# A Comparative Study of Xi’s Tendon Gangrene (Nonischemic Type of Diabetic Foot) and Gangrene (Diabetic Foot Ischemic Type)

Authors: Linfeng Peng; Yuzheng Wang; Cheng Zhao; Zhiguo Zhao; Qi Fei; Pengchao Xin; Hongtao Xu; Yemin Cao
Journal: Computational and Mathematical Methods in Medicine
 (2022)

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## Abstract

Background. Diabetic foot gangrene refers to a lesion in which the tissue of the foot or lower extremities of diabetic patients is damaged, and the cause is the infection of peripheral blood vessels and neuropathy caused by diabetes. Objective. To compare the related indexes of blood glucose, inflammation, blood viscosity, and peripheral neuropathy between the nonischemic diabetic foot and ischemic diabetic foot, the same and different characteristics of the two different types of diabetic foot in pathogenesis were discussed and studied. Methods. A total of 122 patients with diabetic foot were selected from the Department of Vascular Medicine, Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, including 61 cases of ischemic type and 61 cases of nonischemic type. The differences in blood glucose, inflammation, blood supply, and peripheral neuropathy between the nonischemic diabetic foot and ischemic diabetic foot were compared to explore their different characteristics. Results. The blood glucose index, inflammatory index, and plasma fibrinogen in patients with nonischemic diabetic foot were significantly higher than those in patients with ischemic diabetic foot (P<0.05). The patients with ischemic diabetic foot were higher in age and blood lipid index than those with the nonischemic diabetic foot (P<0.05), while having no significant difference in platelet count, plasma viscosity, hematocrit, and end products of glycation (AGEs). Conclusion. The nonischemic diabetic foot is mainly infective necrosis, and the ischemic type is ischemic necrosis. The former occurs in the middle-aged and elderly with good blood supply between 40 and 60 years old, while the latter occurs in the elderly with the severe vascular disease over 60 years old. The blood glucose level of nonischemic patients is significantly higher than that of ischemic patients, but it has little to do with the course of diabetes.


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## Body

## 1. Introduction

After the reform and opening up, the living standards of the people in our country have greatly improved, the number of patients with diabetes has also significantly increased, and diabetic foot gangrene, a complication with a high disability rate of diabetes, has also increased rapidly, which has become a common disease in vascular surgery. It seriously endangers people’s health and brings a heavy burden to individuals and society. The concept of “diabetic foot” was first proposed by Oakley et al. in 1956, and Catterall in 1972 defined diabetic foot as “the foot of diabetic patients who have lost sensation due to neuropathy and lost vitality due to ischemia, and is complicated by infection” [1]. In 1999, WHO defined it as foot infection, ulceration, and/or deep tissue destruction associated with local nerve abnormalities and peripheral vascular lesions distal to the lower extremities. So far, vascular disease, neuropathy, and infection have been fully recognized as the three pathogenic factors of diabetic foot disease, and the relationship between the three and diabetic foot has also been widely studied. At present, the diagnosis and classification of diabetic foot are based on the lesions caused by ischemia, infection, or neurological factors. Studies have shown that 86.7% of patients with the diabetic foot are nonischemic lesions [2]. Only 20% of diabetic foot gangrene is caused entirely by ischemia [3]. The relationship between foot and foot has also been studied and observed a lot, but its specific pathogenesis has not been fully revealed. In recent years, research in this area has been particularly active, putting forward many new theories, mainly including polyol pathway activation and protein nonenzymatic glycosylation theory, activation of protein kinase C (PKC) signalling pathway, and protein kinase A (PKA) activity decreased. Among them, the relationship between advanced glycation end products (AGEs) and its receptor (RAGE) system formed by protein nonenzymatic glycosylation and diabetic foot has become a research hotspot at home and abroad and has been gradually deepened. It has been proved that this system plays an important role in the occurrence of neuropathy and vascular disease in patients with diabetic foot.Through long-term clinical research, Professor Xi Jiuyi, Department of Vascular Medicine, Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, first puts forward the concept of “diabetic foot tendon degeneration and necrosis (gangrene, non-ischemic type of diabetic foot)” in the 1980s. Professor Xi Jiuyi summarized the diabetic foot into five types: skin degeneration and skin lesions type, tendon degeneration and necrosis type (gangrene, diabetic foot nonischemic type), vascular occlusion ischemic type (deganglion, diabetic foot nonischemic type), peripheral neuropathy, and metatarsal degeneration and atrophy [4]. The objective of this study was to study the same and different characteristics of the pathogenesis of the two diabetic feet by comparing blood glucose, inflammation, blood viscosity, and peripheral blood-related indicators, which are also important for the prevention, treatment, and differentiation of different types of diabetic feet.


## 2. Clinical Information

### 2.1. Object of Observation

All the subjects were patients with diabetic foot hospitalized in the Vascular Department of Shanghai Hospital of Integrated Traditional Chinese and Western Medicine. In the end, 61 cases in each group of the Xi’s gangrene group and 122 cases were obtained. Among them, 43 males and 18 females are in the gangrene group, aged 37-81 years, with an average of59.89±9.79 years old; 34 males are in the gangrene group. There were 27 females aged 44-89 years, with an average of 70.90±9.73 years. All patients were graded according to Xi’ s diabetic foot gangrene grading standard [5].


### 2.2. Diagnostic Criteria

#### 2.2.1. Diagnostic Criteria of Xi’s Diabetic Gangrene

Diagnostic criteria of Xi’s diabetic gangrene (refer to the “Quality Control Standard for Diabetic Gangrene of a Single Disease” formulated by the Vascular Department of Shanghai Hospital of Integrated Traditional Chinese and Western Medicine) [6] are as follows.(1) Basic Conditions.
(1)
History of diabetes, diabetes diagnosis, and diabetes diagnostic criteria are shown in Table1 [7](2)
The affected limb has no obvious ischemic symptoms:ABI>0.9; the patient has no history of intermittent claudication, no rest pain, no pale cyanosis, normal or higher skin temperature than the healthy side, the normal pulse of the dorsal foot artery and posterior tibial artery of the affected limb, or diminished but elevated pallor test negativeTable 1
History of diabetes, diabetes diagnosis, and diabetes diagnostic criteria.
Diabeticsymptoms+randomizedplasmaglucose≥11.1 mmol (200 mg/dl)Or + fasting plasmaglucose≥7.0 mmol (126 mg/dl)Or + OGTT 2 h plasmaglucose≥11.1 mmol (200 mg/dl)Note: diabetic symptoms refer to thirst, polyuria, and unexplained weight loss. All diagnoses need to be confirmed once again.(2) Clinical Conditions.
(1)
Localized swelling of the affected foot, such as single or multiple localized swelling of the extensor tendons in the toe body, dorsum of the foot, heel, ankle, etc.(2)
The affected foot can be abnormally swollen, showing a giant toe and giant foot, and the swelling is solid, and tension is obviously increased(3)
The late stage of local swelling showed an inflammatory reaction, flushing and burning, skin necrosis in the central part, purulent, and bloody secretions, often accompanied by rotten smells(4)
Characteristics of foot ulcers: single-chamber ulcers or multiple penetrating ulcers on the dorsum, soles, toes, or ankles(5)
Different degrees of tendon degeneration and necrosis can be seen in the deep necrotic tissue: the deep tendon loses its luster, its elasticity decreases, and its edema increases(6)
The whole body may have toxic symptoms such as high fever, nausea, and vomitingTwo or more of the above conditions can be diagnosed.(3) Physicochemical Examination.
(1)
Diagnostic physical and chemical examination: three high-high blood sugar, high white blood cell, high erythrocyte sedimentation rate, three low-albumin, low red blood cell, low hemoglobin Doppler vascular examination, vascular ultrasound: the blood flow of the dorsal foot artery and the posterior tibial artery of the affected foot is in the normal range, or there is partial stenosis or occlusion(2)
Auxiliary physical and chemical examination: X-ray examination showed foot abnormalities. The pathological examination of the tendon can be performed under experimental conditions. The degeneration, edema, or necrosis of the tendon can be seen


