Status of Diabetic Neuropathy in Korea: A National Health Insurance Service-National Sample Cohort Analysis (2006 to 2015).

This report presents the status of diabetic neuropathy (DN) in Korea as determined using a National Health Insurance ServiceNational Sample Cohort (NHIS-NSC). Annual prevalences of DN were estimated by age and gender using descriptive statistics. Pharmacological treatments for DN were also analyzed. The annual prevalence of DN increased from 24.9% in 2006 to 26.6% in 2007, and thereafter, gradually subsided to 20.8% in 2015. In most cases, pharmacological treatments involved a single drug, which accounted for 91.6% of total prescriptions in 2015. The most commonly used drugs (in decreasing order) were thioctic acid, an anti-convulsive agent, or a tricyclic antidepressant. In conclusion, the prevalence of DN decreased over the 10-year study period. Thioctic acid monotherapy was usually prescribed for DN. To reduce the socio-economic burden of DN, more attention should be paid to the diagnosis of this condition and to the appropriate management of patients.

Lost in Translation? Measuring Diabetic Neuropathy in Humans and Animals.

The worldwide diabetes epidemic is estimated to currently afflict almost 500 million persons. Long-term diabetes damages multiple organ systems with the blood vessels, eyes, kidneys and nervous systems being particularly vulnerable. These complications of diabetes reduce lifespan, impede quality of life and impose a huge social and economic burden on both the individual and society. Peripheral neuropathy is a debilitating complication that will impact over half of all persons with diabetes. There is no treatment for diabetic neuropathy and a disturbingly long history of therapeutic approaches showing promise in preclinical studies but failing to translate to the clinic. These failures have prompted re-examination of both the animal models and clinical trial design. This review focuses on the functional and structural parameters used as indices of peripheral neuropathy in preclinical and clinical studies and the extent to which they share a common pathogenesis and presentation. Nerve conduction studies in large myelinated fibers have long been the mainstay of preclinical efficacy screening programs and clinical trials, supplemented by quantitative sensory tests. However, a more refined approach is emerging that incorporates measures of small fiber density in the skin and cornea alongside these traditional assays at both preclinical and clinical phases.

Clinical Characteristics of the COVID-19 Patients with Pneumonia Detected by Computerized Tomography but Negative for Infiltration by X-ray.

Coronavirus Disease 2019 (COVID-19) has rapidly spread to all corners of the globe. Different diagnostic tools, such as Chest X-ray (CXR), lung ultrasound (LUS), and computerized tomography (CT), have been used to detect active pneumonic lesions associated with COVID-19 with their varying degrees of sensitivity and specificity. This study was undertaken to investigate the clinical characteristics of COVID-19 patients with a pneumonic lung lesion detected by CT that is not detected by CXR. A total of 156 COVID-19 patients hospitalized at three nationally designated South Korean hospitals with no active lesion detected by CXR but on clinical suspicion of pneumonia underwent the CT examination and were enrolled. Medical records, which included demographic and clinical features, including comorbidity, symptoms, radiological, and laboratory findings on admission, were reviewed and analyzed. The risk factors of pneumonia detected by CT for patients without an active lesion detected by CXR were investigated. Of the 156 patients without an active lesion detected by CXR, 35 (22.44%) patients were found to have pneumonia by CT. The patients with pneumonia defined by CT were older than those without (64.1 years vs. 41.2 years). Comorbidities such as hypertension, diabetes, cardiovascular disease, preexisting stroke, and dementia were more common among patients with pneumonia defined by CT than those without. Serum albumin level, C-reactive protein (CRP), stroke, and age ≥ 70 years were significantly associated with pneumonia defined by CT after adjustment for age. In multivariable regression analysis, serum albumin level (adjusted odds ratio (AOR) = 0.123, 95% CI = (0.035-0.429)) and preexisting stroke (AOR = 11.447, 95% CI = (1.168-112.220)) significantly and independently predicted pneumonia detection by CT. Our results suggest that CT scans should be performed on COVID-19 patients negative for a pneumonic lung lesion by CXR who are suspected to be pneumonic on clinical grounds. In addition, older patients with a lower albumin level and a preexisting stroke should be checked for the presence of pneumonia despite a negative CXR finding for an active lesion.

