The Association of Smoking Status with Diabetic Microvascular Complications in Korean Patients with Type 2 Diabetes.

PURPOSE: Few studies have investigated the association between smoking and microvascular complications in the Asian population with type 2 diabetes mellitus (T2DM). We aimed to investigate the relationship between smoking status and microvascular complications in Korean patients with T2DM. MATERIALS AND METHODS: From the Korean National Diabetes Program cohort, we included 2316 Korean male with T2DM who had baseline clinical information available, including their smoking status, and underwent diabetic complication studies. RESULTS: Compared to non-smokers, current smokers had higher odds of any-microvascular complications [adjusted odds ratio (aOR) 1.45, 95% confidence interval (CI) 1.07-1.97, p=0.016]. The odds of neuropathy were significantly higher; however, the odds of retinopathy were significantly lower in current smokers than in nonsmokers (all p<0.05). Among those who underwent repeated complication tests after 3 years, the risk of newly developed retinopathy was significantly increased in ex-smokers [aOR 3.77 (95% CI 1.61-8.87), p=0.002]. Within ex-smokers, long smoking duration and smoking cessation within the recent 5 years were associated with an increased risk of newly developed retinopathy (all p<0.05). CONCLUSION: Male smokers had higher odds of having overall diabetic microvascular complications, including neuropathy. However, the odds of having retinopathy were significantly lower among current smokers. More attention and research are needed regarding the increased risk of retinopathy development in ex-smokers who have recently stopped smoking after a long history of smoking.

Prediction of antidiabetic effect after gastrectomy with Roux-en-Y reconstruction in patients with gastric cancer and type 2 diabetes.

This study investigated the antidiabetic outcomes after gastrectomy with long-limb RY reconstruction (LRYR) and the prognostic factors for remission after 1 year in patients with type 2 diabetes (T2DM) and gastric cancer. In 25 Koreans with T2DM and gastric cancer, plasma glucose and insulin levels were measured during a 75 g oral glucose tolerance test, before and 1 week after gastrectomy with LRYR. Patients were examined after 1 year and we defined glycemic control as "remission" when the HbA1c level after 1 year was <6.0% without medication. One year after surgery, 12 patients achieved HbA1c < 6.0% without medication. Among the preoperative indices, the duration of diabetes was shorter in the remission group than that in the non-remission group (median 2.0 [0-6.5] years vs 7.0 [4.5-10.0] years, P = .023). At 1 week after surgery, significant improvements in fasting, 30 minutes, 60 minutes, 90 minutes stimulated glucose levels and insulin resistance (HOMA-IR and Matsuda index) were found only in the remission group. The multivariable logistic regression analysis results showed that higher 30 minutes stimulated glucose level and HOMA-IR index at 1 week after surgery were independent factors for lower odds of 1-year diabetes remission. Shorter duration of diabetes and early postoperative improvements in 30 minutes stimulated glucose level and HOMA-IR were important determinants of long-term antidiabetic outcomes after gastrectomy with LRYR in patients with T2DM and gastric cancer.

Ezetimibe combination therapy with statin for non-alcoholic fatty liver disease: an open-label randomized controlled trial (ESSENTIAL study).

BACKGROUND: The effect of ezetimibe, Niemann-Pick C1-like 1 inhibitor, on liver fat is not clearly elucidated. Our primary objective was to evaluate the efficacy of ezetimibe plus rosuvastatin versus rosuvastatin monotherapy to reduce liver fat using magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: A randomized controlled, open-label trial of 70 participants with NAFLD confirmed by ultrasound who were assigned to receive either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks. The liver fat change was measured as average values in each of nine liver segments by MRI-PDFF. Magnetic resonance elastography (MRE) was used to measure liver fibrosis change. RESULTS: Combination therapy significantly reduced liver fat compared with monotherapy by MRI-PDFF (mean difference: 3.2%; p = 0.020). There were significant reductions from baseline to study completion by MRI-PDFF for both the combination and monotherapy groups, respectively (18.1 to 12.3%; p < 0.001 and 15.0 to 12.4%; p = 0.003). Individuals with higher body mass index, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to treatment with ezetimibe. MRE-derived change in liver fibrosis was not significantly different (both groups, p > 0.05). Controlled attenuation parameter (CAP) by transient elastography was significantly reduced in the combination group (321 to 287 dB/m; p = 0.018), but not in the monotherapy group (323 to 311 dB/m; p = 0.104). CONCLUSIONS: Ezetimibe and rosuvastatin were found to be safe to treat participants with NAFLD. Furthermore, ezetimibe combined with rosuvastatin significantly reduced liver fat in this population. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (registration number: NCT03434613 ).

