Pioglitazone as Add-on THERAPY in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Dapagliflozin and Metformin: Double-Blind, Randomized, Placebo-Controlled Trial.

Background: This study assessed the efficacy and safety of triple therapy with pioglitazone 15 mg add-on versus placebo in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and dapagliflozin. Methods: In this multicenter, double-blind, randomized, phase 3 study, patients with T2DM with an inadequate response to treatment with metformin (≥1,000 mg/day) plus dapagliflozin (10 mg/day) were randomized to receive additional pioglitazone 15 mg/day (n=125) or placebo (n=125) for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin (HbA1c) levels from baseline to week 24 (ClinicalTrials.gov identifier: NCT05101135). Results: At week 24, the adjusted mean change from baseline in HbA1c level compared with placebo was significantly greater with pioglitazone treatment (-0.47%; 95% confidence interval, -0.61 to -0.33; P<0.0001). A greater proportion of patients achieved HbA1c <7% or <6.5% at week 24 with pioglitazone compared to placebo as add-on to 10 mg dapagliflozin and metformin (56.8% vs. 28% for HbA1c <7%, and 23.2% vs. 9.6% for HbA1c <6.5%; P<0.0001 for all). The addition of pioglitazone also significantly improved triglyceride, highdensity lipoprotein cholesterol levels, and homeostatic model assessment of insulin resistance levels, while placebo did not. The incidence of treatment-emergent adverse events was similar between the groups, and the incidence of fluid retention-related side effects by pioglitazone was low (1.5%). Conclusion: Triple therapy with the addition of 15 mg/day of pioglitazone to dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA1c in patients with T2DM inadequately controlled with dapagliflozin plus metformin.

Mortality in metabolic dysfunction-associated steatotic liver disease: A nationwide population-based cohort study.

BACKGROUND: A new fatty liver disease nomenclature, steatotic liver disease (SLD) has been proposed; however, there are no data on clinical outcomes. We investigated the impact of SLD with metabolic dysfunction (MD; SLD-MD) on all-cause mortality. METHODS: We evaluated nationally representative participants aged ≥19 years using data from the Korea National Health and Nutrition Examination Survey 2007-2015 and their linked death data through 2019. The presence of fatty liver disease was assessed by liver fat score, fatty liver index and significant liver fibrosis was evaluated by the Fibrosis-4 Index, and fibrosis score. SLD-MD was categorized into three groups: metabolic dysfunction-associated steatotic liver disease (MASLD); metabolic alcoholic liver disease (MetALD); and SLD with other combination etiologies. RESULTS: Among 26734 individuals (11561 men and 15173 women, mean age 48.8 years), 1833 (6.9 %) died during a mean follow-up period of 110.6 ± 33.9 months. Mortality risk was significantly higher in individuals with SLD-MD (hazard ratio [HR] = 1.35) than in those without (P < 0.001). Among the three groups, MASLD (HR = 1.32) and SLD with other combination etiologies (HR = 2.06) independently increased mortality risk (all P < 0.001). When individuals with SLD-MD had significant liver fibrosis or diabetes, mortality risk increased further (HR = 1.68 and 1.85, respectively; all P < 0.001). SLD-MD with both significant liver fibrosis and diabetes showed the highest mortality risk (HR = 2.29, P < 0.001). When applied fatty liver index and fibrosis score, similar results were observed. CONCLUSIONS: SLD-MD is associated with a higher mortality risk. When SLD-MD was combined with significant liver fibrosis or diabetes, the mortality risk became much higher. Treatment strategies to reduce fibrotic burden and improve glycemic control in individuals with MASLD are needed.

Appendicular Skeletal Muscle Mass to Visceral Fat Area Ratio Predicts Hepatic Morbidities.

