Genome-Wide Polygenic Risk Score Predicts Incident Type 2 Diabetes in Women With History of Gestational Diabetes.

OBJECTIVE: Women with a history of gestational diabetes mellitus (GDM) are at increased risk of developing type 2 diabetes (T2D). It remains unclear whether genetic information improves prediction of incident T2D in these women. RESEARCH DESIGN AND METHODS: Using five independent cohorts representing four different ancestries (n = 1,895), we investigated whether a genome-wide T2D polygenic risk score (PRS) is associated with increased risk of incident T2D. We also calculated the area under the receiver operating characteristics curve (AUROC) and continuous net reclassification improvement (NRI) following the incorporation of T2D PRS into clinical risk models to assess the diagnostic utility. RESULTS: Among 1,895 women with previous history of GDM, 363 (19.2%) developed T2D in a range of 2 to 30 years. T2D PRS was higher in those who developed T2D (-0.08 vs. 0.31, P = 2.3 × 10-11) and was associated with an increased risk of incident T2D (odds ratio 1.52 per 1-SD increase, 95% CI 1.05-2.21, P = 0.03). In a model that includes age, family history of diabetes, systolic blood pressure, and BMI, the incorporation of PRS led to an increase in AUROC for T2D from 0.71 to 0.74 and an intermediate improvement of NRI (0.32, 95% CI 0.15-0.49, P = 3.0 × 10-4). Although there was variation, a similar trend was observed across study cohorts. CONCLUSIONS: In cohorts of GDM women with diverse ancestry, T2D PRS was significantly associated with future development of T2D. A significant but small improvement was observed in AUROC when T2D PRS was integrated into clinical risk models to predict incident T2D.

Higher Genetic Risk for Type 2 Diabetes Is Associated With a Faster Decline of ß-Cell Function in an East Asian Population.

OBJECTIVE: While most genetic variants of type 2 diabetes (T2D) are suggested to be associated with ß-cell dysfunction cross sectionally, their association with the longitudinal change of ß-cell function remains largely unknown. RESEARCH DESIGN AND METHODS: We analyzed data from 6,311 participants without T2D at baseline (mean [SD] age 51.6 [8.7] years) from a community-based prospective cohort in Korea. Participants underwent biennial 2-h 75-g oral glucose tolerance tests (OGTTs) during 14 years of follow-up, and the OGTT-derived disposition index (DI) was used as a marker for ß-cell function. Genetic risk was quantified using the genome-wide polygenic risk score (PRS) and was stratified into low (1st quintile), intermediate (2nd-4th quintiles), and high (5th quintile) genetic risk. Lifestyle was assessed according to Life's Essential 8. RESULTS: During a mean follow-up of 10.9 years, 374 (29.6%), 851 (22.5%), and 188 (14.9%) participants developed T2D in the high, intermediate, and low genetic risk groups, respectively. Compared with the low genetic risk group, participants in the high genetic risk group had a 25% lower DI at baseline. Furthermore, in longitudinal analysis, we observed a 1.83-fold faster decline in log2-transformed DI per year (-0.034 vs. -0.019, P = 2.1 × 10-3; per 1-SD increase in T2D PRS, P = 1.2 × 10-4). Healthy lifestyle attenuated the rate of decline in DI across all genetic risk groups. CONCLUSIONS: Individuals with a higher genetic risk for T2D exhibited not only a lower OGTT-derived ß-cell function at baseline but also a notably more rapid decline during follow-up. This information could be used to enable a focused precision prevention with lifestyle intervention.

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People With Type 2 Diabetes.

OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs77142250 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea.

Maternally inherited diabetes and deafness (MIDD) is a rare mitochondrial disorder primarily resulting from m.3243A>G mutation. The clinical characteristics of MIDD exhibit significant heterogeneity. Our study aims to delineate these characteristics and determine the potential correlation with m.3243A>G heteroplasmy levels. This retrospective, descriptive study encompassed patients with confirmed m.3243A>G mutation and diabetes mellitus at Seoul National University Hospital. Our cohort comprises 40 patients with MIDD, with a mean age at study enrollment of 33.3±12.9 years and an average % of heteroplasmy of 30.0%± 14.6% in the peripheral blood. The most prevalent comorbidity was hearing loss (90%), followed by albuminuria (61%), seizure (38%), and stroke (33%). We observed a significant negative correlation between % of heteroplasmy and age at diabetes diagnosis. These clinical features can aid in the suspicion of MIDD and further consideration of genetic testing for m.3243A>G mutation.