State-of-the-Art Overview of the Pharmacological Treatment of Non-Alcoholic Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, and non-alcoholic steatohepatitis (NASH), a subtype of NAFLD, can progress to cirrhosis, hepatocellular carcinoma, and death. Nevertheless, the current treatment for NAFLD/NASH is limited to lifestyle modifications, and no drugs are currently officially approved as treatments for NASH. Many global pharmaceutical companies are pursuing the development of medications for the treatment of NASH, and results from phase 2 and 3 clinical trials have been published in recent years. Here, we review data from these recent clinical trials and reports on the efficacy of newly developed antidiabetic drugs in NASH treatment.

Relationships Between Pulmonary Function and Composite Indices of Femoral Neck Strength in Korean Men (KNHANES IV).

BACKGROUND: Despite the close relationship between osteoporosis and chronic pulmonary diseases, few studies have evaluated relationships between pulmonary functions and bone quality. We investigated associations between pulmonary function test results and femoral neck strength indices (SIs) in Korean men. METHODS: This population-based, cross-sectional study was conducted using data from the Korea National Health and Nutrition Examination Survey IV on 936 men aged ≥ 19 years. Pulmonary functions (forced vital capacity [FVC] and forced expiratory volume in one second [FEV1]) were measured using a dry rolling seal spirometer. Femoral neck SIs, relative to load, were calculated by hip dual-energy X-ray absorptiometry for compression strength index (CSI), bending strength index (BSI), and impact strength index (ISI). RESULTS: The 443 (47.3%) of the 936 men were current smokers. FVC, FVC percentage with respect to the expected normal value, FEV1, and FEV1 percentage with respect to the expected normal value (FEV1p) were positively associated with CSI and BSI after adjusting for confounders, including smoking history (ß = 0.003-0.223, P = 0.005-0.036). FEV1 and FEV1p were positively associated with ISI (ß = 0.000-0.014, P = 0.010-0.025). Of components of femoral neck SIs, bone mineral density was correlated with FEV1 and FEV1p (ß = 0.001-0.037, P = 0.017-0.019). After adjusting for all confounders, all femoral neck SIs increased with FVC quintiles (P for trends = 0.001-0.012), and CSI and BSI increased with FEV1 quintiles (P for trends = 0.034-0.043). CONCLUSION: Reduced pulmonary function was correlated with reduced femoral neck strength, even after adjusting for smoking history in Korean men. Femoral neck SIs might be useful tools for evaluating bone health in men with reduced pulmonary function.

Dipeptidyl peptidase-4 inhibitor protects against non-alcoholic steatohepatitis in mice by targeting TRAIL receptor-mediated lipoapoptosis via modulating hepatic dipeptidyl peptidase-4 expression.

Dipeptidyl peptidase-4 inhibitors (DPP4i) are antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP4). DPP4 is ubiquitously expressed, and its hepatic DPP4 expression is upregulated under non-alcoholic steatohepatitis (NASH) conditions. We investigated the effect of DPP4i treatment on NASH pathogenesis, as well as its potential underlying molecular mechanisms. Mice were randomly divided into three groups: Group 1, chow-fed mice treated with vehicle for 20 weeks; Group 2, high-fat, high-fructose, and high-cholesterol Amylin liver NASH (AMLN) diet-fed mice treated with vehicle for 20 weeks; Group 3, AMLN diet-fed mice treated with vehicle for the first 10 weeks, followed by the DPP4i teneligliptin (20 mg/kg/day) for additional 10 weeks. DPP4i administration reduced serum liver enzyme and hepatic triglyceride levels and markedly improved hepatic steatosis and fibrosis in the AMLN diet-induced NASH model. In vivo, NASH alleviation significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and downregulated hepatic DPP4 expression. In vitro, DPP4i treatment significantly decreased the markers of TRAIL receptor-mediated lipoapoptosis and suppressed DPP4 expression in palmitate-treated hepatocytes. In conclusion, DPP4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly by modulating hepatic DPP4 expression.

Prevalence of Thyroid Disease in Patients Surgically Treated for Pituitary Disease.

