Volume 13 · Issue 06 · 2021

Diabetic neuropathy is the most common chronic complication of diabetes, and international consensus and guidelines on diabetic neuropathy are also being updated. Based on this, the Neurological Complications Group of Diabetes Branch of Chinese Medical Association released the Expert Consensus on Diagnosis and Treatment of Diabetic Neuropathy (2021 Edition) (hereinafter referred to as the Consensus). In the consensus, the classification of diabetic neuropathy has changed greatly compared with the past, and the diagnosis and screening are the key content, and some updates are also made, while the treatment is focused on painful neuropathy. Therefore, this article aims at the consensus about the classification, diagnosis, screening and treatment of diabetic neuropathy.

Diabetic neuropathy is the most common chronic complication of diabetes. With the progress of clinical research on diabetic neuropathy, there are some updates on the classification, diagnosis and treatment of diabetic neuropathy in the world. Therefore, the Neurological Complications Group of Diabetes Branch of Chinese Medical Association organized experts to write the Expert Consensus on Diagnosis and Treatment of Diabetic Neuropathy (2021 Edition). This consensus introduces the epidemiology, pathogenesis, classification, screening and diagnosis, prevention and treatment of diabetic neuropathy (mainly distal symmetric polyneuropathy and autonomic neuropathy), and gives key points for important parts. The purpose of this consensus is to guide and help clinicians to carry out standardized comprehensive management of diabetic neuropathy, prevent and treat diabetic neuropathy early, and delay the disease progression.

The article "Research and Paper Quality Evaluation Criteria for the Prevention and Management of Diabetic Foot Ulcers: Basic Contents Needed and Marks of High Quality" is an important article jointly published by the International Diabetic Foot Working Group and the European Wound Management Society. It serves as a standard to measure the quality of clinical research and papers on diabetic foot ulcers that have been published, especially the main standard for selected and cited papers in the 2019 International Diabetic Foot Prevention and Management Series Guidelines. This paper emphasizes the problems that need attention in the design, implementation, results report and paper publication of clinical research on diabetic foot, and puts forward 21 scoring criteria for the scientific quality evaluation of clinical research on diabetic foot ulcer and related papers. The author excerpts, translates and interprets this article.

Evidence-based guidelines suggest that patients with diabetes who are at risk of ulcers often need to use custom footwear. The author excerpted, translated and interpreted the article "Instructions on the Design Scheme of Customized Shoes for Patients with Diabetes and Peripheral Neuropathy", and introduced the design scheme of developing customized shoes for patients with diabetes and peripheral neuropathy, aiming at providing a basis for the clinical use of customized shoes.

To investigate the prevalence and explore the clinical characteristics and risk factors of diabetic cardiac autonomic neuropathy (CAN) in type 2 diabetic patients in Beijing.

This research is a multi-center, randomized, cross-sectional study. From October 2015 to April 2016, type 2 diabetes mellitus (T2DM) patients in 13 hospitals in the urban and suburban areas of Beijing were randomly sampled for questionnaire, physical examination and laboratory examination. Patients were divided into CAN group and non-CAN group according to the results of cardiovascular autonomic reflex tests (CART). The independent t test, the Wilcoxon rank-sum test and the chi-square test were used to compare the differences of continuous data and categorical data between the two groups. Multivariate logistic regression was used to analyze risk factors for CAN.

A total of 1 975 patients with T2DM were included, including 1 236 patients (62.6%) in CAN group and 739 patients (37.4%) in non-CAN group. Compared with non-CAN group, CAN group had older age, longer duration of diabetes, higher glycated hemoglobin A_1c, larger metformin dosage, longer metformin medication time, fewer patients receiving higher education, and more complicated with coronary heart disease, peripheral vascular disease and hypertension (P<0.05). The most common manifestations of CAN included dizziness, standing instability, weakness, postprandial fullness, frequent urination, nocturia, urgent urination and upper body sweating (P<0.05). Logistic regression analysis showed that age was an independent risk factor for CAN in T2DM patients (OR=1.040, 95%CI 1.008 to 1.072,P=0.012).

