Individuals with type 2 diabetes mellitus frequently display heightened levels of palmitic acid (PA) in their serum, which may lead to β-cell damage. The involvement of ferroptosis, a form of oxidative cell death in lipotoxic β-cell injury remains uncertain. Here, we have shown that PA induces intracellular lipid peroxidation, increases intracellular Fe2+ content and decreases intracellular glutathione peroxidase 4 (GPX4) expression. Furthermore, PA causes distinct changes in pancreatic islets and INS-1 cells, such as mitochondrial atrophy and increased membrane density. Furthermore, the presence of the ferroptosis inhibitor has a significant mitigating effect on PA-induced β-cell damage. Mechanistically, PA increased ceramide content and c-Jun N-terminal kinase (JNK) phosphorylation. The ceramide synthase inhibitor effectively attenuated PA-induced β-cell damage and GPX4/Fe2+ abnormalities, while inhibiting JNK phosphorylation. Additionally, the JNK inhibitor SP600125 improved PA-induced cell damage. In conclusion, by promoting ceramide synthesis, PA inhibited GPX4 expression and increased intracellular Fe2+ to induce β-cell ferroptosis. Moreover, JNK may be a downstream mechanism of ceramide-triggered lipotoxic ferroptosis in β-cells.

Epidemiological studies have suggested a correlation between bisphenol A (BPA) and type 2 diabetes (T2DM). The effects of BPA on β-cell dysfunction may reveal the risks from an in vitro perspective. We used the rat insulinoma (INS-1) cell lines (a type of β-cells) to set up normal or damaged models (DM), which were exposed to various concentrations of BPA (0.001, 0.01, 0.1, 1, 10 and 100 μM). An increase in reactive oxygen species (ROS) and apoptosis, and a decrease in cell viability were observed in INS-1 cells exposed to high doses of BPA for 48 h. Interestingly, exposure to lower doses of BPA for 24 h resulted in increased ROS levels and apoptosis rates in INS-1 in the DM group, along with decreased cell viability, suggesting that BPA exerts toxicity to INS-1 cells, particularly to the DM group. Insulin levels and Glut2 expression, glucose consumption, intracellular Ca2+ and insulin secretion were increased in INS-1 cells after 48 h exposure to high dose of BPA. Stronger effects were observed in the DM group, even those exposed to low doses of BPA for 24 h. Moreover, BPA inhibited high glucose-stimulated insulin secretion in these cells. Our research suggests that low doses of BPA exacerbate the dysfunction caused by glucolipotoxicity, implying environmental BPA exposure poses a risk for individuals with prediabetes or T2DM.

The loss or dysfunction of pancreatic β-cells, which are responsible for insulin secretion, constitutes the foundation of all forms of diabetes, a widely prevalent disease worldwide. The replacement of damaged β-cells with regenerated or transplanted cells derived from stem cells is a promising therapeutic strategy. However, inducing the differentiation of stem cells into fully functional glucose-responsive β-cells in vitro has proven to be challenging. Noncoding RNAs (ncRNAs) have emerged as critical regulatory factors governing the differentiation, identity, and function of β-cells. Furthermore, engineered hydrogel systems, biomaterials, and organ-like structures possess engineering characteristics that can provide a three-dimensional (3D) microenvironment that supports stem cell differentiation. This review summarizes the roles and contributions of ncRNAs in maintaining the differentiation, identity, and function of β-cells. And it focuses on regulating the levels of ncRNAs in stem cells to activate β-cell genetic programs for generating alternative β-cells and discusses how to manipulate ncRNA expression by combining hydrogel systems and other tissue engineering materials. Elucidating the patterns of ncRNA-mediated regulation in β-cell biology and utilizing this knowledge to control stem cell differentiation may offer promising therapeutic strategies for generating functional insulin-producing cells in diabetes cell replacement therapy and tissue engineering.

Glutathione (GSH), a robust endogenous antioxidant, actively participates in the modulation of the redox status of cysteine residues in proteins. Previous studies have indicated that GSH can prevent β-cell failure and prediabetes caused by chronic oscillating glucose (OsG) administration. However, the precise mechanism underlying the protective effect is not well understood. Our current research reveals that GSH is capable of reversing the reduction in Nrf2 levels, as well as downstream genes Grx1 and HO-1, in the islet β-cells of rats induced by chronic OsG. In vitro experiments have further demonstrated that GSH can prevent β-cell dedifferentiation, apoptosis, and impaired insulin secretion caused by OsG. Additionally, GSH facilitates the translocation of Nrf2 into the nucleus, resulting in an upregulation of Nrf2-targeted genes such as GCLC, Grx1, HO-1, and NQO1. Notably, when the Nrf2 inhibitor ML385 is employed, the effects of GSH on OsG-treated β-cells are abrogated. Moreover, GSH enhances the S-glutathionylation of Keap1 at Cys273 and Cys288, but not Cys151, in OsG-treated β-cells, leading to the dissociation of Nrf2 from Keap1 and facilitating Nrf2 nuclear translocation. In conclusion, the protective role of GSH against OsG-induced β-cell failure can be partially attributed to its capacity to enhance Keap1 S-glutathionylation, thereby activating the Nrf2 signaling pathway. These findings provide novel insights into the prevention and treatment of β-cell failure in the context of prediabetes/diabetes, highlighting the potential of GSH.