Background/Aims: : Reports on the association between sarcopenic visceral obesity and non-alcoholic fatty liver disease (NAFLD)-associated morbidities remain scarce. We investigated the association between sarcopenia and visceral obesity, and the influence of this association on hepatic and coronary comorbidities. Methods: : The appendicular skeletal muscle mass to visceral fat area ratio (SV ratio) was evaluated using bioelectric impedance analysis. NAFLD and significant liver fibrosis were assessed using transient elastography, and high atherosclerotic cardiovascular disease (ASCVD) risk was defined as a 10-year ASCVD risk score >10%. Sarcopenia was defined as appendicular skeletal muscle mass adjusted by body mass index (<0.789 for men and <0.512 for women). Results: : In total, 82.0% (n=1,205) of the entire study population had NAFLD, and 14.6% of these individuals (n=176) exhibited significant liver fibrosis. Individuals with the lowest SV ratio had a significantly increased risk of NAFLD, significant liver fibrosis, and high ASCVD risk (all p<0.05). Individuals with both the lowest SV ratio and sarcopenia had the highest risk of developing NAFLD (odds ratio [OR]=3.11), significant liver fibrosis (OR=2.03), and high ASCVD risk (OR=4.15), compared with those with a higher SV ratio and without sarcopenia (all p<0.05). Conclusions: : Low SV ratio combined with sarcopenia was significantly associated with an increased risk of NAFLD, significant liver fibrosis, and high ASCVD risk among individuals with a high risk of NAFLD.

Increased expression of sodium-glucose cotransporter 2 and O-GlcNAcylation in hepatocytes drives non-alcoholic steatohepatitis.

AIMS: Steatosis reducing effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in non-alcoholic steatohepatitis (NASH) has been consistently reported in humans, but their mechanism remains uncertain. In this study, we examined the expression of SGLT2 in human livers and investigated the crosstalk between SGLT2 inhibition and hepatic glucose uptake, intracellular O-GlcNAcylation, and autophagic regulation in NASH. MATERIALS AND METHODS: Human liver samples obtained from subjects with/without NASH were analyzed. For in vitro studies, human normal hepatocytes and hepatoma cells were treated with SGLT2 inhibitor under high-glucose and high-lipid conditions. NASH in vivo was induced by a high-fat, -fructose, and -cholesterol Amylin liver NASH (AMLN) diet for 10 weeks followed by an additional 10 weeks with/without SGLT2 inhibitor (empagliflozin 10 mg/kg/day). RESULTS: Liver samples from subjects with NASH were associated with increased SGLT2 and O-GlcNAcylation expression compared with controls. Under NASH condition (in vitro condition with high glucose and lipid), intracellular O-GlcNAcylation and inflammatory markers were increased in hepatocytes and SGLT2 expression was upregulated; SGLT2 inhibitor treatment blocked these changes by directly reducing hepatocellular glucose uptake. In addition, decreased intracellular O-GlcNAcylation by SGLT2 inhibitor promoted autophagic flux through AMPK-TFEB activation. In the AMLN diet-induced NASH mice model, SGLT2 inhibitor alleviated lipid accumulation, inflammation, and fibrosis through autophagy activation related to decreased SGLT2 expression and O-GlcNAcylation in the liver. CONCLUSIONS: This study firstly demonstrates increased SGLT2 expression in NASH and secondly reveals the novel effect of SGLT2 inhibition on NASH through autophagy activation mediated by inhibition of hepatocellular glucose uptake and consequently decreased intracellular O-GlcNAcylation.

MAFLD might be better in identifying subjects with sarcopenia or cardiovascular risk than NAFLD: A nationwide study.

