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Early stage of diabetic kidney disease (DKD) involves loss of podocytes, consequently causing albuminuria. SGLT2 inhibitors demonstrated renoprotective effects in DKD, but the mechanism for protection in early DKD is unclear. Here, we investigated the effects of ertugliflozin in high-fat diet (HFD) -induced DKD model, in vivo and in vitro. 5-week-old male C57BL/6J mice were supplemented with HFD for 24 weeks to develop HFD-induced DKD. Ertugliflozin was administrated orally by pre-mixing with HFD for 16 weeks. We evaluated body weight, random blood glucose levels, albuminuria and glucose and insulin tolerance test were performed at 12 weeks after ertugliflozin administration. The renal cortex was collected for histologic examination and SGLT2 expression on podocytes were measured. Albuminuria was significantly decreased in ertugliflozin group compared with HFD group at 12 weeks of ertugliflozin administration (p=0.011) . Body weight, random and fasting blood glucose was not significantly different between HFD group. Glucose and insulin tolerance test showed significant improvement in ertugliflozin group compared with HFD group at 12 weeks (p=0.0004) . In immunohistochemistry studies, glomerular volume and mesangial expansion were attenuated in the ertugliflozin group by 27.6% and 27.8% respectively, compared to HFD group (p=0.002 and p=0.005, respectively) . Glomerular basement membrane thickness was decreased by 45.4% in ertugliflozin group compared to HFD group (p=0.0004) . Significant increase of SGLT2 mRNA expression by 1.6-4.8 fold after 24 hour-albumin expose was observed and SGLT2 protein was increased 1.1-1.3 fold compared to control. Ertugliflozin attenuated diabetic kidney disease in HFD-induced DKD by mitigating glomerular integrity, preserving podocyte morphology, with decreased albuminuria. Upregulation of SGLT2 in podocyte in albuminuric DKD could be suggested as possible target for renoprotective action of SGLT2 inhibitor. Disclosure H.Kim: None. B.Cha: None. H.Lee: None. B.Lim: None. H.Choi: None. E.Kang: None. Y.Kim: None. R.Kim: None. S.Lee: None. Y.Yang: None. H.Park: None. N.Jeon: None. M.Lee: None. Y.Lee: None. Funding Severance Hospital Research fund for Clinical excellence (SHRC) (C-2021-0007)

Objectives: Nonalcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). However, the causal relationship between NAFLD and the development of CKD is uncertain, particularly in patients with type 2 diabetes. We aimed to investigate the association between the presence and severity of NAFLD and incident CKD in patients with type 2 diabetes. Research Design and Methods: In this longitudinal cohort study of patients with type 2 diabetes, 3,188 patients with preserved renal function were followed for the occurrence of incident CKD. NAFLD was defined as the presence of hepatic steatosis on ultrasonography without any other causes of chronic liver diseases. Advanced liver fibrosis of NAFLD was defined as NAFLD fibrosis score >0.675. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Results: At baseline, 1,729 (54.2%) patients had NAFLD, of whom 94 (5.4%) had advanced liver fibrosis. During the follow-up of 8.3 ± 3.6 years, 472 (14.8%) patients developed incident CKD, 220 (15.1%) in the non-NAFLD group, 226 (12.8%) in the hepatic steatosis alone group and 26 (27.7%) in the advanced liver fibrosis group. There was no increased risk of incident CKD in the NAFLD group compared with the non-NAFLD group (p = 0.79). However, among patients with NAFLD, advanced liver fibrosis was associated with an increased risk of CKD (adjusted hazard ratio [HR] 1.78 (95% confidence interval [CI] 1.14-2.76), p=0.011). Conclusions: Advanced liver fibrosis in NAFLD is independently associated with an increased risk of incident CKD in patients with type 2 diabetes. Disclosure D. Seo: None. Y. Cho: None. S. Ahn: None. S. Seo: None. S. Hong: None. Y. Lee: None. S. Kim: None. Funding National Research Foiundation (2017R1D-1A1B03034581)

