Gap junctions play a critical role in electrical synchronization and exchange of small molecules between neighboring cells; connexins are a family of structurally related transmembrane proteins that assemble to form vertebrate gap junctions. Hyperglycemia changes the structure gap junction proteins and their expression, resulting in obstruction of neural regeneration, vascular function and wound healing, and also promoting vascular atherosclerosis. These pathogenic factors would cause diabetic foot ulcers. This article reviews the involvement of connexins in pathogenesis of diabetic foot.
Atherosclerosis ; Connexins ; metabolism ; Diabetic Foot ; pathology ; Gap Junctions ; metabolism ; Humans ; Hyperglycemia ; physiopathology ; Regeneration ; Wound Healing

The number of patients with diabetic foot ulcer (DFU) has increased progressively year by year. Refractory DFU has brought great burden to the country and individuals. How to accelerate the healing of DFU has become the main emphasis of research. However currently, the mechanism of its refractory healing is not fully elucidated, and the correlation between the various mechanisms are not high. Therefore, its clinical standardization, and precise clinical diagnosis and treatment still face several challenges. Based on the progress of clinical research and basic research at home and abroad, this paper reviewed the specific mechanisms that lead to refractory DFU, with the focus on chronic inflammation, bacteria biofilm formation, high oxidative stress, growth factor inhibition, impaired microcirculation, and accumulation of advanced glycation end products.
Humans ; Diabetic Foot/metabolism* ; Wound Healing ; Glycation End Products, Advanced/metabolism* ; Diabetes Mellitus

Diabetic Foot ; enzymology ; physiopathology ; Humans ; Matrix Metalloproteinases ; metabolism ; Wound Healing ; physiology

OBJECTIVETo compare the difference between the burn wound and diabetic ulcer wound, and to preliminarily analyze the nonhealing mechanism of diabetic unclear.

METHODSThe tissue of foot ulcer of diabete patients and skin wound tissues from burn patients were harvested. The levels of (FGF)2 and VEGF in the wound tissues were determined after tissue cultivation with enzyme-linked immunosorbent assay (ELISA). The changes in micro-vascular density (MVD) were examined by immunohistochemistry. Human umbilical vein endothelial cells were cultured in medium containing different components, and divided into following groups: A (with treatment of 5 mmol/L glucose for 7 days), B (with treatment of 30 mmol/L glucose for 7 days) and C (with treatment of 30 mmol/L Mannitol for 7 days) groups, then the level of VEGF protein was determined by ELISA.

RESULTSThe levels of FGF2 and VEGF protein in the burn wound were (59 +/- 3) ng/ml and (56 +/- 7) pg/ml, respectively, which were obviously lower than those in diabetic ulcer wound [(89 +/- 6) ng/ml, (108 +/- 5) pg/ml, P < 0.05]. There was also obvious difference in MVD between two kinds of wound (P < 0.05). The level of VEGF protein in both wounds were similar after the addition of FGF2 to the cell culture in vitro, while there were statistically significant difference 2 and 5 days after removal of FGF.

CONCLUSIONThe nonhealing mechanism of diabetic ulcer wound may be related to the inhibition of vacuolation and low expression of factors controlling vessel growth.

Burns ; complications ; metabolism ; pathology ; Cells, Cultured ; Diabetic Foot ; pathology ; Fibroblast Growth Factor 2 ; metabolism ; Foot Ulcer ; etiology ; pathology ; Humans ; Neovascularization, Physiologic ; Vascular Endothelial Growth Factor A ; metabolism ; Wound Healing

Involvement of the peripheral nerveous system by diabetes is referred to as diabetic neuropathy. The frequency of diabetic neuropathy ranges from 5% to 60% and the pain management is one of the greatest problem. The patient was a 57-year-old man who has been treated with diabetes(DM type IIa) for about 12 years. The symmetrical pain, swelling and sensory loss on feet were started 3 months before admission and the burning pain was intensified at night with resultant insomnia. The systoms were aggravated 1 month ago and they were not relieved by any medication and physical therapy. We attempted lumbar epidural block to the patient and the result was good. So we performed a permanent lumbar sympathetic ganglion block with neurolytics(99.9% alcohol) for the long term relief of pain. The patient was satisfied with the result of the block and discharged.
Burns ; Diabetic Neuropathies* ; Foot ; Ganglia, Sympathetic ; Humans ; Metabolism ; Middle Aged ; Pain Management* ; Sleep Initiation and Maintenance Disorders ; Sympathetic Nervous System

OBJECTIVETo determine and perform a correlation analysis of the contents of putrescine, cadaverine, and histamine in necrotic tissue, blood, and urine of patients with diabetic foot (DF).

METHODSTen patients with severe wet necrotizing DF hospitalized from January 2011 to January 2012 were assigned as group DF, and 10 orthopedic patients with scar but without diabetes or skin ulcer hospitalized in the same period were assigned as control group. Samples of necrotic tissue from feet of patients in group DF and normal tissue from extremities of patients in control group, and samples of blood and 24-hour urine of patients in both groups were collected, and the amount of each sample was 10 mL. Contents of putrescine, cadaverine, and histamine were determined with high performance liquid chromatography-mass spectrometry. The data got from the determination of blood and urine were processed with t test, and those from necrotic or normal tissue with Wilcoxon rank sum test. The correlation of contents of polyamines between necrotic tissue and blood, blood and urine were processed with simple linear regression analysis.