BACKGROUND AND AIM: Clinical features of non-alcoholic fatty liver disease (NAFLD), but not fulfilling the diagnostic criteria of metabolic dysfunction-associated fatty liver disease (MAFLD), remain unclear. We investigated the risk of sarcopenia and cardiovascular disease (CVD) in MAFLD and non-metabolic risk (MR) NAFLD. METHODS: Subjects were selected from the Korean National Health and Nutrition Examination Surveys 2008-2011. Liver steatosis was assessed using fatty liver index. Significant liver fibrosis was defined using fibrosis-4 index, categorized by age cut-offs. Sarcopenia was defined as the lowest quintile sarcopenia index. Atherosclerotic CVD (ASCVD) risk score > 10% was defined as high probability. RESULTS: A total of 7248 subjects had fatty liver (137 with non-MR NAFLD, 1752 with MAFLD/non-NAFLD, and 5359 with overlapping MAFLD and NAFLD). In non-MR NAFLD group 28 (20.4%) had significant fibrosis. The risk of sarcopenia (adjusted odds ratio [aOR] = 2.71, 95% confidence index [CI] = 1.27-5.78) and high probability of ASCVD (aOR = 2.79, 95% CI = 1.23-6.35) was significantly higher in MAFLD/non-NAFLD group than in non-MR NAFLD group (all P < 0.05). The risk of sarcopenia and high probability of ASCVD was similar between subjects with and without significant fibrosis in non-MR NAFLD group (all P > 0.05). However, the risk was significantly higher in MAFLD group than in non-MR NAFLD group (aOR = 3.38 for sarcopenia and 3.73 for ASCVD; all P < 0.05). CONCLUSIONS: The risks of sarcopenia and CVD were significantly higher in MAFLD group but did not differ according to fibrotic burden in non-MR NAFLD group. The MAFLD criteria might be better for identifying high-risk fatty liver disease than the NAFLD criteria.

The effects of long-term cumulative HbA1c exposure on the development and onset time of dementia in the patients with type 2 diabetes mellitus: Hospital based retrospective study (2005-2021).

AIMS: We examined cumulative effects of long-term glycemic exposure in patients with type 2 diabetes mellitus (T2DM) on the development of dementia. METHODS: The study involved 20,487 records of patients with T2DM identified in the electronic medical record at Severance Hospital, Korea. Cumulative HbA1c (AUCHbA1c) and mean HbA1c over time (HbA1cavg) as measures of long-term glycemic exposure were compared for the development of dementia and the time to dementia. RESULTS: AUCHbA1c and HbA1cavg were significantly higher in patients who later developed dementia than in those who did not (AUCHbA1c: 56.2 ± 26.4 vs. 52.1 ± 26.1 %Year; HbA1cavg: 7.3 ± 1.0 vs. 7.0 ± 1.0%). Odds ratio of dementia increased when HbA1cavg was 7.2% (55 mmol/mol) or above, and when AUCHbA1c was 42 %Year (e.g., HbA1c 7.0% maintained for 6 years) or above. Among those who developed dementia, as HbA1cavg increased, the time to dementia onset decreased (ß = -380.6 days, 95% confidence interval [CI]: -416.2 to -345.0). CONCLUSIONS: Our results indicate poorly controlled T2DM was associated with an increased risk of developing dementia, as measured by AUCHbA1c and HbA1cavg. Higher cumulative glycemic exposure may lead to developing dementia in a shorter time.

Age at Mortality in Patients with Type 2 Diabetes Who Underwent Kidney Transplantation: An Analysis of Data from the Korean National Health Insurance and Statistical Information Service, 2006 to 2018.

BACKGROUND: Although the clinical outcomes of diabetes have improved, diabetes remains the principal cause of end-stage renal disease. The aim of the study is to investigate whether mortality trends in individuals with type 2 diabetes and kidney transplantation (KT) have changed. METHODS: This study analyzed data from the National Health Insurance Service claims database linked to death records from the National Statistical Information Service in Korea. Information from a total of 2521 deaths of KT recipients was collected from 2006 to 2018. RESULTS: The age at death of KT recipients increased from 57.4 years in 2006 to 65.2 years in 2018, with a mean change of +0.65 years/year (p < 0.001). The overall age at death increased by 0.55 and 0.66 years/year in the type 2 diabetes and non-diabetes populations, respectively. The age at death was significantly higher in the type 2 diabetes group, and was maintained during the study period. The proportion of death due to malignancy and cerebrovascular and heart disease was maintained, that due to type 2 diabetes decreased and that due to pneumonia increased. Neither diabetes nor hypertension determined the age at death, and the age at KT was the most prominent factor affecting age at death in KT recipients. CONCLUSIONS: The age at death in KT recipients increased over the 12 years between 2006 and 2018, with similar trends in the type 2 diabetes and non-diabetes groups. The age at KT was higher in patients with type 2 diabetes, and was the main contributor to the age at death in KT recipients.

