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Introduction It is well‐known that when pancreatic β‐cells are chronically exposed to hyperglycemia under diabetic conditions, β‐cell function is gradually deteriorating. Although such phenomena were well‐known as β‐cell glucose toxicity in clinical practice, its molecular mechanism remained unknown. Results It has been revealed that expression levels of insulin gene transcription factors and incretin receptors are downregulated, which is closely associated with β‐cell glucose toxicity. In addition, we have reported that it is more beneficial to use incretin‐based drugs at an early stage of diabetes when incretin receptor expression in β‐cells is preserved. Furthermore, we have reported that it is more beneficial for the prevention of atherosclerosis to use incretin‐based drugs at an early stage when incretin receptor expression in arterial cells is preserved. On the other hand, although clinical trials with imeglimin in human subjects clearly indicated its efficacy and safety, its precise mechanism on β‐cells remained unknown. However, to address this clinical question, we performed some basic experiments and confirmed the beneficial effects of imeglimin on mitochondrial morphology in β‐cells and/or the number and quality of insulin granules, which can explain the effects of imeglimin on β‐cells observed in clinical practice. In addition, we demonstrated that imeglimin exerted favorable effects on the development of atherosclerosis. Conclusion In this review article, we would like to show the importance of translational research bridging clinical practice and basic research, especially focusing on the molecular mechanism for pancreatic β‐cell dysfunction and atherosclerosis and on the protective effects of imeglimin against β‐cell dysfunction and atherosclerosis.

Background Recent studies have demonstrated a relationship between fructose consumption and risk of developing metabolic syndrome. Mechanisms by which dietary fructose mediates metabolic changes are poorly understood. This study compared the effects of fructose, glucose and sucrose consumption on post-postprandial lipemia and low grade inflammation measured as hs-CRP. Methods This was a randomized, single blinded, cross-over trial involving healthy subjects (n = 14). After an overnight fast, participants were given one of 3 different isocaloric drinks, containing 50 g of either fructose or glucose or sucrose dissolved in water. Blood samples were collected at baseline, 30, 60 and 120 minutes post intervention for the analysis of blood lipids, glucose, insulin and high sensitivity C-reactive protein (hs-CRP). Results Glucose and sucrose supplementation initially resulted in a significant increase in glucose and insulin levels compared to fructose supplementation and returned to near baseline values within 2 hours. Change in plasma cholesterol, LDL and HDL-cholesterol (measured as area under curve, AUC) was significantly higher when participants consumed fructose compared with glucose or sucrose (P < 0.05). AUC for plasma triglyceride levels however remained unchanged regardless of the dietary intervention. Change in AUC for hs-CRP was also significantly higher in subjects consuming fructose compared with those consuming glucose (P < 0.05), but not sucrose (P = 0.07). Conclusion This study demonstrates that fructose as a sole source of energy modulates plasma lipids and hsCRP levels in healthy individuals. The significance of increase in HDL-cholesterol with a concurrent increase in LDL-cholesterol and elevated hs-CRP levels remains to be delineated when considering health effects of feeding fructose-rich diets. Registration number for clinical trials ACTRN 12614000431628

Metformin, a drug widely used in type 2 diabetes (T2D), has been shown to protect human β-cells exposed to gluco- and/or lipotoxic conditions and those in islets from T2D donors. We assessed whether metformin could relieve the human β-cell stress induced by pro-inflammatory cytokines (which mediate β-cells damage in type 1 diabetes, T1D) and investigated the underlying mechanisms using shotgun proteomics. Human islets were exposed to 50 U/mL interleukin-1β plus 1000 U/mL interferon-γ for 48 h, with or without 2.4 µg/mL metformin. Glucose-stimulated insulin secretion (GSIS) and caspase 3/7 activity were studied, and a shotgun label free proteomics analysis was performed. Metformin prevented the reduction of GSIS and the activation of caspase 3/7 induced by cytokines. Proteomics analysis identified more than 3000 proteins in human islets. Cytokines alone altered the expression of 244 proteins (145 up- and 99 down-regulated), while, in the presence of metformin, cytokine-exposure modified the expression of 231 proteins (128 up- and 103 downregulated). Among the proteins inversely regulated in the two conditions, we found proteins involved in vesicle motility, defense against oxidative stress (including peroxiredoxins), metabolism, protein synthesis, glycolysis and its regulation, and cytoskeletal proteins. Metformin inhibited pathways linked to inflammation, immune reactions, mammalian target of rapamycin (mTOR) signaling, and cell senescence. Some of the changes were confirmed by Western blot. Therefore, metformin prevented part of the deleterious actions of pro-inflammatory cytokines in human β-cells, which was accompanied by islet proteome modifications. This suggests that metformin, besides use in T2D, might be considered for β-cell protection in other types of diabetes, possibly including early T1D.