Thyroid disease mainly has a thyroid origin but can occasionally have a pituitary origin. Clinicians face several challenges when these conditions occur together. We aimed to determine the prevalence of thyroid disorders in patients undergoing trans-sphenoidal adenomectomy (TSA) for pituitary disease. We reviewed the medical records of patients undergoing TSA for pituitary disease between 2008 and 2017 at Severance Hospital. Thyroid disorders were categorized using blood test results and medical histories at the time of preoperative evaluation. Among 2202 patients, 44 (2%), 218 (9.9%), and 74 (3.4%) had hyperthyroidism, hypothyroidism, and post-thyroidectomy status before TSA, respectively. Among the 44 patients with hyperthyroidism, 30 (68.2%) had central hyperthyroidism. Among the 218 patients with hypothyroidism, 165 (75.7%) had central hypothyroidism. Central hypothyroidism was more common in patients with adrenocorticotropic hormone-secreting pituitary adenomas (aOR (adjusted odds ratio) 1.85), Rathke's cleft cysts (aOR 2.34), and craniopharyngiomas (aOR 2.58) (all p < 0.05) than in those with nonfunctioning pituitary adenomas. Contrastingly, thyroid cancer had an increased prevalence in patients with growth hormone- (aOR 3.17), prolactin- (aOR 3.66), and thyroid-stimulating hormone-secreting (aOR 6.28) pituitary adenomas (all p < 0.05). Pituitary disease sometimes accompanies thyroid disorders; their characteristics vary according to the type of pituitary disease.

Nationwide Trends in Pancreatitis and Pancreatic Cancer Risk Among Patients With Newly Diagnosed Type 2 Diabetes Receiving Dipeptidyl Peptidase 4 Inhibitors.

OBJECTIVE: Dipeptidyl peptidase 4 inhibitors (DPP-4i) are useful incretin-based antidiabetes drugs. However, there is a concern that DPP-4i may adversely impact the exocrine pancreas, owing to their pleiotropic effects. In this study, we investigated whether DPP-4i are associated with pancreatitis and pancreatic cancer using a nationwide population-based cohort study. RESEARCH DESIGN AND METHODS: We included patients newly diagnosed with type 2 diabetes who were treated with antidiabetes drugs (n = 33,208) from 2007 to 2013. The data were obtained from the Korean National Health Insurance Service-Health Screening Cohort database (n = 514,866). Risk was estimated using a Cox proportional hazards model with time-dependent covariates. A 6-month lag time was used to account for a possible latency time. The risk across various time segments since the first prescription of DPP-4i was also analyzed. RESULTS: Out of 33,208 subjects, 10,218 were new users of DPP-4i and 22,990 were new users of other antidiabetes drugs. DPP-4i significantly increased the risks of pancreatitis (adjusted hazard ratio [aHR] 1.24, 95% CI 1.01-1.52; P = 0.037) and pancreatic cancer (aHR 1.81, 95% CI 1.16-2.82; P = 0.009) with a 6-month drug use lag period. The risk of pancreatitis and pancreatic cancer was generally consistent in the first 12 months and 1 year after the initial prescription without showing an increasing trend according to exposure duration. CONCLUSIONS: DPP-4i use is associated with increased risks of pancreatitis and pancreatic cancer in patients with newly diagnosed type 2 diabetes. However, the absence of increasing trend according to exposure duration suggests the chances of reverse causality, and long-term pancreatic safety of DPP-4i has to be further investigated.

Nonalcoholic Fatty Liver Disease in Diabetes. Part I: Epidemiology and Diagnosis.

Nonalcoholic fatty liver disease (NAFLD) and diabetes are common metabolic disorders whose prevalence rates are expected to rise worldwide, corresponding to aging and increasingly obese populations. Compared to the general population (around 25%), 50% to 70% of people with diabetes have NAFLD, and NAFLD severity (including fibrosis) tends to be worsened by the presence of diabetes. NAFLD is considered an emerging risk factor for type 2 diabetes mellitus and a contributor to the development of chronic diabetes-related complications. This reciprocal relationship demonstrates the importance of confirming suspected NAFLD in patients with diabetes. Due to the invasive nature of liver biopsy to assess NAFLD status, various alternative non-invasive modalities have been developed and validated. Here, we summarized the epidemiology of NAFLD in patients with diabetes and reviewed currently available imaging modalities and biomarker-based prediction models for their ability to detect liver steatosis and/or fibrosis.

Statin Use is Associated with Decreased Hepatocellular Carcinoma Recurrence in Liver Transplant Patients.

