Effect of Pravastatin on Kidney Function in Patients with Dyslipidemia and Type 2 Diabetes Mellitus: A Multicenter Prospective Observational Study.

INTRODUCTION: Several studies have reported that pravastatin can mitigate the progression of kidney disease, but limited evidence exists regarding its effects on kidney function in Asian patients. This multicenter prospective observational study aimed to assess the effect of pravastatin on kidney function in Korean patients with dyslipidemia and type 2 diabetes mellitus (T2DM) in clinical practice. METHODS: This 48-week prospective multicenter study included 2604 of 2997 eligible patients with dyslipidemia and T2DM who had available estimated glomerular filtration rate (eGFR) measurements. The primary endpoint was eGFR percent change at week 24 from baseline. We also assessed secondary endpoints, which included percent changes in eGFR at weeks 12 and 48 from baseline, as well as changes in eGFR, metabolic profiles (lipid and glycemic levels) at 12, 24, and 48 weeks from baseline, and safety. RESULTS: We noted a significant improvement in eGFR, with mean percent changes of 2.5%, 2.5%, and 3.0% at 12, 24, and 48 weeks, respectively (all adjusted p < 0.05). The eGFR percent changes significantly increased in subgroups with baseline eGFR 30-90 mL/min/1.73 m2, glycated hemoglobin (HbA1c) ≥ 7 at baseline, no hypertension history, T2DM duration > 5 years, or previous statin therapy. Lipid profiles were improved and remained stable throughout the study, and interestingly, fasting glucose and HbA1c were improved at 24 weeks. CONCLUSION: Our findings suggest that pravastatin may have potential benefits for improving eGFR in Korean patients with dyslipidemia and T2DM. This could make it a preferable treatment option for patients with reduced kidney function. TRIAL REGISTRATION NUMBER: NCT05107063 submitted October 27, 2021.

Metabolic dysfunction-associated fatty liver disease and heavy alcohol consumption increase mortality:A nationwide study.

BACKGROUND: The effects of excessive alcohol consumption on the prognosis of metabolic dysfunction-associated fatty liver disease (MAFLD) remain unclear. We investigated all-cause and cause-specific mortality according to the amount of alcohol consumed by Asian individuals with MAFLD. METHODS: This nationwide retrospective study included 996,508 adults aged 40-79 years who underwent health check-ups between 2009 and 2012. Participants were categorized by the alcohol consumption-non-alcohol, moderate alcohol, and heavy alcohol group (≥ 30 g/day for men, ≥ 20 g/day for women) and by the combination of the presence or absence of MAFLD. Hepatic steatosis was defined as the fatty liver index ≥ 30. Cox analyses were used to analyze the association between alcohol consumption and MAFLD and all-cause and cause-specific mortality. RESULTS: MAFLD significantly increased all-cause, liver-, and cancer-related mortality. Individuals with both MAFLD and heavy alcohol consumption expressed the highest mortality risk in liver-related mortality compared to non-MAFLD and non-alcohol group (adjusted hazard ratio (HR), 9.8; 95% confidence interval (CI), 8.20-12.29). Regardless of MAFLD, heavy alcohol consumption increased the risk of liver- and cancer-related mortality. CONCLUSIONS: MAFLD and heavy alcohol consumption increased all-cause, liver-, and cancer-related mortality. Heavy alcohol consumption and MAFLD synergistically increase liver-related mortality.

Safety and Effectiveness of Dulaglutide in the Treatment of Type 2 Diabetes Mellitus: A Korean Real-World Post-Marketing Study.

