Dual add-on therapy of gemigliptin and dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin alone: The SOLUTION 2 study.

AIM: To evaluate the efficacy and safety of gemigliptin and dapagliflozin dual add-on therapy (GEMI + DAPA) to metformin in type 2 diabetes (T2D) patients who had inadequate glycaemic control on metformin alone, compared with a single add-on of either gemigliptin (GEMI) or dapagliflozin (DAPA) to metformin. MATERIALS AND METHODS: In this randomized, double-blind, double-dummy, active-controlled, parallel-group, phase 3 study, 469 T2D patients treated with a stable dose of metformin for 8 weeks or longer were randomized to receive GEMI + DAPA (n = 157) and either GEMI (n = 156) or DAPA (n = 156). The primary endpoint was change in HbA1c levels from baseline at week 24. RESULTS: Baseline characteristics including body mass index and T2D duration were similar among groups. At week 24, the least square mean changes in HbA1c from baseline were -1.34% with GEMI + DAPA, -0.90% with GEMI (difference between GEMI + DAPA vs. GEMI -0.44% [95% confidence interval {CI}: -0.58% to -0.31%], P < .01) and -0.78% with DAPA (difference between GEMI + DAPA vs. DAPA -0.56% [95% CI: -0.69% to -0.42%], P < .01). Both upper CIs were less than 0, demonstrating the superiority of GEMI + DAPA for lowering HbA1c. The rates of responders achieving HbA1c less than 7% and less than 6.5% were greater with GEMI + DAPA (84.9%, 56.6%) than with GEMI (55.3%, 32.2%) and DAPA (49.3%, 15.3%). The incidence rate of adverse events was similar across groups, with low incidence rates of hypoglycaemia, urinary tract infection and genital infection. CONCLUSIONS: These results suggest that the addition of GEMI + DAPA to metformin as triple combination therapy was effective, safe and well-tolerated, especially for T2D patients who experienced poor glycaemic control on metformin alone.

High remnant-cholesterol levels increase the risk for end-stage renal disease: a nationwide, population-based, cohort study.

BACKGROUND: The effect of remnant-cholesterol (remnant-C) on incident end-stage renal disease (ESRD) has not been studied longitudinally. This retrospective cohort study evaluated the association between remnant-C and the development of ESRD in a nationwide Korean cohort. METHODS: Participants in a National Health Insurance Service health examination (n = 3,856,985) were followed up until the onset of ESRD. The median duration of follow-up was 10.3 years. The Martin-Hopkins equation was used to determine low-density lipoprotein cholesterol (LDL-C) levels from directly measured triglyceride, high-density lipoprotein cholesterol (HDL-C), and total cholesterol levels. Remnant-C levels were determined by subtracting HDL-C and LDL-C from total cholesterol. The risk for incident ESRD was calculated for each quartile of remnant-C, adjusting for conventional risk factors such as baseline renal function, comorbidities, and total cholesterol levels. RESULTS: ESRD developed in 11,073 (0.29%) participants. The risk for ESRD exhibited a gradual increase according to higher levels of remnant-C, with a 61% increased risk in the highest quartile than in the lowest (hazard ratio [HR] 1.61 [95% confidence interval (CI) 1.50-1.72]). The elevated risk for ESRD in the highest quartile versus the lowest quartile was more prominent in younger than in older subjects (20-29 years, HR 4.07 [95% CI 2.85-5.83]; 30-39 years, HR 2.39 [95% CI 1.83-3.13]; ≥ 70 years, HR 1.32 [95% CI 1.16-1.51]). In addition, the increased risk for ESRD related to higher remnant-C levels was greater in females than in males. CONCLUSIONS: Independent of conventional risk factors, remnant-C levels were positively associated with incident ESRD, particularly in younger populations and adult females. Reducing remnant-C levels may be a novel preventive strategy against ESRD.

Cholecystectomy Increases the Risk of Type 2 Diabetes in the Korean Population: Data From the National Health Insurance Cooperation Health Checkup 2010-2017.

