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Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor’s glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects. SGLT2 inhibitors, a class of type 2 diabetes medication, reduce cardiovascular events in patients beyond expectation from blood sugar control. Here the authors report a randomized controlled trial showing that SGLT2 inhibitors reduce inflammasome activation in peripheral macrophages, which may contribute to the cardiovascular protection.

Nonalcoholic fatty liver disease (NAFLD) and sarcopenia have a close association with an increased risk of atherosclerotic cardiovascular disease (ASCVD). This study investigated the influence of NAFLD and sarcopenia on ASCVD risk. Data from the 2008-2011 Korean National Health and Nutrition Examination Surveys database were analyzed (n = 7,191). The sarcopenia index was calculated using dual-energy x-ray absorptiometry. Sarcopenia was defined as the lowest quintile sarcopenia index value (cutoffs = 0.882 for men and 0.582 for women). NAFLD was defined as a comprehensive NAFLD score ≥40. Liver fibrosis was assessed using the fibrosis-4 (FIB-4) index. ASCVD risk was evaluated using American College of Cardiology/American Heart Association guidelines. High probability of ASCVD was defined as ASCVD risk >10%. The prevalence rates of NAFLD and sarcopenia were 31.2% (n = 2,241) and 19.5% (n = 1,400), respectively. The quartile-stratified ASCVD risk scores were positively associated with NAFLD and sarcopenia (all P for trend < 0.001). Subjects with both NAFLD and sarcopenia had a higher risk for high probability of ASCVD (odds ratio = 1.83, P = 0.014) compared with controls without NAFLD and sarcopenia. Among subjects with NAFLD, FIB-4-defined significant liver fibrosis and sarcopenia additively raised the risk for high probability of ASCVD (odds ratio = 3.56, P < 0.001) compared with controls without FIB-4-defined significant liver fibrosis or sarcopenia. NAFLD and sarcopenia were significantly associated with an increased risk of ASCVD in the general population. In addition, NAFLD with significant liver fibrosis and sarcopenia were significantly associated with an increased risk of ASCVD in subjects with NAFLD.

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

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

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and β-cell dysfunction. Among available oral antidiabetic agents, only the thiazolidinediones (TZDs) primarily target insulin resistance. TZDs improve insulin sensitivity by activating peroxisome proliferator-activated receptor γ. Rosiglitazone and pioglitazone have been used widely for T2DM treatment due to their potent glycemic efficacy and low risk of hypoglycemia. However, their use has decreased because of side effects and safety issues, such as cardiovascular concerns and bladder cancer. Lobeglitazone (Chong Kun Dang Pharmaceutical Corporation), a novel TZD, was developed to meet the demands for an effective and safe TZD. Lobeglitazone shows similar glycemic efficacy to pioglitazone, with a lower effective dose, and favorable safety results. It also showed pleiotropic effects in preclinical and clinical studies. In this article, we summarize the pharmacologic, pharmacokinetic, and clinical characteristics of lobeglitazone.

Abstract Context The risk for dementia among subjects who are obese with normal metabolic profiles, or called metabolically healthy obese (MHO), remains uninvestigated. Objective To determine the association between late-life metabolic health and obesity status and risk of incident dementia. Design Retrospective cohort study. Setting The National Health Insurance System, Republic of Korea. Patients A total of 12,296,863 adults >50 years old who underwent health examinations from 2009 to 2012 without baseline history of dementia. Main Outcome Measure Incident overall dementia, Alzheimer’s disease (AD), and vascular dementia (VaD). Results Among subjects ≥60 years old, 363,932 (6.4%) developed dementia during a median follow-up of 65 months (interquartile range 51 to 74 months). The MHO group showed the lowest incidence of overall dementia [hazard ratio (HR) 0.85; 95% CI, 0.84 to 0.86] and AD (HR 0.87; 95% CI, 0.86 to 0.88), but not VaD, compared with the metabolically healthy nonobese group. All components of metabolic syndrome except obesity significantly elevated the risk of dementia, and these associations were more pronounced in VaD. In particular, being underweight dramatically increased the risk of dementia. Conclusions The MHO phenotype in late life demonstrated lower risk of overall dementia and AD but not VaD. Additional studies in other populations are warranted to elucidate current results and may predict individuals most at risk for developing dementia. This large, population-based study analyzed 5,669,488 adults >60 years old and found that the metabolically healthy obese phenotype in late life is associated with lower risk of overall dementia.

Background: This study aimed to investigate the prevalence, management, and comorbidities of diabetes mellitus among Korean adults.Methods: Data from the Korea National Health and Nutrition Examination Survey (2019–2022) were analyzed to assess the prevalence, treatment, risk factors, and comorbidities of diabetes. Comparisons between young and older adults with diabetes were emphasized.Results: Among Korean adults aged ≥30 years, the prevalence of diabetes is 15.5% during 2021–2022. Of these, 74.7% were aware of their condition, 70.9% received antidiabetic treatment, and only 32.4% achieved glycosylated hemoglobin (HbA1c) <6.5%. Moreover, 15.9% met the integrated management targets, which included HbA1c <6.5%, blood pressure <140/85 mm Hg, and low-density lipoprotein cholesterol <100 mg/dL. In young adults aged 19 to 39 years, the prevalence of diabetes was 2.2%. Among them, 43.3% were aware of their condition, 34.6% received treatment, and 29.6% achieved HbA1c <6.5%. Obesity affected 87.1%, and 26.9% had both hypertension and hypercholesterolemia. Among adults aged ≥65 years, the prevalence of diabetes was 29.3%, with awareness, treatment, and control rates of 78.8%, 75.7%, and 31.2%, respectively. Integrated management targets (HbA1c <7.5%, hypertension, and lipids) were achieved by 40.1%.Conclusion: Diabetes mellitus remains highly prevalent among Korean adults, with significant gaps in integrated glycemic, blood pressure, and lipid control. Older adults with diabetes show higher awareness and treatment rates but limited integrated management outcomes. Young adults with diabetes bear a significant burden of obesity and comorbidities, alongside low awareness and treatment rates. Therefore, early intervention programs, education, and strategies tailored to younger populations are urgently required.

