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Background and Objective: Psychological insulin resistance (PIR), which refers to the reluctance of diabetic patients to use insulin, is a frequently encountered clinical issue. Needle-free injection (NFI) offers advantages in terms of expediting insulin absorption and mitigating adverse reactions related to injection. To evaluate the effects of subcutaneous injection of insulin aspart 30 with NFI on PIR and insulin dosage in patients with type 2 diabetes mellitus (T2DM)., Methods: Sixty-four patients with T2DM participated in this randomized, prospective, open, crossover study. Insulin aspart 30 was administered subcutaneously to each subject via QS-P NFI and Novo Pen 5 (NP) successively. The effects of NFI on PIR were analyzed. Differences in insulin dosage, glycemic variability, and injection safety were compared at similar levels of glycemic control., Results: After the administration of NFI, the insulin treatment attitude scale score decreased (53.7 ± 7.3 vs. 58.9 ± 10.7, p<0.001), the insulin treatment adherence questionnaire score increased (46.3 ± 4.9 vs. 43.8 ± 7.1, p<0.001), and the insulin treatment satisfaction questionnaire score increased (66.6 ± 10.5 vs. 62.4 ± 16.5, p<0.001). At the same blood glucose level, NFI required a smaller dosage of insulin aspart 30 compared with that of NP (30.42 ± 8.70 vs. 33.66 ± 9.13 U/d, p<0.001). There were no differences in glycemic variability indices (standard deviation, mean amplitude of glycemic excursion or coefficient of variation) between the two injection methods. Compared with NP, NFI did not increase the incidence of hypoglycemia (17.2% vs. 14.1%, p=0.774), and it decreased the incidence of induration (4.7% vs. 23.4%, p=0.002) and leakage (6.3% vs. 20.3%, p=0.022) while decreasing the pain visual analog scale score (2.30 ± 1.58 vs. 3.11 ± 1.40, p<0.001)., Conclusion: NFI can improve PIR in patients with T2DM and be used with a smaller dose of insulin aspart 30 while maintaining the same hypoglycemic effect., Clinical Trial Registration: https://www.chictr.org.cn/, identifier ChiCTR2400083658., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Men, Wang, Shi, Yin, Li, Zhou and Du.)

Nonalcoholic fatty liver disease (NAFLD) is closely associated with insulin resistance (IR) and type 2 diabetes mellitus (T2DM), which are all complex metabolic disorders. Selenoprotein S (SelS) is an endoplasmic reticulum (ER) resident selenoprotein involved in regulating ER stress and has been found to participate in the occurrence and development of IR and T2DM. However, the potential role and mechanism of SelS in NAFLD remains unclear. Here, we analyzed SelS expression in the liver of high-fat diet (HFD)-fed mice and obese T2DM model (db/db) mice and generated hepatocyte-specific SelS knockout (SelS H-KO ) mice using the Cre-loxP system. We showed that hepatic SelS expression levels were significantly downregulated in HFD-fed mice and db/db mice. Hepatic SelS deficiency markedly increased ER stress markers in the liver and caused hepatic steatosis via increased fatty acid uptake and reduced fatty acid oxidation. Impaired insulin signaling was detected in the liver of SelS H-KO mice with decreased phosphorylation levels of insulin receptor substrate 1 (IRS1) and protein kinase B (PKB/Akt), which ultimately led to disturbed glucose homeostasis. Meanwhile, our results showed hepatic protein kinase Cɛ (PKCɛ) activation participated in the negative regulation of insulin signaling in SelS H-KO mice. Moreover, the inhibitory effect of SelS on hepatic steatosis and IR was confirmed by SelS overexpression in primary hepatocytes in vitro. Thus, we conclude that hepatic SelS plays a key role in regulating hepatic lipid accumulation and insulin action, suggesting that SelS may be a potential intervention target for the prevention and treatment of NAFLD and T2DM., (© 2022. The Author(s).)