OBJECTIVE: This study assessed whether cholecystectomy is a risk factor for newly developed type 2 diabetes mellitus (T2DM) in the Korean population. BACKGROUND: There is a lack of evidence that cholecystectomy is independently associated with insulin resistance and T2DM. METHODS: This study included all patients aged more than 20 years who had undergone cholecystectomy from 2010 to 2015 (n=55,166) and age-matched and sex-matched control subjects without cholecystectomy (n=110,332) using the National Health Insurance Service database. They were followed up until the date of newly developed T2DM or study end and the incidence of T2DM was traced over a maximum observation period of 7 years. RESULTS: Overall, 55,166 patients who underwent cholecystectomy and 110,332 age-matched and sex-matched controls were followed up for ∼4.7 years, during which, incident T2DM occurred in 5982 (3.61%) patients. Cholecystectomy was associated with 20% higher risk of T2DM after adjustment for all covariates. The cumulative incidence of T2DM also significantly increased in the cholecystectomy group for ∼7 years ( P <0.001). The adjusted hazard ratio (HR) for T2DM was the highest in the group with both cholecystectomy and obesity using the control without both cholecystectomy and obesity as a reference [HR=1.41, 95% confidence interval (CI): 1.29-1.56]. The group with cholecystectomy without obesity showed the comparable risk of incident T2DM compared with the group without cholecystectomy with obesity (HR=1.29, 95% CI: 1.20-1.40 for cholecystectomy without obesity and HR=1.24, 95% CI: 1.14-1.36 for control with obesity). CONCLUSIONS: These results provide evidence that cholecystectomy is associated with an increased risk of newly developed T2DM in the Korean population. Further research is required to elucidate the mechanism of the association between cholecystectomy and incident diabetes.

Efficacy and safety of enavogliflozin, a novel SGLT2 inhibitor, in Korean people with type 2 diabetes: A 24-week, multicentre, randomized, double-blind, placebo-controlled, phase III trial.

AIMS: To evaluate the efficacy and safety of a novel sodium-glucose cotransporter 2 inhibitor, enavogliflozin 0.3 mg monotherapy, in Korean people with type 2 diabetes mellitus (T2DM) inadequately controlled with diet and exercise. MATERIALS AND METHODS: This study was a randomized, double-blind, placebo-controlled trial conducted in 23 hospitals. Individuals with haemoglobin A1c (HbA1c) of 7.0%-10.0% after at least 8 weeks of diet and exercise modification were randomized to receive enavogliflozin 0.3 mg (n = 83) or placebo (n = 84) for 24 weeks. The primary outcome was a change in HbA1c at week 24 from baseline. Secondary outcomes included the proportion of participants achieving HbA1c <7.0%, change in fasting glucose, body weight and lipid levels. Adverse events were investigated throughout the study. RESULTS: At week 24, the placebo-adjusted mean change in HbA1c from baseline in the enavogliflozin group was -0.99% (95% confidence interval -1.24%, -0.74%). The proportions of patients achieving HbA1c <7.0% (71% vs. 24%) at week 24 was significantly higher in the enavogliflozin group (p < .0001). Placebo-adjusted mean changes in fasting plasma glucose (-40.1 mg/dl) and body weight (-2.5 kg) at week 24 were statistically significant (p < .0001). In addition, a significant decrease in blood pressure, low-density lipoprotein cholesterol, triglyceride, and homeostasis model assessment of insulin resistance were observed, along with a significant increase in high-density lipoprotein cholesterol. No significant increase in treatment-related adverse events was observed for enavogliflozin. CONCLUSIONS: Monotherapy with enavogliflozin 0.3 mg improved glycaemic control in people with T2DM. Enavogliflozin therapy also exerted beneficial effects on body weight, blood pressure and lipid profile.

Remnant cholesterol and the risk of cardiovascular disease in type 2 diabetes: a nationwide longitudinal cohort study.

BACKGROUND: Elevated remnant cholesterol (remnant-C) is considered a risk factor for cardiovascular disease (CVD); however, whether this notion applies to the East Asian population with type 2 diabetes (T2D) has not been established. This study investigated the association between remnant-C concentrations and the risk of CVD in Korean patients with T2D. METHODS: By using the Korean National Health Insurance Service database, 1,956,452 patients with T2D and without atherosclerotic CVD who underwent regular health checks between 2009 and 2012 were included. Cox regression analyses were conducted to assess the association between remnant-C concentrations and incident CVD comprising myocardial infarction (MI) and ischemic stroke. RESULTS: In total, 50,120 (2.56%) cases of MI and 73,231 (3.74%) cases of ischemic strokes occurred during a median follow-up of 8.1 years. The adjusted hazard ratios for MI and stroke in the highest remnant-C quartile were 1.281 (95% confidence interval [CIs], 1.249-1.314) for MI and 1.22 (1.195-1.247) for ischemic stroke, compared to those in the lowest quartiles. The results were similar, based on stratified analysis by age, sex, use of statin or fibrate, and levels of other cholesterol. The increased risk of CVD in the highest remnant-C quartile was profound in patients who had a longer T2D duration. A remnant-C concentration ≥ 30 mg/dL differentiated patients who were at a higher risk of CVD, compared to patients with a lower concentrations, regardless of whether LDL-C levels were or were not on target at ≤ 100 mg/dL. CONCLUSION: In Korean patients with T2D, remnant-C was associated with CVD, independent of the LDL-C level or other conventional CVD risk factors. Our finding confirmed evidence of the causal role of remnant-C on CVD, as a residual risk of CVD, in East Asian patients with T2D.