The prevalence of CAN in patients with type 2 diabetes in Beijing is high. CAN is often associated with a variety of autonomic neuropathy symptoms and age is an independent risk factor for CAN.

To identify risk factors and metabolic changes related to gestational diabetes mellitus (GDM) patients with adverse pregnancy outcomes.

A retrospective study recruited participants from the University of Hong Kong-Shenzhen Hospital between 2016 and 2018, including 48 GDM patients with adverse pregnancy outcomes and 351 GDM patients without adverse pregnancy outcomes. The general information, pregestational body mass index, total bile acid, total cholesterol, triglyceride, lipoprotein, and pregnancy outcomes of the two groups were collected and serum samples were analyzed using metabolomics approach. The multivariate logistic regression analysis was performed to explore the independent risk factors for adverse pregnancy outcomes. Difference analysis with volcano plot and pathways enrichment analysis were used for screening differentially expressed metabolites. Area under curve (AUC) for receiver operating characteristic curve (ROC) curve was calculated for assessing the predictive value of combined factors.

In the multivariate logistic regression analysis, total cholesterol was the independent risk factor for adverse pregnancy outcomes while high-density lipoprotein cholesterol was a protective factor (odd ratio: 0.309, 95% confidence interval: 0.110 to 0.868, P=0.026). Five differentially expressed metabolites were found through analysis of volcano plot, including taurocholic acid, glycocholic acid, isovaleric acid, taurochenodeoxycholic acid, and taurodeoxycholic acid. Multi-factor combined ROC analysis for predicting adverse pregnancy outcomes had an AUC of 0.748.

Total cholesterol was the independent risk factor for adverse pregnancy outcomes among GDM patients. Metabolic changes of organic acids were correlated to adverse pregnancy outcomes for GDM patients and they had the potential to serve as metabolite biomarkers for adverse pregnancy outcomes among GDM women.

To investigate the relationship between short-term blood glucose fluctuation and chronic kidney disease (CKD) in diabetic patients.

In this prospective cohort study, we analyzed the data from the Guiyang subcenter of the Risk Evalution of cAncers in Chinese dibeTic Individual: alONgitudinal (REACTION) Study. A total of 10 140 residents aged over 40 in Yunyan District of Guiyang were selected from the baseline data by cluster sampling from May 2011 to August 2011, and the above subjects were followed up in 2014, and 400 subjects were eventually included in the study. All subjects were surveyed by questionnaire to collect sociodemographic characteristics, height, weight, blood pressure, fasting plasma glucose (FPG), 2 hours postprandial glucose (2hPG), glycated hemoglobin A_1c (HbA_1c), triglyceride (TG), fasting insulin and serum creatinine. The difference between 2hPG and FPG (2hPG-FPG) was used as an index to evaluate short-term blood glucose fluctuations. According to the HbA_1c levels, the subjects were divided into two groups: patients with good glycemic control (HbA_1c<7%) and patients with poor glycemic control (HbA_1c≥7%), The t test, Chi-square test and non-parametric test were used to compare the differences of indicators in each group. Associations between baseline 2hPG-FPG and CKD were performed by Spearman correlation. Associations between baseline 2hPG-FPG and eGFR after 3 years were performed by linear regression. A logistic regression model was used to analyze the relationship between baseline 2hPG-FPG levels (quartiles) and the risk of new CKD at 3 years. Spearman correlation was used to explore the correlation between baseline 2hPG-FPG and CKD, and linear regression analysis was used to analyze the relationship between baseline 2hPG-FPG and estimated glomerular filtration rate (eGFR) at 3 years. Logistic regression model was used to evaluate the relationship between different levels of baseline 2hPG-FPG (quartiles) and the risk of new onset of CKD at 3 years.