Impaired ketogenesis is associated with metabolic-associated fatty liver disease in subjects with type 2 diabetes.

Aims: The ketogenic pathway is an effective mechanism by which the liver disposes of fatty acids (FAs) to the peripheral tissues. Impaired ketogenesis is presumed to be related to the pathogenesis of metabolic-associated fatty liver disease (MAFLD), but the results of previous studies have been controversial. Therefore, we investigated the association between ketogenic capacity and MAFLD in subjects with type 2 diabetes (T2D). Methods: A total of 435 subjects with newly diagnosed T2D was recruited for the study. They were classified into two groups based on median serum ß-hydroxybutyrate (ß-HB) level: intact vs. impaired ketogenesis groups. The associations of baseline serum ß-HB and MAFLD indices of hepatic steatosis index, NAFLD liver fat score (NLFS), Framingham Steatosis index (FSI), Zhejian University index, and Chinese NAFLD score were investigated. Results: Compared to the impaired ketogenesis group, the intact ketogenesis group showed better insulin sensitivity, lower serum triglyceride level, and higher low-density lipoprotein-cholesterol and glycated hemoglobin levels. Serum levels of liver enzymes were not different between the two groups. Of the hepatic steatosis indices, NLFS (0.8 vs. 0.9, p=0.045) and FSI (39.4 vs. 47.0: p=0.041) were significantly lower in the intact ketogenesis group. Moreover, intact ketogenesis was significantly associated with lower risk of MAFLD as calculated by FSI after adjusting for potential confounders (adjusted odds ratio 0.48, 95% confidence interval 0.25-0.91, p=0.025). Conclusions: Our study suggests that intact ketogenesis might be associated with decreased risk of MAFLD in T2D.

ß-hydroxybutyrate as a biomarker of ß-cell function in new-onset type 2 diabetes and its association with treatment response at 6 months.

AIMS: Increasing attention has been paid to the potential metabolic benefits of ketone bodies, but the clinical relevance of ketone bodies in newly diagnosed type 2 diabetes mellitus (T2D) remains unclear. We investigated the clinical implications of ketone bodies at the time of diagnosis in patients with drug-naïve T2D. METHODS: Clinical data including serum ß-hydroxybutyrate (ßHB) levels, were collected from 369 patients with newly diagnosed drug-naïve T2D from 2017 to 2021. Subjects were categorized into four ßHB groups based on the level of initial serum ßHB. The associations of initial serum ßHB and urinary ketone levels with glucometabolic indices were analyzed. RESULTS: Higher serum ßHB group was associated with higher levels of glycemic parameters including glycated hemoglobin (HbA1c) with lower levels of indices for insulin secretory function at the point of initial diagnosis of T2D. Nevertheless, higher serum ßHB group was an independent determinant of a greater relative improvement in HbA1c after 6 months of anti-diabetic treatment, regardless of the type of anti-diabetic drug. In addition, patients in higher serum ßHB group were more likely to have well-controlled HbA1c levels (≤6.5%) after 6 months of anti-diabetic treatment. CONCLUSION: In patients with newly diagnosed T2D, a higher initial ßHB level was a significant predictive marker of greater glycemic improvement after antidiabetic treatment, despite its associations with hyperglycemia and decreased insulin secretion at baseline.

Intact ketogenesis predicted reduced risk of moderate-severe metabolic-associated fatty liver disease assessed by liver transient elastography in newly diagnosed type 2 diabetes.