Association of the atherogenic index of plasma with cardiovascular risk beyond the traditional risk factors: a nationwide population-based cohort study.

BACKGROUND: The atherogenic index of plasma (AIP) is composed of triglycerides and high-density lipoprotein cholesterol and is a novel marker for assessing the risk of atherogenicity and cardiometabolic health. An association between AIP and greater frequency of major adverse cardiovascular events (MACEs) in patients with type 2 diabetes mellitus and high cardiovascular (CV) disease risk has been reported. However, only few studies have examined the correlation between AIP and CV risk in general populations. We thus aimed to evaluate the relationship between AIP and CV diseases using a large-scale population dataset from the Korean National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS). METHODS: A total of 514,866 participants were enrolled from the NHIS-HEALS and classified according to the AIP quartiles. We performed univariate and multivariate Cox proportional hazards regression analyses to determine the association between AIP and MACEs, CV events, and CV mortality. RESULTS: During follow-up, we documented 12,133, 11,055, and 1942 cases of MACEs, CV events, and CV mortality, respectively. The multivariate-adjusted hazard ratios [HRs; 95% confidence interval (CI)] for MACEs gradually and significantly increased with the AIP quartiles [1.113 (1.054-1.175) in Q2, 1.175 (1.113-1.240) in Q3, and 1.278 (1.209-1.350) in Q4], following an adjustment for the conventional CV risk factors, including age, sex, body mass index, smoking, alcohol drinking, physical activities, household income, fasting glucose, systolic blood pressure, low-density lipoprotein cholesterol, and estimated glomerular filtration rate. In subgroup analyses, the association of AIP with MACEs and CV events was particularly outstanding in patients with diabetes. CONCLUSIONS: AIP was significantly associated with CV risks after adjusting for the traditional risk factors. Therefore, it may be used as an effective mass screening method to identify patients at a high risk of CV events.

Doxorubicin has a synergistic cytotoxicity with cucurbitacin B in anaplastic thyroid carcinoma cells.

In this study, the combined effect of doxorubicin with cucurbitacin B on survival of anaplastic thyroid carcinoma cells was evaluated. For experiments, 8505C and CAL62 human anaplastic thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, and cytotoxic activity were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, multiplexed cytotoxicity assay, and cytotoxicity assay, respectively. Reactive oxygen species production was measured. In experiments, doxorubicin and cucurbitacin B reduced cell viability in a dose- and time-dependent manner. Cotreatment of doxorubicin and cucurbitacin B, compared with treatment of doxorubicin alone, decreased the percentage of viable cells and increased cytotoxic activity. All of the combination index values were lower than 1.0, suggesting the synergism between doxorubicin and cucurbitacin B in induction of cytotoxicity. In cells treated with both doxorubicin and cucurbitacin B, compared with doxorubicin alone, the protein levels of cleaved poly(adenosine diphosphate-ribose) polymerase and cyclooxygenase 2 and reactive oxygen species production were enhanced. In contrast, the protein levels of B-cell chronic lymphocytic leukemia/lymphoma 2 and survivin and B-cell chronic lymphocytic leukemia/lymphoma 2/B-cell chronic lymphocytic leukemia/lymphoma 2-associated x protein ratio were diminished. The protein levels of Janus kinase 2 and signal transducer and activator of transcription 3 were reduced, while phospho-extracellular signal-regulated kinase 1/2 protein levels were elevated without change in total extracellular signal-regulated kinase 1/2 protein levels. These results suggest that doxorubicin synergizes with cucurbitacin B in induction of cytotoxicity in anaplastic thyroid carcinoma cells. Moreover, synergistic cytotoxicity of doxorubicin with cucurbitacin B is mediated by B-cell chronic lymphocytic leukemia/lymphoma 2 family proteins, survivin, and reactive oxygen species and modulated by Janus kinase 2/signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 in anaplastic thyroid carcinoma cells.

Cytotoxic effect of celastrol alone or in combination with paclitaxel on anaplastic thyroid carcinoma cells.