There were 175 patients in good glycemic control group and 225 patients in poor glycemic control group. In patients with poor glycemic control, the TG, FPG, 2hPG and 2hPG-FPG were higher than those in patients with good glycemic control, and the difference between the two groups was statistically significant (P<0.05). In patients with poor glycemic control, baseline 2hPG-FPG was negatively correlated with eGFR at 3 years [β=-1.178, 95% confidence interval (CI) -2.038 to -0.319, P=0.007], and positively correlated with the likelihood of CKD at 3 years (r_s=0.147, P=0.027). Logistic regression analysis showed that the risk of CKD increased with the increase of baseline 2hPG-FPG level (P<0.05). After adjusting for gender, age, body mass index, blood pressure, blood lipid, fasting insulin, smoking, alcohol consumption and disease course, in patients with poor glycemic control, the group with the highest baseline 2hPG-FPG level had a significantly increased risk of developing CKD after 3 years (odds ratio 4.474, 95%CI 1.039 to 19.268,P=0.044).

In previous diabetes patients with poor glycemic control, higher levels of 2hPG-FPG were associated with an increased risk of CKD after 3 years. 2hPG-FPG may be an independent risk factor for CKD.

To investigate the relationship between serum albumin (ALB) and insulin sensitivity in patients with obesity by hyperinsulinemic-euglycemic clamp.

One hundred and forty-four patients who underwent the hyperinsulinemic-euglycemic clamp in the Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanjing Medical University from January 2015 to December 2018 were included retrospectively. All participants were divided into 3 groups including 37 subjects with normal body mass index and normal glucose regulation (NNGR), 34 obese individuals with normal glucose regulation (ONGR) and 73 obese patients with impaired glucose regulation (OIGR). The OIGR group included 15 patients with prediabetes (1 patient with impaired fasting glucose and 14 patients with impaired glucose tolerance) as well as 58 patients with diabetes. Basic characteristics, serum albumin and other laboratory test results were recorded. Glucose infusion rate (GIR) was calculated to evaluate insulin sensitivity. Binary logistic regression analysis was used to analyze the correlation between serum albumin and insulin resistance. Receiver operating characteristic (ROC) curve was used to access the efficacy of homeostasis model assessment of insulin resistance (HOMA-IR) and 1/ALB for the evaluation of insulin resistance.

The ALB level [ (42.28±3.48), (44.04±3.12) vs. (46.33±3.52) g/L, P<0.05] and the GIR level [(3.55±1.46), (4.77±1.60) vs. (10.38±2.97) mg · kg^-1 · min^-1, P<0.05] gradually increased from OIGR group to ONGR group and NNGR group. ALB in 107 obese participants were positively correlated with GIR (r=0.352, P<0.01). ALB level was an independent factor to improve insulin resistance in obese subjects (OR=0.744,P=0.002). GIR was the standard for the ROC curve. The areas under different exponential curves were HOMA-IR+1/ALB (0.834), 1/ALB (0.757) and HOMA-IR (0.710), respectively. HOMA-IR combined with 1/ALB for the evaluation of insulin resistance corresponded to sensitivity at 64.0% and specificity at 92.5%.

Low ALB levels in obese individuals are independently correlated with insulin resistance. HOMA-IR combined with 1/ALB can better evaluate insulin resistance compared with HOMA-IR in obese subjects, with higher sensitivity and specificity.

To assess the effects of cortisol, adrenocorticotropic hormone (ACTH) and their rhythms on diabetes kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM).

This was a retrospective study. A total of 1 080 patients with T2DM who were hospitalized in the Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University School of Medicine from August 2010 to August 2019 were recruited, their general data such as gender, age, blood pressure, body mass index (BMI), and course of diabetes were collected. Cortisol and ACTH levels at 8:00, 16:00, 24:00 were measured, and use the trigonometric function model to calculate their amplitude and phase. Urine microalbumin/creatinine ratio (UACR) was measured, estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease-Epidemiology Collaboration formula based on gender, age and serum creatinine; patients were divided into DKD group (360 cases) and non-DKD group (720 cases) based on UACR and eGFR. According to UACR, patients were divided into no albuminuria group (736 cases), microalbuminuria group (260 cases) and large albuminuria group (84 cases). Differences between groups were compared using independent sample t test, Mann-Whitney U test and one-way analysis of variance. Binary logistic regression analysis was used to explore the relationship among blood ACTH, cortisol levels and their rhythms and DKD.

