Pan-PPAR agonist lanifibranor improves insulin resistance and hepatic steatosis in patients with T2D and MASLD.

Background & Aims: Lanifibranor is a pan-PPAR agonist that improves glucose/lipid metabolism and reverses steatohepatitis and fibrosis in adults with MASH. We tested its effect on insulin resistance at the level of different target tissues in relationship to change in intrahepatic triglyceride (IHTG) content.

Methods: This phase 2, single center, study randomized (1:1) 38 patients with T2D and MASLD to receive lanifibranor 800 mg or placebo for 24 weeks.

Obesity increases the risk of hepatic fibrosis in young adults with type 2 diabetes mellitus: the need to screen.

Objective: The objective of this study was to determine the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in young compared with older adults.

Methods: Individuals (n = 1420) with (63%) and without type 2 diabetes mellitus (T2D; 37%) who attended internal medicine clinics and did not have a known history of MASLD underwent laboratory evaluation and transient elastography to assess for hepatic steatosis and fibrosis. Magnetic resonance elastography and liver biopsy were recommended when indicated.

Insulin resistance is an integral feature of MASLD even in the presence of PNPLA3 variants.

Background & Aims: It has been postulated that carriers of PNPLA3 I148M (CG [Ile/Met] or GG [Met/Met]) develop metabolic dysfunction-associated steatotic liver disease (MASLD) in the absence of insulin resistance or metabolic syndrome. However, the relationship between insulin resistance and MASLD according to the allele has not been carefully assessed.

Methods: A total of 204 participants were recruited and underwent genotyping, an oral glucose tolerance test, liver proton magnetic resonance spectroscopy and percutaneous liver biopsy if diagnosed with MASLD.

Adipose Tissue Insulin Resistance Predicts the Severity of Liver Fibrosis in Patients With Type 2 Diabetes and NAFLD.

Context: Although type 2 diabetes (T2D) is a risk factor for liver fibrosis in nonalcoholic fatty liver disease (NAFLD), the specific contribution of insulin resistance (IR) relative to other factors is unknown.

Objective: Assess the impact on liver fibrosis in NAFLD of adipose tissue (adipose tissue insulin resistance index [adipo-IR]) and liver (Homeostatic Model Assessment of Insulin Resistance [HOMA-IR]) IR in people with T2D and NAFLD.

Design: Participants were screened by elastography in the outpatient clinics for hepatic steatosis and fibrosis, including routine metabolites, cytokeratin-18 (a marker of hepatocyte apoptosis/steatohepatitis), and HOMA-IR/adipo-IR.

Assessing strategies to target screening for advanced liver fibrosis among overweight and obese patients.

Aim: The optimal screening strategy for advanced liver fibrosis in overweight and obese patients is unknown. The aim of this study is to compare the performance of different strategies to select patients at high risk of advanced liver fibrosis for screening using non-invasive tools.

Methods: All patients underwent: liver H-MRS and percutaneous liver biopsy (in those with nonalcoholic fatty liver disease [NAFLD]).

Intact Fasting Insulin Identifies Nonalcoholic Fatty Liver Disease in Patients Without Diabetes.

Context: Patients with nonalcoholic fatty liver disease (NAFLD) are characterized by insulin resistance and hyperinsulinism. However, insulin resistance measurements have not been shown to be good diagnostic tools to predict NAFLD in prior studies.

Objective: We aimed to assess a newly validated method to measure intact molecules of insulin by mass spectrometry to predict NAFLD.

Severity of non-alcoholic steatohepatitis is not linked to testosterone concentration in patients with type 2 diabetes.

Background: Hypogonadism is reported to occur in non-alcoholic fatty liver disease (NAFLD), but earlier studies used low-sensitivity diagnostic techniques (CT, ultrasound), for NAFLD diagnosis. We hypothesized that if hypogonadism was due to NAFLD, and not solely attributable to underlying obesity/diabetes, it would be more severe in the presence of steatohepatitis (NASH). To examine the influence of liver disease on testosterone in males with type 2 diabetes mellitus (T2DM), we used gold-standard liver imaging with MR-spectroscopy (1H-MRS), and performed liver biopsies to grade/stage the NAFLD.

Advanced Liver Fibrosis Is Common in Patients With Type 2 Diabetes Followed in the Outpatient Setting: The Need for Systematic Screening.

Objective: Assess the prevalence of nonalcoholic fatty liver disease (NAFLD) and of liver fibrosis associated with nonalcoholic steatohepatitis in unselected patients with type 2 diabetes mellitus (T2DM).

Research Design And Methods: A total of 561 patients with T2DM (age: 60 ± 11 years; BMI: 33.4 ± 6.

Targeting pheochromocytoma/paraganglioma with polyamine inhibitors.

Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease.

Relationship between non-alcoholic fatty liver disease during pregnancy and abnormal glucose metabolism during and after pregnancy.

While non-alcoholic fatty liver disease (NAFLD) is associated with increased risk of impaired glucose tolerance and type 2 diabetes mellitus (DM) in non-pregnant patients, the clinical significance of NAFLD during pregnancy is still unclear. We hypothesized that sonographic findings of NAFLD during pregnancy would be associated with gestational diabetes mellitus (GDM) and predict abnormal postpartum glucose metabolism. NAFLD was assessed by ultrasound during and after pregnancy.

Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes: A Randomized Controlled Trial.