The influence of celastrol alone or in combination with paclitaxel on survival of anaplastic thyroid carcinoma cells was investigated. In 8505C and SW1736 cells, after treatment of celastrol, cell viability decreased, and cytotoxic activity increased. The protein levels of heat shock protein (hsp) 90, hsp70, Bax, death receptor 5, cleaved caspase-3, cleaved poly (ADP-ribose) polymerase, phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), and phospho-c-Jun N-terminal kinase (JNK) were elevated, and those of Bcl2, phospho-nuclear factor-kappaB (NF-κB), and total and phospho-Akt were reduced. The endoplasmic reticulum stress markers expression and reactive oxygen species production were enhanced. In celastrol-treated cells, N-acetylcysteine increased cell viability and phospho-NF-κB protein levels, and decreased reactive oxygen species production and cytotoxic activity. The protein levels of cyclooxygenase 2, phospho-ERK1/2, phospho-JNK and Bip were diminished. After treatment of both celastrol and paclitaxel, compared with paclitaxel alone, cell viability and the percentage of viable cells were reduced, and death rate and cytotoxic activity were elevated. The protein levels of phospho-ERK1/2, phospho-JNK, Bip, and cyclooxygenase 2, and reactive oxygen species production were enhanced. All of the Combination Index values calculated by Chou-Talalay equation were lower than 1.0, implying the synergism between celastrol and paclitaxel in induction of cell death. In conclusion, our results suggest that celastrol induces cytotoxicity through involvement of Bcl2 family proteins and death receptor, and modulation of phospho-NF-κB, Akt, and mitogen-activated protein kinase in association with endoplasmic reticulum stress and reactive oxygen species production in anaplastic thyroid carcinoma cells. Moreover, celastrol synergizes with paclitaxel in induction of cytotoxicity in anaplastic thyroid carcinoma cells.

The dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with NVP-AUY922 has a cytotoxic activity in thyroid carcinoma cells.

The effect of the dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with the heat shock protein 90 inhibitor NVP-AUY922 (AUY922) on survival of thyroid carcinoma cells was elucidated. The SW1736 and TPC-1 human thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, cytotoxic activity, the percentage of apoptotic cells, and mitochondrial membrane potential were measured. To evaluate the combined effect of gemigliptin with AUY922, the interactions were estimated by calculating combination index. Gemigliptin led to cell death in conjunction with overexpression of the phosphorylated protein levels of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase. In gemigliptin-treated cells, wortmannin augmented cell death, whereas AZD6244 and compound C did not affect cell survival. Wortmannin decreased phosphorylated adenosine monophosphate-activated protein kinase protein levels, and AZD6244 increased phosphorylated Akt protein levels. Meanwhile, cotreatment of both gemigliptin and AUY922, compared with treatment of AUY922 alone, potentiated cell death. All the combination index values were lower than 1.0, suggesting synergistic cytotoxicity of gemigliptin with AUY922. In treatment of both gemigliptin and AUY922, compared with AUY922 alone, the protein levels of total and phosphorylated Akt, phosphorylated extracellular signal-regulated kinase 1/2, and phosphorylated adenosine monophosphate-activated protein kinase increased without alteration in those of total extracellular signal-regulated kinase 1/2 and total adenosine monophosphate-activated protein kinase. The percentage of apoptotic cells increased. The protein levels of Bax and cleaved poly (ADP-ribose) polymerase increased, whereas Bcl2 protein levels were unchanged, resulting in increment of Bax/Bcl2 ratio. Transfection of Bax small interfering RNA did not cause any variation in cell viability, the percentage of viable cells and cytotoxic activity. Our results demonstrate that gemigliptin exerts a cytotoxic activity with concomitant alterations in expression of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase in thyroid carcinoma cells. Furthermore, gemigliptin synergizes with AUY922 in induction of cytotoxicity via regulation of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase as well as involvement of Bcl2 family proteins in thyroid carcinoma cells.

Efficacy and safety of evogliptin monotherapy in patients with type 2 diabetes and moderately elevated glycated haemoglobin levels after diet and exercise.

AIMS: To evaluate the efficacy and safety of evogliptin, a newly developed dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes (T2D) inadequately controlled by diet and exercise. MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled, parallel-group, multicentre, phase III study, 160 patients with T2D were assigned to either evogliptin 5 mg or placebo for 24 weeks. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) from baseline to week 24. RESULTS: The mean baseline HbA1c levels were similar in the evogliptin and the placebo groups (7.20% ± 0.56% vs 7.20% ± 0.63%, respectively). At week 24, evogliptin significantly reduced HbA1c levels from baseline compared with placebo (-0.23% vs 0.05%, respectively, P < .0001). Additionally, the proportion of patients achieving HbA1c <6.5% was significantly higher in the evogliptin group than in the placebo group (33.3% vs 15.2%; P = .008). The overall incidence of adverse events, including hypoglycaemia, was similar in the 2 groups. CONCLUSIONS: In this 24-week study, once-daily evogliptin monotherapy significantly improved glycaemic control and was well tolerated in patients with T2D.