ACTH and serum cortisol levels of the DKD group at 8:00, 16:00, and 24:00 were significantly higher than those of the non-DKD group (P<0.05). The amplitude of ACTH and cortisol in the DKD group was significantly higher than that in the non-DKD group (P<0.05). The blood ACTH and cortisol levels at 8:00, 16:00, 24:00 and their amplitudes were statistically significant (P<0.05) among the no-albuminuria group, microalbuminuria group and macroalbuminuria group. Compared with the microalbuminuria group, the blood cortisol phase of the macroalbuminuria group was delayed, and the difference was statistically significant (P<0.05). The logistic regression analysis showed that with the increase of blood ACTH and cortisol levels, the risk of DKD increased significantly (allP<0.05). After adjusting for age, gender, and BMI, the risk of DKD still exists (allP<0.05).

Increased ACTH and serum cortisol levels and changes in their rhythm are related to the development of DKD in patients with T2DM.

To investigate the clinical efficacy of silver ion dressing in the treatment of chronic wounds in diabetic patients.

A retrospective analysis of 60 diabetic patients with chronic refractory wounds admitted to our hospital and cooperative units between February 2018 and February 2019 was conducted. The patients were divided into the experimental group (silver ion dressing group) and the control group (silver sulfadiazine group) according to the wound treatment. According to the Bates-Jensen Wound Assessment Tool (BWAT), the wound healing, infection and healing time of the two groups were scored and compared. Statistical analysis was performed using Mann-Whitney U test, independent sample t test and χ² and Fisher exact test.

(1) Wound situation. There was no significant difference in the BWAT scores of the two groups on the 7th and 14th days; on the 21st day, the BWAT score of the silver ion dressing group was significantly lower than that of the silver sulfadiazine group (P<0.05). However, there was no significant difference in the BWAT% scores of the two groups on the 7th day; on the 14th and 21st days, the BWAT% score of the silver ion dressing group was significantly lower than that of the silver sulfadiazine group (P<0.05). (2) Wound infection status. The BWAT-I scores of the two groups on the 1st and 7th days were significantly different (P<0.05), and the silver ion dressing group was higher than the silver sulfadiazine group; there was no significant difference in the BWAT-I scores of the two groups on the 14th and the 21st days. There were significant differences in the BWAT-I% between the two groups on the 7th, 14th and 21st days (P<0.05). The silver ion dressing group was significantly lower than the silver sulfadiazine group. (3) Wound healing time. The wound healing time of the silver ion dressing group [34.50 (22.75, 57.25) d] was significantly shorter than that of the silver sulfadiazine group [46.50 (37.75, 64.75) d], and the difference was statistically significant (Z=-2.191, P<0.05).

On the basis of thorough debridement, the topical application of silver ion dressing on chronic wounds in diabetic patients can effectively reduce and control wound infections and speed up the process of wound repair.

To explore the influence of carbohydrate response element-binding protein-β (ChREBP-β) on the browning of white adipose tissue and further clarify its role in glucose metabolism homeostasis.

Rosa-LSL-ChREBP-β transgenic mice were mated with Adiponectin-Cre mice to establish a mouse model with specific overexpression of ChREBP-β in adipose tissue by using Cre/loxP technology (AET-β); the heterozygous AET-β mice were used as the experimental group, and wild-type mice without Cre of the same age and sex were used as the control group. We analyzed the cold tolerance, white adipose tissue morphology, and thermogenic gene expression of inguinal white adipose tissue to explore the influence of ChREBP-β on white adipose tissue browning through acute cold exposure and long-term cold training test. We also analyzed the blood glucose, glucose tolerance, and insulin tolerance of mice fed with normal, high sucrose, and high-fat diet to explore the role of ChREBP-β in glucose metabolism homeostasis. To compare the means between adipose tissue ChREBP-β overexpressing mice and the control group, a Student′s t-test was used. Repeated-measures analysis of variance (ANOVA) was used in the acute cold exposure test. For the multiple comparisons of means in different groups, the least significant difference (LSD) test was applied.