Background: Nonalcoholic steatohepatitis is closely associated with the progression of diabetic kidney disease (DKD) in type 2 diabetes (T2D). We investigated whether urinary N-acetyl-β-D- glucosaminidase(u-NAG), an early renal tubular damage biomarker in DKD, could be related to the degree of hepatic fibrosis in patients with T2D. Methods: A total of 300 patients with T2D were enrolled in the study. Hepatic steatosis and fibrosis were determined using transient elastography. The levels of urinary biomarkers, including u-NAG, albumin, protein, and creatinine, and glucometabolic parameters were measured. Results: Based on the median value of u-NAG to creatinine (u-NCR), subjects were divided into normal and high u-NCR groups. The high u-NCR group showed a significantly longer duration of diabetes, worsened hyperglycemia, and a more enhanced hepatic fibrosis index. A higher u-NCR was associated with a greater odds ratio for the risk of higher hepatic fibrosis stage (F2 OR 1.99; 95% CI [1.04-3.82]; F3 and F4 OR 2.40, 95% CI [1.52-3.80]). In addition, u-NCR was an independent predictive marker for more advanced hepatic fibrosis even after adjusting for several confounding factors (β = 1.58, P Conclusions: The elevation of u-NAG was independently associated with a higher degree of hepatic fibrosis in patients with T2D. Considering the common metabolic milieu of renal and hepatic fibrosis in T2D, the potential use of u-NAG as an effective urinary biomarker reflecting hepatic fibrosis in T2D needs to be validated in the future. Disclosure H. Kim: None. Y. Kim: None. M. Lee: None. Y. Lee: None. E. Kang: None. B. Cha: None. B. Lee: None.

Senescent T cells have been implicated in chronic inflammatory and cardiovascular diseases. In this study, we explored the relationship between senescent T cells and glycemic status in a cohort of 805 participants by investigating the frequency of CD57+ or CD28null senescent T cells in peripheral blood. Participants with normal glucose tolerance (NGT) with follow-up data (N = 149) were included to determine whether hyperglycemia (prediabetes or type 2 diabetes) developed during follow-up (mean 2.3 years). CD8+CD57+ and CD8+CD28null T-cell frequencies were significantly higher in prediabetes and type 2 diabetes compared with NGT. Increased CD57+ or CD28null cells in the CD8+ T-cell subset were independently associated with hyperglycemia. Furthermore, among participants with baseline NGT, the frequency of CD8+CD57+ T cells was an independent predictor of hyperglycemia development. Immunofluorescent analyses confirmed that CD8+CD57+ T-cell infiltration was increased in visceral adipose tissue of patients with prediabetes or type 2 diabetes compared with those with NGT. Our data suggest that increased frequency of senescent CD8+ T cells in the peripheral blood is associated with development of hyperglycemia.

Background: Recent studies investigated the association between nonalcoholic fatty liver disease (NAFLD) and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM) but the results are inconclusive. Here we aimed to investigate the effect of obesity on the association between NAFLD and DKD in a large cohort of participants with T2DM. Methods: In this cross-sectional study, a total of 3,439 patients (1,710 men and 1,729 women) with T2DM were recruited from the Seoul Metabolic Syndrome cohort between 2003 and 2016. NAFLD was defined by ultrasonographic detection of steatosis in the absence of other liver diseases. Advanced fibrosis was defined as FIB4 index ≥ 1.45. DKD was defined as an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2. Obesity was defined as body mass index (BMI) ≥ 25 kg/m2. Results: The mean age was 57.4 ± 10.3 years and duration of diabetes was 7.7 ± 7.1 years. Two hundred and fifty subjects (7.3%) had DKD and 1869 (54.3%) subjects had NAFLD. The prevalence of DKD were 7.0%, 4.5% and 11.9% in no-NAFLD group, liver steatosis only group and advanced fibrosis group respectively (p Conclusion: This study suggests that advanced liver fibrosis, a severe form of NAFLD, was independently associated with increased risk of DKD in non-obese patients with T2DM. Disclosure D. Seo: None. Y. Cho: None. S. Ahn: None. S. Hong: None. Y. Lee: None. Y. Choi: None. B. Huh: None. K. Huh: None. S. Kim: None.