#### 2.2.2. The Diagnostic Criteria of Xi’s Diabetic Foot Degangrene Type

Xi’s diabetic foot degangrene type is now proposed as “diabetic foot limb arterial dissimilation occlusion,” which can refer to the diabetes mellitus formulated by the Chinese Integrated Traditional Chinese and Western Medicine Peripheral Vascular Disease Professional Committee in December 2002. Diagnostic criteria for arteriosclerosis obliterans of the feet and limbs (draft) are as follows [8]:
(1)
The age of onset is over 40 years(2)
Compliance with diagnostic criteria for diabetes (see Table2)(3)
There are manifestations of chronic limb ischemia, limb numbness, fear of cold or heat, intermittent claudication, congestion, changes in nutrition, decreased sensation of the limbs or red and hot skin, and even ulcers or gangrene, often occurring in the extremities, especially in the lower limbs(4)
All kinds of examinations proved that there was an occlusive change of limb artery stenosis, and color Doppler, CT, DSA, vascular ultrasound, and vascular electro-optical volume flow chart confirmed that there was limb artery stenosis or occlusion; angiography mainly focuses on arterial lesions of lower limbs, and popliteal artery lesions are most common in distal arteries, accounting for more than 80%. The morphology of vascular lesions is similar to arteriosclerosis obliterans. Due to extensive limb arteriosclerosis and diabetes, there are fewer collateral vessels, and the vessels can be tortuous, narrow, and occluded. The lower limb artery ankle-brachial ratio decreased significantly; plain X-ray film showed obvious calcification shadows in the aortic arch, abdominal aorta, or lower limb artery(5)
Often accompanied by hypertension, coronary heart disease, hyperlipidemia, renal artery vascular disease, cerebrovascular disease, fundus arterial vascular disease, etc.(6)
Other arterial diseases such as thromboangiitis obliterans, Raynaud’s disease, arteritis macroarteritis, and cold injury vascular disease were excludedTable 2
Comparison of sex and gangrene grade between two groups of patients.
SexualityGangrene gradeGroupMaleFemaleIIIIIIIVVGangrene group431801422232Ischemic group342741824132★=2.852P=0.091Z=−1.692P=0.091Note: ★ means that the chi-square value is equal to 2.852 in the gender comparison between the two groups.


### 2.3. Inclusion Criteria

(1)
Conform to the diagnostic criteria of Xi’s diabetes mellitus gangrene type or ischemic type(2)
There are no patients with severe liver and kidney function injury, mental illness, and other serious diseases(3)
First foot break(4)
Obtain the consent of the patient or his family(5)
Does not violate the requirements of medical ethics


### 2.4. Excluded Criteria

(1)
Those who do not meet the diagnostic criteria of foot gangrenous type or gangrenous type of Xi’s diabetes mellitus(2)
Those with severe liver and kidney damage, mental illness, or other serious diseases(3)
Accompanied by respiratory tract infection, digestive tract infection, urinary tract infection, etc., or taking anti-infective drugs, hormone drugs, and other diseases or drugs that affect white blood cells, C-reactive protein, and other inflammation and infection indicators(4)
Accompanied by diseases such as primary thrombocytopenia, chronic myeloid leukemia, and other factors affecting platelets, such as taking antiplatelet drugs(5)
Accompanied by acute myocardial infarction, acute nephritis, rheumatic fever, and other diseases, and taking antifibrillar drugs and other diseases, drugs and other factors that affect plasma fibrinogen(6)
Associated with multiple myeloma, systemic lupus erythematosus and other diseases and other factors such as taking anticoagulants and other diseases and drugs that affect plasma viscosity(7)
Patients and their families are unwilling to cooperate


## 2.1. Object of Observation

All the subjects were patients with diabetic foot hospitalized in the Vascular Department of Shanghai Hospital of Integrated Traditional Chinese and Western Medicine. In the end, 61 cases in each group of the Xi’s gangrene group and 122 cases were obtained. Among them, 43 males and 18 females are in the gangrene group, aged 37-81 years, with an average of59.89±9.79 years old; 34 males are in the gangrene group. There were 27 females aged 44-89 years, with an average of 70.90±9.73 years. All patients were graded according to Xi’ s diabetic foot gangrene grading standard [5].


## 2.2. Diagnostic Criteria

### 2.2.1. Diagnostic Criteria of Xi’s Diabetic Gangrene

Diagnostic criteria of Xi’s diabetic gangrene (refer to the “Quality Control Standard for Diabetic Gangrene of a Single Disease” formulated by the Vascular Department of Shanghai Hospital of Integrated Traditional Chinese and Western Medicine) [6] are as follows.(1) Basic Conditions.
(1)
History of diabetes, diabetes diagnosis, and diabetes diagnostic criteria are shown in Table1 [7](2)
The affected limb has no obvious ischemic symptoms:ABI>0.9; the patient has no history of intermittent claudication, no rest pain, no pale cyanosis, normal or higher skin temperature than the healthy side, the normal pulse of the dorsal foot artery and posterior tibial artery of the affected limb, or diminished but elevated pallor test negativeTable 1
History of diabetes, diabetes diagnosis, and diabetes diagnostic criteria.
Diabeticsymptoms+randomizedplasmaglucose≥11.1 mmol (200 mg/dl)Or + fasting plasmaglucose≥7.0 mmol (126 mg/dl)Or + OGTT 2 h plasmaglucose≥11.1 mmol (200 mg/dl)Note: diabetic symptoms refer to thirst, polyuria, and unexplained weight loss. All diagnoses need to be confirmed once again.(2) Clinical Conditions.
(1)
Localized swelling of the affected foot, such as single or multiple localized swelling of the extensor tendons in the toe body, dorsum of the foot, heel, ankle, etc.(2)
The affected foot can be abnormally swollen, showing a giant toe and giant foot, and the swelling is solid, and tension is obviously increased(3)
The late stage of local swelling showed an inflammatory reaction, flushing and burning, skin necrosis in the central part, purulent, and bloody secretions, often accompanied by rotten smells(4)
Characteristics of foot ulcers: single-chamber ulcers or multiple penetrating ulcers on the dorsum, soles, toes, or ankles(5)
Different degrees of tendon degeneration and necrosis can be seen in the deep necrotic tissue: the deep tendon loses its luster, its elasticity decreases, and its edema increases(6)
The whole body may have toxic symptoms such as high fever, nausea, and vomitingTwo or more of the above conditions can be diagnosed.(3) Physicochemical Examination.
(1)
Diagnostic physical and chemical examination: three high-high blood sugar, high white blood cell, high erythrocyte sedimentation rate, three low-albumin, low red blood cell, low hemoglobin Doppler vascular examination, vascular ultrasound: the blood flow of the dorsal foot artery and the posterior tibial artery of the affected foot is in the normal range, or there is partial stenosis or occlusion(2)
Auxiliary physical and chemical examination: X-ray examination showed foot abnormalities. The pathological examination of the tendon can be performed under experimental conditions. The degeneration, edema, or necrosis of the tendon can be seen