Compared with the control mice, AET-β mice had decreased core body temperature and local temperature in brown adipose tissue under acute cold exposure (P<0.05), while the thermogenic gene expression of white adipose tissue was not significantly changed after long-term cold training (P>0.05), and glucose tolerance was slightly improved on high-fat diet (P<0.05).

The constitutive activation of ChREBP-β in adipose tissue can significantly inhibit brown adipose tissue thermogenesis, but the effect on glucose metabolism homeostasis and cold-induced white adipose tissue browning is very limited.

To study the effects of metformin on lipid deposition induced by high uric acid in HepG2 cells and its underlying mechanisms.

HepG2 cells were divided into five groups according to different treatment factors: control group (no intervention), high uric acid group (12 mg/dl uric acid), high uric acid+metformin group (12 mg/dl uric acid+10 μmol/L metformin), high uric acid+metformin+adenosine monophosphate activated protein kinase (AMPK) inhibitor group (after pretreatment with 10 μmol/L AMPK inhibitor Compound C for 30 min, 12 mg/dl uric acid and 10 μmol/L metformin were added), high uric acid+metformin+nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) inhibitor group (after pretreatment with 100 μmol/L AMPK inhibitor Apocynin for 30 min, 12 mg/dl uric acid and 10 μmol/L metformin were added). Each group was set three parallels and incubated for 48 h. Oil Red O stain was used to detect intracellular lipid droplet distribution. The biochemical kits were used to measure intracellular triglyceride levels (TG), mitochondrial reactive oxygen species (ROS), mitochondrial malondialdehyde (MDA), the activity of mitochondrial xanthine oxidase (XO) and glutathione peroxidase (GSH-Px). The real-time polymerase chain reaction was used to measure mRNA levels of lipid synthesis related genes and mitochondrial nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). Western blotting was used to detect the protein levels of AMPK, phosphorylated AMPK (p-AMPK) and mitochondrial NOX4. immunofluorescence staining was used to detect NOX4 concentrations in mitochondria. One-way analysis of variance and t test were used for comparison among groups.

Compared with high uric acid group, metformin significantly decreased the number of intracellular lipid droplets and TG contents (t=8.181, P<0.05), reduced the mitochondrial ROS and MDA levels, inhibited the activity of mitochondrial XO, increased the activity of mitochondrial GSH-Px (t=5.327-8.242, all P<0.05), down-regulated the mRNA expression of lipid synthesis related genes (t=7.835-11.013, all P<0.05), significantly increased the phosphorylation of AMPK protein (t=7.000, P<0.05), reduced the mRNA and protein expressions of NOX4 in mitochondria (t=6.190-14.199, all P<0.05), and the differences were statistically significant. Compared with high uric acid+metformin group, AMPK inhibition attenuated the effects of metformin, NOX4 inhibition further enhanced those effects, and the differences were statistically significant (all P<0.05).

Metformin could reduce high uric acid-induced intracellular lipid deposition in HepG2 cells via a mechanism related to activation of AMPK/NOX4 signaling pathway and improvement of mitochondrial oxidative stress.

Diabetic foot disease complicated with melanoma is rare in clinic, and its early manifestations are similar to those of simple ischemic diabetic foot disease, which is easy to be misdiagnosed and misdiagnosed. In this paper, the clinical data, diagnosis and treatment process and prognosis of 4 patients were retrospectively analyzed, and the clinical characteristics of diabetic foot disease complicated with melanoma were summarized, so as to provide experience for early identification. Diabetic foot disease complicated with melanoma is highly malignant, and good curative effect can be obtained by early diagnosis, extended surgical resection combined with comprehensive tumor treatment; Misdiagnosis and missed diagnosis or improper treatment lead to poor prognosis.

