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Background and Purpose: Nonalcoholic fatty liver disease refers to liver pathologies, ranging from steatosis to steatohepatitis, with fibrosis ultimately leading to cirrhosis and hepatocellular carcinoma. Although several mechanisms have been suggested, including insulin resistance, oxidative stress, and inflammation, its pathophysiology remains imperfectly understood. Over the last decade, a dysfunctional unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress emerged as one of the multiple driving factors. In parallel, growing evidence suggests that insulin-degrading enzyme (IDE), a highly conserved and ubiquitously expressed metallo-endopeptidase originally discovered for its role in insulin decay, may regulate ER stress and UPR., Experimental Approach: We investigated, by genetic and pharmacological approaches, in vitro and in vivo, whether IDE modulates ER stress-induced UPR and lipid accumulation in the liver., Key Results: We found that IDE-deficient mice display higher hepatic triglyceride content along with higher inositol-requiring enzyme 1 (IRE1) pathway activation. Upon induction of ER stress by tunicamycin or palmitate in vitro or in vivo, pharmacological inhibition of IDE, using its inhibitor BDM44768, mainly exacerbated ER stress-induced IRE1 activation and promoted lipid accumulation in hepatocytes, effects that were abolished by the IRE1 inhibitors 4μ8c and KIRA6. Finally, we identified that IDE knockout promotes lipolysis in adipose tissue and increases hepatic CD36 expression, which may contribute to steatosis., Conclusion and Implications: These results unravel a novel role for IDE in the regulation of ER stress and development of hepatic steatosis. These findings pave the way to innovative strategies modulating IDE to treat metabolic diseases., (© 2024 British Pharmacological Society.)

We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARβ/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARβ/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Metformin is a first-line oral antidiabetic therapy for patients with type 2 diabetes mellitus. Metformin-associated lactate acidosis (MALA) is a well-known, life-threatening, but rare side effect of metformin therapy. Chronic kidney disease (CKD) patients have a much greater risk of MALA. We report the case of a severe refractory MALA despite hemodialysis (HD) treatment, associated with hypoglycemia, hypothermia, and bradycardia in a neglected and thus untimely-recognized CKD patient with type 2 diabetes mellitus. Despite the recent rehabilitation of metformin as a treatment of choice for type 2 diabetes mellitus, the drug should be prescribed with caution as it can be associated with life-threatening refractory acidosis, particularly in CKD patients. Moreover, HD treatment could occasionally be ineffective, resulting in a fatal outcome.
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Background: Metabolic syndrome (MS) is found in approximately% 30-40% of patients with type 1 diabetes mellitus (T1DM). Meal-induced glucagon-like peptide-1 (GLP-1) secretion in T1DM patients with MS is yet to be clarified. The aim of the present study was to analyse the relationship between total fasting GLP-1 concentrations and the meal-induced GLP-1 response with MS prevalence in T1DM patients compared with lean, normal glucose tolerance (NGT), control subjects., Methods: The study included 77 T1DM patients (61% male), 26 (34%) with MS, who had a mean age of 45.08 years, mean body mass index (BMI) of 25.42 kg/m(2) , and median diabetes duration of 21 years. Ten age-, gender, and BMI-matched NGT control subjects were also included in the study. Circulating GLP-1 concentrations ere measured before and 30 min after a meal by ELISA. The difference between the 30-min postprandial and fasting GLP-1 concentration (ΔGLP-1) was calculated by subtracting fasting GLP-1 concentrations from postprandial GLP-1 concentrations., Results: The NGT group had significantly higher total fasting, postprandial, and meal-induced GLP-1 concentrations than the T1DM groups. The T1DM patients without MS had a higher increase in circulating GLP-1 concentrations compared with the T1DM group with MS. After adjustment for age, gender, disease duration, and meal caloric value, GLP-1 response levels were inversely correlated with MS prevalence in binary logistic regression analysis., Conclusion: A higher meal-induced GLP-1 response is associated with lower MS prevalence, but whether GLP-1 has a protective role in MS development is yet to be determined. This may provide further insight into the implementation of GLP-1-based therapies in the T1DM population., (© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.)