Mortality Rate and Predictors of Mortality in Hospitalized COVID-19 Patients with Diabetes.

Studies have confirmed COVID-19 patients with diabetes are at higher risk of mortality than their non-diabetic counterparts. However, data-driven evidence of factors associated with increased mortality risk among hospitalized COVID-19 patients with diabetes is scarce in South Korea. This study was conducted to determine the mortality rate and identify risk factors of mortality among hospitalized COVID-19 patients with type 2 diabetes in Gyeongsangbuk-do province, South Korea. In this hospital-based, cross-sectional study, we enrolled a total of 324 patients with confirmed COVID-19, hospitalized at two of the tertiary level healthcare facilitates of Gyeongsangbuk-do, South Korea from 18 February to 30 June 2020. Demographic and clinical data and laboratory profiles were analyzed and multivariate logistic regression analysis was used to identify risk factors of mortality among diabetic patients with COVID-19. Of the 324 patients, 55 (16.97%) had diabetes mellitus. The mean age of all study subjects was 55 years, and the mean age of those with diabetes was greater than that of those without (69.8 years vs. 51.9 years). Remarkably, the mortality rate was much higher among those with diabetes (20.0% vs. 4.8%). Multivariate logistic regression analysis revealed that an older age (≥70 years) and a high serum lactate dehydrogenase (LDH) levels significantly predicted mortality among hospitalized COVID-19 patients with diabetes. Our study cautions more attention to be paid to patients with diabetes mellitus hospitalized for COVID-19, especially those aged ≥ 70 years and those with a high serum LDH level, to reduce the risk of mortality.

Clinical Characteristics and Mortality Predictors of COVID-19 Patients Hospitalized at Nationally-Designated Treatment Hospitals.

BACKGROUND: Coronavirus disease 2019 (COVID-19) was first reported in December 2019 in China, and then it has disseminated worldwide. In Korea, a religious group-related super-spreading event triggered a sudden outbreak in Daegu city and Gyeongsangbuk-do in southeast Korea. This study was undertaken to document the clinical characteristics of patients hospitalized in Gyeongsangbuk-do. METHODS: Three hundred and fifty-two patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection hospitalized at Dongguk University Gyeongju Hospital or at the Andong Medical Center between February 18th and June 30th were enrolled in this study. Medical records were reviewed and demographic and clinical features, including comorbidities, symptoms, radiological and laboratory findings on admission were analyzed. In addition, we sought to identify risk factors of mortality. RESULTS: Mean age of the 352 study subjects was 56 years (range, 14-95). The mortality rate was 6.8% and mean age at death was 81 years (range, 57-91). The most common symptom was cough (31.8%) followed by a febrile sensation (28.4%), sputum (17.0%), sore throat (15.6%), and myalgia (13.1%). Eighty-one (23.0%) patients were asymptomatic, but a half of these patients exhibited pneumonic infiltration at presentation. Chest radiology showed no active lesion in 41.8% of the study subjects, bilateral pneumonia in 46.9%, and unilateral pneumonic infiltration in 11.4%. Among 24 patients that died, 18 subjects were transferred from a care facility. An age of ≥ 70 years, previous history of malignancy or diabetes, and fever (≥ 37.5°C) on admission were found to be significant risk factors of mortality. CONCLUSION: Patients aged ≥ 70 years, those with fever on admission, and patients with an underlying malignancy or diabetes were found to be more likely to succumb to COVID-19. Elderly in care facilities or hospitalized patients with an underlying disease should receive more attention and be considered for preventive quarantine.

