humulin-s and Non-alcoholic-Fatty-Liver-Disease

Diabetic and obese patients have a high prevalence of non-alcoholic fatty liver disease (NAFLD). This condition groups a spectrum of conditions varying from simple steatosis to non-alcoholic steatohepatitis (NASH), with or without fibrosis. Multiple factors are involved in the development of NAFLD. However, details about its pathogenesis and factors that promote the progression to NASH are still missing. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) regulate metabolic, immune, and hepatic stellate cell functions. Increasing evidence suggests they may have roles in the progression from NAFLD to NASH. Following the PRISMA reporting guidelines, we conducted a systematic review to evaluate all clinical and experimental studies published in the literature correlating GH and IGF-1 to inflammation and fibrosis in NAFLD and NASH. Our results showed that GH and IGF-1 have a fundamental role in the pathogenesis of NASH, acting in slightly different ways to produce a synergic effect. Indeed, GH may mediate its protective effect in the pathogenesis of NASH by regulating lipogenesis pathways, while IGF-1 has the same effect by regulating cholesterol transport. Therefore, they could be used as therapeutic strategies in preventing NAFLD progression to NASH.

Topics: Growth Hormone; Hepatitis; Human Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Insulin, Regular, Human; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease

Topics: Adiposity; Animals; Diet, High-Fat; Female; Insulin; Insulin, Regular, Human; Leptin; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; PPAR gamma

Non-Alcoholic Fatty Liver Disease (NAFLD) is a raising concern in type 1 diabetes (T1D) patients. We evaluated whether multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) may differentially affect NAFLD.. NAFLD was assessed by Fatty Liver Index (FLI) and Hepatic Steatosis Index (HSI) in 659 T1D patients treated by MDI (n = 414, 65% men) or CSII (n = 245, 50% men) without alcohol abuse or other liver diseases. Clinical and metabolic differences between MDI and CSII participants were also evaluated according to sex.. Compared with the MDI cohort, CSII users had a significantly lower FLI (20.2 ± 21.2 vs. 24.8 ± 24.3; p = 0.003), HSI (36.2 ± 4.4 vs. 37.4 ± 4.4; p = 0.003), waist circumference (84.6 ± 11.8 vs. 86.9 ± 13.7 cm; p = 0.026), plasma triglyceride (76.0 ± 45.8 vs. 84.7 ± 58.3 mg/dl; p = 0.035), and daily insulin dose (0.53 ± 0.22 vs. 0.64 ± 0.25 IU/kg body weight; p < 0.001). In CSII users, lower FLI and HSI were observed in women (p = 0.009 and p = 0.033, respectively) but not in men (p = 0.676 and p = 0.131, respectively). Women on CSII also had lower daily insulin doses, plasma triglyceride, and visceral adiposity index than women on MDI.. CSII is associated with lower NAFLD indices in women with T1D. This may relate to the lower peripheral insulin in the context of a permissive hormonal milieu.

Topics: Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Infusion Systems; Insulin, Regular, Human; Non-alcoholic Fatty Liver Disease