Fibroblast growth factor-21 (FGF-21) appears to have an important role in glucose and lipid metabolism. FGF-21 secretion is mainly determined by nutritional status. The aim of this study was to measure basal and postprandial FGF-21 and postprandial change of FGF-21 concentration in type 1 diabetes mellitus (T1DM) patients and in healthy controls, and to investigate the differences between the groups. The cross-sectional study included 30 C-peptide negative T1DM patients, median age 37 years (20-59), disease duration 22 years (3-45), and nine healthy controls, median age 30 years (27-47). Basal and postprandial FGF-21 concentrations were measured by ELISA. The associations of FGF-21 with glucose, lipids, and insulin were analyzed. Individuals with T1DM showed significantly lower basal FGF-21 concentration (P=0.046) when compared with healthy controls (median value 28.2 vs 104 pg/mL) and had significantly different postprandial change (∆ 30'-0') of FGF-21 (P=0.006) in comparison with healthy controls (median value -1.1 vs -20.5 pg/mL). The glucose and lipid status did not correlate with FGF-21. In healthy controls, postprandial insulin level correlated with basal FGF-21 (ρ=0.7, P=0.036). Multiple regression analysis showed that they are independently associated after adjustment for confounding factors (β=1.824, P=0.04). We describe the pathological pattern of basal and postprandial change of FGF-21 secretion not associated with glucose, lipid levels, or insulin therapy in patients with T1DM. Since FGF-21 has numerous protective metabolic effects in the experimental model, the lower basal FGF-21 concentration in T1DM patients opens the question about the potential role of recombinant FGF-21 therapy.

Background: The role of glucagon-like peptide-1 (GLP-1) has become a new scientific interest in the field of pathophysiology of type 1 diabetes mellitus (T1DM), but the results of the published studies were contradictory. The aim of our study was therefore to measure fasting and postprandial GLP-1 concentrations in T1DM patients and in healthy controls and to examine the difference in those concentrations between the two groups of subjects., Methods: The cross-sectional study included 30 C-peptide negative T1DM patients, median age 37 years (20-59), with disease duration 22 years (3-45), and 10 healthy controls, median age 30 years (27-47). Fasting and postprandial total and active GLP-1 concentrations were measured by ELISA (ALPCO, USA). The data were statistically analysed by SPSS, and significance level was accepted at P < 0.05., Results: Both fasting total and active GLP-1 concentrations were significantly lower in T1DM patients (total 0.4 pmol/L, 0-6.4 and active 0.2 pmol/L, 0-1.9) compared with healthy controls (total 3.23 pmol/L, 0.2-5.5 and active 0.8 pmol/L, 0.2-3.6), P = 0.008 for total GLP-1 and P = 0.001 for active GLP-1. After adjustment for age, sex and body mass index, binary logistic regression showed that both fasting total and active GLP-1 remained significantly independently lower in T1DM patients (total GLP-1: OR 2.43, 95% CI 1.203-4.909 and active GLP-1: OR 8.73, 95% CI 1.472-51.787)., Conclusions: T1DM patients had independently lower total and active GLP-1 fasting concentrations in comparison with healthy people, which supports the potential therapeutic role of incretin therapy, along with insulin therapy, in T1DM patients., (© The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Lysosomal acid lipase deficiency is an autosomal recessive disorder with two distinct clinical phenotypes. Wolman disease is rapidly progressive with onset in early infancy. Complete enzyme deficiency results in massive accumulation of cholesterol esters and triglycerides in intestines, liver, spleen and other monocyte-macrophage system cells causing malabsorption, hepatosplenomegaly, liver failure and death in early infancy. Cholesterol ester storage disease may be diagnosed in childhood or later in life. It is characterized by chronic course and variable progression. Main features are variously expressed hepatopathy, including cirrhosis and liver failure, hypercholesterolemia and premature atherosclerosis. Characteristic is pathohistological finding of microvesicular steatosis and fibrosis and patognomonic are typical cholesterol ester crystals. Diagnosis is confirmed by enzyme assay and/or gene analysis. Until recently treatment was symptomatic. Ongoing clinical trials of enzyme replacement therapy have shown very promising results. We are presenting an infant with Wolman disease and two children with cholesterol ester storage disease with the aim to raise awareness about this disease and to start optimal care early.