaling pathway activated by cinaciguat mediated the favorable effects of the combined application on improving implant fixation under T2DM condition.

Keywords

Cinaciguat; Cyclic guanosine monophosphate (cGMP); Insulin; Osseointegration; Protein kinase G II (PKG II); Type 2 diabetes mellitus.

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