BACKGRUOUND: To investigate the real-world safety and effectiveness of dulaglutide in Korean adults with type 2 diabetes mellitus (T2DM). METHODS: This was a real-world, prospective, non-interventional post-marketing safety study conducted from May 26, 2015 to May 25, 2021 at 85 Korean healthcare centers using electronic case data. Data on patients using dulaglutide 0.75 mg/0.5 mL or the dulaglutide 1.5 mg/0.5 mL single-use pens were collected and pooled. The primary objective was to report the frequency and proportion of adverse and serious adverse events that occurred. The secondary objective was to monitor the effectiveness of dulaglutide at 12 and 24 weeks by evaluating changes in glycosylated hemoglobin (HbA1c ), fasting plasma glucose, and body weight. RESULTS: Data were collected from 3,067 subjects, and 3,022 subjects who received ≥1 dose (of any strength) of dulaglutide were included in the safety analysis set (53% female, mean age 56 years; diabetes duration 11.2 years, mean HbA1c 8.8%). The number of adverse events reported was 819; of these, 68 (8.3%) were serious adverse events. One death was reported. Adverse events were mostly mild in severity; 60.81% of adverse events were considered related to dulaglutide. This study was completed by 72.73% (2,198/3,022) of subjects. At 12/24 weeks there were significant (P<0.0001) reductions from baseline in least-squares mean HbA1c (0.96%/0.95%), fasting blood glucose (26.24/24.43 mg/dL), and body weight (0.75/1.21 kg). CONCLUSION: Dulaglutide was generally well tolerated and effective in real-world Korean individuals with T2DM. The results from this study contribute to the body of evidence for dulaglutide use in this population.

Clinical Characteristics, Diagnosis, and Treatment of Thyroid Stimulating Hormone-Secreting Pituitary Neuroendocrine Tumor (TSH PitNET): A Single-Center Experience.

BACKGRUOUND: Thyroid-stimulating hormone (TSH)-secreting pituitary neuroendocrine tumor (TSH PitNET) is a rare subtype of PitNET. We investigated the comprehensive characteristics and outcomes of TSH PitNET cases from a single medical center. Also, we compared diagnostic methods to determine which showed superior sensitivity. METHODS: A total of 17 patients diagnosed with TSH PitNET after surgery between 2002 and 2022 in Samsung Medical Center was retrospectively reviewed. Data on comprehensive characteristics and treatment outcomes were collected. The sensitivities of diagnostic methods were compared. RESULTS: Seven were male (41%), and the median age at diagnosis was 42 years (range, 21 to 65); the median follow-up duration was 37.4 months. The most common (59%) initial presentation was hyperthyroidism-related symptoms. Hormonal co-secretion was present in four (23%) patients. Elevated serum alpha-subunit (α-SU) showed the greatest diagnostic sensitivity (91%), followed by blunted response at thyrotropin-releasing hormone (TRH) stimulation (80%) and elevated sex hormone binding globulin (63%). Fourteen (82%) patients had macroadenoma, and a specimen of one patient with heavy calcification was negative for TSH. Among 15 patients who were followed up for more than 6 months, 10 (67%) achieved hormonal and structural remission within 6 months postoperatively. A case of growth hormone (GH)/TSH/prolactin (PRL) co-secreting mixed gangliocytoma-pituitary adenoma (MGPA) was discovered. CONCLUSION: The majority of the TSH PitNET cases was macroadenoma, and 23% showed hormone co-secretion. A rare case of GH/TSH/PRL co-secreting MGPA was discovered. Serum α-SU and TRH stimulation tests showed great diagnostic sensitivity. Careful consideration is needed in diagnosing TSH PitNET. Achieving remission requires complete tumor resection. In case of nonremission, radiotherapy or medical therapy can improve the long-term remission rate.

Association between total cholesterol levels and all-cause mortality among newly diagnosed patients with cancer.

We aimed to determine the association between cholesterol values and the risk of all-cause mortality in newly diagnosed patients with cancer in a large-scale longitudinal cohort. Newly diagnosed patients with cancer were reviewed retrospectively. Cox proportional hazards regression models determined the association between baseline levels of total cholesterol (TC), triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol and the risk of all-cause mortality. A restricted cubic spline curve was used to identify the association between total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol with the risk of death on a continuous scale and to present the lowest values of lipid measurements associated with death. The median follow-up duration of the study was 5.77 years. Of the 59,217 patients with cancer, 12,624 patients were expired. The multivariable adjusted hazard ratio (aHR) for all-cause mortality in patients with cancer with 1st-5th (≤ 97 mg/dL) and 96th-100th (> 233 mg/dL) in TC levels was 1.54 (95% CI 1.43-1.66) and 1.28 (95% CI 1.16-1.41), respectively, compared to 61st-80th (172-196 mg/dL). The TC level associated with the lowest mortality risk in the multivariable model was 181 mg/dL. In comparison with LDL-C levels in the 61st-80th (115-136 mg/dL), the multivariable aHR for all-cause mortality in cancer patients with LDL-C levels in the 1st-5th (≤ 57 mg/dL) and 96th-100th (> 167 mg/dL) was 1.38 (95% CI 1.14-1.68) and 0.94 (95% CI 0.69-1.28), respectively. The 142 mg/dL of LDL cholesterol showed the lowest mortality risk. We demonstrated a U-shaped relationship between TC levels at baseline and risk of mortality in newly diagnosed patients with cancer. Low LDL levels corresponded to an increased risk of all-cause death.