Aim: Hepatic ketogenesis is a key metabolic pathway that regulates energy homeostasis. Some related controversies exist regarding the pathogenesis of metabolic-associated fatty liver disease (MAFLD). We aimed to investigate whether intact ketogenic capacity could reduce the risk of MAFLD based on transient electrography (TE) in patients with newly diagnosed type 2 diabetes (T2D). Methods: A total of 361 subjects with newly diagnosed T2D were recruited and classified into two groups based on the median serum ß-hydroxybutyrate (ßHB) level, referred to as the intact and impaired ketogenesis groups. The glucometabolic relevance of ketogenic capacity and associations of the baseline serum ß-HB and MAFLD assessed with TE were investigated. Results: Compared to the impaired ketogenesis group, the intact ketogenesis group showed better insulin sensitivity, lower serum triglyceride levels, and higher glycated hemoglobin levels. The controlled attenuation parameter (CAP) was lower in the intact ketogenesis group without statistical significance (289.7 ± 52.1 vs. 294.5 ± 43.6; p=0.342) but the prevalence of moderate-severe steatosis defined by CAP ≥260 dB/m was significantly lower in the intact group. Moreover, intact ketogenesis was significantly associated with a lower risk of moderate-severe MAFLD after adjusting for potential confounders (adjusted odds ratio 0.55, 95% confidence interval 0.30-0.98; p=0.044). Conclusion: In drug-naïve, newly diagnosed T2D patients, intact ketogenesis predicted a lower risk of moderate-severe MAFLD assessed by TE.

Protective Effect of Delta-Like 1 Homolog Against Muscular Atrophy in a Mouse Model.

BACKGRUOUND: Muscle atrophy is caused by an imbalance between muscle growth and wasting. Delta-like 1 homolog (DLK1), a protein that modulates adipogenesis and muscle development, is a crucial regulator of myogenic programming. Thus, we investigated the effect of exogenous DLK1 on muscular atrophy. METHODS: We used muscular atrophy mouse model induced by dexamethasone (Dex). The mice were randomly divided into three groups: (1) control group, (2) Dex-induced muscle atrophy group, and (3) Dex-induced muscle atrophy group treated with DLK1. The effects of DLK1 were also investigated in an in vitro model using C2C12 myotubes. RESULTS: Dex-induced muscular atrophy in mice was associated with increased expression of muscle atrophy markers and decreased expression of muscle differentiation markers, while DLK1 treatment attenuated these degenerative changes together with reduced expression of the muscle growth inhibitor, myostatin. In addition, electron microscopy revealed that DLK1 treatment improved mitochondrial dynamics in the Dex-induced atrophy model. In the in vitro model of muscle atrophy, normalized expression of muscle differentiation markers by DLK1 treatment was mitigated by myostatin knockdown, implying that DLK1 attenuates muscle atrophy through the myostatin pathway. CONCLUSION: DLK1 treatment inhibited muscular atrophy by suppressing myostatin-driven signaling and improving mitochondrial biogenesis. Thus, DLK1 might be a promising candidate to treat sarcopenia, characterized by muscle atrophy and degeneration.

Effects of a Phosphodiesterase inhibitor on the Browning of Adipose Tissue in Mice.

Cilostazol is a selective inhibitor of phosphodiesterase type 3 (PDE3) that increases intracellular cyclic adenosine monophosphate (cAMP), which plays a critical role in the development of the beige phenotype and the activation of its thermogenic program in white adipose tissue (WAT). We investigated the metabolic effects of PDE3B inhibition with cilostazol treatment in the adipose tissue of high-fat diet (HFD)-fed mice. Seven-week-old male C57BL/6J mice were randomly assigned to either the cilostazol or control group. The control group was divided into two groups: the chow diet and HFD. The expression of uncoupling Protein 1 (UCP1) and other brown adipocyte markers was compared. In the HFD-fed cilostazol group, C57BL/6J mice displayed improvements in systemic metabolism, including improved glucose tolerance and lipid profile, but only modest effects on body weight were observed. In the visceral WAT of HFD-fed cilostazol-treated mice, cAMP/protein kinase A (PKA) signaling pathways were activated, resulting in the "browning" phenotype, smaller fat deposits, and enhanced mRNA expression of UCP1 and other brown adipocyte markers. PDE3B appears to be an important regulator of lipid metabolism, insulin sensitivity, and thermogenic programs in adipose tissues. An increase in intracellular cAMP via PDE3B inhibition with cilostazol treatment promoted the browning of visceral WAT.