Objective: Ketones may be regarded as a thrifty fuel for peripheral tissues, but their clinical prognostic significance still remains unclear. We investigated the association between spontaneous fasting ketonuria and incident diabetes in conjunction with changes in metabolic parameters in a large population-based, observational study. Research Design and Methods: We analyzed a total of 8,703 individuals free of diabetes at baseline in the Korean Genome and Epidemiology Study, a community-based, 12-year prospective study. Subjects with (n=195) or without fasting ketonuria were 1:4 matched by propensity score. Incident diabetes was defined as: fasting plasma glucose ≥126 mg/dL, 2-hour glucose ≥200 mg/dL on biennial 75g oral glucose tolerance test, or current antidiabetic medication. Using Cox regression models, hazard ratios for developing diabetes associated with the presence of ketonuria at baseline were analyzed. Results: Over 12 years, of the 925 subjects in the propensity score matched cohort, 190 (20.5%) developed diabetes. The incidence rate of diabetes was significantly lower in subjects with spontaneous ketonuria compared to those without ketonuria (adjusted hazard ratio 0.64 [95% confidence interval=0.42-0.99]. This result was replicated in the whole cohort (HR 0.67 [95% CI: 0.46-0.98] after multivariate adjustment). During follow-up, subjects with ketonuria at baseline maintained lower 1-hour and 2-hour glucose levels, and a higher insulinogenic index during follow-up despite comparable baseline values. Conclusions: The presence of spontaneous fasting ketonuria was significantly associated with a reduced incidence rate of diabetes, independently of metabolic parameters. Our findings suggest spontaneous fasting ketonuria is a stable phenotype and a novel signature in the modulation of glucose metabolism. Disclosure S.J. Cho: None. I. Lee: None. S. Lee: None. E. Kang: None. E. Ferrannini: None. Y. Lee: None. G. Kim: None. B. Cha: None.

Background: Sarcopenia, an age-related decline in skeletal muscle mass, leads to metabolic and vascular abnormalities. However, little is known regarding the independent relationship between skeletal muscle mass and atherosclerosis in patients with type 2 diabetes mellitus (T2DM). The purpose of this study was to evaluate the association of skeletal muscle mass with markers of carotid atherosclerosis, carotid intima-media thickness (CIMT) and carotid artery plaque, in men and women with T2DM. Methods: In this cross-sectional study, a total of 8,918 patients (4,520 men and 4,398 women) with T2DM were recruited from the outpatient clinic of Huh’s Diabetes Center from 2003 to 2016. Skeletal muscle mass was estimated from bioimpedance analysis measurements and skeletal muscle mass index (SMI, %) was defined as skeletal muscle mass (kg)/total body weight (kg) × 100. Carotid ultrasonography was performed to measure mean CIMT of both common carotid arteries. Carotid artery plaque was defined as a focal structure protruding into the lumen of the vessel of ≥50% than the surrounding area. Results: In both men and women, the presence of carotid artery plaque was higher with decreasing SMI quartiles. In men, this association remained significant after adjustment for additional risk factors (ptrend Conclusion: Low muscle mass is associated with the presence of carotid artery plaque in men with T2DM. Disclosure M. Nam: None. D. Seo: None. M. Jung: None. S. Ahn: None. S. Hong: None. Y. Lee: None. Y. Choi: None. B. Huh: None. K. Huh: None. S. Kim: None. Funding National Research Foundation of Korea (2017R1D-1A1B03034581)

Background: Obese individuals with normal metabolic profiles, so-called “metabolically healthy obese (MHO)” status has shown better clinical outcomes via previous studies. However, studies dealing with the association between MHO and dementia, which is deeply associated with metabolic disorders, were still insufficient. We designed this study to assess the association between MHO and the risk of incident dementia. Methods: The present study is a retrospective cohort study, including 5,669,488 patients aged 60 years old or over without any history of dementia, by using the National Health Insurance System of South Korea. Subjects were divided into 4 groups based on their metabolic health and obesity status. Metabolic health was determined based on the criteria of metabolic syndrome by Adult Treatment Panel-III. Obesity was judged based on the baseline body mass index. The incidence of dementia was checked and compared longitudinally between 4 groups. Results: When we put the metabolically healthy non-obese group to the reference value (hazard ratio (HR) = 1), MHO group showed the lowest incidence of dementia (HR 0.87, 95% confidence interval (CI) 0.86-0.88). This trend was more prominent when we followed up the risk of Alzheimer’s disease as a subgroup analysis (HR 0.85, 95% CI 0.83-0.86). Non-obese subjects with metabolic syndrome showed significantly increased risk for overall dementia (HR 1.20, 95% CI 1.19-1.21), especially for vascular dementia (HR 1.41, 95% CI 1.38-1.45). Conclusion: MHO status was associated with lower risk for dementia, especially for Alzheimer’s disease. Disclosure J. Bae: None. J. Lee: None. Y. Cho: None. M. Lee: None. S. Lee: None. I. Lee: None. E. Kang: None. S.J. Cho: None. K. Han: None. B. Cha: None. Y. Lee: None.