Glucolipotoxicity Suppressed Autophagy and Insulin Contents in Human Islets, and Attenuation of PERK Activity Enhanced Them in an ATG7-Dependent Manner.

BACKGRUOUND: Administration of pancreatic endoplasmic reticulum kinase inhibitor (PERKi) improved insulin secretion and hyperglycemia in obese diabetic mice. In this study, autophagic balance was studied whether to mediate it. METHODS: Human islets were isolated from living patients without diabetes. PERKi GSK2606414 effects were evaluated in the islets under glucolipotoxicity by palmitate. Islet insulin contents and secretion were measured. Autophagic flux was assessed by microtubule associated protein 1 light chain 3 (LC3) conversion, a red fluorescent protein (RFP)-green fluorescent protein (GFP)- LC3 tandem assay, and P62 levels. For mechanical analyses, autophagy was suppressed using 3-methyladenine in mouse islets. Small interfering RNA for an autophagy-related gene autophagy related 7 (Atg7) was transfected to interfere autophagy. RESULTS: PERKi administration to mice decreased diabetes-induced P62 levels in the islets. Glucolipotoxicity significantly increased PERK phosphorylation by 70% and decreased insulin contents by 50% in human islets, and addition of PERKi (40 to 80 nM) recovered both. PERKi also enhanced glucose-stimulated insulin secretion (6-fold). PERKi up-regulated LC3 conversion suppressed by glucolipotoxicity, and down-regulated P62 contents without changes in P62 transcription, indicating enhanced autophagic flux. Increased autophagosome-lysosome fusion by PERKi was visualized in mouse islets, where PERKi enhanced ATG7 bound to LC3. Suppression of Atg7 eliminated PERKi-induced insulin contents and secretion. CONCLUSION: This study provided functional changes of human islets with regard to autophagy under glucolipotoxicity, and suggested modulation of autophagy as an anti-diabetic mechanism of PERKi.

Partial Deletion of Perk Improved High-Fat Diet-Induced Glucose Intolerance in Mice.

Although pancreatic endoplasmic reticulum kinase (PERK) is indispensable to beta cells, low-dose PERK inhibitor improved glucose- stimulated insulin secretion (GSIS) and hyperglycemia in diabetic mice. Current study examined if partial deletion of Perk (Perk+/-) recapitulated the effects of PERK inhibitor, on the contrary to the complete deletion. Perk+/- mice and wild-type controls were fed with a high-fat diet (HFD) for 23 weeks. Glucose tolerance was evaluated along with serum insulin levels and islet morphology. Perk+/- mice on normal chow were comparable to wild-type mice in various metabolic features. HFD-induced obesity was not influenced by Perk reduction; however, HFD-induced glucose intolerance was significantly improved since 15-week HFD. HFD-induced compromises in GSIS were relieved by Perk reduction, accompanied by reductions in phosphorylated PERK and activating transcription factor 4 (ATF4) in the islets. Meanwhile, HFD-induced islet expansion was not significantly affected. In summary, partial deletion of Perk improved glucose tolerance and GSIS impaired by diet-induced obesity, without changes in body weights or islet mass.

Periostin deficiency attenuates kidney fibrosis in diabetic nephropathy by improving pancreatic ß-cell dysfunction and reducing kidney EMT.