Oxidative stress is implicated in hyperglycemia-induced alterations in cell signaling pathways. We examined the toxicity of high glucose in primary rat hepatocytes and its amelioration by naringenin. Incubation of hepatocytes with 40 mM glucose for 1.5 h exhibited significant decrease in cell viability confirmed by MTT reduction and Alamar blue assay. At the same time primary rat hepatocytes exhibited significant decrease in mitochondrial membrane potential indicating organelle dysfunction. Enhanced translocation of Cyt-c from mitochondria to cytosol and AIF/Endo-G from mitochondria to nucleus, activation of caspase-9/3, DNA damage, and chromatin condensation were observed in glucose-stressed hepatocytes, indicating the involvement of mitochondrial pathway in high glucose-induced apoptosis. Transcript levels of antioxidant enzymes were significantly altered along with corresponding changes in their enzymatic activities. The level of intracellular antioxidant glutathione as well as superoxide dismutase, catalase, and glutathione peroxidase activities were observed to be significantly decreased in hepatocytes treated with high concentration of glucose. Naringenin, a flavanone, was effective in preventing loss of cell viability, reactive oxygen species generation, and decline in antioxidant defense. Translocation of AIF, Endo-G, and Cyt-c from mitochondria was also inhibited by naringenin in glucose-stressed cells. Messenger RNA expression of anti-apoptotic and apoptotic genes, externalization of phosphatidyl serine, DNA damage, chromatin condensation, and sub-diploid cell population were effectively altered by naringenin indicating its anti-apoptotic potential in vitro. Our data suggests that naringenin can prevent apoptosis induced by high glucose through scavenging of reactive oxygen species and modulation of mitochondria-mediated apoptotic pathway.

Type 2 diabetes is characterized by a relentless decline in pancreatic islet beta cell function and worsening hyperglycemia despite optimal medical treatment. Our central hypothesis is that residual hyperglycemia, especially after meals, generates reactive oxygen species (ROS), which in turn causes chronic oxidative stress on the beta cell. This hypothesis is supported by several observations. Exposure of isolated islets to high glucose concentrations induces increases in intracellular peroxide levels. The beta cell has very low intrinsic levels of antioxidant proteins and activities and thus is very vulnerable to ROS. Treatment with antioxidants protects animal models of type 2 diabetes against complete development of phenotypic hyperglycemia. The molecular mechanisms responsible for the glucose toxic effect on beta cell function involves disappearance of two important regulators of insulin promoter activity, PDX-1 and MafA. Antioxidant treatment in vitro prevents disappearance of these two transcription factors and normalizes insulin gene expression. These observations suggest that the ancillary treatment with antioxidants may improve outcomes of standard therapy of type 2 diabetes in humans.

Carbon dots (CDs) are photoluminescent nanomaterials with wide-ranging applications. Despite their photoactivity, it remains unknown whether CDs degrade under illumination and whether such photodegradation poses any cytotoxic effects. Here, we show laboratory-synthesized CDs irradiated with light degrade into molecules that are toxic to both normal (HEK-293) and cancerous (HeLa and HepG2) human cells. Eight days of irradiation photolyzes 28.6-59.8% of the CDs to <3 kilo Dalton molecules, 1431 of which are detected by high-throughput, non-target high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Molecular network and community analysis further reveal 499 cytotoxicity-related molecules, 212 of which contain polyethylene glycol, glucose, or benzene-related structures. Photo-induced production of hydroxyl and alkyl radicals play important roles in CD degradation as affected by temperature, pH, light intensity and wavelength. Commercial CDs show similar photodegraded products and cytotoxicity profiles, demonstrating that photodegradation-induced cytotoxicity is likely common to CDs regardless of their chemical composition. Our results highlight the importance of light in cytocompatibility studies of CDs. Carbon dots have attracted much attention for biomedical applications but potential degradation and associated toxicity are still poorly understood. Here, the authors report on a study into the photo-degradation of carbon dots, the products produced and associated cytotoxicity.