Statins have been reported to prevent the development of hepatocellular carcinoma (HCC). We examined whether statin therapy is associated with decreased HCC recurrence in patients who underwent liver transplantation for HCC. Three hundred forty-seven patients ≥ 20 years old who underwent liver transplantation for HCC from 2006 to 2016 were enrolled in this study. Statin therapy was defined as the administration of statins for more than 30 days after liver transplantation. One hundred twelve (32.3%) patients treated with statins over 30 days were defined as the statin group, and the remaining 235 (67.7%) were defined as the non-statin group. Several risk factors reported to be associated with HCC recurrence, such as proportion of underlying liver disease, above Milan criteria, differentiation of HCC, vascular invasion, and preoperative alpha-fetoprotein level were not different between the two groups. Time-dependent Cox regression analysis showed that statin treatment was associated with significantly lower recurrence risk of HCC after adjusting for other risk factors (hazard ratio = 0.32, 95% CI = 0.11-0.89).

Aromatase inhibitor use is a risk factor of carotid plaque presence in endocrine-responsive breast cancer patients.

BACKGROUND/AIMS: The aromatase inhibitors (AIs) are well known anti-hormonal therapy in endocrine-responsive breast cancer patients. It can lead to dyslipidemia and be the risk factor of cardiovascular disease due to low estrogen level. However, some recent studies comparing AIs with placebo have shown controversial results. The aim of this study was to investigate lipid profiles, measurement of carotid intima-media thickness (IMT) and the presence of plaque among endocrine-responsive breast cancer treated with AIs compared to ones that were not treated with AIs. METHODS: A total of 85 postmenopausal women, who underwent breast cancer surgery during the age of 50 to 64 without history of statin use were included. There were 42 patients who were treated with AIs over 1 year (group 1) and 43 patients without AIs use (group 2). Serum total cholesterol, high density lipoprotein cholesterol, triglycerides, fasting blood glucose, carotid IMT, and presence of plaque were assessed. RESULTS: The baseline characteristics were similar between two groups and there was no significant difference in carotid IMT irrespective of AIs administration. However, ultrasonographic evaluation of carotid artery revealed that the presence of plaque in AI users was significantly higher than in non-AI users (66.7% vs. 41.9%, p = 0.02; odds ratio, 4.21 in adjusted model; p = 0.01). History of diabetes was also the significant risk factor for the plaque formation. CONCLUSION: There was no significant difference in lipid profile itself between two groups, but more importantly the presence of the plaque was much higher indicating possible detrimental effect of AI on cardiovascular system.

The association between skin auto-fluorescence of palmoplantar sites and microvascular complications in Asian patients with type 2 diabetes mellitus.

Skin auto-fluorescence (SAF) has generated broad interest about the prospects for non-invasive advanced glycation end product assessment and its direct interplay with the development of microvascular complications, but clinical application of the existing SAF measuring of non-palmoplantar sites in non-Caucasian subjects with dark skin type is still controversial. Here, we tested the diabetic complication screening performance of a novel SAF measuring system in Asian type 2 diabetes mellitus (T2DM) subjects. A total of 166 Korean patients with T2DM were enrolled in this study and palmoplantar SAF was measured by a newly developed transmission-geometry noninvasive optical system. We found that transmitted SAF values of palmoplantar sites, 1st dorsal interossei muscles of the hand, in a complication group were significantly higher than in a non-complication group while no differences were observed between the two groups in reflected SAF of non-palmoplantar sites. The transmitted SAF values of palmoplantar sites were dramatically increased in subjects with multiple complications and were tightly correlated with the duration of microvascular complications. In conclusion, the SAF measurement in the palmoplantar sites with a non-invasive transmission-geometry optical system provided better microvascular complication screening performance compared to the SAF measurement of non-palmoplantar sites specifically in Asian T2DM subjects.

Body Mass Index Is Associated with Hypercholesterolemia following Thyroid Hormone Withdrawal in Thyroidectomized Patients.

Thyroid hormone withdrawal (THW) for postoperative radioiodine adjuvant therapy or diagnostic radioiodine whole body scan in patients with differentiated thyroid cancers results in acute thyroid hormone deficiency and abnormal lipid profiles. To better clarify the clinical pattern of dyslipidemia occurring after THW, we retrospectively analyzed the association between serum total cholesterol level after THW and various clinical factors in a total of 61 patients who underwent total thyroidectomy due to papillary thyroid cancers from January 2010 to March 2012, in Severance Hospital, Seoul, Korea. Preoperative baseline total cholesterol was significantly correlated with post-THW total cholesterol level; however, age, gender, or elevated TSH level after THW itself was not correlated with post-THW total cholesterol level. A significant correlation between preoperative measured BMI and post-THW total cholesterol level was found (r = 0.263, P = 0.041). In multiple logistic analysis, BMI was an independent determining factor of post-THW total cholesterol level (P = 0.012).