Association between lipid variability and the risk of mortality in cancer patients not receiving lipid-lowering agents.

Aim: We investigated the association between total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride (TG) variability and cancer patient mortality risk. Methods: We retrospectively analyzed 42,539 cancer patients who were not receiving lipid-lowering agents and who had at least three TC measurements within 2 years of their initial cancer diagnosis. Using a multivariable Cox regression model, the risk of mortality was evaluated. Results: In multivariable analysis, Q2 (adjusted hazard ratio [aHR]: 1.32, 95% confidence interval (CI): 1.24-1.41), Q3 (aHR: 1.66, 95% CI: 1.56-1.76), and Q4 (aHR: 1.96, 95% CI: 1.84-2.08) of coefficient of variation (CV) in TC were significantly associated with mortality risk compared to Q1, showing a linear association between higher TC variability and mortality (P for trend<0.001). Q2 (aHR: 1.34, 95% CI: 1.06-1.77), Q3 (aHR: 1.40, 95% CI: 1.06-1.85), and Q4 (aHR: 1.50, 95% CI: 1.14-1.97) were all significantly associated with a higher risk of death compared to Q1 in multivariable Cox regression for the association between CV in LDL and all-cause mortality (P for trend=0.005). Conclusion: In cancer patients who do not receive lipid-lowering agents, high variability in total cholesterol and LDL cholesterol levels was found to pose significant role in mortality risk.

Association of weight change following smoking cessation with the risk of tuberculosis development: A nationwide population-based cohort study.

BACKGROUND: Smoking or weight loss is a risk of tuberculosis (TB) development. However, the impact of weight change after smoking cessation on the occurrence of TB remains elusive. We aimed to determine the relationship between weight change after smoking cessation and the risk of TB development. METHODS: We conducted a population-based cohort study using the national database in Republic of Korea. Of the 10,490,491 subjects who underwent health check-up in 2009, we enrolled 9,953,124 subjects without a previous TB history and followed them until 2017. We divided all study participants into the following three groups: never, former, and current smokers. The primary endpoint was newly developed TB. RESULTS: Among 9,953,124 subjects analyzed, 5,922,845 (59.5%) were never smokers, 1,428,209 (14.4%) were former smokers, and 2,602,080 (26.1%) were current smokers. The risk of TB development was significantly higher in current smokers than in never smokers (adjusted hazard ratio (aHR) 1.158; 95% confidence interval [CI] 1.131-1.186). Among current smokers, individuals who stopped smoking and maintained weight after baseline evaluation had a significantly lower risk of TB development compared with those who continued to smoke (aHR 0.771; 95% CI 0.741-0.892). However, even after smoking cessation, individuals who lost weight were at a significantly higher risk of TB development compared with those who continued to smoke (aHR 1.327; 95% CI 1.119-1.715). CONCLUSIONS: Our findings suggest that smoking is a risk factor for TB and weight maintenance (neither gaining or losing) after quitting smoking might reduce the risk of TB development.

Serum Prolactin Level to Tumor Size Ratio as a Potential Parameter for Preoperative Differentiation of Prolactinomas from Hyperprolactinemia-Causing Non-functional Pituitary Adenomas.