The effects of the voglibose on non-alcoholic fatty liver disease in mice model.

The α-glucosidase inhibitor (α-GI) delays the intestinal absorption of glucose, which reduces postprandial hepatic glucose intake. This mechanism is considered to be effective in treating non-alcoholic fatty liver disease (NAFLD). Here, we investigated the effect of voglibose, an α-glucosidase inhibitor, on high-fat, high-fructose (HFHFr) diet-induced NAFLD models. Seven-week-old male C57BL/6J mice were randomly placed in a chow diet group or an HFHFr diet group. After 10 weeks, mice in the HFHFr group were randomly assigned to one of three groups: HFHFr diet with vehicle, HFHFr with voglibose, or HFHFr with pioglitazone. Each diet and treatment was continued for 10 weeks. The HFHFr diet induced severe NAFLD in terms of steatosis, hepatitis, and fibrosis. Administration of voglibose improved all aspects of NAFLD, comparable to those of pioglitazone, a positive control. In voglibose-treated mice, gene expressions of hepatic lipogenesis markers were significantly downregulated. In the in vitro experiment, reducing the influx of glucose into hepatocytes significantly reduced steatosis and de novo lipogenesis even in the presence of sufficient fructose and fat, demonstrating that the mechanism of voglibose could be effective in treating HFHFr diet-induced NAFLD. These results indicate that voglibose improves HFHFr diet-induced NAFLD by suppressing hepatic de novo lipogenesis.

Tolerability and Effectiveness of Switching to Dulaglutide in Patients With Type 2 Diabetes Inadequately Controlled With Insulin Therapy.

Aims: Glucagon-like peptide 1 (GLP-1) receptor agonists have demonstrated strong glycemic control. However, few studies have investigated the effects of switching from insulin to GLP-1 receptor agonists. We aimed to investigate, using real-world data, whether switching to dulaglutide improves glycemic control in patients with type 2 diabetes mellitus (T2D) inadequately controlled with conventional insulin treatment. Materials and methods: We retrospectively evaluated 138 patients with T2D who were switched from insulin to dulaglutide therapy. We excluded 20 patients who dropped out during the follow-up period. The participants were divided into two groups according to whether they resumed insulin treatment at 6 months after switching to a GLP-1 receptor agonist (group I) or not (group II). A multiple logistic regression analysis was performed to evaluate the parameters associated with the risk of resuming insulin after replacement with dulaglutide. Results: Of 118 patients initiated on the GLP-1 receptor agonist, 62 (53%) resumed insulin treatment (group I), and 53 (47%) continued with GLP-1 receptor agonists or switched to oral anti-hypoglycemic agents (group II). Older age, a higher insulin dose, and lower postprandial glucose levels while switching to the GLP-1 receptor agonist were associated with failure to switch to the GLP-1 receptor agonist from insulin. Conclusions: A considerable proportion of patients with T2D inadequately controlled with insulin treatment successfully switched to the GLP-1 receptor agonist. Younger age, a lower dose of insulin, and a higher baseline postprandial glucose level may be significant predictors of successful switching from insulin to GLP-1 receptor agonist therapy.

Improvement in Age at Mortality and Changes in Causes of Death in the Population with Diabetes: An Analysis of Data from the Korean National Health Insurance and Statistical Information Service, 2006 to 2018.

BACKGRUOUND: Diabetes is a leading cause of death that is responsible for 1.6 million annual deaths worldwide. However, the life expectancy and age at death of people with diabetes have been a matter of debate. METHODS: The National Health Insurance Service claims database, merged with death records from the National Statistical Information Service in Korea from 2006 to 2018, was analyzed. RESULTS: In total, 1,432,567 deaths were collected. The overall age at death increased by 0.44 and 0.26 year/year in the diabetes and control populations, respectively. The disparity in the mean age at death between the diabetes and control populations narrowed from 5.2 years in 2006 to 3.0 years in 2018 (p<0.001). In a subgroup analysis according to the presence of comorbid diseases, the number and proportion of deaths remained steady in the group with diabetes only, but steadily increased in the groups with diabetes combined with dyslipidemia and/or hypertension. Compared to the control population, the increase in the mean death age was higher in the population with diabetes. This trend was more prominent in the groups with dyslipidemia and/or hypertension than in the diabetes only group. Deaths from vascular disease and diabetes decreased, whereas deaths from cancer and pneumonia increased. The decline in the proportion of deaths from vascular disease was greater in the diabetes groups with hypertension and/or dyslipidemia than in the control population. CONCLUSION: The age at death in the population with diabetes increased more steeply and reached a comparable level to those without diabetes.