SGLT2 inhibitors significantly reduce cardiovascular events in humans with T2D; however, the underlying mechanism remains unclear. Activation of NLRP3 inflammasome and subsequent IL-1β release induces atherosclerosis and heart failure. Recently, it was revealed that ketone bodies, i.e., β-hydroxybutyrate (BHB) suppresses activation of NLRP3 inflammasome in macrophages. As SGLT2 inhibitors cause increases in serum BHB by pharmacologic profile, we assessed the effect of SGLT2 inhibitor on NLRP3 inflammasome activity. In a randomized, active-controlled study, a total of 61 patients with T2D and high cardiovascular risk (mean age and HbA1C were 64.4 years and 7.32%, respectively) received SGLT2 inhibitor or sulfonylurea for 30 days. NLRP3 inflammasome activation was analyzed in macrophages and the serum levels of glucose, BHB, and insulin from baseline to the end of treatment were tested. While SGLT2 inhibitor’s glucose-lowering capacity was similar to sulfonylurea, it significantly decreased IL-1β secretion compared to baseline (2,394 ± 236 to 1,748 ± 295 pg/mL, p In conclusion, SGLT2 inhibitors attenuate NLRP3 inflammasome activation, in part, via increased serum BHB and decreased serum insulin and glucose, which might help to explain the cardioprotective effects of SGLT2 inhibitor (clinicaltrials.gov NCT02964572). Disclosure Y. Lee: None. S. Kim: None. J. Bae: None. B. Lee: None. E. Kang: None. C. Ahn: None. B. Cha: None.

Skeletal muscle degeneration is accelerated in elderly patients with diabetes and the imbalance between muscle growth and wasting can lead to metabolic dysfunction. DLK1 is a member of the EGF-like family and essential for skeletal muscle development and regeneration. To identify whether exogenous DLK1 treatment can prevent muscle wasting, we assessed muscle mass as well as muscle differentiation and atrophy markers in two different models: dexamethasone and high fat diet (HFD)-induced obesity mice models (n=7-8 per each group). In the dexamethasone model, mice were divided into (1) control, (2) dexamethasone treatment (1mg/Kg, 2 weeks), and (3) DLK1 (0.8mg/Kg, 2 weeks) and dexamethasone treatment groups. In the HFD model, mice were divided into (1) control, (2) HFD (60% calories from fat, 8 weeks), and (3) HFD with DLK1 treatment (0.8mg/Kg, 8 weeks) groups. The expressions of genes related to muscle differentiation and atrophy were determined using RT-PCR. We observed that dexamethasone reduced muscle mass and markedly increased atrophy makers including atrogin-1 and murf-1. DLK1 treatment attenuated these degenerative changes. Furthermore, the level of myostatin, which inhibits muscle cell growth, was reduced in DLK1 treatment group compared to dexamethasone group. Additionally, compared to HFD group, DLK1 inhibited muscle atrophy by increasing the differentiation marker: myoD, and decreasing the atrophy markers: mysotatin, atrogin-1, and murf-1. Taken together, these results suggest that DLK1 attenuates both dexamethasone and HFD-induced muscle atrophy in mice by suppressing the downstream signaling of myostatin/atrogin-1/murf-1 pathway. The increased expression of myoD indicates that DLK1 treatment can also improve the quality of muscle formation. Our study implies that DLK1 could be a promising candidate in the treatment of aging or diabetes-related sarcopenia, characterized by muscle atrophy and dysfunction. Disclosure J. Lee: None. M. Lee: None. H. Jung: None. J. Lee: None. Y. Cho: None. J. Bae: None. Y. Lee: None. B. Lee: None. E. Kang: None. B. Cha: None.