OBJECTIVE: Preoperative diagnosis of prolactinomas is critical because dopamine agonists have been regarded as a primary treatment. However, serum prolactin level alone is suboptimal for differentiating prolactinomas from hyperprolactinemia-causing non-functioning pituitary adenomas (NFPAs). By using the tumor size, the authors tried to investigate an effective parameter for the discrimination. METHODS: We performed a retrospective review of patients who underwent trans-sphenoidal surgery for pituitary lesions in a single institute between January 2015 and May 2021. Using receiver operating curve (ROC) analyses, we compared performances of serum prolactin levels (PRL), a ratio of serum PRL levels to maximal tumor diameter (MD) (PRL/MD; PDR1), and MD squared (PRL/[MD]2; PDR2) in preoperative diagnosis of prolactinomas. RESULTS: A total of 223 patients with NFPAs (n = 175) and prolactinomas (n = 48) were included in the analysis. A moderate correlation was found between serum prolactin levels and MDs in prolactinomas (Pearson's rprl = 0.43, P = 0.002), whereas a weak correlation was observed in NFPAs (Pearson's rnfpa = 0.17, P = 0.028). Among diagnostic parameters, PDR2 exhibited the optimal diagnostic performance with the cutoff value of 0.83 [㎍/L]/mm2 (area under the curve [AUC] = 0.945), compared with the PDR1 (8.93 [㎍/L]/mm with AUC 0.938) and PRL (99.4 ㎍/L with AUC 0.910). In the external validation study, PDR2 maintained superior performance over PDR1 and PRL (accuracy of 94.8%, 91.8%, and 75.8%, respectively). CONCLUSIONS: PDR2 was a more effective indicator than prolactin alone in the preoperative differential diagnosis of prolactinomas and NFPAs, which may help select patients who need medical treatment first.

Changes in Metabolic Syndrome Status are Associated With Altered Risk of Pancreatic Cancer: A Nationwide Cohort Study.

BACKGROUND AND AIMS: Metabolic syndrome (MetS) is reversible; however, the effect of changes in MetS status on pancreatic cancer risk is unknown. We aimed to investigate the effects of changes and persistence in MetS status on pancreatic cancer risk. METHODS: This nationwide cohort study included 8,203,492 adults without cancer who underwent 2 consecutive biennial health screenings provided by the Korean National Health Insurance System between 2009 and 2012 and were followed up until 2017. MetS was defined as the presence of 3 of its 5 components, which were evaluated at 2 consecutive biennial health screenings. Participants were categorized into the MetS-free, MetS-recovered, MetS-developed, or MetS-persistent group. Multivariable Cox proportional hazards regression models were used. RESULTS: During the 40,464,586 person-years of follow-up (median, 5.1 years), 8010 individuals developed pancreatic cancer. Compared with the MetS-free group, the MetS-persistent group had the highest risk of pancreatic cancer (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.23-1.37), followed by the MetS-developed group (HR, 1.17; 95% CI, 1.09-1.25) and the MetS-recovered group (HR, 1.12; 95% CI, 1.04-1.21) after adjusting for potential confounders (P for trend <.001). The MetS-recovered group was associated with a lower risk of pancreatic cancer than that in the MetS-persistent group (P < .001). The association between changes in MetS status and pancreatic cancer risk did not differ according to sex or obesity (all P for interactions >.05). CONCLUSIONS: In this study, recovering from MetS was associated with a reduced risk of pancreatic cancer compared with persistent MetS, suggesting that pancreatic cancer risk can be altered by changes in MetS.

Early mortality and cardiovascular disease, varied association with body mass index and its changes in insulin-treated diabetes: a nationwide study.

BACKGROUND/OBJECTIVES: We investigated the hazards of cardiovascular diseases (CVDs) and all-cause death during follow-up according to baseline body mass index (BMI) and percent change in BMI among adults with insulin-treated diabetes. SUBJECTS/METHODS: Using the Korean National Health Insurance Service datasets (2002-2017), the hazards of myocardial infarction (MI), stroke, and all-cause mortality during follow-up were analyzed according to baseline BMI and percent change in BMI among adults with insulin-treated diabetes and without baseline CVD and/or malignancy (N = 44,055). RESULTS: At baseline, 67.3% of total subjects were either obese or overweight. During a mean 3.8 years, 1,081 MI and 1,562 stroke cases developed; 2,847 deaths occurred over a mean 3.9 years. Compared with normal weight, overweight and obesity were associated with lower hazards of outcomes [hazard ratio (95% CI): 0.836 (0.712-0.981), 0.794 (0.687-0.917) for MI; 0.829 (0.726-0.946), 0.772 (0.684-0.870) for stroke; 0.740 (0.672-0.816), 0.666 (0.609-0.728) for death, respectively]. Underweight was associated with a higher hazard of all-cause death during follow-up [hazard ratio (95% CI): 2.035 (1.695-2.443)]. When the group with minimum absolute value for percent change in BMI was set as a reference, the relative reduction in BMI was associated with increased hazards of MI, stroke, and all-cause death, and relative increase in BMI was associated with increased hazards of stroke and all-cause death during follow-up. CONCLUSIONS: Among adults with insulin-treated diabetes, a high prevalence of overweight and obesity was observed, and baseline BMI category was inversely associated with CVD incidence and all-cause death during follow-up. Both weight loss and gain were associated with increased CVD incidence and all-cause death during follow-up, showing a U-shaped relationship between weight change and outcome. Stable body weight might be a predictor of a lower risk of CVDs and premature death among individuals with insulin-treated diabetes.