Hyperglycemia, oxidative stress and apoptosis have key roles in pathogenesis of diabetic neuropathy. There are local renin-angiotensin systems (RASs) in different tissues such as neural tissue. Local RASs are involved in physiological and pathophysiological processes such as inflammation, proliferation and apoptosis. This study aimed to investigate the role of local renin-angiotensin system on high glucose-induced cell toxicity, apoptosis and reactive oxygen species (ROS) production in PC12 cells, as a cell model of diabetic neuropathy. PC12 cells were exposed to a high glucose concentration (27 mg/ml), captopril (ACE inhibitor), telmisartan and losartan (AT1 antagonists), and also PD123319 (AT2 antagonist) were administered before and after induction of high glucose toxicity. Then cell viability was assessed by MTT assay and apoptotic cells and intracellular ROS production were detected by annexin V-propidium iodide and DCFDA, respectively, using flow cytometry. High glucose concentration decreased cell viability, and increased apoptotic cells. Intracellular ROS production was also increased. In PC12 cells pretreatment and treatment by the drugs showed a significant improvement in cell viability and reduced apoptosis in captopril, telmisartan and PD123319 but only captopril and telmisartan were able to reduce ROS production. Losrtan significantly lowered ROS but didn't show any improvements in cell viability and apoptotic cells. The results of the present study showed that RAS inhibitors reduced cell toxicity and apoptosis and ROS production was induced by high glucose. It may be suggested that local RAS has a role in high glucose toxicity.

Diabetes mellitus is a disease characterized by a range of metabolic complications involving an individual's blood glucose levels, and its main regulator, insulin. These complications can vary largely from person to person depending on their current biophysical state. Biomedical research day-by-day makes strides to impact the lives of patients of a variety of diseases, including diabetes. One large stride that is being made is the generation of techniques to assist physicians to ``personalize medicine''.From available physiological data, biological understanding of the system, and dimensional analysis, a differential equation-based mathematical model was built in a sequential matter, to be able to elucidate clearly how each parameter correlates to the patient's current physiological state. We developed a simple mathematical model that accurately simulates the dynamics between glucose, insulin, and pancreatic β -cells throughout disease progression with constraints to maintain biological relevance. The current framework is clearly capable of tracking the patient's current progress through the disease, dependent on factors such as latent insulin resistance or an attrite β -cell population. Further interests would be to develop tools that allow the direct and feasible testing of how effective a given plan of treatment would be at returning the patient to a desirable biophysical state.

O-GlcNAcylation has been implicated in the tumorigenesis of various tissue origins, but its function in liver tumorigenesis is not clear. Here, we demonstrate that O-GlcNAcylation can enhance the expression, stability and function of Yes-associated protein (YAP), the downstream transcriptional regulator of the Hippo pathway and a potent oncogenic factor in liver cancer. O-GlcNAcylation induces transformative phenotypes of liver cancer cells in a YAP-dependent manner. An O-GlcNAc site of YAP was identified at Thr241, and mutating this site decreased the O-GlcNAcylation, stability, and pro-tumorigenic capacities of YAP, while increasing YAP phosphorylation. Importantly, we found via in vitro cell-based and in vivo mouse model experiments that O-GlcNAcylation of YAP was required for high-glucose-induced liver tumorigenesis. Interestingly, a positive feedback between YAP and global cellular O-GlcNAcylation is also uncovered. We conclude that YAP O-GlcNAcylation is a potential therapeutic intervention point for treating liver cancer associated with high blood glucose levels and possibly diabetes. Yap is a transcriptional factor involved in tumorigenesis. Here the authors show that a previously unknown post-translational modification of Yap, O-GlcNAcylation, increases its transcriptional activity and is required for high glucose-induced liver cancer development.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are anti-hyperglycemic agents that prevent glucose reabsorption in proximal tubular cells. SGLT2i improves renal outcomes in both diabetic and non-diabetic patients, indicating it may have beneficial effects beyond glycemic control. Here, we demonstrate that SGLT2i affects energy metabolism and podocyte lipotoxicity in experimental Alport syndrome (AS). In vitro, we found that the SGLT2 protein was expressed in human and mouse podocytes to a similar extent in tubular cells. Newly established immortalized podocytes from Col4a3 knockout mice (AS podocytes) accumulate lipid droplets along with increased apoptosis when compared to wild-type podocytes. Treatment with SGLT2i empagliflozin reduces lipid droplet accumulation and apoptosis in AS podocytes. Empagliflozin inhibits the utilization of glucose/pyruvate as a metabolic substrate in AS podocytes but not in AS tubular cells. In vivo, we demonstrate that empagliflozin reduces albuminuria and prolongs the survival of AS mice. Empagliflozin-treated AS mice show decreased serum blood urea nitrogen and creatinine levels in association with reduced triglyceride and cholesterol ester content in kidney cortices when compared to AS mice. Lipid accumulation in kidney cortices correlates with a decline in renal function. In summary, empagliflozin reduces podocyte lipotoxicity and improves kidney function in experimental AS in association with the energy substrates switch from glucose to fatty acids in podocytes.