OBJECTIVE: Our study aimed to analyze how hepatic insulin resistance (IR) influences the efficacy of 48 weeks of metformin treatment in newly diagnosed type 2 diabetes patients.
METHODS: We chose 291 participants who were allocated to a 48-week metformin treatment in the \"Metformin and Acarbose in Chinese as initial Hypoglycemic treatment\" (MARCH) trial and calculated their hepatic insulin resistance indexes (HIRI). We equally grouped the subjects into tertiles: low, medium, and high HIRI groups based on baseline HIRI; Low, medium, and high ΔHIRI groups based on the decreasing extent of HIRI after a 48-week metformin treatment.
RESULTS: Multiple linear regression showed that baseline HIRI was positively associated with the rising degree of Matsuda index and the falling range of fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and HIRI. Furthermore, baseline fasting insulin, homeostatic model assessment of β cell function (HOMA-β), HOMA-IR, and HIRI were positively associated with the decreasing extent of HIRI, while baseline Matsuda index had a negative association with the falling extent of HIRI.
CONCLUSIONS: Patients with higher levels of hepatic IR obtained better curative effects from metformin in terms of glycemic control, insulin saving, insulin sensitivity enhancement, and IR improvement. Higher fasting blood glucose, fasting insulin, HOMA-β, IR, and lower Matsuda index were indicators of better hepatic IR improvement.

Statins, the first-line medication for dyslipidemia, are linked to an increased risk of type 2 diabetes. But exactly how statins cause diabetes is yet unknown. In this study, a developed short-term statin therapy on hyperlipidemia mice show that hepatic insulin resistance is a cause of statin-induced diabetes. Statin medication raises the expression of progesterone and adiponectin receptor 9 (PAQR9) in liver, which inhibits insulin signaling through degradation of protein phosphatase, Mg2+/Mn2+ dependent 1 (PPM1α) to activate ERK pathway. STIP1 homology and U-box containing protein 1 (STUB1) is found to mediate ubiquitination of PPM1α promoted by PAQR9. On the other hand, decreased activity of hepatocyte nuclear factor 4 alpha (HNF4α) seems to be the cause of PAQR9 expression under statin therapy. The interventions on PAQR9, including deletion of PAQR9, caloric restriction and HNF4α activation, are all effective treatments for statin-induced diabetes, while liver specific over-expression of PPM1α is another possible tactic. The results reveal the importance of HNF4α-PAQR9-STUB1-PPM1α axis in controlling the statin-induced hepatic insulin resistance, offering a fresh insight into the molecular mechanisms underlying statin therapy.

Metabolic dysfunction associated-steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) is the liver manifestation of metabolic syndrome, which is characterized by insulin resistance, hyperglycemia, hypertension, dyslipidemia, and/or obesity. Environmental pollutant exposure has been recently identified as a risk factor for developing MASH. Heterocyclic amines (HCAs) are mutagens generated when cooking meat at high temperatures or until well-done. Recent epidemiological studies reported that dietary HCA exposure may be linked to insulin resistance and type II diabetes, and we recently reported that HCAs induce insulin resistance and glucose production in human hepatocytes. However, no previous studies have examined the effects of HCAs on hepatic lipid homeostasis. In the present study, we assessed the effects of two common HCAs, MeIQx (2-amino-3, 8-dimethylimidazo [4, 5-f] quinoxaline) and PhIP (2-amino-1-methyl-6-phenylimidazo[4, 5-b] pyridine), on lipid homeostasis in cryopreserved human hepatocytes. Exposure to a single concentration of 25 μM MeIQx or PhIP in human hepatocytes led to dysregulation of lipid homeostasis, typified by significant increases in lipid droplets and triglycerides. PhIP significantly increased expression of lipid droplet-associated genes, PNPLA3 and HSD17B13, and both HCAs significantly increased PLIN2. Exposure to MeIQx or PhIP also significantly increased expression of several key genes involved in lipid synthesis, transport and metabolism, including FASN, DGAT2, CPT1A, SCD, and CD36. Furthermore, both MeIQx and PhIP significantly increased intracellular cholesterol and decreased expression of PON1 which is involved in cholesterol efflux. Taken together, these results suggest that HCAs dysregulate lipid production, metabolism, and storage. The current study demonstrates, for the first time, that HCA exposure may lead to fat accumulation in hepatocytes, which may contribute to hepatic insulin resistance and MASH.