Urinary Free Metanephrines for Diagnosis of Pheochromocytoma and Paraganglioma.

BACKGROUND: Pheochromocytoma and paraganglioma (PPGL) is diagnosed through biochemical confirmation of excessive catecholamines in urine and plasma. Recent technological developments have allowed us to measure urinary free metanephrines; however, the diagnostic accuracy of these new methods and the diagnostic cutoff values have not been evaluated. METHODS: This is a retrospective study of 595 subjects, including 71 PPGL cases and 524 controls. PPGL was based on pathological confirmation. Subjects with no evidence of PPGL over 2 years were included in the control group. RESULTS: Urinary free metanephrines yielded similar area under the curve (AUC) to urinary fractionated metanephrines and plasma free metanephrines. However, urinary free normetanephrine yielded a better AUC than did urinary fractionated normetanephrine. The optimal cutoff for urinary free metanephrine and normetanephrine corrected for urinary creatinine yielded 97.2% sensitivity and 98.1% specificity. CONCLUSION: Urinary free metanephrines are a reliable method for diagnosing PPGL in Asian populations compared with existing biochemical methods.

Early hormonal recovery following endoscopic transsphenoidal surgery for silent non-functioning pituitary adenomas with hormone dysfunction.

PURPOSE: The role of transsphenoidal surgery in the recovery of preexisting hormone dysfunction from pituitary tumors remains controversial. This study aimed to investigate the incidence of hormone dysfunction among asymptomatic non-functioning pituitary adenomas and their recovery following endoscopic transsphenoidal surgery. METHODS: Eligibility criteria included age under 80 years, presence of a non-functioning pituitary adenoma compressing the normal gland resulting in deviation of the stalk, absence of visual symptoms, and availability for regular follow-up using MRI and pre- and post-operative endocrinological assessments. 182 patients with silent non-functioning pituitary adenomas were included in this study between March 2014 and December 2018. All patients underwent endoscopic transsphenoidal surgery and complete hormonal evaluation, with basal hormone assays and a combined pituitary function test before and after surgery until the end of last follow-up. RESULTS: Preoperative assessment of hormonal function revealed that 124 of 182 patients (68.1%) had at least a single hormone dysfunction preoperatively. Among these, 61 of 124 (49.2%) had a dysfunction in a single axis, and 63 (50.8%) had a hormone dysfunction in two or more axes. Overall, the median endocrinological follow-up duration was 15.0 months (6-57 months). At 1 month following surgery, 91 patients (73.4%) with hormone dysfunction experienced improvement in at least a single hormone axis. Prolactin was the most common hormone among those that recovered at the last follow up (92.8% improvement) followed by growth hormone (GH, 50.0%), thyroid stimulating hormone (TSH, 50.0%), gonadotropin (Gn, 46.9%), and adrenocorticotropic hormone (ACTH, 45.0%). Time to recovery varied from 1.1 months (for prolactin) to 2.2 months (for gonadotropin, and ACTH). In patients with preoperative deficiency in GH, and ACTH, postoperative transient diabetes insipidus was associated with poor recovery (GH: HR = 0.50, p = 0.048; ACTH: HR = 0.39, p = 0.023). CONCLUSIONS: Non-functioning pituitary adenomas with silent hormone dysfunction are often overlooked by clinicians and patients. We suggest that even silent hormone dysfunction in patients with non-functioning pituitary adenomas can be improved with effective surgical decompression and these tumors may be potential indications of endoscopic transsphenoidal surgery.

An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer.