Dual growth factor-loaded in situ gel-forming bulking agent: passive and bioactive effects for the treatment of urinary incontinence.

Stress urinary incontinence (SUI) is one of the major medical problems for adult females and has a devastating effect on their quality of life. The major cause of the development of the SUI is dysfunction of the urethral supporting tissues as a result of aging and childbirth. In this study, in situ gel-forming bulking agent loaded with dual growth factors, nerve growth factor (NGF) and basic fibroblast growth factor (bFGF), was fabricated. The bulking agent consisted of three components; (i) polycaprolactone (PCL) beads, (ii) bFGF-loaded nanogels, and (iii) NGF-loaded in situ gel forming solution. The bulking agent can provide an initial passive bulking effect (from the PCL beads) and regenerate malfunctioning tissues around the urethra (from the sequential and continuous release of growth factors from the hydrogel) for the effective treatment of SUI. The PCL beads were located stably at the applied urethra site (urinary incontinent SD rat) without migration to provide a passive bulking effect. The sequential release of the growth factors (NGF within a week and bFGF for more than 4 weeks) from the bulking agent provided regeneration of damaged nerve and smooth muscle, and thus enhanced biological function around the urethra. From the findings, we suggest that dual growth factor (NGF and bFGF)-loaded in situ gel-forming bulking agent may be a promising injectable bioactive system for the treatment for SUI.

Herbimycin A inhibits cell growth with reversal of epithelial-mesenchymal transition in anaplastic thyroid carcinoma cells.

We aimed to elucidate the effect of herbimycin A (HMA), a heat shock protein 90 inhibitor, on cell growth and epithelial-mesenchymal transition (EMT) in anaplastic thyroid carcinoma (ATC) cells. HMA inhibited cell growth and migration concomitantly with increase of E-cadherin as well as decrease of N-cadherin and vimentin. Moreover, HMA upregulated p21 and p27, while it downregulated p53 and Akt. In HMA-treated condition, knockdown of E-cadherin and overexpression of p53 increased N-cadherin and vimentin, and mitigated the inhibitory effects of HMA on cell growth and migration. Furthermore, knockdown of p21 and p27 ameliorated inhibition of cell growth and reversal of EMT. In addition, the activation of Akt attenuated growth inhibition, cell death and EMT reversal. Therefore, we propose that HMA suppresses cell growth, and reverses EMT in conjunction with the activation of E-cadherin, p21 and p27 and the inactivation of p53 and PI3K/Akt signaling in ATC cells.

The hsp70 inhibitor VER155008 induces paraptosis requiring de novo protein synthesis in anaplastic thyroid carcinoma cells.

In this study, we evaluated the effect of the hsp70 inhibitor VER155008 on survival of anaplastic thyroid carcinoma (ATC) cells. In ATC cells, VER155008 increased the percentages of dead cells and vacuolated cells. VER155008 did not lead to the cleavage of caspase-3 protein regardless of pretreatment with z-VAD-fmk. VER155008 increased LC3-II protein levels but the protein levels were not changed by autophagy inhibitors. VER155008 caused the dilatation of endoplasmic reticulum (ER), and the increased mRNA levels of Bip and CHOP, suggesting paraptosis. VER155008-induced paraptosis was attenuated by pretreatment with cycloheximide. In conclusion, VER155008 induces paraptosis characterized by cytoplasmic vacuolation, independence of caspase, dilatation of ER and induction of ER stress markers in ATC cells. Moreover, VER155008-induced paraptosis requires de novo protein synthesis in ATC cells.

Association of remnant cholesterol with risk of dementia: a nationwide population-based cohort study in South Korea.