### 2.2.2. The Diagnostic Criteria of Xi’s Diabetic Foot Degangrene Type

Xi’s diabetic foot degangrene type is now proposed as “diabetic foot limb arterial dissimilation occlusion,” which can refer to the diabetes mellitus formulated by the Chinese Integrated Traditional Chinese and Western Medicine Peripheral Vascular Disease Professional Committee in December 2002. Diagnostic criteria for arteriosclerosis obliterans of the feet and limbs (draft) are as follows [8]:
(1)
The age of onset is over 40 years(2)
Compliance with diagnostic criteria for diabetes (see Table2)(3)
There are manifestations of chronic limb ischemia, limb numbness, fear of cold or heat, intermittent claudication, congestion, changes in nutrition, decreased sensation of the limbs or red and hot skin, and even ulcers or gangrene, often occurring in the extremities, especially in the lower limbs(4)
All kinds of examinations proved that there was an occlusive change of limb artery stenosis, and color Doppler, CT, DSA, vascular ultrasound, and vascular electro-optical volume flow chart confirmed that there was limb artery stenosis or occlusion; angiography mainly focuses on arterial lesions of lower limbs, and popliteal artery lesions are most common in distal arteries, accounting for more than 80%. The morphology of vascular lesions is similar to arteriosclerosis obliterans. Due to extensive limb arteriosclerosis and diabetes, there are fewer collateral vessels, and the vessels can be tortuous, narrow, and occluded. The lower limb artery ankle-brachial ratio decreased significantly; plain X-ray film showed obvious calcification shadows in the aortic arch, abdominal aorta, or lower limb artery(5)
Often accompanied by hypertension, coronary heart disease, hyperlipidemia, renal artery vascular disease, cerebrovascular disease, fundus arterial vascular disease, etc.(6)
Other arterial diseases such as thromboangiitis obliterans, Raynaud’s disease, arteritis macroarteritis, and cold injury vascular disease were excludedTable 2
Comparison of sex and gangrene grade between two groups of patients.
SexualityGangrene gradeGroupMaleFemaleIIIIIIIVVGangrene group431801422232Ischemic group342741824132★=2.852P=0.091Z=−1.692P=0.091Note: ★ means that the chi-square value is equal to 2.852 in the gender comparison between the two groups.


## 2.2.1. Diagnostic Criteria of Xi’s Diabetic Gangrene

Diagnostic criteria of Xi’s diabetic gangrene (refer to the “Quality Control Standard for Diabetic Gangrene of a Single Disease” formulated by the Vascular Department of Shanghai Hospital of Integrated Traditional Chinese and Western Medicine) [6] are as follows.(1) Basic Conditions.
(1)
History of diabetes, diabetes diagnosis, and diabetes diagnostic criteria are shown in Table1 [7](2)
The affected limb has no obvious ischemic symptoms:ABI>0.9; the patient has no history of intermittent claudication, no rest pain, no pale cyanosis, normal or higher skin temperature than the healthy side, the normal pulse of the dorsal foot artery and posterior tibial artery of the affected limb, or diminished but elevated pallor test negativeTable 1
History of diabetes, diabetes diagnosis, and diabetes diagnostic criteria.
Diabeticsymptoms+randomizedplasmaglucose≥11.1 mmol (200 mg/dl)Or + fasting plasmaglucose≥7.0 mmol (126 mg/dl)Or + OGTT 2 h plasmaglucose≥11.1 mmol (200 mg/dl)Note: diabetic symptoms refer to thirst, polyuria, and unexplained weight loss. All diagnoses need to be confirmed once again.(2) Clinical Conditions.
(1)
Localized swelling of the affected foot, such as single or multiple localized swelling of the extensor tendons in the toe body, dorsum of the foot, heel, ankle, etc.(2)
The affected foot can be abnormally swollen, showing a giant toe and giant foot, and the swelling is solid, and tension is obviously increased(3)
The late stage of local swelling showed an inflammatory reaction, flushing and burning, skin necrosis in the central part, purulent, and bloody secretions, often accompanied by rotten smells(4)
Characteristics of foot ulcers: single-chamber ulcers or multiple penetrating ulcers on the dorsum, soles, toes, or ankles(5)
Different degrees of tendon degeneration and necrosis can be seen in the deep necrotic tissue: the deep tendon loses its luster, its elasticity decreases, and its edema increases(6)
The whole body may have toxic symptoms such as high fever, nausea, and vomitingTwo or more of the above conditions can be diagnosed.(3) Physicochemical Examination.
(1)
Diagnostic physical and chemical examination: three high-high blood sugar, high white blood cell, high erythrocyte sedimentation rate, three low-albumin, low red blood cell, low hemoglobin Doppler vascular examination, vascular ultrasound: the blood flow of the dorsal foot artery and the posterior tibial artery of the affected foot is in the normal range, or there is partial stenosis or occlusion(2)
Auxiliary physical and chemical examination: X-ray examination showed foot abnormalities. The pathological examination of the tendon can be performed under experimental conditions. The degeneration, edema, or necrosis of the tendon can be seen


## 2.2.2. The Diagnostic Criteria of Xi’s Diabetic Foot Degangrene Type

Xi’s diabetic foot degangrene type is now proposed as “diabetic foot limb arterial dissimilation occlusion,” which can refer to the diabetes mellitus formulated by the Chinese Integrated Traditional Chinese and Western Medicine Peripheral Vascular Disease Professional Committee in December 2002. Diagnostic criteria for arteriosclerosis obliterans of the feet and limbs (draft) are as follows [8]:
(1)
The age of onset is over 40 years(2)
Compliance with diagnostic criteria for diabetes (see Table2)(3)
There are manifestations of chronic limb ischemia, limb numbness, fear of cold or heat, intermittent claudication, congestion, changes in nutrition, decreased sensation of the limbs or red and hot skin, and even ulcers or gangrene, often occurring in the extremities, especially in the lower limbs(4)
All kinds of examinations proved that there was an occlusive change of limb artery stenosis, and color Doppler, CT, DSA, vascular ultrasound, and vascular electro-optical volume flow chart confirmed that there was limb artery stenosis or occlusion; angiography mainly focuses on arterial lesions of lower limbs, and popliteal artery lesions are most common in distal arteries, accounting for more than 80%. The morphology of vascular lesions is similar to arteriosclerosis obliterans. Due to extensive limb arteriosclerosis and diabetes, there are fewer collateral vessels, and the vessels can be tortuous, narrow, and occluded. The lower limb artery ankle-brachial ratio decreased significantly; plain X-ray film showed obvious calcification shadows in the aortic arch, abdominal aorta, or lower limb artery(5)
Often accompanied by hypertension, coronary heart disease, hyperlipidemia, renal artery vascular disease, cerebrovascular disease, fundus arterial vascular disease, etc.(6)
Other arterial diseases such as thromboangiitis obliterans, Raynaud’s disease, arteritis macroarteritis, and cold injury vascular disease were excludedTable 2
Comparison of sex and gangrene grade between two groups of patients.
SexualityGangrene gradeGroupMaleFemaleIIIIIIIVVGangrene group431801422232Ischemic group342741824132★=2.852P=0.091Z=−1.692P=0.091Note: ★ means that the chi-square value is equal to 2.852 in the gender comparison between the two groups.


## 2.3. Inclusion Criteria

(1)
Conform to the diagnostic criteria of Xi’s diabetes mellitus gangrene type or ischemic type(2)
There are no patients with severe liver and kidney function injury, mental illness, and other serious diseases(3)
First foot break(4)
Obtain the consent of the patient or his family(5)
Does not violate the requirements of medical ethics


## 2.4. Excluded Criteria

(1)
Those who do not meet the diagnostic criteria of foot gangrenous type or gangrenous type of Xi’s diabetes mellitus(2)
Those with severe liver and kidney damage, mental illness, or other serious diseases(3)
Accompanied by respiratory tract infection, digestive tract infection, urinary tract infection, etc., or taking anti-infective drugs, hormone drugs, and other diseases or drugs that affect white blood cells, C-reactive protein, and other inflammation and infection indicators(4)
Accompanied by diseases such as primary thrombocytopenia, chronic myeloid leukemia, and other factors affecting platelets, such as taking antiplatelet drugs(5)
Accompanied by acute myocardial infarction, acute nephritis, rheumatic fever, and other diseases, and taking antifibrillar drugs and other diseases, drugs and other factors that affect plasma fibrinogen(6)
Associated with multiple myeloma, systemic lupus erythematosus and other diseases and other factors such as taking anticoagulants and other diseases and drugs that affect plasma viscosity(7)
Patients and their families are unwilling to cooperate


## 3. Materials and Observation Methods

### 3.1. Test Equipment

A 128 Hz tuning fork is used for scoring diabetic peripheral neuropathy. An AGE-reader detector provided by Shanghai Ruijin Hospital, a Dutch company, reflects the AGE content of human skin by detecting the fluorescence spectrum of human skin. French ATYS vascular analysis workstation, provided by the vascular examination room of the Vascular Department of Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, is used to detect ABI of both lower limbs.