OBJECTIVE: Early evaluation of β-cell dysfunction of hyperglycemic patients in asymptomatic adults would be valuable for timely prevention of the diabetes. This study aimed to evaluate functional changes in the pancreas using intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and determine whether it could be used as a non-invasive method of assessing β-cell dysfunction.
METHODS: This prospective cohort study was conducted from August 2022 to November 2022 in Jinan University Affiliated Guangdong Second General Hospital. Three groups were enrolled and underwent IVIM-DWI: confirmed patients with type 2 diabetes (T2DM); hyperglycemic patients in asymptomatic adults; and the volunteers with normal glucose tolerance (NGT). Imaging parameters were obtained: apparent diffusion coefficient (ADC), the true diffusion coefficient (Dt), the pseudo-diffusion coefficient (Dp), and the perfusion fraction (f). The β-cell function indexes were calculated from blood examinations: composite insulin sensitivity index (ISI), 60-min insulinogenic index (IGI60), and the disposition index (DI). We compared imaging parameters among three groups, calculated the diagnostic performance of them for differentiating different groups, and the reproducibility of them was evaluated using intraclass correlation coefficient (ICC).
RESULTS: The imaging parameters except f gradually decreased among the groups with significant differences for ADC (p < 0.0001), Dt (p < 0.0001), and Dp (p = 0.013). Dt demonstrated the best diagnostic performance for differentiating asymptomatic patients from NGT (Area Under Curve [AUC] = 0.815, p < 0.0001). IVIM-DWI parameters correlated with composite ISI and DI, of which, Dt has the highest correlation with DI (Pearson correlation coefficient [r] = 0.546, p < 0.0001). The ICC of IVIM-DWI parameters was very good, Dt was highest (Interobserver ICC = 0.938, 95% Confidence Interval [CI], 0.899-0.963; Intraobserver ICC = 0.941, 95% CI, 0.904-0.965).
CONCLUSIONS: IVIM-DWI is a non-invasive quantitative method that can identify β-cell dysfunction in the pancreas.

OBJECTIVE: FoxO1 is an important factor in the β-cell differentiation in type 2 diabetes mellitus (T2DM). Sirt3 is found to be involved in FoxO1 function. This study investigated the role of Sirt3 in the β-cell dedifferentiation and its mechanism.
METHODS: Twelve-week-old db/db mice and INS1 cells transfected with Sirt3-specific short hairpin RNA (shSirt3) were used to evaluate the dedifferentiation of β-cell. Insulin levels were measured by enzyme linked immunosorbent assay. The proteins of Sirt3, T-FoxO1, Ac-FoxO1 and differentiation indexes such as NGN3, OCT4, MAFA were determined by western blot or immunofluorescence staining. The combination of Sirt3 and FoxO1 was determined by the co-immunoprecipitation assay. The transcriptional activity of FoxO1 was detected by dual luciferase reporter assay.
RESULTS: Both the in vivo and in vitro results showed that Sirt3 was decreased along with β-cell dedifferentiation and decreased function of insulin secretion under high glucose conditions. When Sirt3 was knocked down in INS1 cells, increased β-cell dedifferentiation and lowered insulin secretion were observed. This effect was closely related to the amount loss and the decreased deacetylation of FoxO1, which resulted in a reduction in transcriptional activity.
CONCLUSIONS: Downregulation of Sirt3 contributes to β-cell dedifferentiation in high glucose via FoxO1. Intervention of Sirt3 may be an effective approach to prevent β-cell failure in T2DM.