BACKGROUND: The association between remnant cholesterol (remnant-C) and cardiovascular disease risk is well established, but its association with dementia remains unclear. We aimed to examine this association using a large-scale population dataset. METHODS: We did a nationwide, population-based cohort study in which we identified participants aged 40 years and older who underwent the national health examination in 2009 from South Korea's National Health Insurance Service. We excluded people who were younger than 40 years and those with a triglyceride concentration of 400 mg/dL or higher due to concerns regarding the accuracy of calculated low-density lipoprotein cholesterol concentration in individuals with extremely high triglyceride concentrations. People who were previously diagnosed with dementia before the index date, and those who had any missing variables were also excluded. To minimise the influence of possible reverse causation, we excluded individuals who had developed any type of dementia within 1 year of the baseline measurements. We calculated hazard ratios (HRs) for all-cause dementia, Alzheimer's disease, and vascular dementia in each quartile of remnant-C using the Cox proportional hazards model adjusted for age, sex, body-mass index, estimated glomerular filtration rate, income level, smoking status, alcohol consumption, regular exercise, diabetes, hypertension, statin and fibrate use, and total cholesterol concentrations. We also did subgroup analyses to investigate the association between remnant-C and the risk of dementia stratified by age, sex, obesity, glycaemic status (normoglycaemia, impaired fasting glucose, new-onset type 2 diabetes, type 2 diabetes with a duration of less than 5 years, and type 2 diabetes with a duration of 5 years or more), hypertension, chronic kidney disease, and dyslipidaemia, using likelihood ratio tests. FINDINGS: 4 234 415 individuals who underwent the national health examination in 2009 were deemed eligible for inclusion. We excluded 1 612 819 individuals on the basis of age, triglyceride concentration, missing variables, or having dementia at baseline. We identified 2 621 596 participants aged 40 years and older (1 305 556 men and 1 316 040 women) who underwent the national health examination and followed them up until the date of any incident of dementia or the end of the study period of Dec 31, 2020. During a median follow-up of 10·3 years (IQR 10·1-10·6), 146 991 (5·6%) participants developed all-cause dementia, 117 739 (4·5%) developed Alzheimer's disease, and 14 536 (0·6%) developed vascular dementia. The risk of dementia increased progressively with higher remnant-C concentrations. Compared with the lowest quartile of remnant-C (quartile 1), HRs in the highest quartile (quartile 4) were 1·11 (95% CI 1·09-1·13) for all-cause dementia, 1·11 (1·08-1·13) for Alzheimer's disease, and 1·15 (1·09-1·21) for vascular dementia. Subgroup analyses revealed that the risk of dementia associated with high remnant-C concentrations was higher in middle-aged people aged 40-59 years than in older people. The risk of dementia associated with high concentrations of remnant-C was notably more pronounced in individuals with diabetes compared with those without diabetes, and the risk increased steeply with a longer duration of diabetes. INTERPRETATION: Results showed that higher remnant-C concentrations were independently associated with increased risks of all-cause dementia, Alzheimer's disease, and vascular dementia. More research is needed to determine the mechanisms underlying this finding. Monitoring and managing higher concentrations of remnant-C might have important implications for reducing the risk of dementia. FUNDING: None.

Improved transplantation outcome through delivery of DNA encoding secretion signal peptide-linked glucagon-like peptide-1 into mouse islets.

Glucagon-like peptide-1 (GLP-1) stimulates cell proliferation and has anti-apoptotic effects on pancreatic islet ß cells. In our previous study, the transduction of mouse islets with a recombinant adenovirus containing GLP-1 cDNA enhanced islet graft survival. In this study, we sought to deliver the GLP-1 gene using a nonviral vector, which raises fewer safety issues in clinical application. We constructed a plasmid, pß-SP-GLP-1, in which a secretion signal peptide (SP) was inserted to increase GLP-1 secretion, and transfected mouse islets using the nonviral carrier Effectene. Transfection of pß-SP-GLP-1 induced a significant increase in bioactive GLP-1 levels in islet cultures. Islets transfected with pß-SP-GLP-1 were protected from H2 O2 -induced cell damage in vitro. In addition, glucose-stimulated insulin secretion was significantly increased in pß-SP-GLP-1-transfected islets. Diabetic syngeneic mice transplanted under the kidney capsule with a marginal mass of pß-SP-GLP-1-transfected islets rapidly became normoglycemic, with 88% of recipients being normoglycemic at 30 days post-transplantation compared with 52% of mice that received pß-transfected islet grafts (P < 0.05). Islet grafts retrieved 7 days after transplantation revealed that the pß-SP-GLP-1-transfected group had significantly more Ki67-positive cells as compared with the pß-transfected group. In conclusion, delivery of a plasmid containing a secretion SP and GLP-1 cDNA using a nonviral carrier leads to efficient secretion of GLP-1 in mouse islet cells, enhances islet cell survival during the early post-transplant period, and improves islet transplantation outcome.

Remnant Cholesterol Is an Independent Predictor of Type 2 Diabetes: A Nationwide Population-Based Cohort Study.