This paper reports a case of diabetic foot disease with purulent infection and ulcer. No pathogen was detected by traditional microbiological detection methods. New abscess and ulcer appeared during empirical antibiotic treatment, and the inflammatory index did not decrease. Finally, the pathogen high-throughput DNA detection technology was used to diagnose a case of incidental mycobacterium complex infection. The case was finally cured by combined treatment with moxifloxacin + clarithromycin and foot soaking with chlorhexidine. This case suggests that in the treatment of diabetic foot infection, if the pathogen cannot be detected by routine detection methods after multiple samples, high-throughput DNA detection technology of pathogen can be considered; Topical application of chlorhexidine antibacterial treatment may avoid the outcome of amputation.

Irrational diet and cardiovascular disease risk factors are closely related. As one of the three major nutrients, carbohydrate has attracted much attention in recent years on the effects of its quantity and quality on health. With the continuous optimization of dietary assessment methods, the influence of carbohydrate quality on blood pressure, blood lipids and blood sugar is gradually clear. Low blood sugar load diet, increasing whole grain and dietary fiber intake, and controlling the total carbohydrate intake can improve blood pressure, blood lipids, blood sugar and other cardiovascular disease risk factors.

Insulin resistance and metabolic syndrome play a key role in the pathogenesis of type 2 diabetes. The core pathophysiological disorder of type 1 diabetes mellitus (T1DM) is insulin deficiency. More and more evidence shows that diabetes exhibits spectral continuous changes in genetic background, autoimmunity, rate of islet failure, clinical manifestations and insulin resistance. In addition, recent cohort studies have shown that metabolic syndrome and insulin resistance are closely related to the clinical phenotype and risk of cardiovascular events of T1DM. Cardiovascular events are an important cause of disability and death caused by T1DM. Therefore, paying attention to the relationship between insulin resistance and T1DM is of great significance for understanding the disease spectrum of insulin resistance distribution, reducing the risk of cardiovascular complications and guiding clinical treatment.

Glucose-dependent insulinotropic peptide (GIP) is an incretin-secreting peptide synthesized and secreted by small intestinal mucosal epithelial K cells, which can stimulate the secretion of insulin and glucagon. Recent studies have found that the GIP-GIP receptor (GIPR) signaling pathway plays an important role in obesity and its related metabolic abnormalities. Polymorphisms of GIP and GIPR genes were significantly associated with obesity susceptibility. Activation of GIP-GIPR pathway can increase fat synthesis and storage, and promote the occurrence of obesity; Blocking the GIP-GIPR pathway can inhibit fat synthesis and storage, and reduce body weight. Recent animal experiments have found that the combined use of GIP and weight loss drugs-glucagon-like peptide 1 (GLP-1) receptor agonist can further enhance the sensitivity of mice to GLP-1. Therefore, the GIP-GIPR signaling pathway is expected to be a target for the treatment of obesity and its related metabolic abnormalities in the future.

Randomized controlled trials (RCTs) are the gold standard for evaluating the safety and effectiveness of certain drugs or interventions. Rational design is the core of high-quality RCTs and scientific judgment of trial results. How to improve the rigor, rationality and perfection of RCT design and how to ensure the quality of RCT implementation is a common confusion for many clinical researchers. Taking the classical clinical trial of diabetes as an example, the author discusses the key points of RCT design, hoping to provide reference for the design and development of RCT research on diabetes prevention and treatment in the future.

Diabetic microvascular disease is a common specific complication of diabetes, which can involve kidney, nerve, retina, myocardium and other tissues and organs in the whole body. As a classical microcirculation improver, pancreatic kininogenase can be used to treat a variety of diabetic microvascular complications. The mechanisms may involve protecting endothelial cells, affecting microvascular angiogenesis and permeability, and reducing tissue fibrosis, oxidative stress, inflammatory response and apoptosis. While controlling blood glucose, improving microcirculation is of great significance for preventing, delaying and treating various microvascular complications of diabetes.