### 3.2. Observation Method

#### 3.2.1. The Subjects Were Divided into Two Groups

The cases were collected according to the above inclusion and exclusion criteria, and the subjects were divided into two groups: the muscle gangrene damp-heat syndrome group and gangrene damp-heat syndrome group.


#### 3.2.2. Determination of AGEs

After turning on the power supply, turn on the computer switch of the AGE-reader detector, enter the AGE-reader system, wait for the system to warm up for three minutes, and start to enter the detection state. At the same time, tell the person to roll the sleeve of the right arm above the elbow, close the exposed front and medial skin of the right arm to the detector window, and pay attention to avoid scars, rashes, obvious blood vessels, etc.; click the start detection button to start the detection, and wait for the computer to jump out of the test results automatically. The detected person can move the arm away, and the test results will be saved automatically. The detection mode is set to three repetitions, and the result with reflectivity greater than 0.06 is regarded as the credible value.


#### 3.2.3. Toronto Nerve Score

The Toronto neurological score consists of three parts: neurological symptom score, neuro reflex score, and sensory function test score. The neurological symptom score includes five items of lower limb numbness, pain, acupuncture-like pain, balance ability, and similar symptoms of the upper limb, each with a total of five points, and the nerve reflex includes bilateral knee reflex and ankle reflex. It is divided into three grades: normal (0), weakened (1), and disappearance (2), with a total of eight points. The sensory function test refers to the five items of pain, temperature, touch, vibration, and position sense of the right thumb, with one point for each item and five points and nineteen points for the entire test. No peripheral neuropathy is below 6 points, grade 0; no less than 6 is divided into mild neuropathy, grade I; no less than 9 is divided into moderate neuropathy, grade II; there is no less than 12 points for severe neuropathy, grade III.


#### 3.2.4. Lower Limb Artery Ankle-Brachial Ratio (ABI)

The ABI value of the lower extremities was measured by ultrasonic Doppler, and the left and right lower limbs were measured at the same time. The lower limb with a lower ABI value was statistically analyzed.


#### 3.2.5. Observation Indicator

(1)
Physical and chemical criterion: fasting blood glucose (FBG), 2 h postprandial blood glucose (PBG), glycosylated hemoglobin (GHb), leukocyte (WBC), neutrophils (NE), C-reactive protein (CRP), interleukin-6 (IL-6), platelet count (PLT), plasma fibrinogen (FIB), blood plasma viscosity, hematocrit (PCV), serum total cholesterol (TC), and triglycerides (TG)(2)
Lower extremity arterial ankle-brachial ratio (ABI)(3)
Glycation end product detection value (AGEs)(4)
Toronto Neuropathy Score (TCSS score)


#### 3.2.6. Statistical Method

The statistical software SPSS 15.0 was used for statistical analysis of experimental data, and measurement data were expressed assamplemean±standarddeviation (x¯±s). A two-sample t-test was used for those who conform to the normal test and homogeneity of variance, and nonparametric test was used for those that do not conform to the normal test and homogeneity of variance. The enumeration data were tested by chi-square test; the grade data was tested by nonparametric test; the correlation between the two variables was analyzed by linear regression analysis, and P<0.05 was considered statistically significant.


## 3.1. Test Equipment

A 128 Hz tuning fork is used for scoring diabetic peripheral neuropathy. An AGE-reader detector provided by Shanghai Ruijin Hospital, a Dutch company, reflects the AGE content of human skin by detecting the fluorescence spectrum of human skin. French ATYS vascular analysis workstation, provided by the vascular examination room of the Vascular Department of Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, is used to detect ABI of both lower limbs.


## 3.2. Observation Method

### 3.2.1. The Subjects Were Divided into Two Groups

The cases were collected according to the above inclusion and exclusion criteria, and the subjects were divided into two groups: the muscle gangrene damp-heat syndrome group and gangrene damp-heat syndrome group.


### 3.2.2. Determination of AGEs

After turning on the power supply, turn on the computer switch of the AGE-reader detector, enter the AGE-reader system, wait for the system to warm up for three minutes, and start to enter the detection state. At the same time, tell the person to roll the sleeve of the right arm above the elbow, close the exposed front and medial skin of the right arm to the detector window, and pay attention to avoid scars, rashes, obvious blood vessels, etc.; click the start detection button to start the detection, and wait for the computer to jump out of the test results automatically. The detected person can move the arm away, and the test results will be saved automatically. The detection mode is set to three repetitions, and the result with reflectivity greater than 0.06 is regarded as the credible value.


### 3.2.3. Toronto Nerve Score

The Toronto neurological score consists of three parts: neurological symptom score, neuro reflex score, and sensory function test score. The neurological symptom score includes five items of lower limb numbness, pain, acupuncture-like pain, balance ability, and similar symptoms of the upper limb, each with a total of five points, and the nerve reflex includes bilateral knee reflex and ankle reflex. It is divided into three grades: normal (0), weakened (1), and disappearance (2), with a total of eight points. The sensory function test refers to the five items of pain, temperature, touch, vibration, and position sense of the right thumb, with one point for each item and five points and nineteen points for the entire test. No peripheral neuropathy is below 6 points, grade 0; no less than 6 is divided into mild neuropathy, grade I; no less than 9 is divided into moderate neuropathy, grade II; there is no less than 12 points for severe neuropathy, grade III.


### 3.2.4. Lower Limb Artery Ankle-Brachial Ratio (ABI)

The ABI value of the lower extremities was measured by ultrasonic Doppler, and the left and right lower limbs were measured at the same time. The lower limb with a lower ABI value was statistically analyzed.


### 3.2.5. Observation Indicator

(1)
Physical and chemical criterion: fasting blood glucose (FBG), 2 h postprandial blood glucose (PBG), glycosylated hemoglobin (GHb), leukocyte (WBC), neutrophils (NE), C-reactive protein (CRP), interleukin-6 (IL-6), platelet count (PLT), plasma fibrinogen (FIB), blood plasma viscosity, hematocrit (PCV), serum total cholesterol (TC), and triglycerides (TG)(2)
Lower extremity arterial ankle-brachial ratio (ABI)(3)
Glycation end product detection value (AGEs)(4)
Toronto Neuropathy Score (TCSS score)


### 3.2.6. Statistical Method

The statistical software SPSS 15.0 was used for statistical analysis of experimental data, and measurement data were expressed assamplemean±standarddeviation (x¯±s). A two-sample t-test was used for those who conform to the normal test and homogeneity of variance, and nonparametric test was used for those that do not conform to the normal test and homogeneity of variance. The enumeration data were tested by chi-square test; the grade data was tested by nonparametric test; the correlation between the two variables was analyzed by linear regression analysis, and P<0.05 was considered statistically significant.


## 3.2.1. The Subjects Were Divided into Two Groups

The cases were collected according to the above inclusion and exclusion criteria, and the subjects were divided into two groups: the muscle gangrene damp-heat syndrome group and gangrene damp-heat syndrome group.


## 3.2.2. Determination of AGEs

After turning on the power supply, turn on the computer switch of the AGE-reader detector, enter the AGE-reader system, wait for the system to warm up for three minutes, and start to enter the detection state. At the same time, tell the person to roll the sleeve of the right arm above the elbow, close the exposed front and medial skin of the right arm to the detector window, and pay attention to avoid scars, rashes, obvious blood vessels, etc.; click the start detection button to start the detection, and wait for the computer to jump out of the test results automatically. The detected person can move the arm away, and the test results will be saved automatically. The detection mode is set to three repetitions, and the result with reflectivity greater than 0.06 is regarded as the credible value.