Diagnosis and Treatment of Growth Hormone Deficiency: A Position Statement from Korean Endocrine Society and Korean Society of Pediatric Endocrinology.

Growth hormone (GH) deficiency is caused by congenital or acquired causes and occurs in childhood or adulthood. GH replacement therapy brings benefits to body composition, exercise capacity, skeletal health, cardiovascular outcomes, and quality of life. Before initiating GH replacement, GH deficiency should be confirmed through proper stimulation tests, and in cases with proven genetic causes or structural lesions, repeated GH stimulation testing is not necessary. The dosing regimen of GH replacement therapy should be individualized, with the goal of minimizing side effects and maximizing clinical improvements. The Korean Endocrine Society and the Korean Society of Pediatric Endocrinology have developed a position statement on the diagnosis and treatment of GH deficiency. This position statement is based on a systematic review of evidence and expert opinions.

Comparison of Serum PCSK9 Levels in Subjects with Normoglycemia, Impaired Fasting Glucose, and Impaired Glucose Tolerance.

We investigated proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations in individuals with normoglycemia, impaired fasting glucose (IFG), and impaired glucose tolerance (IGT). This was a pilot, cross-sectional study including 92 individuals who had not been diagnosed with or treated for diabetes. We measured PCSK9 levels in three groups of subjects; namely, normoglycemia (n=57), IFG (n=21), and IGT (n=14). Individuals with IFG and IGT showed higher PCSK9 concentrations than those in the normoglycemic group, with the highest serum PCSK9 concentrations found in individuals with IGT (55.25±15.29 ng/mL for normoglycemia, 63.47±17.78 ng/mL for IFG, 72.22±15.46 ng/mL for IGT, analysis of variance P=0.001). There were no significant differences in high- or low-density lipoprotein cholesterol among groups. Serum PCSK9 levels are increased in patients with prediabetes compared to subjects with normoglycemia.

γ-Linolenic Acid versus α-Lipoic Acid for Treating Painful Diabetic Neuropathy in Adults: A 12-Week, Double-Placebo, Randomized, Noninferiority Trial.

BACKGROUND: This study was a multicenter, parallel-group, double-blind, double-dummy, randomized, noninferiority trial to evaluate the efficacy and safety of γ-linolenic acid (GLA) relative to α-lipoic acid (ALA) over a 12-week treatment period in type 2 diabetes mellitus (T2DM) patients with painful diabetic peripheral neuropathy (DPN). METHODS: This study included 100 T2DM patients between 20 and 75 years of age who had painful DPN and received either GLA (320 mg/day) and placebo or ALA (600 mg/day) and placebo for 12 weeks. The primary outcome measures were mean changes in pain intensities as measured by the visual analogue scale (VAS) and the total symptom scores (TSS). RESULTS: Of the 100 subjects who initially participated in the study, 73 completed the 12-week treatment period. Per-protocol analyses revealed significant decreases in the mean VAS and TSS scores compared to baseline in both groups, but there were no significant differences between the groups. The treatment difference for the VAS (95% confidence interval [CI]) between the two groups was -0.65 (-1.526 to 0.213) and the upper bound of the 95% CI did not exceed the predefined noninferiority margin (δ1=0.51). For the TSS, the treatment difference was -0.05 (-1.211 to 1.101) but the upper bound of the 95% CI crossed the noninferiority margin (δ2=0.054). There were no serious adverse events associated with the treatments. CONCLUSION: GLA treatment in patients with painful DPN was noninferior to ALA in terms of reducing pain intensity measured by the VAS over 12 weeks.

Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement.