Diabetic nephropathy (DN) is associated with kidney fibrosis. A previous study revealed that periostin (POSTN) contributes to kidney fibrosis. This study examined the role of POSTN in DN. The urinary concentrations of POSTN and TNC increased according to the severity of DN in human samples. Streptozotocin (STZ) was administered after unilateral nephrectomy (UNXSTZ) to induce DN in wild-type and Postn-null mice. Four experimental groups were generated: wild-typeham (WT Sham), wild-type UNXSTZ (WT STZ), Postn-null Sham (KO Sham), and Postn-null UNXSTZ (KO STZ). After 20 weeks, the KO STZ group had lower levels of urine albumin excretion, glomerular sclerosis, and interstitial fibrosis than those of the WT STZ group. Additionally, the KO STZ group had lower expression of fibrosis markers, including TNC. The KO STZ group showed better glucose regulation than the WT STZ model. Furthermore, the KO STZ group exhibited significantly preserved pancreatic islet integrity and insulin expression. HK-2 cells were used to observe the aggravation of fibrosis caused by POSTN under TGF-ß conditions. We stimulated INS-1 cells with streptozotocin and evaluated the viability of these cells. The anti-POSTN antibody treatment of INS-1 cells with streptozotocin resulted in higher cell viability than that with treatment with streptozotocin alone. The absence of POSTN in DN contributes to renal fibrosis alleviation by improving pancreatic ß-cell function. Additionally, there is an association between POSTN and TNC.

SUMO-specific protease 2 regulates lipid droplet size through ERRα-mediated CIDEA expression in adipocytes.

Lipid droplets are not only lipid storage sites but also are closely related to lipid metabolism. Lipid droplet growth increases lipid storage capacity and suppresses lipolysis via lipase associated with the lipid droplet surface. The cell death-inducing DFF45-like effector (CIDE) family of proteins mediates lipid droplet fusion, which mainly contributes to lipid droplet growth. We previously demonstrated small ubiquitin-like modifier (SUMO)-specific protease 2 (SENP2) plays important roles in lipid metabolism and induction/maintenance of adipogenesis. In this study, we determined whether SENP2 regulates lipid droplet size in adipocytes. Overexpression of SENP2 increased lipid droplet size in differentiated 3T3-L1 adipocytes and facilitated CIDEA transcription. We found SENP2 increased CIDEA expression mainly through desumoylation of estrogen-related receptor α (ERRα), which acted in coordination with peroxisome proliferator-activated receptor γ-coactivator α. In addition, palmitate treatment increased SENP2 and CIDEA mRNA levels. Specific small interfering RNA-mediated knockdown of SENP2, as well as ERRα knockdown, eliminated palmitate-induced CIDEA expression. These results suggest SENP2 enhances CIDEA expression by modulating ERRα when SENP2 is upregulated, such as after palmitate treatment, to increase lipid droplet size in adipocytes.

Triglyceride-Glucose Index Predicts Future Atherosclerotic Cardiovascular Diseases: A 16-Year Follow-up in a Prospective, Community-Dwelling Cohort Study.

BACKGRUOUND: While the triglyceride-glucose (TyG) index is a measure of insulin resistance, its association with cardiovascular disease (CVD) has not been well elucidated. We evaluated the TyG index for prediction of CVDs in a prospective large communitybased cohort. METHODS: Individuals 40 to 70 years old were prospectively followed for a median 15.6 years. The TyG index was calculated as the Ln [fasting triglycerides (mg/dL)×fasting glucose (mg/dL)/2]. CVDs included any acute myocardial infarction, coronary artery disease or cerebrovascular disease. We used a Cox proportional hazards model to estimate CVD risks according to quartiles of the TyG index and plotted the receiver operating characteristics curve for the incident CVD. RESULTS: Among 8,511 subjects (age 51.9±8.8 years; 47.5% males), 931 (10.9%) had incident CVDs during the follow-up. After adjustment for age, sex, body mass index, diabetes mellitus, hypertension, total cholesterol, smoking, alcohol, exercise, and C-reactive protein, subjects in the highest TyG quartile had 36% increased risk of incident CVD compared with the lowest TyG quartile (hazard ratio, 1.36; 95% confidence interval, 1.10 to 1.68). Carotid plaque, assessed by ultrasonography was more frequent in subjects in the higher quartile of TyG index (P for trend=0.049 in men and P for trend <0.001 in women). The TyG index had a higher predictive power for CVDs than the homeostasis model assessment of insulin resistance (HOMA-IR) (area under the curve, 0.578 for TyG and 0.543 for HOMA-IR). Adding TyG index on diabetes or hypertension alone gave sounder predictability for CVDs. CONCLUSION: The TyG index is independently associated with future CVDs in 16 years of follow-up in large, prospective Korean cohort.