## 3.2.3. Toronto Nerve Score

The Toronto neurological score consists of three parts: neurological symptom score, neuro reflex score, and sensory function test score. The neurological symptom score includes five items of lower limb numbness, pain, acupuncture-like pain, balance ability, and similar symptoms of the upper limb, each with a total of five points, and the nerve reflex includes bilateral knee reflex and ankle reflex. It is divided into three grades: normal (0), weakened (1), and disappearance (2), with a total of eight points. The sensory function test refers to the five items of pain, temperature, touch, vibration, and position sense of the right thumb, with one point for each item and five points and nineteen points for the entire test. No peripheral neuropathy is below 6 points, grade 0; no less than 6 is divided into mild neuropathy, grade I; no less than 9 is divided into moderate neuropathy, grade II; there is no less than 12 points for severe neuropathy, grade III.


## 3.2.4. Lower Limb Artery Ankle-Brachial Ratio (ABI)

The ABI value of the lower extremities was measured by ultrasonic Doppler, and the left and right lower limbs were measured at the same time. The lower limb with a lower ABI value was statistically analyzed.


## 3.2.5. Observation Indicator

(1)
Physical and chemical criterion: fasting blood glucose (FBG), 2 h postprandial blood glucose (PBG), glycosylated hemoglobin (GHb), leukocyte (WBC), neutrophils (NE), C-reactive protein (CRP), interleukin-6 (IL-6), platelet count (PLT), plasma fibrinogen (FIB), blood plasma viscosity, hematocrit (PCV), serum total cholesterol (TC), and triglycerides (TG)(2)
Lower extremity arterial ankle-brachial ratio (ABI)(3)
Glycation end product detection value (AGEs)(4)
Toronto Neuropathy Score (TCSS score)


## 3.2.6. Statistical Method

The statistical software SPSS 15.0 was used for statistical analysis of experimental data, and measurement data were expressed assamplemean±standarddeviation (x¯±s). A two-sample t-test was used for those who conform to the normal test and homogeneity of variance, and nonparametric test was used for those that do not conform to the normal test and homogeneity of variance. The enumeration data were tested by chi-square test; the grade data was tested by nonparametric test; the correlation between the two variables was analyzed by linear regression analysis, and P<0.05 was considered statistically significant.


## 4. Test Results

The comparative results of sex, grade of gangrene, age, and the course of diabetes between the two groups are shown in the following table (Tables2 and 3).Table 3
Comparison of age and course of diabetes between the two groups (x¯±s).
GroupCasesAgeDiabetic courseGangrene6159.89±9.7912.71±7.29Ischemic6170.90±9.7313.31±8.25P<0.0010.672From the statistical results, we can see that there is no significant difference in sex, grade of gangrene, and the course of diabetes between the two groups, but in the comparison of age, gangrene is more common in the middle-aged and elderly people aged about 50-70, and gangrene is more common in the elderly aged about 60-80 years old. The difference between the two is statistically significant.The comparison of fasting blood glucose, postprandial blood glucose, and glycosylated hemoglobin between the two groups is shown in the following table (Table4).Table 4
Comparison of fasting blood glucose, postprandial blood glucose, and glycosylated hemoglobin between two groups of patients (x¯±s).
GroupCasesFasting blood glucosePBGGHbGangrene group619.63±3.3914.61±5.1610.44±2.03Ischemic group617.22±2.7211.64±5.037.88±1.53P<0.0010.002<0.001From the statistical analysis results, it can be seen that in the comparison of fasting blood glucose, postprandial blood glucose and glycosylated hemoglobin between the two groups, theP values were all less than 0.05, and the difference was statistically significant. Moreover, the average values of the gangrene group were 9.63, 14.60, and 10.443, which were significantly higher than 7.22, 11.64, and 7.88 in the gangrene group. It can be considered that the fasting blood glucose, postprandial blood glucose, and glycosylated hemoglobin in the gangrene group were significantly higher than those in the gangrene group.The comparison of leukocytes, neutrophils, CRP, and IL-6 between the two groups is shown in the following table (Table5).Table 5
Comparison of leukocytes, neutrophils, CRP, and interleukin-6 in two groups of patients (x¯±s).
GroupCasesLeukocytesNeutrophilsCRPIL-6Gangrene group619.16±3.527.47±5.5264.16±58.6949.11±40.95Ischemic group617.42±2.5322.30±26.635.35±2.4628.90±35.74P0.0030.007<0.0010.004It can be seen from the statistical analysis results that theP values of white blood cells, neural cells, CRP, and IL-6 in the two groups were all less than 0.05, and the difference was statistically significant. The mean values of 9.16, 7.47, 64.16, and 49.11 in the gangrene group were significantly higher than 7.42, 5.35, 22.30, and 28.90 in the gangrene group. It can be considered that the infection and inflammatory indexes of white blood cells, neutrophils, CRP, and interleukin-6 in the gangrene group were significantly higher than those in the gangrene group.The comparison results of platelet count, plasma fibrinogen, plasma viscosity, and hematocrit between the two groups are shown in Table6.Table 6
Comparison of PLT, FIB, plasma viscosity, and PCV between two groups (x¯±s).
GroupCasesPLTFIBbpvPCVGangrene group61278.54±113.734.89±0.971.51±0.130.36±0.05Ischemic group61250.98±99.153.74±1.211.50±0.130.35±0.01P0.156<0.0010.8430.890It can be seen from the statistical analysis results that in the comparison of platelet count, plasma fibrinogen, plasma viscosity, and hematocrit between the two groups, theP value was less than 0.001 in the comparison of FIB, and the difference was statistically significant. The mean value of the gangrene group was significantly greater than that of the degangrene group. It can be considered that the plasma fibrinogen of the gangrene group was higher than that of the degangrene group. There was no significant difference in platelet count, plasma viscosity, and hematocrit between the two groups, and the mean difference was not significant.The comparison of total serum cholesterol (TC) and triglyceride (TG) between the two groups is shown in the following table (Table7).Table 7
Comparison of TC and TG between the two groups of patients (x¯±s).
GroupCasesTCTGGangrene group613.64±1.041.09±0.07Ischemic group614.16±1.261.22±0.P0.0130.222From the results of statistical analysis, we can see that in the comparison of TC and TG between the two groups, the average value of gangrene group is smaller than that of gangrene group. However, the difference in total serum cholesterol is statistically significant, but there is no significant difference in triglyceride.The comparison results of the AGE detection value (Table8) and TCSS score (Table 9) of the two groups of patients are shown in the following table.Table 8
Comparison of AGE value and TCSS score between the two groups.
AGEsTCSS grading scaleGroup0IIIIIIGangrene group2.55±0.50401155Ischemic group2.63±0.54331675P=0.378Z=−1.132P=0.257Table 9
Comparison of the number of patients with TCSSscore≥6 in two groups.
Group≥6 points<6 pointsGangrene group2140Ischemic group28331.671★P=0.196★The chi-square value is equal to 1.671 in the comparison of the number of TCSSscores≥6 between the two groups.From the statistical analysis results, we can see that no matter the AGE test value or TCSS score, there is no significant difference between the two groups, and there is no significant difference between the two groups. There was no significant difference in the number of cases of diabetic peripheral neuropathy (TCSSscore≥6).The comparison results of the lower extremity arterial ankle-brachial ratio (ABI) of the two groups of patients are shown in Table10 and Figure 1.Table 10
Comparison of ABI between two groups of patients.
GroupCasesABIGangrene group610.88±0.25Ischemic group610.40±0.24Z=−7.642P<0.001Figure 1
The comparison of ABI between two groups of patients.From the results of statistical analysis, we can see that the average value of ABI in the gangrenous group is significantly higher than that in the gangrenous group, and there is a statistically significant difference between the two groups, indicating that the blood supply in the gangrenous group is significantly better than that in the gangrenous group.