Metformin is known to alleviate hepatosteatosis by inducing 5’ adenosine monophosphate (AMP)-kinase-independent, sirtuin 1 (SIRT1)-mediated autophagy. Dysfunctional mitophagy in response to glucolipotoxicities might play an important role in hepatosteatosis. Here, we investigated the mechanism by which metformin induces mitophagy through restoration of the suppressed Parkin-mediated mitophagy. To this end, our ob/ob mice were divided into three groups: (1) ad libitum feeding of a standard chow diet; (2) intraperitoneal injections of metformin 300 mg/kg; and (3) 3 g/day caloric restriction (CR). HepG2 cells were treated with palmitate (PA) plus high glucose in the absence or presence of metformin. We detected enhanced mitophagy in ob/ob mice treated with metformin or CR, whereas mitochondrial spheroids were observed in mice fed ad libitum. Metabolically stressed ob/ob mice and PA-treated HepG2 cells showed an increase in expression of endoplasmic reticulum (ER) stress markers and cytosolic p53. Cytosolic p53 inhibited mitophagy by disturbing the mitochondrial translocation of Parkin, as demonstrated by immunoprecipitation. However, metformin decreased ER stress and p53 expression, resulting in induction of Parkin-mediated mitophagy. Furthermore, pifithrin-α, a specific inhibitor of p53, increased mitochondrial incorporation into autophagosomes. Taken together, these results indicate that metformin treatment facilitates Parkin-mediated mitophagy rather than mitochondrial spheroid formation by decreasing the inhibitory interaction with cytosolic p53 and increasing degradation of mitofusins.

Betatrophin/angiopoietin-like protein 8 (ANGPTL8) is a liver-secreted protein recently identified as a potent stimulator of beta cell proliferation in mice. However, it is unclear how betatrophin is regulated in humans with non-alcoholic fatty liver disease (NAFLD). We investigated the role of betatrophin in mice and in humans with and without NAFLD. Serum betatrophin levels were examined by ELISA in 164 subjects, including 96 patients with NAFLD. Levels were significantly elevated in subjects with NAFLD compared with controls (1.301 ± 0.617 vs. 0.900 ± 0.574 μg/L, P < 0.001), even after stratification by diabetic or obesity status. Circulating betatrophin positively correlated with obesity or glycemic indices, liver enzyme profiles, and NAFLD status, and was confirmed by multivariate regression analyses (β = 0.195, P = 0.040). However, when including insulin resistance index in the model, the significant association between betatrophin level and NAFLD was diminished due to a mediation effect of insulin resistance on this relationship. Palmitate or tunicamycin increased betatrophin expression in HepG2 cells, while a chemical chaperone blocked its induction. Hepatic expression of betatrophin was elevated in mice with NAFLD including db/db or ob/ob mice and mice with a high-fat or methionine-choline deficient diet. In conclusion, circulating betatrophin was increased in mice and humans with NAFLD and its expression was induced by endoplasmic reticulum stress in hepatocytes (Clinical trial no. NCT02285218).

Background The close interplay between metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes supports the need to identify beneficial combination therapies of antidiabetic medications targeted for the treatment of MASLD. This study aimed to investigate the complementary effects of combination therapy with pioglitazone (PIO) and empagliflozin (EMPA) on MASLD in individuals with type 2 diabetes. Methods In a randomized, open-label trial, 50 participants with type 2 diabetes and MASLD were assigned 1:1:1 to receive PIO 15 mg, EMPA 10 mg, or a combination (PIO 15 mg plus EMPA 10 mg) daily for 24 weeks. Liver fat fraction and stiffness were evaluated using magnetic resonance imaging-proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE), respectively. Results Combination therapy resulted in the largest reduction in liver fat and stiffness among treatment groups. Participants experiencing a relative reduction ≥ 30% or an absolute reduction ≥ 5% in liver fat were the most prevalent in the combination group (100.0% vs. 57.1% in PIO and 87.5% in EMPA, p  = 0.010). In addition, the combination group showed the highest proportion of individuals with a relative reduction ≥ 30% in liver fat and ≥ 20% in liver stiffness than the monotherapy groups (50.0% vs. 21.4% in PIO and 6.3% in EMPA, p  = 0.029). Combination therapy did not induce the changes in subcutaneous fat deposition observed in the monotherapy groups, but it did show the most substantial reduction in visceral fat, concurrently showing the largest increase in adiponectin level across the three groups ( p  = 0.036). Conclusions Combination therapy of PIO with EMPA showed synergistic benefits for MASLD in individuals with type 2 diabetes, compensating for the inadequate or unfavorable effects of monotherapies; ClincialTrials.gov number, NCT03646292. Trial registration The trial was registered at ClinicalTrials.gov (registration number: NCT03646292).