OBJECTIVE: Although the atherogenic effect of remnant cholesterol (remnant-C) has been widely recognized, the relationship between remnant-C and glucose metabolism remains unclear. This retrospective, longitudinal study investigated the relationship between remnant-C and incident type 2 diabetes (T2D) in a nationwide cohort of Korean adults. RESEARCH DESIGN AND METHODS: A total of 8,485,539 Korean adults without diabetes participated in the national health screening in 2009 and were followed up until 2019. The relationship between remnant-C quartiles and incident T2D was examined by Cox regression models. The risk of incident T2D over the continuum of remnant-C was examined with cubic spline analysis. RESULTS: During the median follow-up period of 9.28 years, 584,649 individuals (6.8%) developed T2D. In multivariable-adjusted analyses, participants in the upper quartile of remnant-C had a higher risk of T2D, with hazard ratios of 1.25 (95% CI 1.24-1.27) in the second quartile, 1.51 (95% CI 1.50-1.53) in the third quartile, and 1.95 (95% CI 1.93-1.97) in the fourth quartile, compared with the lowest quartile. The increase in the risk of T2D owing to high remnant-C concentration was more profound in individuals with fewer traditional T2D risks, such as women, and absence of metabolic abnormalities, including impaired fasting glucose, hypertension, and atherogenic dyslipidemia. Moreover, the magnitude of the increased risk for incident T2D in individuals with higher remnant-C quartiles was higher in younger participants than older participants. CONCLUSIONS: These findings indicate that remnant-C profiles provide additional information in predicting future progression of T2D, independent of the conventional lipid parameters.

Association between Sleep Duration and Incident Diabetes Mellitus in Healthy Subjects: A 14-Year Longitudinal Cohort Study.

BACKGROUND: This study aimed to investigate whether sleep duration and/or quality are associated with incident diabetes mellitus (DM). METHODS: A total of 8816 of 10,030 healthy participants were enrolled in a prospective cohort study. Sleep duration and quality questionnaires were completed. Sleep quality was assessed using the Epworth Sleepiness Scale (ESS), which measures excessive daytime sleepiness in individuals. RESULTS: During the 14-year follow-up period, 18% (1630/8816) were diagnosed with DM. A U-shaped relationship was observed between sleep duration and incident DM, with the highest risk observed when sleep duration was ≥10 h/day (hazard ratios (HR) 1.65 [1.25-2.17]). This group exhibited decreased insulin glycogenic index, a marker of insulin secretory function, during the study period. Among study participants who slept less than 10 h/day, the risk of incident DM increased when the ESS score was >10. CONCLUSIONS: We found that the association between sleep duration and incident DM was U-shaped; both short (≤5 h) and long (≥10 h) sleep durations were associated with an increased risk for the occurrence of incident DM. When sleep duration was 10 h or longer per day, there was a tendency to develop DM due to decreased insulin secretory function.

Waist circumference and end-stage renal disease based on glycaemic status: National Health Insurance Service data 2009-2018.

BACKGROUND: Obesity is associated with an increased risk of developing type 2 diabetes mellitus (T2DM) and end-stage renal disease (ESRD). This study aimed to examine the effect of waist circumference (WC) on the risk for ESRD based on glycaemic status in a Korean population-based sample. METHODS: This cohort study with a 9.2-year follow-up period used a population-based National Health Insurance Service health checkup database with approximately 10 585 852 participants who were followed up from 2009 to the time of ESRD diagnosis. WC was categorized into seven levels in 5-cm increments, with Level 4 as the reference group. Glycaemic status was categorized into the following groups: normal fasting glucose (NFG), impaired fasting glucose (IFG), newly diagnosed T2DM, T2DM treated with ≤2 oral hypoglycaemic agents (OHAs) and diabetes treated with ≥3 OHAs or insulin. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for ESRD according to WC values and glycaemic status of the participants. RESULTS: The study finally included 10 177 245 patients with a mean age of 47.1 (13.8) years. The study population included 5 604 446 men (55.1%) and 4 572 799 women (45.9%). In total, 8.3% (n = 877 143) of the study population had diabetes. During the mean follow-up of 9.2 (1.0) years (93 554 951 person-years of follow-up), 23 031 individuals were newly diagnosed with ESRD. The ESRD risk increased in parallel with an increase in WC in participants without T2DM, that is, the NFG and IFG groups (adjusted HRs [95% CIs] of WC Levels 4, 5 and 6: 1.17 [1.09-1.26], 1.37 [1.25-1.51] and 1.84 [1.63-2.07] in the NFG group and 1.06 [0.97-1.16], 1.23 [1.10-1.38] and 1.80 [1.57-2.06] in the IFG group, respectively). In patients with T2DM, the risk for ESRD was significantly increased in those with a low WC (adjusted HRs [95% CIs] of WC Level 1: 2.23 [1.77-2.80], 3.18 [2.70-3.74] and 10.31 [9.18-11.59] in patients with newly diagnosed diabetes, patients on ≤2 OHAs and those on ≥3 OHAs or insulin, respectively). The association between WC and ESRD thus showed a J-shaped pattern in patients with newly diagnosed T2DM and a U-shaped pattern in those on ≤2 OHAs and on ≥3 OHAs or insulin. CONCLUSIONS: Central obesity substantially increases the risk of developing ESRD regardless of glycaemic status. The harmful effects of low WC only become significant with the progression of T2DM.