Short Term Isocaloric Ketogenic Diet Modulates NLRP3 Inflammasome Via B-hydroxybutyrate and Fibroblast Growth Factor 21.

A ketogenic diet (KD) is known to have beneficial health effects. Various types of KD interventions have been applied to manage metabolic syndrome based on modification of diet parameters such as duration of intervention, macronutrient components, and total calories. Nevertheless, the beneficial health impact of isocaloric KD is largely unknown, especially in healthy subjects. The present study investigated the acute effects of a 3-day isocaloric KD. In this non-randomized intervention study, we recruited 15 healthy volunteers aged 24-38 years (7 men and 8 women) and placed them on an isocaloric KD restricting intake of carbohydrates but not energy (75% fat, 20% protein, 5% carbohydrate) for 3 days. Biochemical profiles and laboratory measurements were performed. Peripheral blood monocular cells were cultured, and measured cell stimulated cytokines. After short-term isocaloric KD, subjects lost body weight and serum free fatty acid levels were increased. These results accompanied elevated serum ß-hydroxybutyrate (BHB) concentration and fibroblast growth factor 21 (FGF21) levels and improved insulin sensitivity. Regarding the direct effect of BHB on inflammasome activation, interleukin-1ß (IL-1ß) and tumor necrosis factor-α secretion in response to adenosine triphosphate or palmitate stimulation in human macrophages decreased significantly after isocaloric KD. In ex-vivo experiments with macrophages, both FGF21 and BHB further reduced IL-1ß secretion compared to either BHB or FGF21 alone. The inhibitory effect of FGF21 on IL-1ß secretion was blunted with bafilomycin treatment, which blocked autophagy flux. In conclusion, isocaloric KD for 3 days is a promising approach to improve metabolic and inflammatory status. Clinical Trial Registration: clinicaltrials.gov (NCT02964572).

Sodium Glucose Cotransporter-2 Inhibitors as an Add-on Therapy to Metformin Plus Dipeptidyl Peptidase-4 Inhibitor in Patients with Type 2 Diabetes.

PURPOSE: To date, no study has compared the effects of adding sodium glucose cotransporter-2 (SGLT-2) inhibitors to the combination of metformin plus dipeptidyl peptidase-4 (DPP-4) inhibitors to the effects of adding other conventional anti-diabetic drugs (ADDs) to the dual therapy. We aimed to compare the effect of adding SGLT-2 inhibitors with that of adding sulfonylurea (SU) in type 2 diabetes (T2D) patients inadequately controlled with metformin plus DPP-4 inhibitors. MATERIALS AND METHODS: This study was designed to evaluate the non-inferiority of SGLT-2 inhibitor to SU as an add-on therapy to the dual combination of metformin plus DPP-4 inhibitors. A total of 292 T2D patients who started SU or SGLT-2 inhibitors as an add-on therapy to metformin plus DPP-4 inhibitors due to uncontrolled hyperglycemia, defined as glycated hemoglobin (HbA1c) ≥7%, were recruited. After propensity score matching, 90 pairs of patients remained, and 12-week changes in HbA1c levels were reviewed to assess glycemic effectiveness. Data from these patients were analyzed retrospectively. RESULTS: After 12 weeks of triple therapy, both groups showed significant changes in HbA1c levels, with a mean of -0.9% in each group. The inter-group difference was 0.01% [95% confidence interval (CI): -0.26-0.27], and the upper limit of the 95% CI was within the limit for non-inferiority (0.40%). There were no inter-group differences in the changes of liver enzyme levels and kidney function. CONCLUSION: Adding SGLT-2 inhibitors is not inferior to adding SU as a third-line ADD to metformin plus DPP-4 inhibitor combination therapy.

