Insulin resistance, defined as the inability of the insulin-target tissues including skeletal muscles to insulin action, has been identified as a major pathophysiology associated with the development of metabolic disorders including type 2 diabetes mellitus. Palmitic acid (PA) and related saturated free fatty acids contribute significantly to the development of insulin resistance by perturbing the redox homeostasis in the cells. The deficiency of the intracellular antioxidant - glutathione (GSH) has been documented in insulin-resistant states, and dietary supplementation of GSH and its precursors has been associated with the alleviation of oxidative stress, restoration of intra-abdominal fat levels, enhancement of insulin sensitivity and glucose metabolism. However, the key metabolic pathways targeted by GSH in mediating this protection need to be identified so that they can be targeted for effective management of insulin resistance. In this study, we aimed to elucidate whether preconditioning and supplementation with GSH (0.1 and 1 mM) could alleviate the oxidative stress, mitochondrial dysfunction, and metabolic perturbations induced by PA in the L6 skeletal myotubes. Metabolic perturbations associated with the same were identified using 1H NMR spectroscopy. It was observed GSH supplementation at concentrations of 1 mM in the myotubes experiencing lipotoxicity led to the partial restoration of metabolic imbalances observed in levels of nucleotides (UMP, adenosine, AMP), GSH metabolism intermediates (glutamine, pyroglutamate), acetate, amino acids including proline, aspartate, threonine; phospholipid intermediates (o-phosphocholine, choline), niacinamide, TCA cycle intermediates (citrate), and glycerol. Thus, we believe that these metabolic pathways can be targeted for the management of lipotoxicity and insulin resistance.

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder caused by the loss of insulin-producing pancreatic β-cells. This study aims to explore the correlation between hyperglycemia and concurrent metabolic perturbations during T1DM development to help identify biomarkers that differentiate between the early and established stages. Streptozotocin (STZ), a glucosamine nitrosourea compound, induces T1DM. Dose- and time-dependent studies were conducted in 7-8-week-old male C57BL/6 mice, who were administered increasing numbers of STZ injections (N = 0-5) and were followed for 15 (early) and 60 (late) days. The development of hyperglycemia was confirmed by performing an oral glucose tolerance test and an insulin tolerance test. A total of 50 abundant aqueous serum metabolites were identified and quantified using 1H NMR spectroscopy. In addition to glucose, a well-established biomarker for T1DM, a panel of 5 significantly perturbed metabolites (namely, leucine, choline, lactate, lysine, and mannose), Diagnostic Molecular Fingerprint (DMF), was identified. Unlike glucose levels, the proposed DMF (in combination with glucose) could differentiate not only between early and established stages of T1DM but also between young and aged healthy controls. However, these results need validation in humanized animal models and well-characterized patient cohorts of different ethnicities. In conclusion, the results obtained have contributed toward increasing the understanding of the pathophysiology and mechanism of T1DM establishment and progression that would possibly aid in accurate diagnosis, prognosis, risk prediction, defining the distinct stages of T1DM, and help in enhancing patient outcomes in the future.

The development of insulin resistance (IR) in the skeletal muscle has been identified as one of the hallmarks of Type 2 diabetes mellitus (T2DM). Studies have shown that palmitic acid (PA), a saturated free fatty acid (FFA), can contribute to the development of IR in various insulin-responsive tissues via the induction of oxidative stress and mitochondrial dysfunction. The specific molecular mechanisms and metabolic changes that lead to IR development are not completely defined, and a better understanding of these mechanisms is needed. Our study aims to identify metabolites linked with the development of IR in skeletal muscles using PA and map the major metabolic pathways involved. Rat-derived L6 myotubes were exposed to PA to establish IR. Cellular and biochemical experiments were performed, and the metabolic perturbations associated with the induction of oxidative stress and IR were identified using 1H NMR-based metabolomics. PA exposure was associated with a loss of cellular viability due to lipid accumulation in the myotubes. This was associated with an induction of oxidative stress, loss of function, and reduced mitochondrial membrane potential. The metabolic fingerprint linked with the development of oxidative stress and IR in skeletal muscles was identified, wherein significant perturbations in the levels of methanol, dimethylamine, serine, lysine, proline, glycerol, and alanine (p < 0.05) were observed. The dysregulated metabolites and pathways identified in this study can be proposed as biomarkers for detecting palmitate-induced oxidative stress and development of IR in the skeletal myotubes - phenotypes associated with T2DM and related metabolic disorders.