RESULTS(1) Contents of putrescine, cadaverine, and histamine in the necrotic tissue of group DF were (186.1 ± 26.8), (78.553 ± 12.441), (33 ± 10) mg/kg, which were significantly higher than those in normal tissue of control group [(2.2 ± 1.2), (1.168 ± 0.014), 0 mg/kg, with Z values respectively -3.780, -3.781, -4.038, P values all below 0.01]. The content of putrescine in necrotic tissue of group DF was significantly higher than those of cadaverine and histamine (with Z values respectively -3.780, -3.630, P values all below 0.01). (2) Contents of putrescine, cadaverine, and histamine in the blood of group DF were (0.075 ± 0.013), (0.022 ± 0.003), (0.052 ± 0.014) mg/L, and they were significantly higher than those in the blood of control group [(0.014 ± 0.009), (0.013 ± 0.003), (0.016 ± 0.008) mg/L, with t values respectively 6.591, 2.207, 3.568, P < 0.05 or P<0.01]. The content of putrescine in the blood of group DF was significantly higher than those of cadaverine and histamine (with t values respectively 13.204, 3.096, P values all below 0.01). (3) Contents of putrescine, cadaverine, and histamine in the urine of group DF were (0.735 ± 0.088), (0.450 ± 0.012), (0.1623 ± 0.0091) mg/L, and only the contents of putrescine and cadaverine were significantly higher than those in the urine of control group [(0.050 ± 0.014), (0.035 ± 0.007) mg/L, with t values respectively 3.270, 4.705, P<0.05 or P<0.01]. The content of putrescine in the urine of group DF was significantly higher than that of cadaverine (t = 6.686, P < 0.01). (4) There were significant and positive correlations in contents of putrescine, cadaverine, and histamine between necrotic tissue and blood in patients of group DF (with r values respectively 0.981, 0.994, 0.821, P values all below 0.01). There were no significant correlations in contents of putrescine, cadaverine, and histamine between blood and urine in patients of group DF (with r values respectively 0.150, 0.239, 0.177, P values all above 0.05).

CONCLUSIONSPutrescine, cadaverine, and histamine exist in the necrotic tissue of patients with DF in high concentrations, among which putrescine predominates. These polyamines can be absorbed into the blood through wound and excreted through the urine.

Adult ; Aged ; Cadaverine ; blood ; metabolism ; urine ; Case-Control Studies ; Diabetic Foot ; blood ; metabolism ; urine ; Female ; Histamine ; blood ; metabolism ; urine ; Humans ; Male ; Middle Aged ; Necrosis ; Putrescine ; blood ; metabolism ; urine

OBJECTIVETo investigate the effects of local injection of insulin on the level of systemic blood glucose and granulation tissue formation of wound in patients with diabetic foot ulcer.

METHODSThirty-two patients with diabetic foot ulcer hospitalized in our wards from June 2009 to June 2010 were divided into insulin (I, n = 16) and control (C, n = 16) groups according to the random number table. For patients in I group, after debridement, one half of calculated dose of insulin diluted with equal amount of normal saline was injected diffusely into the base of the ulcer, and another half dose of insulin was subcutaneously injected into abdominal wall for 7 days, two times a day. For patients in C group, after debridement, primary insulin was subcutaneously injected into abdominal wall, 1 mL saline was subcutaneously injected into basal layer of ulcer for 7 days, two times a day. Before injection and 0.5, 1.0, 2.0, and 4.0 hours after injection (PIH), level of fasting blood glucose was determined. Before injection and on post injection day (PID) 3, 5, and 7, the growth of granulation tissue was assessed, and wound specimens were harvested for observation of CD34 expression and calculation of microvessel density (MVD). Data were processed with t test.

RESULTSThe levels of fasting blood glucose in both groups during observational time points ranged from 6.6 mmol/L to 12.8 mmol/L with a mean of (10.0 ± 2.2) mmol/L, and there was no statistical difference (with t values from 0.000 to 2.209, P values all above 0.05). Growth of granulation tissue in I group was more exuberant from PID 5, especially on PID 7 [(59.06 ± 1.58)%], which was significantly richer than that in C group [(23.61 ± 1.57)%, t = 17.420, P = 0.000]. New vessels were observed in I group from PID 3 as indicated by CD34 expression. There was no obvious difference in the number of MVD between I group and C group on PID 3 (t = 0.247, P > 0.05). The number of MVD per 200 times visual field in I group was respectively 8.34 ± 0.48, 11.22 ± 0.97 on PID 5 and 7, which was respectively higher than that in C group (4.42 ± 0.14, 5.44 ± 1.13, with t value respectively 16.568, 27.664, P values all below 0.01).