Diabetes is associated with cognitive impairment and increases risk of dementia, but until now the role of gamma-glutamyltransferase (γ-GT) in dementia has not been studied. We thus investigated the impacts of γ-GT and glycemic status on incident dementia in a nationwide cohort study. We determined incident dementia including Alzheimer’s disease and vascular dementia, analyzing data from participants aged 40 years or older in the National Health Insurance Database, collected by the National Health Insurance Service in Korea, from January 2009 to December 2015. During a median follow-up of 7.6 years, 272,657 participants (5.4%) were diagnosed as having dementia at a mean age of 76.5 years. Higher serum γ-GT was associated with increased risk of dementia (HR=1.22, 95% CI=1.20-1.24), and had a strong positive association with early onset dementia (HR=1.32, 95% CI=1.24-1.40). An additive impact of higher γ-GT on dementia was observed regardless of glycemic status, and prevalent diabetes with the highest γ-GT quartile had a 1.8-fold increased dementia risk (HR=1.82, 95% CI=1.78-1.85). This effect of γ-GT concentration in diabetes was more prominent in individuals with vascular dementia (HR=1.94, 95% CI=1.84-2.04). In subgroup analysis, young age, male sex, and relatively healthy subjects with a higher γ-GT quartile had more increased dementia risk. In conclusion, γ-GT concentration as well as glycemic status could be a future risk factor for dementia in the general population. Disclosure E. Han: None. M. Lee: None. Y. Cho: None. B. Lee: None. C. Ahn: None. B. Cha: None. Y. Lee: None.

Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging TGFβ superfamily member. GDF15 administration or GDF15 overexpression has been reported to have anti-obesity and antidiabetic effects. Although nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is frequently associated with metabolic syndrome or diabetes, the functional role of endogenous GDF15 and therapeutic effect of exogenous GDF15 in NASH associated metabolic syndrome have not been addressed. We studied whether GDF15 has therapeutic effects on NASH and associated metabolic syndrome. To this end, Gdf15-knockout and Gdf15-transgenic mice were employed, and mice were fed Amylin liver NASH (AMLN) diet as a physiologically relevant dietary mouse model of NASH associated with metabolic syndrome. GDF15 expression was increased in the livers of mice fed AMLN diet and human subjects with NASH. Elevated expression of GDF15 was due to diet-induced endoplasmic reticulum (ER) stress in the liver. Importantly, Gdf15-knockout mice exhibited deteriorated metabolic syndrome and aggravated NASH phenotypes such as increased steatosis, hepatic inflammation, fibrosis and liver injury. Furthermore, we found that GDF15 directly suppresses expression of fibrosis-related genes and osteopontin (OPN) in the liver in vivo. OPN expression was increased in hepatocytes and stellate cells in the liver of Gdf15-knockout mice. Finally, we found that GDF15-transgenic mice showed attenuated NASH phenotypes and improved glucose tolerance in mice fed AMLN diet. Our results suggest that induction of endogenous GDF15 is a compensatory mechanism to protect against NASH associated with metabolic syndrome and that GDF15 could be an attractive therapeutic candidate for treatment of these diseases. Disclosure M. Lee: Other Relationship; Self; Jeil Pharmaceutical Co. Ltd.. Y. Lee: None. S. Kim: None. K. Kim: None.

The insulin receptor substrate-1 (IRS1) is a critical element in insulin-signaling pathways, and mutations in the IRS1 gene have been reported to have a role in determining susceptibility to traits related to type 2 diabetes. In gene expression studies of tissue biopsies from nondiabetic Pima Indians, IRS1 mRNA levels were reduced in adipocytes from obese subjects compared with lean subjects, and IRS1 mRNA levels were also reduced in skeletal muscle from insulin-resistant subjects compared with insulin-sensitive subjects (all P < 0.05). Based on these expression differences and the known physiologic role of IRS1, this gene was investigated as a candidate gene for susceptibility to type 2 diabetes in Pima Indians, a population with an extremely high incidence and prevalence of type 2 diabetes. Thirteen variants were identified, and among these variants, several were in complete linkage disequilibrium. Four genotypically unique variants were further genotyped in 937 DNA samples from full-heritage Pima Indians. Three of the variants were modestly associated with type 2 diabetes (P < 0.05), one of which was additionally associated with 2-h plasma insulin and glucose as well as insulin action at physiologic and maximally stimulating insulin concentrations (all P < 0.05). The association of variants in IRS1 with type 2 diabetes and type 2 diabetes-related phenotypes and the differential expression of IRS1 in adipocytes and skeletal muscle suggest a role of this gene in the pathogenesis of type 2 diabetes in Pima Indians.