Defining the regulators of cell metabolism and signaling is essential to design new therapeutic strategies in obesity and NAFLD/NASH. E3 ubiquitin ligases control diverse cellular functions by ubiquitination-mediated regulation of protein targets, and thus their functional aberration is associated with many diseases. The E3 ligase Ube4A has been implicated in human obesity, inflammation, and cancer. However, its in vivo function is unknown, and no animal models are available to study this novel protein.. A whole-body Ube4A knockout (UKO) mouse model was generated, and various metabolic parameters were compared in chow- and high fat diet (HFD)-fed WT and UKO mice, and in their liver, adipose tissue, and serum. Lipidomics and RNA-Seq studies were performed in the liver samples of HFD-fed WT and UKO mice. Proteomic studies were conducted to identify Ube4A's targets in metabolism. Furthermore, a mechanism by which Ube4A regulates metabolism was identified.. Although the body weight and composition of young, chow-fed WT and UKO mice are similar, the knockouts exhibit mild hyperinsulinemia and insulin resistance. HFD feeding substantially augments obesity, hyperinsulinemia, and insulin resistance in both sexes of UKO mice. HFD-fed white and brown adipose tissue depots of UKO mice have increased insulin resistance and inflammation and reduced energy metabolism. Moreover, Ube4A deletion exacerbates hepatic steatosis, inflammation, and liver injury in HFD-fed mice with increased lipid uptake and lipogenesis in hepatocytes. Acute insulin treatment resulted in impaired activation of the insulin effector protein kinase Akt in liver and adipose tissue of chow-fed UKO mice. We identified the Akt activator protein APPL1 as a Ube4A interactor. The K63-linked ubiquitination (K63-Ub) of Akt and APPL1, known to facilitate insulin-induced Akt activation, is impaired in UKO mice. Furthermore, Ube4A K63-ubiquitinates Akt in vitro.. Ube4A is a novel regulator of obesity, insulin resistance, adipose tissue dysfunction and NAFLD, and preventing its downregulation may ameliorate these diseases.

Topics: Adipose Tissue, Brown; Animals; Female; Homeostasis; Humans; Inflammation; Insulin; Insulin Resistance; Insulin, Regular, Human; Male; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Proteomics; Proto-Oncogene Proteins c-akt; Ubiquitin-Protein Ligases

Scant West African data on non-alcoholic fatty liver disease (NAFLD) means there is little representation of this population in the modelling used to derive biomarkers and predictive indices for risk stratification of patients for the presence of hepatic steatosis. This study evaluates the performance of the fatty liver index (FLI), hepatic steatosis index (HSI) and triglyceride-glucose (TyG) index and its derivatives in predicting ultrasound detected NAFLD in a locally resident population of Ghanaian participants.. A post hoc analysis of data from a cross sectional assessment of NAFLD and cardiovascular risk was performed. Data from 210 participants without significant alcohol intake, or secondary causes of fatty liver and not on steatogenic drugs was evaluated. A structured questionnaire had been used to collect demographic data, medical and drug history. Anthropometry, blood sampling for liver chemistry and fasting lipids were performed. Hepatic steatosis was detected by ultrasonography. A retrospective analysis involving multivariate binary logistic regression assessed FLI, HIS, TyG (and its derivatives) as predictors of NAFLD with p < .05 considered statistically significant. Sensitivity, specificity, predictive values, likelihood ratios were calculated and accuracy of the proxies evaluated from area under the receiver operating characteristics curve (AUROC). All the biomarkers and indices were significantly associated with NAFLD (p ≤ .001). All the lipid and fatty liver indices assessed performed acceptably as predictors of NAFLD. FLI (AUC = 0.8, 95% CI [0.74-0.87]), TyG-WC (AUC = 0.81, 95% CI [0.75-0.88]) and TyG-WHtR (AUC = 0.81, 95% CI [0.74-0.88]) performed best at predicting NAFLD. Whilst in all cases the markers had good specificity (>90%) they lacked sufficient sensitivity with FLI having the highest sensitivity of 36.7%. Their overall accuracy was greater than 70% in each case.. The overall accuracy of HSI, FLI, TyG index and its derivatives (TyG WHtR, TyG BMI, TyG WC) was acceptable for predicting NAFLD in this population. Given their performance in this study and in light of their low cost, accessibility, easy interpretation and non-invasive nature; they are suitable tools for screening in the Ghanaian population.

Topics: Biomarkers; Cross-Sectional Studies; Ghana; Glucose; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Non-alcoholic Fatty Liver Disease; Retrospective Studies; Triglycerides

Topics: Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Liver; Non-alcoholic Fatty Liver Disease

Topics: Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Liver; Non-alcoholic Fatty Liver Disease