Modulation of intracellular chloride ion concentration by artificially developed ion transporters has been known to induce apoptosis in cancer cells. However, most of these transporters cause harm to healthy cells as well, limiting their applicability in real biological systems. Here, we report a pyrrole-linked benzimidazolyl-hydrazone that self-assembles to form a nanochannel assembly across the lipid bilayer, enabling the selective translocation of HCl, a system rarely reported in the literature. The channel shows an extraordinarily high HCl transport activity with an EC50 value as low as 0.016 mol%, relative to lipid. We demonstrate solid-state evidence that compound 1 self-assembles in the presence of HCl to produce organized arrays that include chloride-filled and water-filled channels. The formation of a stable HCl channel across the lipid bilayer membrane was verified through electrophysiological experiments, detailed molecular dynamics (MD) simulations, and quantum mechanical calculations. When tested in cellular systems, the compound showed pronounced toxicity toward cancerous cell lines while remaining relatively nontoxic to cell lines of non-cancerous origin. Interestingly, compound 1 was also found to inhibit the growth and proliferation of MCF-7-derived 3D spheroids with higher efficiency when compared to the commercially available anticancer drug─doxorubicin (DOX).

Amyloid deposits formed by misfolding and aggregation of human islet amyloid polypeptide (hIAPP) are one of the key pathophysiological features of type 2 diabetes mellitus (T2DM) and have been associated with the loss of function and viability of the pancreatic β-cells. The molecular processes by which hIAPP induces cytotoxicity in these cells are not well understood. To the best of our knowledge, this is the first report describing findings from the combined analysis of Affymetrix microarray and high-throughput sequencing (HTS) Gene Expression Omnibus (GEO) datasets of hIAPP-transgenic (Tg) mice islets. In brief, using GEO data, we compared in silico the pancreatic islets obtained from hIAPP-Tg and wild-type mice. Affymetrix microarray datasets (GSE84423, GSE85380, and GSE94672) and HTS datasets (GSE135276 and GSE148809) were chosen. Weighted gene coexpression network analysis was performed using GSE135276 to identify the coexpressed gene networks and establish a correlation pattern between gene modules and hIAPP overexpression under hyperglycemic conditions. Subsequently, we analyzed differential gene expression with the remaining datasets. Network analysis was performed to identify hub genes and the associated pathways using Cytoscape. Key findings from the present study include identification of seven hub genes, namely, Ins2, Agt, Jun, Fos, CD44, Igf1, and Ppar-γ, significantly involved in the process(es) of insulin synthesis and secretion, development of insulin resistance, oxidative stress, inflammation, mitophagy, and apoptosis. In conclusion, we propose that these hub genes can help explain T2DM pathogenesis and can be potentially utilized to develop therapeutic interventions targeting hIAPP for clinical management of T2DM.

Few synthetic ion transporters have been reported incorporating indole as the core moiety. We have developed a novel bisindole-based transporter capable of efficient transmembrane anion antiport. This system induced cytotoxicity in MCF-7 breast cancer cells via chloride ion homeostasis disruption and the associated ROS generation, mitochondrial membrane depolarization, and lysosomal deacidification.

A novel, non-toxic cis-dioxomolybdenum-maltolate was synthesized as a model molybdopterin mimic for bioinspired oxidation reactions, which shows potential as a micronutrient supplement for molybdenum.