We have reported that autophagy is crucial for clearance of amyloidogenic human IAPP (hIAPP) oligomer, suggesting that an autophagy enhancer could be a therapeutic modality against human diabetes with amyloid accumulation. Here, we show that a recently identified autophagy enhancer (MSL-7) reduces hIAPP oligomer accumulation in human induced pluripotent stem cell-derived ß-cells (hiPSC-ß-cells) and diminishes oligomer-mediated apoptosis of ß-cells. Protective effects of MSL-7 against hIAPP oligomer accumulation and hIAPP oligomer-mediated ß-cell death are significantly reduced in cells with knockout of MiTF/TFE family members such as Tfeb or Tfe3. MSL-7 improves glucose tolerance and ß-cell function of hIAPP+ mice on high-fat diet, accompanied by reduced hIAPP oligomer/amyloid accumulation and ß-cell apoptosis. Protective effects of MSL-7 against hIAPP oligomer-mediated ß-cell death and the development of diabetes are also significantly reduced by ß-cell-specific knockout of Tfeb. These results suggest that an autophagy enhancer could have therapeutic potential against human diabetes characterized by islet amyloid accumulation.

Transcriptional profiling of PPARα-/- and CREB3L3-/- livers reveals disparate regulation of hepatoproliferative and metabolic functions of PPARα.

BACKGROUND: Peroxisome Proliferator-Activated receptor α (PPARα) and cAMP-Responsive Element Binding Protein 3-Like 3 (CREB3L3) are transcription factors involved in the regulation of lipid metabolism in the liver. The aim of the present study was to characterize the interrelationship between PPARα and CREB3L3 in regulating hepatic gene expression. Male wild-type, PPARα-/-, CREB3L3-/- and combined PPARα/CREB3L3-/- mice were subjected to a 16-h fast or 4 days of ketogenic diet. Whole genome expression analysis was performed on liver samples. RESULTS: Under conditions of overnight fasting, the effects of PPARα ablation and CREB3L3 ablation on plasma triglyceride, plasma ß-hydroxybutyrate, and hepatic gene expression were largely disparate, and showed only limited interdependence. Gene and pathway analysis underscored the importance of CREB3L3 in regulating (apo)lipoprotein metabolism, and of PPARα as master regulator of intracellular lipid metabolism. A small number of genes, including Fgf21 and Mfsd2a, were under dual control of PPARα and CREB3L3. By contrast, a strong interaction between PPARα and CREB3L3 ablation was observed during ketogenic diet feeding. Specifically, the pronounced effects of CREB3L3 ablation on liver damage and hepatic gene expression during ketogenic diet were almost completely abolished by the simultaneous ablation of PPARα. Loss of CREB3L3 influenced PPARα signalling in two major ways. Firstly, it reduced expression of PPARα and its target genes involved in fatty acid oxidation and ketogenesis. In stark contrast, the hepatoproliferative function of PPARα was markedly activated by loss of CREB3L3. CONCLUSIONS: These data indicate that CREB3L3 ablation uncouples the hepatoproliferative and lipid metabolic effects of PPARα. Overall, except for the shared regulation of a very limited number of genes, the roles of PPARα and CREB3L3 in hepatic lipid metabolism are clearly distinct and are highly dependent on dietary status.

Long-Term Efficacy and Tolerability of Gamma Knife Radiosurgery for Growth Hormone-Secreting Adenoma: A Retrospective Multicenter Study (MERGE-001).

OBJECTIVE: Little is known about the long-term efficacy, prognostic factors, and tolerability of gamma knife radiosurgery (GKS) for acromegaly. The aim of this study was to investigate long-term hormonal effects, prognostic factors, and tolerability of GKS in patients with growth hormone-secreting adenoma. METHODS: A retrospective multicenter study over 25 years with a median follow-up of 85.2 months was performed. A total of 138 patients from 3 tertiary referral centers in South Korea were included in this study between 1991 and 2017. Main outcome measures were endocrine remission, endocrine control under somatostatin analogues, and hypopituitarism. RESULTS: With a mean follow-up period of 85.2 months (range, 12-304 months), overall median time to the endocrine remission and control under long-acting somatostatin analogues was 138 months and 96 months, respectively. Female sex, normal age-adjusted insulin growth factor-1 (IGF-1) ≤ 2, and GKS as an adjuvant treatment were significantly favorable factors for remission (P = 0.004, P = 0.001, P = 0.010, respectively). The early response group had a significantly lower proportion of normal age-adjusted IGF-1 levels >2 than did the late response group (22.2% vs. 51.7%, P = 0.035); also, the early response group had lower radiation dose than the late response group (24.3 Gy vs. 27.0 Gy, P = 0.003). The incidence of GKS-induced hypopituitarism (1 or more) was 12 of 138 patients (8.6%) at the last follow-up. CONCLUSIONS: In acromegalic patients, women with normal age-adjusted IGF-1 ≤ 2 and GKS as an adjuvant treatment have a better response to GKS. We should take into account the variability of radiosensitivity of the tumor according to the gender and IGF-1 level.