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD. METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D. RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance (P<5.0×10-8): rs147138607 (intergenic variant between CACNA1E and ZNF648) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, P=3.6×10-9, rs11444867 (intergenic variant near HS3ST1) with HR 1.89, 95% CI 1.52 - 2.35, P=9.9×10-9, and rs335407 (intergenic variant between TFB1M and NOX3) HR 1.25, 95% CI 1.16 - 1.35, P=1.5×10-8. Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with P<0.05, and 5 were significant after Bonferroni correction (P<0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase (P=1.0×10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Direct Differentiation of Bone Marrow Mononucleated Cells Into Insulin-Producing Cells Using 4 Specific Soluble Factors.

Bone marrow-derived stem cells are self-renewing and multipotent adult stem cells that differentiate into several types of cells. Here, we investigated a unique combination of 4 differentiation-inducing factors (DIFs), including putrescine (Put), glucosamine (GlcN), nicotinamide, and BP-1-102, to develop a differentiation method for inducing mature insulin-producing cells (IPCs) and apply this method to bone marrow mononucleated cells (BMNCs) isolated from mice. BMNCs, primed with the 4 soluble DIFs, were differentiated into functional IPCs. BMNCs cultured under the defined conditions synergistically expressed multiple genes, including those for PDX1, NKX6.1, MAFA, NEUROG3, GLUT2, and insulin, related to pancreatic beta cell development and function. They produced insulin/C-peptide and PDX1, as assessed using immunofluorescence and flow cytometry. The induced cells secreted insulin in a glucose-responsive manner, similar to normal pancreatic beta cells. Grafting BMNC-derived IPCs under kidney capsules of mice with streptozotocin (STZ)-induced diabetes alleviated hyperglycemia by lowering blood glucose levels, enhancing glucose tolerance, and improving glucose-stimulated insulin secretion. Insulin- and PDX1-expressing cells were observed in the IPC-bearing graft sections of nephrectomized mice. Therefore, this study provides a simple protocol for BMNC differentiation, which can be a novel approach for cell-based therapy in diabetes mellitus.

Efficacy and safety of monotherapy with enavogliflozin in Korean patients with type 2 diabetes mellitus: Results of a 12-week, multicentre, randomized, double-blind, placebo-controlled, phase 2 trial.

AIMS: The study aimed to evaluate and compare the efficacy and safety of enavogliflozin, a newly developed sodium-glucose cotransporter 2 inhibitor, with placebo in Korean patients with type 2 diabetes mellitus. MATERIALS AND METHODS: Patients with glycated haemoglobin (HbA1c) of 7.0-10.0%, entered a 2-week placebo run-in period, and were randomized to receive once-daily enavogliflozin (0.1, 0.3 or 0.5 mg) or placebo for 12 weeks. The primary efficacy endpoint was the change in HbA1c from baseline at week 12. RESULTS: Overall, 194 patients were included in the full analysis set [placebo, n = 46; enavogliflozin (0.1 mg, n = 49; 0.3 mg, n = 50; 0.5 mg, n = 49)]. Patients receiving 0.1, 0.3 and 0.5 mg enavogliflozin showed significantly reduced HbA1c compared with those receiving placebo at week 12 (-0.79%, -0.89%, -0.92% and -0.08%, respectively; p < .001 vs. placebo). Mean changes in fasting plasma glucose from baseline at week 12 were -30.5, -31.1, -35.0 and 4.9 mg/dl in patients receiving enavogliflozin doses and placebo, respectively. The proportion of patients achieving HbA1c <7.0% at week 12 was significantly higher in the three enavogliflozin groups than in the placebo group (42.9%, 44.0%, 61.2% and 17.4%, respectively). A higher proportion of patients showed HbA1c reduction by >0.5% after receiving enavogliflozin doses than those receiving placebo (61.2%, 72.0%, 65.3% and 26.1%, respectively). There were no significant differences in incidences of adverse events of hypoglycaemia and genital infection between the groups. CONCLUSIONS: Once-daily enavogliflozin monotherapy for 12 weeks is an effective, safe, and well-tolerated treatment for Korean patients with type 2 diabetes mellitus.