Background: The prevalence of type 2 diabetes mellitus (T2DM), a progressive metabolic disorder characterized by chronic hyperglycemia and the development of insulin resistance, has increased globally, with worrying statistics coming from children, adolescents, and young adults from developing countries like India. Here, we investigated unique circulating metabolic signatures associated with prediabetes and T2DM in an Indian cohort using NMR-based metabolomics. Materials and methods: The study subjects included healthy volunteers (N = 101), prediabetic subjects (N = 75), and T2DM patients (N = 108). Serum metabolic profiling was performed using 1 H NMR spectroscopy and major perturbed metabolites were identified by multivariate analysis and receiver operating characteristic (ROC) modules. Results: Of the 36 aqueous abundant metabolites, 24 showed a statistically significant difference between healthy volunteers, prediabetics, and established T2DM subjects. On performing multivariate ROC curve analysis with 5 commonly dysregulated metabolites (namely, glucose, pyroglutamate, o-phosphocholine, serine, and methionine) in prediabetes and T2DM, AUC values obtained were 0.96 (95 % confidence interval (CI) = 0.93, 0.98) for T2DM; and 0.88 (95 % CI = 0.81, 0.93) for prediabetic subjects, respectively. Conclusion: We propose that the identified metabolite panel can be used in the future as a biomarker for clinical diagnosis, patient surveillance, and for predicting individuals at risk for developing diabetes.

The human islet amyloid polypeptide (hIAPP) tends to misfold and self-assemble to form amyloid fibrils, which has been associated with the loss of function and viability of pancreatic (3-cells in type 2 diabetes mellitus (T2DM). The role of hIAPP in the development of insulin resistance (a hallmark of T2DM) in skeletal muscles - the major sites for glucose utilization - needs further investigation. Even though, insulin-resistant conditions have been known to stimulate hIAPP aggregation, the events that lead to the development of insulin resistance due to hIAPP aggregation in skeletal muscles remain unidentified. Here, we have attempted to identify metabolic perturbations in L6 myotubes that were exposed to increasing concentrations of recombinant hIAPP for different time durations. It was observed that hIAPP exposure was associated with increased mitochondrial and cellular ROS levels, loss in mitochondrial membrane potential and viability of the myotubes. Metabolomic investigations of hIAPP-treated myotubes revealed significant perturbations in o-phosphocholine, sn-glycero-3-phosphocholine and dimethylamine levels (p < 0.05). Therefore, we anticipate that defects in glycerophospholipid metabolism and the associated oxidative stress and membrane damage may play key roles in the development of insulin resistance due to protein misfolding in skeletal muscles. In summary, the perturbed metabolites and their pathways have not only the potential to be used as early biomarkers to predict the onset of insulin resistance and T2DM but also as therapeutic targets for the effective management of the same.

A short monodisperse poly(ethylene glycol) (PEG) and a neutral organic rotamer conjugate TEG-BTA-2 amphiphile was designed for the construction of a stimuli-responsive switchable self-assembled structure for drug encapsulation by noncovalent interaction and targeted controlled delivery. A short PEG, tetraethylene glycol (TEG) was covalently attached with a neutral organic rotamer benzothiazole dye (BTA-2) affording the neutral TEG-BTA-2 (<500 D). The TEG-BTA-2 is self-assembled into a microsphere in an aqueous medium, but remarkably undergoes morphology change switching to a rice-like microcapsule for curcumin encapsulation. Curcumin-loaded microcapsules were stable in an aqueous solution, however, were noticed disintegrating upon the addition of BSA protein. This is possibly due to an interaction with BSA protein leading to a protein affinity-controlled curcumin release in a neutral PBS buffer. Moreover, cell internalization of the neutral amphiphile TEG-BTA-2 into A549 cells was observed by fluorescence microscopy, providing an opportunity for application as a molecular vehicle for targeted drug delivery and monitoring.

Correction for 'Molybdenum-maltolate as a molybdopterin mimic for bioinspired oxidation reaction' by Swapnil S. Pawar et al., Dalton Trans., 2024, 53, 5770-5774, https://doi.org/10.1039/D3DT04296K.