CONCLUSIONSLocal injection of insulin has a significant effect on systemic blood glucose in patients with diabetic foot ulcer, and it can promote the growth of granulation tissue and wound healing.

Adult ; Aged ; Aged, 80 and over ; Blood Glucose ; metabolism ; Diabetic Foot ; drug therapy ; metabolism ; Female ; Humans ; Injections ; Insulin ; administration & dosage ; therapeutic use ; Male ; Middle Aged ; Wound Healing

OBJECTIVETo explore the expression characteristic of fibronectin gene in hypertrophic scars and diabetic ulcer tissues.

METHODSThe biopsies from normal skins, hypertrophic scars and diabetic foot ulcers were taken. The technique of quantitative polymerase chain reaction (PCR) was used to evaluate the gene expression of fibronectin in the above biopsies.

RESULTSFibronectin gene expression was enhanced in hypertophic scars and decreased in diabetic foot ulcers compared with that in normal skins. Quantitative comparison showed about 2-fold increase of fibronectin mRNA level in hypertrophic scars and about 3-fold decrease of fibronectin mRNA level in diabetic ulcers as compared with that in normal skins.

CONCLUSIONSFibronectin gene expression is influenced by the tissue environment. Different expression and synthesis of fibronectin may cause different outcomes in wound healing.

Adolescent ; Adult ; Aged ; Cicatrix, Hypertrophic ; metabolism ; Diabetic Foot ; metabolism ; Female ; Fibronectins ; biosynthesis ; genetics ; Gene Expression ; Humans ; Male ; Middle Aged ; RNA, Messenger ; genetics

The suitable experimental animal model is important in research of pathogenesis and therapeutic strategies of diabetic foot ulcer, and the murine model is the most commonly used one at present. It can be divided into two types: the animal model simulating pathological conditions and the model simulating clinical symptoms. This article reviews the current research progress on the mechanisms of diabetic ulcer pathogenesis, and relevant treatment strategies, including the inhibition of matrix metalloproteinases (MMPs) expression, promotion of angiogenesis and anti-inflammatory therapy.
Animals ; Anti-Inflammatory Agents ; therapeutic use ; Diabetic Foot ; etiology ; genetics ; therapy ; Disease Models, Animal ; Humans ; Matrix Metalloproteinase Inhibitors ; therapeutic use ; Matrix Metalloproteinases ; genetics ; metabolism ; Mice ; Neovascularization, Physiologic ; physiology

OBJECTIVE: To assess the therapeutic effect of treating diabetic foot ulcers (DFUs) in rats by subcutaneously transplanting around the wounds and intramuscularly into the leg with bone marrow derived mesenchymal stem cells (BM-MSCs). METHODS: BM-MSCs from male Wistar rats were cultured by the whole bone marrow adherence method until the third generation. The BM-MSCs were labeled by 4,6-diamino-2-phenylindole (DAPI) in vitro. Forty-eight male Wistar rats were randomly divided into 4 groups: group A (n=12), rats with DFUs receiving BM-MSCs subcutaneous transplantation; group B (n=12), rats with DFUs receiving BM-MSCs intramuscular transplantation; group C (n=12), nondiabetic rats with foot ulcers; and group D (n=12), rats with DFUs receiving no BM-MSCs. A diabetic rat model was induced by intraperitoneally injecting streptozotocin (STZ). Then DFU model was established by removing a 3 mm × 7 mm rectangular full-thickness skin on the 2 back dorsum pedis surfaces. On day 2, 5, 8 and 11 after the transplantation, the rate of wound closure was raised; trace of DAPI labeled-BM-MSCs in the wound tissues was observed on frozen sections and the thickness of granulation tissues was detected by HE stain. Immunohistochemistry was performed to detect the expression of CD31 and Ki-67. The expression of vascular endothelial growth factor (VEGF) in the wound tissues was detected by ELISA and RT-PCR. RESULTS: The wound closure in group C was faster than in other groups (P<0.05). The rate of wound healing in group B was higher than group A on day 11 (P<0.05). The intensity and area of the fluorescence in group B were higher than group A on day 2 and 5 on the frozen sections. HE stain showed that the granulation tissue formation in group B was thicker than group A on day 5. Immunohistochemistry of CD31 demonstrated that the mean number of small blood vessels in group B was more than in group A on day 5 and 8 (P<0.05). Immunohistochemistry of Ki-67 showed it had no difference between group A and group B. ELISA and RT-PCR revealed that the expression level of VEGF in the wound tissues in group B was higher than in group A on day 8 and 11 (P<0.05, P<0.001, respectively). CONCLUSION Both transplantations promote the wound healing of DFUs in rats. The intramuscular transplantation into the leg shows a better persistence and a higher expression level of VEGF in the wound tissues at later stages.
Animals ; Bone Marrow Cells ; cytology ; Diabetes Mellitus, Experimental ; complications ; Diabetic Foot ; therapy ; Male ; Mesenchymal Stem Cell Transplantation ; methods ; Rats ; Rats, Wistar ; Vascular Endothelial Growth Factor A ; metabolism ; Wound Healing