As an environmental toxicant, arsenic exposure may cause insulin resistance (IR). Previous studies have shown that pyroptosis plays an important role in the occurrence and development of IR. Although gasdermin D (GSDMD) functions as an executor of pyroptosis, the relationship between GSDMD-mediated pyroptosis and hepatic IR remains unclear. Here, we observed that sodium arsenite (NaAsO 2 ) activated NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasomes, promoted GSDMD activation, induced pyroptosis and hepatic IR, while GSDMD knockdown attenuated pyroptosis and hepatic IR caused by NaAsO 2 . However, GSDMD interference did not affect NLRP3 activation. Ubiquitination modification is widely involved in protein regulation and intracellular signal transduction, and whether it regulates GSDMD and affects its degradation, and exerts effects on arsenic-induced pyroptosis remain unclear. We observed that NaAsO 2 reduced the K48- and K63-linked ubiquitination of GSDMD, thereby inhibiting its degradation through the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP), causing GSDMD to accumulate and lyse into GSDMD-N, which promoted pyroptosis. In summary, we demonstrated that GSDMD participated in arsenic-induced hepatic IR. Moreover, NaAsO 2 reduced GSDMD ubiquitination and decreased its intracellular degradation, aggravating pyroptosis and hepatic IR. We have revealed the molecular mechanism underpinning arsenic-induced IR, and we provide potential solutions for the prevention and treatment of type 2 diabetes (T2D)., (Copyright © 2021. Published by Elsevier Ltd.)

Interleukin-8 (IL-8, also named CXCL8) binds to its receptors (CXCR1 and CXCR2) with subsequent recruitment of neutrophils and enhancement of their infiltration into inflamed sites, which exaggerates inflammation in many diseases. Recent studies have proposed that metabolic disorders can be attenuated by counteracting certain inflammatory signal pathways. In this study, we examined whether intervention with G31P, an antagonist of CXCL8, could attenuate tissue inflammation and development of metabolic disorders in db/db mice. The db/m and db/db mice were subcutaneously injected with G31P or equivalent normal saline once a day for 6 wk. The physical and metabolic parameters, glucose tolerance, insulin sensitivity, hepatic lipid accumulation, and inflammation markers were measured. G31P improved hepatic insulin sensitivity by modulating expression of genes related to gluconeogenesis and phosphorylated Akt levels. The expressions of several genes encoding proteins involved in de novo lipogenesis were decreased in G31P-treated db/db mice. Meanwhile, immune cell infiltration and cytokine release were attenuated in db/db mice with G31P treatment. G31P also improved the ratio of proinflammatory M1 and anti-inflammatory M2 macrophages. Furthermore, G31P ameliorates metabolic disturbances via inhibition of CXCR1 and CXCR2 pathways in db/db mice. These data suggest that the selective inhibition of CXC chemokines may have therapeutic effects on symptoms associated with obesity and diabetes.

Defects in the development, maintenance or expansion of β-cell mass can result in impaired glucose metabolism and diabetes. N 6-methyladenosine affects mRNA stability and translation efficiency, and impacts cell differentiation and stress response. To determine if there is a role for m6A in β-cells, we investigated the effect of Mettl14 , a key component of the m6A methyltransferase complex, on β-cell survival and function using rat insulin-2 promoter-Cre-mediated deletion of Mettl14 mouse line (βKO). We found that βKO mice with normal chow exhibited glucose intolerance, lower levels of glucose-stimulated insulin secretion, increased β-cell death and decreased β-cell mass. In addition, HFD-fed βKO mice developed glucose intolerance, decreased β-cell mass and proliferation, exhibited lower body weight, increased adipose tissue mass, and enhanced insulin sensitivity due to enhanced AKT signaling and decreased gluconeogenesis in the liver. HFD-fed βKO mice also showed a decrease in de novo lipogenesis, and an increase in lipolysis in the liver. RNA sequencing in islets revealed that Mettl14 deficiency in β-cells altered mRNA expression levels of some genes related to cell death and inflammation. Together, we showed that Mettl14 in β-cells plays a key role in β-cell survival, insulin secretion and glucose homeostasis. • Mice with METTL14 deficiency showed glucose intolerance. • β-Cell mass was significantly decreased in β-cell METTL14 deficient mice. • Insulin secretion was decreased in METTL14 deficient mice. • METTL14 deficiency in β-cells impaired compensatory islet expansion on HFD. • Mettl14 deficiency in β-cells altered mRNA levels of cell death and inflammation genes. [ABSTRACT FROM AUTHOR]