Role of SUMO-Specific Protease 2 in Leptin-Induced Fatty Acid Metabolism in White Adipocytes.

BACKGROUND: Leptin is a 16-kDa fat-derived hormone with a primary role in controlling adipose tissue levels. Leptin increases fatty acid oxidation (FAO) acutely through adenosine monophosphate-activated protein kinase (AMPK) and on delay through the SUMO-specific protease 2 (SENP2)-peroxisome proliferator-activated receptor δ/γ (PPARδ/γ) pathway in skeletal muscle. Leptin also directly increases FAO and decreases lipogenesis in adipocytes; however, the mechanism behind these effects remains unknown. Here, we investigated the role of SENP2 in the regulation of fatty acid metabolism by leptin in adipocytes and white adipose tissues. METHODS: The effects of leptin mediated by SENP2 on fatty acid metabolism were tested by siRNA-mediated knockdown in 3T3-L1 adipocytes. The role of SENP2 was confirmed in vivo using adipocyte-specific Senp2 knockout (Senp2-aKO) mice. We revealed the molecular mechanism involved in the leptin-induced transcriptional regulation of carnitine palmitoyl transferase 1b (Cpt1b) and long-chain acyl-coenzyme A synthetase 1 (Acsl1) using transfection/reporter assays and chromatin immunoprecipitation. RESULTS: SENP2 mediated the increased expression of FAO-associated enzymes, CPT1b and ACSL1, which peaked 24 hours after leptin treatment in adipocytes. In contrast, leptin stimulated FAO through AMPK during the initial several hours after treatment. In white adipose tissues, FAO and mRNA levels of Cpt1b and Acsl1 were increased by 2-fold 24 hours after leptin injection in control mice but not in Senp2-aKO mice. Leptin increased PPARα binding to the Cpt1b and Acsl1 promoters in adipocytes through SENP2. CONCLUSION: These results suggest that the SENP2-PPARα pathway plays an important role in leptin-induced FAO in white adipocytes.

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.

Earlier Age at Type 2 Diabetes Diagnosis Is Associated With Increased Genetic Risk of Cardiovascular Disease.

OBJECTIVE: We investigated genetic risk of cardiovascular disease (CVD) by age at type 2 diabetes (T2D) diagnosis. RESEARCH DESIGN AND METHODS: We compared incident CVD events by age at T2D diagnosis using UK Biobank (N = 12,321) and the Seoul National University Hospital (SNUH) cohort (N = 1,165). Genetic risk was quantified using polygenic risk score (PRS). RESULTS: Individuals with earlier T2D diagnosis had higher CVD risk. In UK Biobank, the effect size of coronary artery disease (CAD) PRS on incident CAD was largest in individuals diagnosed with T2D at ages 30-39 years (hazard ratio 2.25; 95% CI 1.56-3.26) and decreased as age at diagnosis increased: ages 40-49 (1.51; 1.30-1.75), 50-59 (1.36; 1.24-1.50), and 60-69 years (1.30; 1.14-1.48) (Pinteraction = 0.0031). A similar trend was observed in the SNUH cohort. This increased genetic risk associated with earlier T2D diagnosis was largely mitigated by a healthy lifestyle. CONCLUSIONS: Individuals with an earlier T2D diagnosis have a higher genetic risk of CAD, and this information could be used to tailor lifestyle interventions.

Genome-Wide Association Study on Longitudinal Change in Fasting Plasma Glucose in Korean Population.