COVID-19 disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to enormous morbidity and mortality worldwide. After gaining entry into the human host, the virus initially infects the upper and lower respiratory tract, subsequently invading multiple organs, including the pancreas. While on one hand, diabetes mellitus (DM) is a significant risk factor for severe COVID-19 infection and associated death, recent reports have shown the onset of DM in COVID-19-recovered patients. SARS-CoV-2 infiltrates the pancreatic islets and activates stress response and inflammatory signaling pathways, impairs glucose metabolism, and consequently leads to their death. Indeed, the pancreatic autopsy samples of COVID-19 patients reveal the presence of SARS-CoV-2 particles in β-cells. The current review describes how the virus enters the host cells and activates an immunological response. Further, it takes a closer look into the interrelationship between COVID-19 and DM with the aim to provide mechanistic insights into the process by which SARS-CoV-2 infects the pancreas and mediates dysfunction and death of endocrine islets. The effects of known anti-diabetic interventions for COVID-19 management are also discussed. The application of mesenchymal stem cells (MSCs) as a future therapy for pancreatic β-cells damage to reverse COVID-19-induced DM is also emphasized.

Fluctuations in the intracellular chloride ion concentration, mediated by synthetic ion transporters, have been known to induce cytotoxicity in cells by disrupting ionic homeostasis. However, the activity of these transporters in modulating autophagy remains largely unexplored. Here, we report a benzoylbenzohydrazide (1c) that self-assembles to form a supramolecular nanochannel lumen that allows selective and efficient transport of chloride ions across the cell membranes, disrupts ion homeostasis, and thus leads to the induction of apoptosis in cancer cells. It is important to note that the transporter was relatively nontoxic to cells of noncancerous origin. 1c was also shown to induce the deacidification of lysosomes, thereby disrupting autophagy in cancer cells. Taken together, these findings provide a rare example of an artificial ion channel that specifically targets cancer cells by induction of apoptosis via disruption of autophagy.

Type 2 diabetes mellitus (T2DM) is a non-communicable, metabolic disorder in which the loss of function and/or mass of pancreatic β-cells occurs. The incidence of T2DM is increasing worldwide and needs more efficient biomarkers for diagnosis along with better therapeutic interventions with fewer side effects. Transcriptomics analysis provides a complete overview of the molecular mechanisms involved at the system level to identify the set of genes that have stayed unnoticed so far for complex diseases, like T2DM. This study has been conducted to identify novel hub gene candidates for T2DM. Five human GEO datasets from pancreatic islets of normal healthy volunteers and T2DM subjects, namely, GSE118139, GSE20966, GSE25724, GSE38642 and GSE41762 were chosen and the differentially expressed genes were shortlisted. The overlapping hub genes between these datasets were identified, which included ERBB2, HGF, MET, MMP1, PDGFRA and PLAU as upregulated genes; and ABCC8, G6PC2, IAPP, PCSK1 and SLC2A2 as downregulated genes in the pancreatic islets from T2DM subjects. These hub genes could be developed as a panel for diagnosis/prognosis of T2DM in the population and can be targeted for drug development for more effective management of T2DM in the future.

Many synthetic glucokinase activators (GKAs), modulating glucokinase (GK), an important therapeutic target in diabetes have failed to clear clinical trials. In this study, an in silico structural similarity search with differing scaffolds of reference GKAs have been used to identify derivatives from natural product databases. Ten molecules with good binding score and similar interactions to that in the co-crystallized GK as well good activation against recombinant human GK experimentally were identified. Tetrahydropalmatine, an alkaloid present in formulations and drugs from medicinal plants, has not been explored as an antidiabetic agent and no information regarding its mechanism of action or GK activation exists. Tetrahydropalmatine activates GK with EC50 value of 71.7 ± 17.9 μM while lowering the S0.5 (7.1 mM) and increasing Vmax (9.22 μM/min) as compared to control without activator (S0.5 = 10.37 mM; Vmax = 4.8 μM/min). Kinetic data (α and β values) suggests it to act as mixed, nonessential type activator. Using microscale thermophoresis, Kd values of 3.8 μM suggests a good affinity for GK. In HepG2 cell line, the compound potentiated the uptake of glucose and maintained glucose homeostasis by increasing the expression of GK, glycogen synthase, and insulin receptor genes and lowering the expression of glucokinase regulatory protein (GKRP) and glucagon. Tetrahydropalmatine at low concentrations could elicit a good response by reducing expression of GKRP, increasing expression of GK while also activating it. Thus, it could be used alone or in combination as therapeutic drug as it could effectively modulate GK and alter glucose homeostasis.