OBJECTIVE: Mitochondria-associated membranes (MAMs) serve pivotal functions in hepatic insulin resistance (IR). Our aim was to explore the potential role of MAMs in mitigating hepatic IR through exercise and to compare the effects of different intensities of exercise on hepatic MAMs formation in high-fat diet (HFD) mice.
METHODS: Male C57BL/6J mice were fed an HFD and randomly assigned to undergo supervised high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT). IR was evaluated using the serum triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-C), glucose tolerance test (GTT), and insulin tolerance test (ITT). Hepatic steatosis was observed using hematoxylin-eosin (H&E) and oil red O staining. The phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase 3 beta (PI3K-AKT-GSK3β) signaling pathway was assessed to determine hepatic IR. MAMs were evaluated through immunofluorescence (colocalization of voltage-dependent anion-selective channel 1 [VDAC1] and inositol 1,4,5-triphosphate receptor [IP3R]).
RESULTS: After 8 weeks on an HFD, there was notable inhibition of the hepatic PI3K/Akt/GSK3β signaling pathway, accompanied by a marked reduction in hepatic IP3R-VDAC1 colocalization levels. Both 8-week HIIT and MICT significantly enhanced the hepatic PI3K/Akt/GSK3β signaling and colocalization levels of IP3R-VDAC1 in HFD mice, with MICT exhibiting a stronger effect on hepatic MAMs formation. Furthermore, the colocalization of hepatic IP3R-VDAC1 positively correlated with the expression levels of phosphorylation of protein kinase B (p-AKT) and phosphorylation of glycogen synthase kinase 3 beta (p-GSK3β), while displaying a negative correlation with serum triglyceride/high-density lipoprotein cholesterol levels.
CONCLUSIONS: The reduction in hepatic MAMs formation induced by HFD correlates with the development of hepatic IR. Both HIIT and MICT effectively bolster hepatic MAMs formation in HFD mice, with MICT demonstrating superior efficacy. Thus, MAMs might wield a pivotal role in exercise-induced alleviation of hepatic IR.

OBJECTIVE: Impaired insulin sensitivity is central in the etiology of type 2 diabetes in people with obesity. The effectiveness of resistance training (RE) alone in improving insulin sensitivity in people with obesity is undetermined. This study aimed to determine the influence of obesity on insulin sensitivity responses to RE.
METHODS: Nineteen sedentary men were allocated to Lean (BMI 22.7 ± 2.5 kg m-2; n = 10) or Obese group (BMI 33.2 ± 3.2 kg m-2; n = 9). Participants were evaluated before and after a 10-week supervised progressive RE (3 sets of 10 repetition maximum (RM), 3 d/wk) for insulin sensitivity indexes using an oral glucose tolerance test, body composition using anthropometrics, and strength using 1RM.
RESULTS: Groups were matched at baseline for all variables except for body composition and absolute strength. Body fat was not changed in both groups. Matsuda insulin sensitivity index, hepatic insulin resistance, and insulin area under the curve improved by 64.3 ± 61.9 unit, - 58.2 ± 102.9 unit, 2.3 ± 4.1 unit, and - 721.6 ± 858.2 µU/ml, respectively, only in the Lean group. The increased 1RM% for leg press was greater in the Lean (49.5 ± 18.7%) than in the Obese (31.5 ± 13.9), but not different for bench press (18.0 ± 9.1% vs. 16.4 ± 6.0%, respectively).
CONCLUSIONS: Sustained obesity precludes insulin sensitivity improvements and attenuates strength gains in response to progressive RE. Additional strategies such as caloric restriction might be necessary for RE to improve insulin sensitivity, particularly at high levels of obesity.

UNASSIGNED: In this study, the combined effect of two stressors, namely, electromagnetic fields (EMFs) from mobile phones and fructose consumption, on hypothalamic and hepatic master metabolic regulators of the AMPK/SIRT1-UCP2/FOXO1 pathway were elucidated to delineate the underlying molecular mechanisms of insulin resistance.
UNASSIGNED: Weaned Wistar rats (28 days old) were divided into 4 groups: Normal, Exposure Only (ExpO), Fructose Only (FruO), and Exposure and Fructose (EF). Each group was provided standard laboratory chow ad libitum for 8 weeks . Additionally, the control groups, namely, the Normal and FruO groups, had unrestricted access to drinking water and fructose solution (15%), respectively. Furthermore, the respective treatment groups, namely, the ExpO and EF groups, received EMF exposure (1,760 MHz, 2 h/day x 8 weeks). In early adulthood, mitochondrial function, insulin receptor signaling, and oxidative stress signals in hypothalamic and hepatic tissues were assessed using western blotting and biochemical analysis.
UNASSIGNED: In the hypothalamic tissue of EF, SIRT1, FOXO 1, p-PI3K, p-AKT, Complex III, UCP2, MnSOD, and catalase expressions and OXPHOS and GSH activities were significantly decreased ( P < 0.05) compared to the Normal, ExpO, and FruO groups. In hepatic tissue of EF, the p-AMPKα, SIRT1, FOXO1, IRS1, p-PI3K, Complex I, II, III, IV, V, UCP2, and MnSOD expressions and the activity of OXPHOS, SOD, catalase, and GSH were significantly reduced compared to the Normal group ( P < 0.05).
UNASSIGNED: The findings suggest that the combination of EMF exposure and fructose consumption during childhood and adolescence in Wistar rats disrupts the closely interlinked and multi-regulated crosstalk of insulin receptor signals, mitochondrial OXPHOS, and the antioxidant defense system in the hypothalamus and liver.