The Korean Endocrine Society (KES) published clinical practice guidelines for the treatment of acromegaly in 2011. Since then, the number of acromegaly cases, publications on studies addressing medical treatment of acromegaly, and demands for improvements in insurance coverage have been dramatically increasing. In 2017, the KES Committee of Health Insurance decided to publish a position statement regarding the use of somatostatin analogues in acromegaly. Accordingly, consensus opinions for the position statement were collected after intensive review of the relevant literature and discussions among experts affiliated with the KES, and the Korean Neuroendocrine Study Group. This position statement includes the characteristics, indications, dose, interval (including extended dose interval in case of lanreotide autogel), switching and preoperative use of somatostatin analogues in medical treatment of acromegaly. The recommended approach is based on the expert opinions in case of insufficient clinical evidence, and where discrepancies among the expert opinions were found, the experts voted to determine the recommended approach.

Negative Association of Hepatitis B Virus With Hearing Impairment.

PURPOSE: Hearing impairment is one of the most common chronic diseases causing deterioration of the quality of life in elderly individuals. Several viral infections have been suggested to cause hearing impairment. We investigated association of hepatitis B virus (HBV) infection with hearing impairment using a representative sample of the Korean population. METHOD: Participants included 6,583 men and 8,702 women, who were ≥ 20 years of age from the Korea National Health and Nutritional Examination Surveys of the Korean population (2010-2012). Air-conduction pure-tone thresholds were measured in a soundproof booth using an automatic audiometer for each ear at 6 frequencies (500, 1000, 2000, 3000, 4000, and 6000 Hz). An audiometric test and a laboratory examination, including an HBV surface antigen (HBsAg) test, were performed. RESULTS: Subjects who are HBsAg positive had lower average of pure-tone thresholds and lower prevalence of hearing impairment at both low/mid and high frequency compared with those without. Adjusted means of hearing thresholds were also lower among subjects who are HBsAg positive compared with subjects who are HBsAg negative. After the adjustment for age and gender, the odds of high-frequency mild hearing impairment were lower for subjects with HBV infection. In the multiple logistic regression analyses adjusting for confounding variables, the significant negative association between HBV infection and high-frequency mild hearing impairment still remained. CONCLUSIONS: Contrary to previous reports, subjects who are HBsAg positive had a lower prevalence of hearing impairment compared with subjects who are HBsAg negative. Further studies are warranted to investigate the underlying mechanism regarding their negative relationship.

Association between diabetic peripheral neuropathy and heart rate variability in subjects with type 2 diabetes.

AIM: This study evaluated the association of Heart rate variability (HRV) measurements with diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes. METHODS: This study included 102 Korean subjects with type 2 diabetes. The Michigan neuropathy screening instrument (MNSI) questionnaire score, the MNSI examination score (MNSIES) and the total symptom score were examined for DPN evaluation. Noninvasive HRV measurements were performed using photoelectric plethysmography. Patients with a MNSIES > 2 were considered to have DPN. RESULTS: The MNSIES showed significant negative associations with the high frequency (HF) (r = -0.212, p = 0.033) and low frequency (LF) (r = -0.286, p = 0.004) powers. Multiple linear regression analysis revealed that only HF power maintained a significant negative association with the MNSIES (ß = -0.184; 95% CI -0.365 to -0.003; p = 0.047), after controlling for significant related confounders, with HRV parameters in male patients with type 2 diabetes. The HF (p = 0.010) and LF (p = 0.025) powers differed significantly between male patients without and those with DPN according to the MNSIES. CONCLUSIONS: This study revealed a negative association of DPN, as assessed by the MNSIES, with HF power in male patients with type 2 diabetes. DPN defined by foot examination was predictive of cardiac autonomic neuropathy.

Intraventricular administration of Tenebrio molitor larvae extract regulates food intake and body weight in mice with high-fat diet-induced obesity.