Objective: While vitamin E has shown to improve nonalcoholic steatohepatitis (NASH) in patients without diabetes, information on patients with type 2 diabetes mellitus (T2DM) is lacking. The aim of this study was to determine whether vitamin E, alone or combined with pioglitazone, improves histology in patients with T2DM and NASH.

Research Design And Methods: This was a proof-of-concept, randomized, double-blind, placebo-controlled trial conducted from 2010 to 2016.

Use of Plasma Fragments of Propeptides of Type III, V, and VI Procollagen for the Detection of Liver Fibrosis in Type 2 Diabetes.

Objective: This study assessed the utility of plasma fragments of propeptides of type III (PRO-C3), V (PRO-C5), and VI (PRO-C6) procollagen for the detection of liver fibrosis in patients with type 2 diabetes mellitus (T2DM).

Research Design And Methods: Patients with T2DM ( = 191) underwent an oral glucose tolerance test, a liver H-MRS, and a liver biopsy when indicated. PRO-C3, PRO-C5, and PRO-C6 were blindly assessed.

Impact of exenatide on mitochondrial lipid metabolism in mice with nonalcoholic steatohepatitis.

Exenatide (Exe) is a glucagon-like peptide (GLP)-1 receptor agonist that enhances insulin secretion and is associated with induction of satiety with weight loss. As mitochondrial dysfunction and lipotoxicity are central features of nonalcoholic steatohepatitis (NASH), we tested whether Exe improved mitochondrial function in this setting. We studied C57BL/6J mice fed for 24 weeks either a control- or high-fructose, high-trans-fat (TFD)-diet (i.

Plasma Fibroblast Growth Factor 21 Is Associated With Severity of Nonalcoholic Steatohepatitis in Patients With Obesity and Type 2 Diabetes.

Context: The relationship between plasma fibroblast growth factor 21 (FGF21), insulin resistance, and steatohepatitis has not been systematically assessed.

Objective: To determine if higher plasma FGF21 is associated with worse steatohepatitis on liver biopsy in patients with nonalcoholic fatty liver disease (NAFLD).

Design And Setting: Cross-sectional study in a university hospital.

Pioglitazone improves hepatic mitochondrial function in a mouse model of nonalcoholic steatohepatitis.

Pioglitazone is effective in improving insulin resistance and liver histology in patients with nonalcoholic steatohepatitis (NASH). Because dysfunctional mitochondrial metabolism is a central feature of NASH, we hypothesized that an important target of pioglitazone would be alleviating mitochondrial oxidative dysfunction. To this end, we studied hepatic mitochondrial metabolism in mice fed high-fructose high-transfat diet (TFD) supplemented with pioglitazone for 20 wk, using nuclear magnetic resonance-based C isotopomer analysis.

Use of a metabolomic approach to non-invasively diagnose non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus.

Aims: To assess the utility of existing metabolomics scores to classify liver disease in patients with type 2 diabetes mellitus (T2DM).

Materials And Methods: A total of 220 patients with T2DM were recruited. Patients underwent routine laboratory tests, liver proton magnetic resonance spectroscopy ( H-MRS), a 75-g oral glucose tolerance test, and liver biopsy if H-MRS findings indicated non-alcoholic fatty liver disease.

Response to Pioglitazone in Patients With Nonalcoholic Steatohepatitis With vs Without Type 2 Diabetes.

Background & Aims: Pioglitazone is effective for long-term treatment of patients with nonalcoholic steatohepatitis (NASH) with prediabetes or type 2 diabetes. However, it is not clear how the presence of type 2 diabetes affects the drug's efficacy. We compared metabolic and histologic responses to pioglitazone in patients with NASH and prediabetes vs type 2 diabetes.

Clinical and Histologic Characterization of Nonalcoholic Steatohepatitis in African American Patients.

Objective: There has been a widespread misconception among physicians that African Americans are protected from developing nonalcoholic steatohepatitis (NASH). However, a formal histologic and metabolic comparison against well-matched Caucasians has never been performed.

Research Design And Methods: Sixty-seven African American patients were matched 2:1 to Caucasians ( = 134) for age, sex, BMI, hemoglobin A, and prevalence of type 2 diabetes mellitus (T2DM).

Corrigendum: Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance.

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Concentration-dependent response to pioglitazone in nonalcoholic steatohepatitis.

Background: Pioglitazone is a safe and effective option to manage patients with type 2 diabetes and nonalcoholic steatohepatitis (NASH). However, there is marked variability in treatment response.

Aim: To evaluate the relationship between concentrations of pioglitazone and its active metabolites and treatment outcomes in patients with NASH.

Lipotoxicity in steatohepatitis occurs despite an increase in tricarboxylic acid cycle activity.

The hepatic tricarboxylic acid (TCA) cycle is central to integrating macronutrient metabolism and is closely coupled to cellular respiration, free radical generation, and inflammation. Oxidative flux through the TCA cycle is induced during hepatic insulin resistance, in mice and humans with simple steatosis, reflecting early compensatory remodeling of mitochondrial energetics. We hypothesized that progressive severity of hepatic insulin resistance and the onset of nonalcoholic steatohepatitis (NASH) would impair oxidative flux through the hepatic TCA cycle.

Plasma thyroid hormone concentration is associated with hepatic triglyceride content in patients with type 2 diabetes.

The underlying mechanisms responsible for the development and progression of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) are unclear. Since the thyroid hormone regulates mitochondrial function in the liver, we designed this study in order to establish the association between plasma free T4 levels and hepatic triglyceride accumulation and histological severity of liver disease in patients with T2DM and NAFLD. This is a cross-sectional study including a total of 232 patients with T2DM.