BACKGROUND: Genome-wide association studies (GWAS) on type 2 diabetes mellitus (T2DM) have identified more than 400 distinct genetic loci associated with diabetes and nearly 120 loci for fasting plasma glucose (FPG) and fasting insulin level to date. However, genetic risk factors for the longitudinal deterioration of FPG have not been thoroughly evaluated. We aimed to identify genetic variants associated with longitudinal change of FPG over time. METHODS: We used two prospective cohorts in Korean population, which included a total of 10,528 individuals without T2DM. GWAS of repeated measure of FPG using linear mixed model was performed to investigate the interaction of genetic variants and time, and meta-analysis was conducted. Genome-wide complex trait analysis was used for heritability calculation. In addition, expression quantitative trait loci (eQTL) analysis was performed using the Genotype-Tissue Expression project. RESULTS: A small portion (4%) of the genome-wide single nucleotide polymorphism (SNP) interaction with time explained the total phenotypic variance of longitudinal change in FPG. A total of four known genetic variants of FPG were associated with repeated measure of FPG levels. One SNP (rs11187850) showed a genome-wide significant association for genetic interaction with time. The variant is an eQTL for NOC3 like DNA replication regulator (NOC3L) gene in pancreas and adipose tissue. Furthermore, NOC3L is also differentially expressed in pancreatic ß-cells between subjects with or without T2DM. However, this variant was not associated with increased risk of T2DM nor elevated FPG level. CONCLUSION: We identified rs11187850, which is an eQTL of NOC3L, to be associated with longitudinal change of FPG in Korean population.

Genetic association-based functional analysis detects HOGA1 as a potential gene involved in fat accumulation.

Although there are a number of discoveries from genome-wide association studies (GWAS) for obesity, it has not been successful in linking GWAS results to biology. We sought to discover causal genes for obesity by conducting functional studies on genes detected from genetic association analysis. Gene-based association analysis of 917 individual exome sequences showed that HOGA1 attains exome-wide significance (p-value < 2.7 × 10-6) for body mass index (BMI). The mRNA expression of HOGA1 is significantly increased in human adipose tissues from obese individuals in the Genotype-Tissue Expression (GTEx) dataset, which supports the genetic association of HOGA1 with BMI. Functional analyses employing cell- and animal model-based approaches were performed to gain insights into the functional relevance of Hoga1 in obesity. Adipogenesis was retarded when Hoga1 was knocked down by siRNA treatment in a mouse 3T3-L1 cell line and a similar inhibitory effect was confirmed in mice with down-regulated Hoga1. Hoga1 antisense oligonucleotide (ASO) treatment reduced body weight, blood lipid level, blood glucose, and adipocyte size in high-fat diet-induced mice. In addition, several lipogenic genes including Srebf1, Scd1, Lp1, and Acaca were down-regulated, while lipolytic genes Cpt1l, Ppara, and Ucp1 were up-regulated. Taken together, HOGA1 is a potential causal gene for obesity as it plays a role in excess body fat development.

Effects of Patient-Driven Lifestyle Modification Using Intermittently Scanned Continuous Glucose Monitoring in Patients With Type 2 Diabetes: Results From the Randomized Open-label PDF Study.

OBJECTIVE: To investigate the effects of patient-driven lifestyle modification using intermittently scanned continuous glucose monitoring (isCGM) in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a 12-week, open-label, randomized controlled trial. A total of 126 participants were 1:1 randomized to either the intervention group (structured education + isCGM) or the control group (standard care with blood glucose monitoring). The Self-Evaluation Of Unhealthy foods by Looking at postprandial glucose (SEOUL) algorithm was developed and applied to aid structured education in guiding patients to follow healthy eating behavior depending on the postprandial glycemic response. The primary end point was the change in HbA1c level from baseline. RESULTS: Implementation of the SEOUL algorithm with isCGM was associated with greater improvement in HbA1c than with standard care (risk-adjusted difference -0.50%, 95% CI -0.74 to -0.26, P < 0.001). Participants in the intervention group had a greater reduction in fasting blood glucose and body weight (-16.5 mg/dL, 95% CI -30.0 to -3.0, P = 0.017; -1.5 kg, 95% CI -2.7 to -0.3, P = 0.013, respectively). The score sum for the Korean version of the revised Summary of Diabetes Self-Care Activities Questionnaire increased in both groups but to a greater extent in the intervention group (mean difference 4.8, 95% CI 1.7-8.0, P = 0.003). No severe hyperglycemia or hypoglycemia was reported in either group of patients. CONCLUSIONS: Patient-driven lifestyle modification primarily focused on eating behavior using isCGM effectively lowered HbA1c levels in patients with T2D.