We recently reported the in vitro and in vivo antiobesity effects of Tenebrio molitor larvae, a traditional food in many countries, but it remains unknown how the larvae affect appetite regulation in mice with diet-induced obesity. We hypothesized that the extract of T molitor larvae mediates appetite by regulating neuropeptide expression. We investigated T molitor larvae extract's (TME's) effects on anorexigenesis and endoplasmic reticulum (ER) stress-induced orexigenic neuropeptide expression in the hypothalami of obese mice. Intracerebroventricular TME administration suppressed feeding by down-regulating the expression of the orexigenic neuropeptides neuropeptide Y and agouti-related protein. T molitor larvae extract significantly reduced the expression of ER stress response genes. These results suggest that TME and its bioactive components are potential therapeutics for obesity and ER stress-driven disease states.

Algae Undaria pinnatifida Protects Hypothalamic Neurons against Endoplasmic Reticulum Stress through Akt/mTOR Signaling.

Increased endoplasmic reticulum (ER) stress is known to be one of the causes of hypothalamic neuronal damage, as well as a cause of metabolic disorders such as obesity and diabetes. Recent evidence has suggested that Undaria pinnatifida (UP), an edible brown algae, has antioxidant activity. However, the neuroprotective effect of UP has yet to be examined. In this study, to investigate the neuroprotective effect of UP on ER stress-induced neuronal damage in mouse hypothalamic neurons, mice immortal hypothalamic neurons (GT1-7) were incubated with extract of UP. ER stress was induced by treating with tunicamycin. Tunicamycin induced apoptotic cell death was compared with the vehicle treatment through excessive ER stress. However UP protected GT1-7 cells from cell death, occurring after treatment with tunicamycin by reducing ER stress. Treatment with UP resulted in reduced increment of ATF6 and CHOP, and recovered the decrease of phosphorylation of Akt/mTOR by tunicamycin and the increment of autophagy. These results show that UP protects GT1-7 cells from ER stress induced cell death through the Akt/mTOR pathway. The current study suggests that UP may have a beneficial effect on cerebral neuronal degeneration in metabolic diseases with elevated ER stress.

Protective effect of carbenoxolone on ER stress-induced cell death in hypothalamic neurons.

Hypothalamic endoplasmic reticulum (ER) stress is known to be increased in obesity. Induction of ER stress on hypothalamic neurons has been reported to cause hypothalamic neuronal apoptosis and malfunction of energy balance, leading to obesity. Carbenoxolone is an 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitor that converts inactive glucocorticoid into an active form. In addition to its metabolic effect via enzyme inhibitory action, carbenoxolone has shown anti-apoptotic activity in several studies. In this study, the direct effects of carbenoxolone on ER stress and cell death in hypothalamic neurons were investigated. Carbenoxolone attenuated tunicamycin induced ER stress-mediated molecules such as spliced XBP1, ATF4, ATF6, CHOP, and ROS generation. In vivo study also revealed that carbenoxolone decreased tunicamycin-induced ER stress in the hypothalamus. In conclusion, the results of this study show that carbenoxolone has protective effects against tunicamycin induced-ER stress and apoptosis in hypothalamic neurons, suggesting its direct protective effects against obesity. Further study is warranted to clarify the effects of carbenoxolone on hypothalamic regulation of energy balance in obesity.

Association of periodontitis with insulin resistance, ß-cell function, and impaired fasting glucose before onset of diabetes.

Periodontitis and insulin resistance (IR) show bidirectional relationship. No studies have assessed the associations of periodontitis with IR, impaired ß-cell function, and impaired fasting glucose (IFG) in the general population. We investigated these associations in a representative sample of the Korean population. The subjects were 8,248 males and 10,874 females, who were ≥ 20 years of age and participants in the third, fourth, and fifth Korea National Health and Nutritional Examination Surveys (2008-2010). Periodontitis was defined as community periodontal index (CPI) ≥ code 3 according to World Health Organization criteria. Homeostasis model assessments of IR and ß-cell function (HOMA-IR and HOMA-ß) were calculated. Participants with periodontitis showed a higher prevalence of diabetes than those without periodontitis. Among subjects without diabetes, after adjustment for confounding factors including age, gender, body mass index, systolic blood pressure, serum total cholesterol, smoking status, alcohol consumption, region, and regular exercise, a comparison of participants with periodontitis vs those without showed a significantly higher prevalence of IFG (28.5% vs. 17.7%, p<0.001) and lower HOMA-ß (115.2 vs. 130.8, p<0.001). Periodontitis was identified as a risk factor for IFG (OR, 1.301; 95% CI, 1.193∼1.418; p<0.001). Conversely, participants with and without periodontitis had similar HOMA-IR. In conclusion, periodontitis showed an association with decreased ß-cell function and increased prevalence of IFG before onset of diabetes as well as increased prevalence of diabetes in the Korean population. Future longitudinal studies are warranted to elucidate the shared pathophysiology between periodontal disease and diabetes mellitus.