The skeleton is traditionally known for its structural support, organ protection, movement, and maintenance of mineral homeostasis. Over the last 10 years, bone has emerged as an endocrine organ with diverse physiological functions. The two key molecules in this context are fibroblast growth factor 23 (FGF23), secreted by osteocytes, and osteocalcin, a hormone produced by osteoblasts. FGF23 affects mineral homeostasis through its actions on the kidneys, and osteocalcin has beneficial effects in improving glucose homeostasis, muscle function, brain development, cognition, and male fertility. In addition, another osteoblast-derived hormone, lipocalin 2 (LCN2) has emerged into the researchers\' field of vision. In this review, we mainly focus on LCN2\'s role in appetite regulation and glucose metabolism and also briefly introduce its effects in other pathophysiological conditions, such as nonalcoholic fatty liver disease, sarcopenic obesity, and cancer-induced cachexia.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a frequently occurring complication during pregnancy and has adverse effects on both mother and offspring. β-Cell dysfunction and inflammation play important roles in GDM pathogenesis. Cornuside (CNS) is an iridoid glycoside that exhibits anti-inflammation activities. In the present study, we explored the effects of CNS on β-cell and GDM.
METHODS: MIN6 β-cell line cells were treated with varying concentrations of CNS. The content and secretion of insulin were measured.
METHODS: The expression of Pdx1, Rac1, Piezo, and NeuroD1 and cell proliferation in CNS-treated MIN6 cells were detected. CNS was administered to GDM mice, and the symptoms of GDM, expression of IL-6 and TNF-α, and activation of NF-κB in GDM mice were measured.
RESULTS: CNS promoted cell proliferation of MIN6 cells, enhanced insulin content and secretion, and expression of Pdx1, Rac1, Piezo, and NeuroD1 in MIN6 cells. CNS alleviated symptoms of GDM mice and decreased serum levels of IL-6 and TNF-α in GDM mice. CNS suppressed the expression of IL-6 and TNF-α, as well as the activation of NF-κB in the placenta of GDM mice.
CONCLUSIONS: CNS ameliorates GDM symptoms by suppressing inflammation and enhancing β-cell functions.

Protein phosphatase 2A (PP2A) is one of the most common serine/threonine phosphatases in mammalian cells, and it primarily functions to regulate cell signaling, glycolipid metabolism and apoptosis. The catalytic subunit of PP2A (PP2Ac) plays an important role in the functions of the protein. However, there are few reports on the regulatory role of PP2Ac in pancreatic β-cells under lipotoxic conditions. In the present study, mouse insulinoma 6 (MIN6) pancreatic cells were transfected with short hairpin RNAs to generate PP2Ac knockdown cells and incubated with palmitate (PA) to establish a lipotoxicity model. Serine/threonine phosphatase assay system, Cell Counting Kit-8, flow cytometry, enzyme-linked immunosorbent assay and western blotting were used to measure PP2A activity, cell viability, apoptosis, oxidative stress and insulin secretion in the cells. In addition, a mouse model of lipotoxicity was established with a high-fat diet (HFD) and the knockdown of PP2Ac using adeno-associated viruses to interfere with PP2Ac expression in the pancreatic tissues. The activity of PP2A in the mouse pancreatic tissue and the serum insulin level were measured. Furthermore, the proliferation of mouse pancreatic β-cells was assessed using pancreatic tissue immunofluorescence. PP2Ac knockdown inhibited lipotoxicity-induced PP2A hyperactivation, increased the resistance of pancreatic β-cells to lipotoxicity and attenuated PA-induced apoptosis in MIN6 cells. It also protected the endoplasmic reticulum and mitochondria, and ameliorated insulin secretion. The results of mRNA sequencing and western blotting analysis suggested that the protective effects of PP2Ac knockdown in MIN6 cells may be mediated via the MAPK pathway. Moreover, the results of the animal experiments suggested that specific knockdown of pancreatic PP2Ac effectively attenuated HFD-induced insulin resistance and reduced the compensatory proliferation of pancreatic β-cells in mice. In summary, the present study revealed the effects of interfering with PP2Ac gene expression on pancreatic β-cells in vivo and in vitro and the underlying mechanisms, which may provide insights for the treatment of type 2 diabetes mellitus in the clinic.

Oleanolic acid (OA) and moderate drinking have been reported to attenuate diabetes. However, the underlying mechanism of OA and moderate drinking alone or in combination on the islet β-cell deficiency induced diabetes is not fully elucidated.
Male Sprague Dawley (SD) rats were intraperitoneally injected with 55 mg/kg streptozotocin (STZ) to induce β-cell deficiency. OA, 5% ethanol (EtOH), or a mixture of OA in 5% ethanol (OA+EtOH) were applied to three treatment groups of hyperglycemia rats for 6 weeks.
STZ caused the increase of fast blood glucose (FBG) level.OA and EtOH treatment alone or in combination decreased the STZ increased FBG level during the 6 weeks of treatment. In addition, OA treatment also significantly increased the β-cell to total islet cell ratio. Both EtOH and OA+EtOH treatments promoted the increase of total islet cell number and α-cell to β-cell ratio when compared to OA group. STZ induced hyperglycemia dramatically reduced the glucagon-like peptide-1 receptor (GLP-1R) positive cells in islets, all the three treatments significantly increased the pancreatic GLP-1R positive cell number. In the meantime, STZ induced hyperglycemia suppressed the insulin mRNA expression and boosted the glucagon mRNA expression. EtOH and OA+EtOH treatments increased the insulin mRNA expression, but none of the 3 treatments altered the elevated glucagon level.
GLP-1R positive cell ratio in islets is crucial for the blood glucose level of diabetes. OA and 5% ethanol alone or in combination suppresses the blood glucose level of β-cell deficiency induced diabetes by increasing islet GLP-1R expression.