Ion channels and transporters play key roles in various biological processes, including cell proliferation and programmed cell death. Recently, we reported that 2,4-dinitrobenzene-sulfonyl-protected N1,N3-dihexy-2hydroxyisophthalamide (1) forms ion channels upon activation by glutathione (GSH) and results in the induction of apoptosis by depleting the intracellular GSH reservoir in cancer cells. However, the detailed molecular events leading to the induction of apoptosis by these synthetic transport systems in cancer cells still need to be uncovered. Along these lines, we investigated the alterations in cellular metabolites and the associated metabolic pathways by performing untargeted global metabolic profiling of breast cancer cells - MCF-7 - using 1H NMRbased metabolomics. The evaluation of spectral profiles from MCF-7 cells exposed to 1 and their comparison with those corresponding to untreated (control) cells identified 14 significantly perturbed signature metabolites. These metabolites belonged mostly to antioxidant defence, energy metabolism, amino acid biosynthesis, and lipid metabolism pathways and included GSH, o-phosphocholine, malate, and aspartate, to name a few. These results would help us gain deeper insights into the molecular mechanism underlying 1-mediated cytotoxicity of MCF-7 cells and eventually help identify potential novel therapeutic targets for more effective cancer management.

NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a detoxifying enzyme overexpressed in tumors, plays a key role in protecting cancer cells against oxidative stress and thus has been considered an attractive candidate for activating prodrug(s). Herein, we report the first use of NQO1 for the selective activation of 'protransporter' systems in cancer cells leading to the induction of apoptosis. Salicylamides, easily synthesizable small molecules, have been effectively used for efficient H+ /Cl- symport across lipid membranes. The ion transport activity of salicylamides was efficiently abated by caging the OH group with NQO1 activatable quinones via either ether or ester linkage. The release of active transporters, following the reduction of quinone caged 'protransporters' by NQO1, was verified. Both the transporters and protransporters exhibited significant toxicity towards the MCF-7 breast cancer line, mediated via the induction of oxidative stress, mitochondrial membrane depolarization, and lysosomal deacidification. Induction of cell death via intrinsic apoptotic pathway was verified by monitoring PARP1 cleavage.

Type 2 diabetes mellitus (T2DM) and other metabolic disorders are often silent and go unnoticed in patients because of the lack of suitable prognostic and diagnostic markers. The current therapeutic regimens available for managing T2DM do not reverse diabetes; instead, they delay the progression of diabetes. Their efficacy (in principle) may be significantly improved if implemented at earlier stages. The misfolding and aggregation of human islet amyloid polypeptide (hIAPP) or amylin has been associated with a gradual decrease in pancreatic β-cell function and mass in patients with T2DM. Hence, hIAPP has been recognized as a therapeutic target for managing T2DM. This review summarizes hIAPP's role in mediating dysfunction and apoptosis in pancreatic β-cells via induction of endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction, inflammatory cytokine secretion, autophagy blockade, etc. Furthermore, it explores the possibility of using intermediates of the hIAPP aggregation pathway as potential drug targets for T2DM management. Finally, the effects of common antidiabetic molecules and repurposed drugs; other hIAPP mimetics and peptides; small organic molecules and natural compounds; nanoparticles, nanobodies, and quantum dots; metals and metal complexes; and chaperones that have demonstrated potential to inhibit and/or reverse hIAPP aggregation and can, therefore, be further developed for managing T2DM have been discussed.