Prevalence and clinical characteristics of blepharoptosis in patients with diabetes in the Korea National Health and Nutrition Examination Survey (KNHANES) 2009-2010.

We investigated the prevalence and clinical characteristics of ptosis in patients with diabetes in the general Korean population. This cross-sectional study is based on data from the fourth and fifth Korea National Health and Nutrition Examination Surveys , conducted in 2009 and 2010 among members of the Korean population. Participants included 5,811 males and 7,650 females 20 years of age or older. Ptosis was defined as the marginal reflex distance 1 of <2 mm. Homeostatic model assessment of insulin resistance was calculated in participants without diabetes. HbA1c was measured and diabetic retinopathy was defined in participants with diabetes by ophthalmologic examination. The prevalence of ptosis was 20.8 and 9.4 % among participants with diabetes (n = 1,379) and those without diabetes (n = 12,082), respectively. Results of multiple regression analyses of the correlation between ptosis and the study variables showed that diabetes was a significant determinant in the general population. Patients with diabetes and ptosis had longer duration of diabetes (7.49 ± 0.51 vs. 6.19 ± 0.23 years, P = 0.012), higher serum creatinine level (80.4 ± 1.76 vs. 76.9 ± 0.88 mmol/l, P = 0.009), and higher prevalence of hypertension (60.3 vs. 47.9 %, P < 0.001), and were older (67.0 ± 0.6 vs. 60.5 ± 0.4 years, P < 0.001) compared to those without ptosis. Prevalence of ptosis was found to be remarkably higher in subjects with diabetes compared to those without diabetes. Diabetes is an independent risk factor for ptosis in the general Korean population. Screening for ptosis is warranted for patients with diabetes and longer duration, higher serum creatinine, hypertension, and old age.

Relationship of lean body mass with bone mass and bone mineral density in the general Korean population.

We investigated association of lean body mass with bone mass (BM) and bone mineral density (BMD) according to gender and menopausal status in the general Korean population. Participants included 4,299 males and 5,226 females who were 20 years of age or older from the fourth and fifth Korea National Health and Nutritional Examination Surveys (2009-2010). Dual-energy X-ray absorptiometry was used for measurement of BMD and body composition. BMD was measured in the femur and lumbar spine. Appendicular skeletal muscle mass (ASM) was defined as the sum of the lean soft tissue masses for the arms and legs. Analysis was performed after categorizing participants into four groups (males <50 years, males ≥ 50 years, premenopausal females, and postmenopausal females). In males, the highest ASM was observed in the 20-29-year group and then showed a gradual decrease as age increased, and BM and BMD showed similar patterns of change, while in females, ASM, BMD, and BM reached the peak level in the 40-49-year group and then decreased. In multiple regression analysis, after adjusting for confounding factors, the results showed an independent association of ASM with an increase in BM and BMD (P < 0.05). After adjusting for confounding factors, total fat mass showed a significant association with BM (P < 0.05). These aforementioned relationships were commonly observed on both femur and lumbar spine in every group. Lean body mass showed an independent association with increased BM and BMD, regardless of gender, age in men, and menopausal status in women.