Color Doppler Ultrasonography Is a Useful Tool for Diagnosis of Peripheral Artery Disease in Type 2 Diabetes Mellitus Patients with Ankle-Brachial Index 0.91 to 1.40.

BACKGROUND: The clinical utility of ankle-brachial index (ABI) is not clear in subjects with less severe or calcified vessel. Therefore, we investigated the usefulness of color Doppler ultrasonography for diagnosing peripheral artery disease (PAD) in type 2 diabetes mellitus (T2DM) subjects. METHODS: We analyzed 324 T2DM patients who concurrently underwent ABI and carotid intima-media thickness (CIMT) measurements and color Doppler ultrasonography from 2003 to 2006. The degree of stenosis in patients with PAD was determined according to Jager's criteria, and PAD was defined as grade III (50% to 99% stenosis) or IV stenosis (100% stenosis) by color Doppler ultrasonography. Logistic regression analysis and receiver operating characteristic curve analysis were performed to evaluate the risk factors for PAD in patients with ABI 0.91 to 1.40. RESULTS: Among the 324 patients, 77 (23.8%) had ABI 0.91 to 1.40 but were diagnosed with PAD. Color Doppler ultrasonography demonstrated that suprapopliteal arterial stenosis, bilateral lesions, and multivessel involvement were less common in PAD patients with ABI 0.91 to 1.40 than in those with ABI ≤0.90. A multivariate logistic regression analysis demonstrated that older age, current smoking status, presence of leg symptoms, and high CIMT were significantly associated with the presence of PAD in patients with ABI 0.91 to 1.40 after adjusting for conventional risk factors. CIMT showed significant power in predicting the presence of PAD in patients with ABI 0.91 to 1.40. CONCLUSION: Color Doppler ultrasonography is a useful tool for the detection of PAD in T2DM patients with ABI 0.91 to 1.40 but a high CIMT.

Elevated serum uric acid predicts the development of moderate coronary artery calcification independent of conventional cardiovascular risk factors.

BACKGROUND AND AIMS: Hyperuricemia was frequently noted in subjects with a high risk of cardiovascular disease (CVD). This study aimed to elucidate whether serum uric acid (SUA) is associated with development of moderate coronary artery calcification in generally healthy adults. METHODS: A total of 9297 subjects underwent multidetector CT for the evaluation of CAC at least two times during their annual health examinations. Among them, 4461 participants without CVD history and who had no (scores 0) or minimal CAC (scores 1-10) in their first examination were enrolled. The association between SUA as a continuous and categorical variable and development of moderate coronary artery calcification (CAC score > 100) was assessed by Cox regression analysis. Receiver-operating characteristic (ROC) curves were constructed to investigate the diagnostic efficacy of SUA. RESULTS: During a median follow-up of 4.1 years, 131 incident cases of moderate calcification developed. Baseline SUA concentration was significantly higher in subjects with progression to moderate coronary artery calcification (6.6 ±â€¯1.3 vs. 5.8 ±â€¯1.3 mg/dL, p < 0.001). SUA as a continuous variable (per 1 mg/dL) and divided into quartiles was positively associated with a higher risk of development of moderate calcification after adjustment for conventional CVD risk factors. The addition of SUA to the conventional CVD risk factors improved the predictive power for development of moderate coronary artery calcification. CONCLUSIONS: SUA was an independent predictor for development of moderate coronary artery calcification in subjects with no or minimal calcification.

Alterations in Gut Microbiota and Immunity by Dietary Fat.