## 5. Discussion

In the results of this test, there were no significant differences in gender, gangrene grade, and duration of diabetes between the two groups, indicating that these factors have no different effects on the incidence of gangrene and gangrene, especially in the mean comparison of the duration of diabetes. Numerous studies have shown that the development of diabetic feet into gangrene is not related to the timing of elevated blood sugar. Of course, we cannot rule out that this data is due to the economic and medical levels, the delay in diagnosing diabetes in the elderly patients in the gangrene group, and the inaccurate results brought about by the relatively early diagnosis of the gangrene group.There is a significant difference in age between the two groups because age and atherosclerosis are closely related, which has been recognized and will not be discussed in detail here. This also reflects a significant point of the onset of the two groups of patients: whether the blood supply is good or bad, gangrene is infection-based necrosis that occurs when the blood supply is good; gangrene occurs when blood vessels are damaged. Necrosis is dominated by ischemia in severe cases.


### 5.1. Comparison of Blood Glucose Indexes between the Two Groups

Diabetes is a metabolic disease caused by insufficient insulin secretion and/or action [5]. The disorder of glucose metabolism characterized by hyperglycemia is the basis of diabetes and all its complications, including the diabetic foot. Fasting blood glucose can represent basic insulin secretion and reflect the function of islet β cells, while postprandial blood glucose can reflect the early pathological changes of diabetes. Glycosylated hemoglobin is the product of the combination of hemoglobin and blood sugar in human red blood cells. Its content is parallel to the value of blood sugar and is not easy to decompose after it is produced. It can well reflect the blood glucose control of patients in the past 8 to 12 weeks. It is a good sensitive index for monitoring blood glucose levels within 3 months [9]. This experiment found that the fasting blood glucose, postprandial blood glucose, and glycosylated hemoglobin in the diabetic foot gangrene group were significantly higher than those in the diabetic foot gangrene group, and the difference was statistically significant. It shows that hyperglycemia is an important basis for the occurrence of gangrene, and the blood glucose value formed by gangrene belongs to a high level in diabetes, with an average fasting blood glucose of 9.63, postprandial blood glucose of 14.61, and glycosylated hemoglobin of 10.44.The mechanism of the diabetic foot caused by hyperglycemia is very complicated. At present, the proposed theories mainly include endothelial cell damage and dysfunction caused by hyperglycemia [10], long-term blood hypercoagulability, protein nonenzymatic glycosylation theory, oxidative stress theory, polyol pathway theory and protein kinase C (PKC) activation theory, lipid peroxidation, and so on [11, 12]. These theories explain the mechanism of foot gangrene caused by hyperglycemia from various aspects; some have been confirmed, and others need more research to prove. The degeneration and necrosis of diabetic foot tendons caused by hyperglycemia may be related to the increase of reactive oxygen species in the body, the decrease of antioxidant capacity, the oxidative stress of foot tendons and fascia, and the accumulation of sorbitol in the foot through polyol pathway. At the same time, hyperglycemia leads to a large amount of nonenzymatic glycosylation of proteins in the tendon and fascia, which is associated with immune dysfunction caused by hyperglycemia. Make patients more prone to infection, and the gangrenous type appears. Of course, this needs more research to confirm and reveal.Leukocytes, neutrophils, CRP, and interleukin-6 are all important signs of infection and inflammation in the body, and they are also the most commonly used clinical indicators of infection and inflammation. Leukocytes are the main cells in the human body to resist foreign infections and produce immunity, including neutrophils and lymphocytes; neutrophils are a type of white blood cells, which are mainly increased when the body has a purulent infection. CRP is produced when the body is stimulated by inflammation. Acute phase protein synthesized by hepatocytes is generally regarded as a very sensitive marker of inflammation and tissue damage [13]. It is also directly involved in the whole process of the inflammatory response [14]. Interleukin-6 is a cytokine produced by fibroblasts, monocytes/macrophages, etc., which can stimulate proliferation and differentiation and improve the function of cells involved in immune response, including the production of CRP. In this experiment, we found that the leukocytes, neutrophils, CRP, and IL-6 in the diabetic foot gangrene group were significantly higher than those in the diabetic foot gangrene group, and the difference was statistically significant, which indicated that the gangrenous infection was more serious than the ischemic infection, and the inflammatory reaction was more severe.Since 1972, Catterall defined diabetic foot as “diabetic patients have lost their senses due to neuropathy and lost their energy due to ischemia, and infected feet.” The infection has been widely recognized as the three basic elements of diabetic foot. Diabetic patients are susceptible to infection due to hyperglycemia and peripheral neuropathy resulting from immune dysfunction and damage. Diabetic foot patients have abnormal inflammatory responses without foot gangrene or diabetes. In a study conducted in the United States, 5888 elderly people were followed up for 3-4 years. The results showed that the incidence of diabetes in patients with elevated CRP increased by 2.3 times [15]. Diabetic patients are prone to infection due to hyperglycemia, immune dysfunction and injury, and peripheral neuropathy [16]. In diabetic patients, once infected, ulceration will stimulate the body to produce more CRP and IL-6, aggravating the body’s inflammatory response. The reason for infection and inflammatory reaction of tendon gangrene type is heavier than ischemic type. The main reason may be that the vascular lesions of the two types are different. The vascular injury of tendon gangrene type is small, the blood supply is mostly good, and the blood glucose of the foot is concentrated in the unruptured period, which makes it easy to be infected. The abnormal inflammatory reaction of early diabetes is also easy to spread to the foot tendon and other tissues, but once the infection occurs, the stimulating factors produced by the necrotic tissue of the foot can also reach the organs and tissues produced by immune cells such as liver and bone marrow through blood circulation. Thus, the infection and inflammation indexes of patients with gangrenous type are significantly increased. The degangrene type is due to severe vascular disease. Most of the lower extremity arteries are narrowed or occluded, less blood glucose accumulation in the feet before ulceration, and less early abnormal inflammatory response to the foot tendons and other tissues, so necrosis and ulceration are mostly caused by ischemia. The stimulatory factors produced by the necrotic tissue after rupture may also be difficult to reach the bone marrow, liver, thymus, and other tissues and organs of the body through the blood circulation to produce an immune-stimulating effect.Due to hyperglycemia and hyperlipidemia in diabetic foot patients, the viscosity of blood will inevitably change. Platelets are the main substances for coagulation and hemostasis, forming thrombus and repairing damaged blood vessels; plasma fibrinogen is the precursor of plasma fibrin. Plasma viscosity reflects the viscosity of plasma and is also an