Gender differences in risk factors for the 2 year development of sarcopenia in community-dwelling older adults.

BACKGROUND: Sarcopenia is an age-related chronic condition that can lead to mobility disabilities. This study aimed to evaluate the risk factors for incident sarcopenia in older Korean adults. METHODS: The Korean Frailty and Aging Cohort Study (KFACS) is a multicentre prospective study with a baseline examination in 2016-2017. A prospective follow-up study was conducted in 2018-2019. Changes in muscle-related variables were evaluated for subjects aged 70-84 years lacking sarcopenia at baseline. Sarcopenia was diagnosed according to the 2019 updated Asian Working Group for Sarcopenia consensus. RESULTS: Among the 1636 participants (54.4% women, age 75.9 ± 3.7) who did not have sarcopenia at baseline, 101 men (13.5%) and 104 women (11.7%) developed sarcopenia by the follow-up. Those who developed sarcopenia were older (men, 77.9 ± 3.9 vs. 75.7 ± 3.5, P < 0.001; women, 77.5 ± 4.0 vs. 75.5 ± 3.6, P < 0.001) with a lower body mass index at baseline (men, 23.9 ± 2.4 vs. 24.5 ± 2.9 kg/m2 , P = 0.025; women, 23.7 ± 2.8 vs. 25.2 ± 2.9 kg/m2 , P < 0.001) compared with older adults who remained nonsarcopenic; levels of glycated haemoglobin (men, 6.2 ± 1.0% vs. 5.9 ± 0.8%, P = 0.029) and the homeostasis model assessment of insulin resistance (men, 2.0 ± 1.3 vs. 1.7 ± 1.2, P = 0.022) were higher in men who progressed to sarcopenia but not in women. Development of sarcopenia was associated with older age and the frequency of resistance training (≥2 per week) after adjusting for potential risk factors in men [age, odds ratio (OR) 1.17, 95% confidence interval (CI) 1.10-1.25; frequent resistance training, OR 0.50, 95% CI 0.30-0.82]. In women, advanced age, poor nutritional status, and physical inactivity contributed to the development of sarcopenia (age, OR 1.14, 95% CI 1.08-1.21; mini nutritional assessment short form, OR 0.79, 95% CI 0.70-0.90; moderate to high physical activity, OR 0.57, 95% CI 0.34-0.95). CONCLUSIONS: In this 2 year KFACS follow-up, modifiable risk factors for incident sarcopenia differed between genders. Resistance training (≥2 per week) helped to prevent sarcopenia in these community-dwelling older men. In older women, adequate nutritional support and being physically active might play a role in preventing progression to sarcopenia.

SENP2 suppresses browning of white adipose tissues by de-conjugating SUMO from C/EBPß.

The adipose tissue is a key site regulating energy metabolism. One of the contributing factors behind this is browning of white adipose tissue (WAT). However, knowledge of the intracellular determinants of the browning process remains incomplete. By generating adipocyte-specific Senp2 knockout (Senp2-aKO) mice, here we show that SENP2 negatively regulates browning by de-conjugating small ubiquitin-like modifiers from C/EBPß. Senp2-aKO mice are resistant to diet-induced obesity due to increased energy expenditure and heat production. Senp2 knockout promotes beige adipocyte accumulation in inguinal WAT by upregulation of thermogenic gene expression. In addition, SENP2 knockdown promotes thermogenic adipocyte differentiation of precursor cells isolated from inguinal and epididymal WATs. Mechanistically, sumoylated C/EBPß, a target of SENP2, suppresses expression of HOXC10, a browning inhibitor, by recruiting a transcriptional repressor DAXX. These findings indicate that a SENP2-C/EBPß-HOXC10 axis operates for the control of beige adipogenesis in inguinal WAT.