Gut microbiota play critical physiological roles in energy extraction from the intestine and in the control of systemic immunity, as well as local intestinal immunity. Disturbance of gut microbiota leads to the development of several diseases, such as colitis, inflammatory bowel diseases, metabolic disorders, cancer, etc. From a metabolic point of view, the gut is a large metabolic organ and one of the first to come into contact with dietary fats. Interestingly, excessive dietary fat has been incriminated as a primary culprit of metabolic syndrome and obesity. After intake of high-fat diet or Western diet, extensive changes in gut microbiota have been observed, which may be an underlying cause of alterations in whole body metabolism and nutrient homeostasis. Here, we summarize recent data on changes in the gut microbiota and immunity associated with dietary fat, as well as their relationships with the pathogenesis of metabolic syndrome. These findings may provide insight into the understanding of the complex pathophysiology related to the development of metabolic diseases and offer an opportunity to develop novel candidates for therapeutic agents.

Hormetic effect of triiodothyronine in metabolically healthy obese persons.

PURPOSE: Metabolically healthy obese is the designation for a subgroup of obese individuals with normal metabolic features. However, metabolically healthy obese individuals are prone to developing metabolic syndrome. Serum triiodothyronine (T3) levels are associated with various metabolic risk factors including obesity. Therefore, this longitudinal study aimed to explore the possible correlation between serum T3 concentration and the onset of MetS in metabolically healthy obese persons. METHODS: A retrospective analysis of 992 euthyroid metabolically healthy obese subjects who underwent yearly health checkups over 6 years was performed. The risk of developing MetS was analyzed according to baseline T3 concentration, as both tertiles and continuous values, using Cox regression analysis. Serum T3 concentration at the end of the study was further analyzed according to the final metabolic phenotype. RESULTS: The incidence of MetS was 464 cases (46.8%) during a median 3.3 years of follow-up (3168.2 person-years). The hazard ratio for incident MetS enhanced with increasing T3 concentration in both the crude and adjusted models. Higher baseline serum T3 levels were associated with unfavorable metabolic parameters. However, over the course of the study, serum T3 concentration significantly increased in subjects who sustained metabolically healthy phenotypes compared to baseline value, while it significantly decreased in the subjects who developed MetS. CONCLUSIONS: Serum T3 concentrations exhibit distinct associations with development of metabolic syndrome in euthyroid metabolically healthy obese persons, but its increment during follow-up maintained metabolically healthy state. These findings suggest that serum T3 modulation might be an adaptive process to protect against metabolic deterioration.

An information and communication technology-based centralized clinical trial to determine the efficacy and safety of insulin dose adjustment education based on a smartphone personal health record application: a randomized controlled trial.

BACKGROUND: A Personal Health Record (PHR) is an online application that allows patients to access, manage, and share their health data. PHRs not only enhance shared decision making with healthcare providers, but also enable remote monitoring and at-home-collection of detailed data. The benefits of PHRs can be maximized in insulin dose adjustment for patients starting or intensifying insulin regimens, as frequent self-monitoring of glucose, self-adjustment of insulin dose, and precise at-home data collection during the visit-to-visit period are important for glycemic control. The aim of this study is to examine the efficacy and safety of insulin dose adjustment based on a smartphone PHR application in patients with diabetes mellitus (DM) and to confirm the validity and stability of an information and communication technology (ICT)-based centralized clinical trial monitoring system. METHODS: This is a 24-week, open-label, randomized, multi-center trial. There are three follow-up measures: baseline, post-intervention at week 12, and at week 24. Subjects diagnosed with type 1 DM, type 2 DM, and/or post-transplant DM who initiate basal insulin or intensify their insulin regimen to a basal-bolus regimen are included. After education on insulin dose titration and prevention for hypoglycemia and a 1-week acclimation period, subjects are randomized in a 1:1 ratio to either an ICT-based intervention group or a conventional intervention group. Subjects in the conventional intervention group will save and send their health information to the server via a PHR application, whereas those in ICT-based intervention group will receive additional algorithm-based feedback messages. The health information includes level of blood glucose, insulin dose, details on hypoglycemia, food diary, and step count. The primary outcome will be the proportion of patients who reach an optimal insulin dose within 12 weeks of study enrollment, without severe hypoglycemia or unscheduled clinic visits. DISCUSSION: This clinical trial will reveal whether insulin dose adjustment based on a smartphone PHR application can facilitate the optimization of insulin doses in patients with DM. In addition, the process evaluation will provide information about the validity and stability of the ICT-based centralized clinical trial monitoring system in this research field. TRIAL REGISTRATION: Clinicaltrials.gov NCT 03112343 . Registered on 12 April 2017.