important factor affecting the viscosity of the whole blood; hematocrit is the volume percentage of blood cells in whole blood, which can also be used to reflect the viscosity of human blood. These four can affect or reflect the viscosity of human blood, so they are discussed together.This experiment found that the number of platelets in the gangrenous group was higher than that in the gangrenous group, which may be due to excessive platelet consumption in a specific state. Although both production and consumption increased, but the consumption was more than that in the gangrenous group. Therefore, the ischemic group with obvious occlusion or stenosis of blood vessels is lower than the gangrenous group with basically normal blood flow, which is similar to the observation of many scholars at home and abroad [17, 18]. There was no statistically significant difference in this experiment, indicating that platelets were the same in these two types.Due to the influence of hyperglycemia and hyperlipidemia in diabetic patients, plasma fibrinogen is higher than that of normal people, and high plasma fibrinogen can lead to the occurrence of atherosclerosis [19]. This is an important factor in the occurrence of diabetic foot gangrene. The two groups of patients with plasma fibrinogen levels were significantly higher than the normal value (normal 1.5-3.5 g/l), However, the number of patients in the gangrene group was higher than that in the gangrene group, and the difference was statistically significant because the gangrene group had a severe inflammatory response, and the inflammatory response would stimulate the production of plasma fibrinogen, which has been confirmed by many studies [20, 21]. Here, we also see that the gangrene type and the degangrene type cannot be completely separated. The plasma fibrinogen of the gangrene type is high, and it is easy to form thrombosis and cause atherosclerosis of the arterial blood vessels. In addition, the long-term hyperglycemia of the gangrene type causes damage to the blood vessels. It can be said that the gangrene type is gradually changing to the degangrene type over time.Plasma viscosity is significantly increased in patients with diabetic foot, which has been confirmed by many studies [22]. Its elevation will eventually lead to arterial stenosis or even occlusion. Plasma viscosity is mainly affected by plasma fibrinogen and lipids, especially triglycerides. In this experiment, there is no statistical difference in plasma viscosity between the two groups, and the average value of the two groups is almost the same, which may be due to the high plasma fibrinogen in the gangrene group and the high triglyceride in the gangrene group.The increase of hematocrit is mainly seen in severe dehydration, large area burn, and so on, but it has also been found in patients with diabetic foot [23]. The results showed that there was no significant difference between the two groups, and the mean value was significantly lower than that of normal people. Maybe patients and observation patients were treated with infusion therapy, so the hematocrit was significantly smaller, which reminds us that we need to develop more stringent observation methods to exclude the impact of these other factors.Serum total cholesterol is the total cholesterol contained in all lipoproteins in the blood, and triglycerides are the most abundant lipids in the body. Both of them play an important role in the formation of diabetic foot, especially in the formation of diabetic foot degangrene. This is because lipids, especially triglycerides, are closely related to the formation of atherosclerosis [24, 25], and atherosclerosis is one of the basic factors of diabetes.In this test, the total cholesterol and triglyceride in serum of the degangrene group were higher than those in the gangrene group, and the comparison of serum total cholesterol and triglyceride showed no difference, which fully demonstrated that lipid and arterial atherosclerosis are closely related. The mechanism of hyperlipidemia causing atherosclerosis is very complex, which may be related to the formation of small and dense low-density lipoproteins, reducing high-density lipoproteins, and promotion of plasma fibrinogen production and the oxidative modification of lipoproteins [26].AGEs are the product of nonenzymatic glycosylation (Maillard reaction) and protein oxidation with aldose without enzyme. It has the characteristics of stability and irreversibility, fluorescence, protein cross-linking, and biological effects caused by binding to AGEs receptor (RAGEs). Normal people will continue to accumulate as they age. Many recent studies have confirmed that the production and accumulation of AGEs in diabetic patients are much higher than that in normal people, which is closely related to various complications of diabetes such as diabetic coronary heart disease, diabetic retinopathy, diabetic nephropathy, and diabetic foot. The occurrence of the diabetic foot may be related to the production of glycation end products, which can damage peripheral nerves [27, 28], damage arteries [29, 30], and cause skin degeneration [31].In this experiment, the detection values of AGEs in the two groups were significantly higher than those in the normal group, indicating that AGEs may be an important factor in the formation of diabetic foot, but the difference between the two groups was not statistically significant. This may be because AGEs increased with age, and it was also related to the blood glucose value of the human body. The age of patients in the degangrene group was significantly older than that in the gangrene group, and the blood glucose value in the gangrene group was significantly higher than that in the degangrene group, which led to significantly higher detection values in both groups, but there was no significant difference between the two groups.The TCSS score is a peripheral neuropathy scoring system developed in Toronto, Canada, in 2001. Compared with the gold index for the diagnosis of peripheral neuropathy, the nerve conduction velocity test, the scoring system has the characteristics of simple application conditions and low cost and is suitable for clinical use. It is widely used in screening, and it has a good consistency and high accuracy with nerve conduction velocity testing [32, 33]. The system can also evaluate different grades of peripheral neuropathy. At present, ≥ 6 is generally divided into whether there is a cutoff point of peripheral neuropathy, ≥ 9 is divided into moderate lesions, and ≥ 12 is divided into severe lesions. Test due to funding, energy, patient acceptance, and other conditions, we use this scoring system as a diagnostic criterion for peripheral neuropathy.Peripheral neuropathy is one of the basic factors in the pathogenesis of diabetic foot, and its relationship with the pathogenesis of diabetic foot has been generally recognized and will not be discussed in detail here. In the results of this test, there was no significant difference in the number of cases of peripheral neuropathy and the grade of peripheral neuropathy between the two groups, indicating that peripheral neuropathy exists in both types, which is a common factor not just the presence of peripheral neuropathy in a certain type. Of course, it is also possible that the TCSS score is not completely equivalent to the nerve conduction velocity test, which leads to errors. This requires those who have the conditions to use the nerve conduction velocity test as the gold indicator to do more research.In conclusion, this study found the same and different characteristics of the pathogenesis of two types of diabetic foot by comparing blood glucose, inflammation, blood viscosity, and peripheral blood-related indicators and provided a reference for the prevention, treatment, and identification of different types of diabetic foot.