OBJECTIVE: To characterize potential mechanisms of fisetin on hepatic insulin resistance (IR) using network pharmacology and in vitro validation.
METHODS: Putative targets of fisetin were retrieved from the Traditional Chinese Medicine Systems Pharmacology database, whereas the potential genes of hepatic IR were obtained from GeneCards database. A protein-protein interaction (PPI) network was constructed according to the intersection targets of fisetin and hepatic IR using the Venn diagram. The biological functions and potential pathways related to genes were determined using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Cell experiments were also conducted to further verify the mechanism of fisetin on hepatic IR.
RESULTS: A total of 118 potential targets from fisetin were associated with hepatic IR. The areas of nodes and corresponding degree values of TP53, AKT1, TNF, IL6, CASP3, CTNNB1, JUN, SRC, epidermal growth factor receptor (EGFR), and HSP90AA1 were larger and could be easily found in the PPI network. Furthermore, GO analysis revealed that these key targets were significantly involved in multiple biological processes that participated in oxidative stress and serine/threonine kinase activity. KEGG enrichment analysis showed that the PI3K/AKT signaling pathway was a significant pathway involved in hepatic IR. Our in vitro results demonstrated that fisetin treatment increased the expressions of EGFR and IRS in HepG2 and L02 cells under normal or IR conditions. Western blot results revealed that p-AKT/AKT levels were significantly up-regulated, suggesting that fisetin was involved in the PI3K/AKT signaling pathway to regulate insulin signaling.
CONCLUSIONS: We explored the pharmacological actions and the potential molecular mechanism of fisetin in treating hepatic IR from a holistic perspective. Our study lays a theoretical foundation for the development of fisetin for type 2 diabetes.

The etiology of numerous metabolic disorders is characterized by hepatic insulin resistance (IR). Uncertainty surrounds miR-34a\'s contribution to high-fat-induced hepatic IR and its probable mechanism. The role and mechanism of miR-34a and its target gene ENO3 in high-fat-induced hepatic IR were explored by overexpressing/suppressing miR-34a and ENO3 levels in in vivo and in vitro experiments. Moreover, as a human hepatic IR model, the miR-34a/ENO3 pathway was validated in patients with non-alcoholic fatty liver disease (NAFLD). The overexpression of hepatic miR-34a lowered insulin signaling and altered glucose metabolism in hepatocytes. In contrast, reducing miR-34a expression significantly reversed hepatic IR indices induced by palmitic acid (PA)/HFD. ENO3 was identified as a direct target gene of miR-34a. Overexpression of ENO3 effectively inhibited high-fat-induced hepatic IR-related indices both in vitro and in vivo. Moreover, the expression patterns of members of the miR-34a/ENO3 pathway in the liver tissues of NAFLD patients was in line with the findings of both cellular and animal studies. A high-fat-induced increase in hepatic miR-34a levels attenuates insulin signaling and impairs glucose metabolism by suppressing the expression of its target gene ENO3, ultimately leading to hepatic IR. The miR-34a/ENO3 pathway may be a potential therapeutic target for hepatic IR and related metabolic diseases.

OBJECTIVE: Defective insulin signalling and dysfunction of the endoplasmic reticulum (ER), driven by excessive lipid accumulation in the liver, is a characteristic feature in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Thromboxane A2 (TXA2 ), an arachidonic acid metabolite, is significantly elevated in obesity and plays a crucial role in hepatic gluconeogenesis and adipose tissue macrophage polarization. However, the role of liver TXA2 /TP receptors in insulin resistance and lipid metabolism is largely unknown.
METHODS: TP receptor knockout (TP-/- ) mice were generated and fed a high-fat diet for 16 weeks. Insulin sensitivity, ER stress responses and hepatic lipid accumulation were assessed. Furthermore, we used primary hepatocytes to dissect the mechanisms by which the TXA2 /TP receptor axis regulates insulin signalling and hepatocyte lipogenesis.
RESULTS: TXA2 was increased in diet-induced obese mice, and depletion of TP receptors in adult mice improved systemic insulin resistance and hepatic steatosis. Mechanistically, we found that the TXA2 /TP receptor axis disrupts insulin signalling by activating the Ca2+ /calcium calmodulin-dependent kinase II γ (CaMKIIγ)-protein kinase RNA-like endoplasmic reticulum kinase (PERK)-C/EBP homologous protein (Chop)-tribbles-like protein 3 (TRB3) axis in hepatocytes. In addition, our results revealed that the TXA2 /TP receptor axis directly promoted lipogenesis in primary hepatocytes and contributed to Kupffer cell inflammation.
CONCLUSIONS: The TXA2 /TP receptor axis facilitates insulin resistance through Ca2+ /CaMKIIγ to activate PERK-Chop-TRB3 signalling. Inhibition of hepatocyte TP receptors improved hepatic steatosis and inflammation. The TP receptor is a new therapeutic target for NAFLD and metabolic syndrome.

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