Obesity is an important determinant of severity in newly defined metabolic dysfunction-associated fatty liver disease.

BACKGROUND: The recently proposed definition of metabolic dysfunction-associated fatty liver disease (MAFLD) is based on the co-existence of hepatic steatosis with other metabolic disorders, including obesity and metabolic risk abnormalities such as hyperglycemia, high blood pressure and dyslipidemia. This study aimed to assess MAFLD severity according to the presence of metabolic abnormalities and obesity. METHODS: Using transient elastography, hepatic steatosis and fibrosis severity were assessed by measuring the controlled attenuation parameter and liver stiffness measurement. A total of 1163 patients with MAFLD were categorized into the following four groups according to metabolic risk abnormalities and obesity presence: non-obese without metabolic risk abnormality group (Group 1; reference group); non-obese with metabolic risk abnormality group (Group 2); obese without metabolic risk abnormality group (Group 3); and obese with metabolic risk abnormality group (Group 4). A multiple logistic regression analysis was performed to determine severe hepatic steatosis and fibrosis risk in each group in both unadjusted and adjusted models. RESULTS: In the adjusted model, the odds ratios (ORs) [95% confidence interval (CI)] for severe hepatic steatosis in Groups 2, 3, and 4 were 1.07 (0.61-1.88), 2.43 (1.44-4.08), and 4.07 (2.56-6.48), respectively (Ptrend < 0.001). For liver fibrosis, compared with Group 1, Group 2 showed no significant increases in OR, whereas Groups 3 and 4 (obese groups) showed significant increases (OR = 4.70, 95% CI: 1.24-17.82 and OR = 6.43, 95% CI: 1.88-22.02, respectively). CONCLUSIONS: Obesity, rather than metabolic abnormality, is the principal determinant of severe hepatic steatosis and fibrosis in patients with MAFLD.

Fibrotic Burden Determines Cardiovascular Risk among Subjects with Metabolic Dysfunction-Associated Fatty Liver Disease.

Background/Aims: Metabolic dysfunction associated fatty liver disease (MAFLD) has recently been introduced to compensate for the conventional concept of nonalcoholic fatty liver disease (NAFLD). We explored whether fibrotic burden determines the risk of atherosclerotic cardiovascular disease (ASCVD) among subjects with MAFLD. Methods: We recruited 9,444 participants from the Korea National Health and Nutrition Examination Survey (2008 to 2011). Liver fibrosis was identified using the fibrosis-4 (FIB-4) index and NAFLD fibrosis score. The 10-year ASCVD risk score (>10%) was used to determine a high probability ASCVD risk. For sensitivity analysis, propensity score matching was assessed to subjects with aged 40 to 75 years free from ASCVD. Results: The prevalence of MAFLD was 38.0% (n=3,592). The ASCVD risk scores stratified in quartile were positively correlated to MAFLD and FIB-4 defined-significant liver fibrosis (p for trend <0.001). Individuals with both MAFLD and FIB-4 defined-significant liver fibrosis had a greater chance of high probability ASCVD risk (odds ratio [OR]=2.40; p<0.001) than those without MAFLD. The impact of MAFLD on high probability ASCVD risk was greater than that of significant liver fibrosis (OR=4.72 for MAFLD vs OR=1.88 for FIB-4 defined-significant liver fibrosis; all p<0.001). Among participants with MAFLD, low muscle mass enhanced the risk of significant liver fibrosis (OR=1.56 to 2.43; p<0.001). When NAFLD fibrosis score was applied to define significant liver fibrosis, similar findings were observed. Conclusions: Individuals with MAFLD had a substantial ASCVD risk compared to those without MAFLD. Accompanying significant liver fibrosis further enhanced the risk of ASCVD among subjects with MAFLD.