Cholecystectomy increases the risk of metabolic syndrome in the Korean population: a longitudinal cohort study.

Background: Cholecystectomy is a common surgical procedure to treat symptomatic gallstones; however, the long-term outcomes after cholecystectomy are unknown. Therefore, we aimed to investigate whether incident metabolic syndrome (MetS) is associated with cholecystectomy through a large, population-based, longitudinal study. Methods: Subjects aged ≥20 years who underwent cholecystectomy from 2010 to 2014 (n=76,485) and controls (n=76,485), matched for age and sex, were identified from the Korean National Health Insurance Corporation. Cox proportional hazards analyses were performed to evaluate the association between cases and incident MetS, and hazard ratios and 95% confidence intervals (CIs) were calculated. Results: A total of 152,970 patients were included. Mean age was 52.47±12.76 years, and 50.65% of participants were male. During the follow-up period, there were 38,979 (25.48%) newly diagnosed MetS cases in the study participants. The risk of MetS in the cholecystectomy group was approximately 20% higher than that in the control group [adjusted odds ratio (OR), 1.20; 95% CI: 1.17-1.23]. In the fully adjusted models, the corresponding ORs for new-onset high waist circumference (WC), low high-density lipoprotein cholesterol (HDL-C) levels, high triglycerides (TG) levels, high blood pressure (BP), and high blood glucose levels were 1.16 (1.13-1.19), 1.19 (1.16-1.22), 1.25 (1.22-1.28), 1.27 (1.23-1.31), and 1.21 (1.18-1.24), respectively. Cholecystectomy was an independent risk factor of incident MetS, after adjusting for potential confounding factors. In the subgroup analyses, the cholecystectomy group had a higher risk of MetS than the control group in subjects without hypertension or dyslipidemia, respectively. Conclusions: In this large, population-based study, cholecystectomy was associated with an increased risk of developing MetS, independent of other confounding factors. Therefore, careful monitoring of metabolic variables and long-term follow-up are required to evaluate MetS risk after cholecystectomy.

Efficacy of Gemigliptin Add-on to Dapagliflozin and Metformin in Type 2 Diabetes Patients: A Randomized, Double-Blind, Placebo-Controlled Study (SOLUTION).

BACKGRUOUND: This study evaluated the efficacy and safety of add-on gemigliptin in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with metformin and dapagliflozin. METHODS: In this randomized, placebo-controlled, parallel-group, double-blind, phase III study, 315 patients were randomized to receive either gemigliptin 50 mg (n=159) or placebo (n=156) with metformin and dapagliflozin for 24 weeks. After the 24-week treatment, patients who received the placebo were switched to gemigliptin, and all patients were treated with gemigliptin for an additional 28 weeks. RESULTS: The baseline characteristics were similar between the two groups, except for body mass index. At week 24, the least squares mean difference (standard error) in hemoglobin A1c (HbA1c) changes was -0.66% (0.07) with a 95% confidence interval of -0.80% to -0.52%, demonstrating superior HbA1c reduction in the gemigliptin group. After week 24, the HbA1c level significantly decreased in the placebo group as gemigliptin was administered, whereas the efficacy of HbA1c reduction was maintained up to week 52 in the gemigliptin group. The safety profiles were similar: the incidence rates of treatment-emergent adverse events up to week 24 were 27.67% and 29.22% in the gemigliptin and placebo groups, respectively. The safety profiles after week 24 were similar to those up to week 24 in both groups, and no new safety findings, including hypoglycemia, were noted. CONCLUSION: Add-on gemigliptin was well tolerated, providing comparable safety profiles and superior efficacy in glycemic control over placebo for long-term use in patients with T2DM who had poor glycemic control with metformin and dapagliflozin.