## 5.1. Comparison of Blood Glucose Indexes between the Two Groups

Diabetes is a metabolic disease caused by insufficient insulin secretion and/or action [5]. The disorder of glucose metabolism characterized by hyperglycemia is the basis of diabetes and all its complications, including the diabetic foot. Fasting blood glucose can represent basic insulin secretion and reflect the function of islet β cells, while postprandial blood glucose can reflect the early pathological changes of diabetes. Glycosylated hemoglobin is the product of the combination of hemoglobin and blood sugar in human red blood cells. Its content is parallel to the value of blood sugar and is not easy to decompose after it is produced. It can well reflect the blood glucose control of patients in the past 8 to 12 weeks. It is a good sensitive index for monitoring blood glucose levels within 3 months [9]. This experiment found that the fasting blood glucose, postprandial blood glucose, and glycosylated hemoglobin in the diabetic foot gangrene group were significantly higher than those in the diabetic foot gangrene group, and the difference was statistically significant. It shows that hyperglycemia is an important basis for the occurrence of gangrene, and the blood glucose value formed by gangrene belongs to a high level in diabetes, with an average fasting blood glucose of 9.63, postprandial blood glucose of 14.61, and glycosylated hemoglobin of 10.44.The mechanism of the diabetic foot caused by hyperglycemia is very complicated. At present, the proposed theories mainly include endothelial cell damage and dysfunction caused by hyperglycemia [10], long-term blood hypercoagulability, protein nonenzymatic glycosylation theory, oxidative stress theory, polyol pathway theory and protein kinase C (PKC) activation theory, lipid peroxidation, and so on [11, 12]. These theories explain the mechanism of foot gangrene caused by hyperglycemia from various aspects; some have been confirmed, and others need more research to prove. The degeneration and necrosis of diabetic foot tendons caused by hyperglycemia may be related to the increase of reactive oxygen species in the body, the decrease of antioxidant capacity, the oxidative stress of foot tendons and fascia, and the accumulation of sorbitol in the foot through polyol pathway. At the same time, hyperglycemia leads to a large amount of nonenzymatic glycosylation of proteins in the tendon and fascia, which is associated with immune dysfunction caused by hyperglycemia. Make patients more prone to infection, and the gangrenous type appears. Of course, this needs more research to confirm and reveal.Leukocytes, neutrophils, CRP, and interleukin-6 are all important signs of infection and inflammation in the body, and they are also the most commonly used clinical indicators of infection and inflammation. Leukocytes are the main cells in the human body to resist foreign infections and produce immunity, including neutrophils and lymphocytes; neutrophils are a type of white blood cells, which are mainly increased when the body has a purulent infection. CRP is produced when the body is stimulated by inflammation. Acute phase protein synthesized by hepatocytes is generally regarded as a very sensitive marker of inflammation and tissue damage [13]. It is also directly involved in the whole process of the inflammatory response [14]. Interleukin-6 is a cytokine produced by fibroblasts, monocytes/macrophages, etc., which can stimulate proliferation and differentiation and improve the function of cells involved in immune response, including the production of CRP. In this experiment, we found that the leukocytes, neutrophils, CRP, and IL-6 in the diabetic foot gangrene group were significantly higher than those in the diabetic foot gangrene group, and the difference was statistically significant, which indicated that the gangrenous infection was more serious than the ischemic infection, and the inflammatory reaction was more severe.Since 1972, Catterall defined diabetic foot as “diabetic patients have lost their senses due to neuropathy and lost their energy due to ischemia, and infected feet.” The infection has been widely recognized as the three basic elements of diabetic foot. Diabetic patients are susceptible to infection due to hyperglycemia and peripheral neuropathy resulting from immune dysfunction and damage. Diabetic foot patients have abnormal inflammatory responses without foot gangrene or diabetes. In a study conducted in the United States, 5888 elderly people were followed up for 3-4 years. The results showed that the incidence of diabetes in patients with elevated CRP increased by 2.3 times [15]. Diabetic patients are prone to infection due to hyperglycemia, immune dysfunction and injury, and peripheral neuropathy [16]. In diabetic patients, once infected, ulceration will stimulate the body to produce more CRP and IL-6, aggravating the body’s inflammatory response. The reason for infection and inflammatory reaction of tendon gangrene type is heavier than ischemic type. The main reason may be that the vascular lesions of the two types are different. The vascular injury of tendon gangrene type is small, the blood supply is mostly good, and the blood glucose of the foot is concentrated in the unruptured period, which makes it easy to be infected. The abnormal inflammatory reaction of early diabetes is also easy to spread to the foot tendon and other tissues, but once the infection occurs, the stimulating factors produced by the necrotic tissue of the foot can also reach the organs and tissues produced by immune cells such as liver and bone marrow through blood circulation. Thus, the infection and inflammation indexes of patients with gangrenous type are significantly increased. The degangrene type is due to severe vascular disease. Most of the lower extremity arteries are narrowed or occluded, less blood glucose accumulation in the feet before ulceration, and less early abnormal inflammatory response to the foot tendons and other tissues, so necrosis and ulceration are mostly caused by ischemia. The stimulatory factors produced by the necrotic tissue after rupture may also be difficult to reach the bone marrow, liver, thymus, and other tissues and organs of the body through the blood circulation to produce an immune-stimulating effect.Due to hyperglycemia and hyperlipidemia in diabetic foot patients, the viscosity of blood will inevitably change. Platelets are the main substances for coagulation and hemostasis, forming thrombus and repairing damaged blood vessels; plasma fibrinogen is the precursor of plasma fibrin. Plasma viscosity reflects the viscosity of plasma and is also an important factor affecting the viscosity of the whole blood; hematocrit is the volume percentage of blood cells in whole blood, which can also be used to reflect the viscosity of human blood. These four can affect or reflect the viscosity of human blood, so they are discussed together.This experiment found that the number of platelets in the gangrenous group was higher than that in the gangrenous group, which may be due to excessive platelet consumption in a specific state. Although both production and consumption increased, but the consumption was more than that in the gangrenous group. Therefore, the ischemic group with obvious occlusion or stenosis of blood vessels is lower than the gangrenous group with basically normal blood flow, which is similar to the observation of many scholars at home and abroad [17, 18]. There was no statistically significant difference in this experiment, indicating that platelets were the same in these two types.Due to the influence of hyperglycemia and hyperlipidemia in diabetic patients, plasma fibrinogen is higher than that of normal people, and high plasma fibrinogen can lead to the occurrence of atherosclerosis [19]. This is an important factor in the occurrence of diabetic foot gangrene. The two groups of patients with plasma fibrinogen levels were significantly higher than the normal value (normal 1.5-3.5 g/l), However, the number of patients in the gangrene group was higher than that in the gangrene group, and the difference was statistically significant because the gangrene group had a severe inflammatory response, and the inflammatory response would stimulate the production of plasma fibrinogen, which has been confirmed by many studies [20, 21]. Here, we also see that the gangrene type and the degangrene type cannot be completely separated. The plasma fibrinogen of the gangrene type is high, and it is easy to form thrombosis and cause atherosclerosis of the arterial blood vessels. In addition, the long-term hyperglycemia of the gangrene type causes damage to the blood vessels. It can be said that the gangrene type is gradually changing to the degangrene type over time.Plasma viscosity is significantly increased in patients with diabetic foot, which has been confirmed by many studies [22]. Its elevation will eventually lead to arterial stenosis or even occlusion. Plasma viscosity is mainly affected by plasma fibrinogen and lipids, especially triglycerides. In this experiment, there is no statistical difference in plasma viscosity between the two groups, and the average value of the two groups is almost the same, which may be due to the high plasma fibrinogen in the gangrene group and the high triglyceride in the gangrene group.The increase of hematocrit is mainly seen in severe dehydration, large area burn, and so on, but it has also been found in patients with diabetic foot [23]. The results showed that there was no significant difference between the two groups, and the mean value was significantly lower than that of normal people. Maybe patients and observation patients were treated with infusion therapy, so the hematocrit was significantly smaller, which reminds us that we need to develop more stringent observation methods to exclude the impact of these other factors.Serum total cholesterol is the total cholesterol contained in all lipoproteins in the blood, and triglycerides are the most abundant lipids in the body. Both of them play an important role in the formation of diabetic foot, especially in the formation of diabetic foot degangrene. This is because lipids, especially triglycerides, are closely related to the formation of atherosclerosis [24, 25], and atherosclerosis is one of the basic factors of diabetes.In this test, the total cholesterol and triglyceride in serum of the degangrene group were higher than those in the gangrene group, and the comparison of serum total cholesterol and triglyceride showed no difference, which fully demonstrated that lipid and arterial atherosclerosis are closely related. The mechanism of hyperlipidemia causing atherosclerosis is very complex, which may be related to the formation of small and dense low-density lipoproteins, reducing high-density lipoproteins, and promotion of plasma fibrinogen production and the oxidative modification of lipoproteins [26].AGEs are the product of nonenzymatic glycosylation (Maillard reaction) and protein oxidation with aldose without enzyme. It has the characteristics of stability and irreversibility, fluorescence, protein cross-linking, and biological effects caused by binding to AGEs receptor (RAGEs). Normal people will continue to accumulate as they age. Many recent studies have confirmed that the production and accumulation of AGEs in diabetic patients are much higher than that in normal people, which is closely related to various complications of diabetes such as diabetic coronary heart disease, diabetic retinopathy, diabetic nephropathy, and diabetic foot. The occurrence of the diabetic foot may be related to the production of glycation end products, which can damage peripheral nerves [27, 28], damage arteries [29, 30], and cause skin degeneration [31].In this experiment, the detection values of AGEs in the two groups were significantly higher than those in the normal group, indicating that AGEs may be an important factor in the formation of diabetic foot, but the difference between the two groups was not statistically significant. This may be because AGEs increased with age, and it was also related to the blood glucose value of the human body. The age of patients in the degangrene group was significantly older than that in the gangrene group, and the blood glucose value in the gangrene group was significantly higher than that in the degangrene group, which led to significantly higher detection values in both groups, but there was no significant difference between the two groups.The TCSS score is a peripheral neuropathy scoring system developed in Toronto, Canada, in 2001. Compared with the gold index for the diagnosis of peripheral neuropathy, the nerve conduction velocity test, the scoring system has the characteristics of simple application conditions and low cost and is suitable for clinical use. It is widely used in screening, and it has a good consistency and high accuracy with nerve conduction velocity testing [32, 33]. The system can also evaluate different grades of peripheral neuropathy. At present, ≥ 6 is generally divided into whether there is a cutoff point of peripheral neuropathy, ≥ 9 is divided into moderate lesions, and ≥ 12 is divided into severe lesions. Test due to funding, energy, patient acceptance, and other conditions, we use this scoring system as a diagnostic criterion for peripheral neuropathy.Peripheral neuropathy is one of the basic factors in the pathogenesis of diabetic foot, and its relationship with the pathogenesis of diabetic foot has been generally recognized and will not be discussed in detail here. In the results of this test, there was no significant difference in the number of cases of peripheral neuropathy and the grade of peripheral neuropathy between the two groups, indicating that peripheral neuropathy exists in both types, which is a common factor not just the presence of peripheral neuropathy in a certain type. Of course, it is also possible that the TCSS score is not completely equivalent to the nerve conduction velocity test, which leads to errors. This requires those who have the conditions to use the nerve conduction velocity test as the gold indicator to do more research.In conclusion, this study found the same and different characteristics of the pathogenesis of two types of diabetic foot by comparing blood glucose, inflammation, blood viscosity, and peripheral blood-related indicators and provided a reference for the prevention, treatment, and identification of different types of diabetic foot.



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