Hyperglycemia In Mice Research Articles

THE EFFECT OF CORN SILK ETHANOL EXTRACT (Zea mays L.) ON THE BLOOD GLUCOSE LEVELS AND HISTOPATHOLOGY OF PANCREAS IN ALLOXAN-INDUCED MICE

Diabetes Mellitus is a metabolic disorder that occurs because pancreatic cells produce insulin in small amounts. The purpose of this study was to determine the effect of giving corn silk (Stigma maydis) to alloxan-induced mice to determine the effective dose of corn silk extract that can reduce blood glucose levels in hyperglycemic mice and histopathological features. This research is an experimental type that uses 24 male white mice as experimental animals, divided into 6 groups and each group consists of 4 mice consisting of negative control, positive control, dose variation 100mg/kgBW, 200mg/kgBW, 400mg/kgBW and the comparison group (Glibenclamide 0.65mg/kgBW). The inducer used was alloxan 150 mg/kg bw. Alloxan induction was carried out for 3 days and then the test preparation was given until the 17th day. Mice's blood was taken through the lateral tail vein to see blood sugar levels. Based on the results of measuring the blood glucose levels of mice on day 17, the average value of blood glucose levels was negative control (86.25 mg/dl), positive control (223 mg/dl), dose 100 mg/kgbb (109.75 mg /dl), dose 200 mg/kgbb (103.5 mg/dl), dose 400 mg/kgbb (92.5 mg/dl), glibenclamide 0.65mg/kgbb (95 mg/dl). Based on the results of statistical data analysis, two-way ANOVA showed significantly different results (p<0.05). The results of reducing blood glucose levels that were closest to the negative control were shown by corn silk extract at a dose of 400 mg/kgbb, while histopathological observations of the pancreas after administration of ethanol extract of corn silk at a dose of 200 mg/kgbb showed the best healing in the islets of Langerhans.

Sequential extraction and characterization of tea cell wall polysaccharides: Exploring the synergistic hypoglycemic potential with tea polyphenols via TGR5/GLP-1 pathway

Tea polyphenols (TP) and tea polysaccharides (TPS) are the two main hypoglycemic substances in tea. While the hypoglycemic activities of TPS and TP have been extensively reported, there remains a paucity of evidence regarding their synergistic regulation of hypoglycemic function. In this study, water-soluble polysaccharides and cell wall polysaccharides were firstly prepared from Yichang roasted green tea using sequential extraction method. Different types of tea polysaccharides, especially tea cell wall polysaccharides, exhibited diverse chemical compositions, molecular structures, and biological activities. The tea cell wall polysaccharides extracted with 4M NaOH (p4M-TPS) exhibited the highest inhibitory activity against different glycosidases. Furthermore, TPS (p4M-TPS) and TP (Epigallocatechin gallate, EGCG) were combined in different proportions to assess their hypoglycemic effect on hyperglycemic mice, and p4M-TPS-TP1:2 exhibited the most pronounced effect in promoting the expression of the TGR5/GLP-1 pathway to exert the synergistic anti-diabetic potential. This study firstly purified and characterized tea cell wall polysaccharide, and explored its potential hypoglycemic activity, thereby providing a valuable reference for the development of natural hypoglycemic functional products originating from tea active ingredients and their combinations, indicating the synergistic effect of tea active ingredients rather than just a single active ingredient.

Targeted deletion of the pancreatic β-cell oxytocin receptor and its effects on metabolic regulation and β-cell health

The neuropeptide oxytocin (OXT) and its receptor (OXTR) have been shown to play an important role in glucose metabolism, and pancreatic islets express this ligand and receptor. In the current study, OXTR expression was identified in α-, β-, and δ-cells of the pancreatic islet by in situ RNA hybridization, and OXT protein expression was observed only in β-cells. In order to examine the contribution of islet OXT/OXTR in glycemic control and islet β-cell heath, we developed a β-cell specific OXTR knock-out (β-KO) mouse. In isolated islets from control mice, OXT enhanced glucose stimulated secretion of insulin, but this response was abolished in the β-KO mice. In vivo, supraphysiological doses of OXT reduced blood glucose levels in hyperglycemic Control mice and during a glucose tolerance test. Once again, this response was abolished in the β-KO mice, suggesting that β-cell OXTR may play a role in glycemic regulation. Despite these findings, β-cell deletion of OXTR had no effect on fasting glucose, fasting insulin or glucose tolerance in mice fed a low fat- or high fat-diet for 23 weeks. The low fat or high fat diets did not alter β-cell mass by immundetection or a measure of apoptosis, however, β-KO mice on a high fat diet did exhibit increased β-cell proliferation. In mice treated with the cytotoxic agent, streptozotocin, deletion of OXTR resulted in greater hyperglycemia in β-KO mice relative control mice, suggesting that β-cell OXTR may provide some cytoprotection. In conclusion, the present study provides mixed support for a role of the β-cell OXTR in glycemic regulation. On one hand, in vitro experiments and in vivo pharmacologic experiments provided evidence that under hyperglycemia, OXTR activation can potentiate insulin secretion and glucose suppression. On the other hand, β-KO followed by chronic dietary manipulation had no effect on whole body glucose regulation in vivo. In terms of β-cell health, our data suggests a role of the OXTR in β-cell proliferation and cytoprotection following metabolic or cytotoxic challenge.

Preparation of Menthyl 3-amino-4-(2,4,5-trifluorophenyl) Butyrate and Investigation of its Hypoglycemic Activity.

3-Amino-4-(2,4,5-trifluorophenyl) butyric acid has potential pharmacological effects in promoting insulin secretion. Menthol promotes drug transdermal absorption and hypoglycemic effects. The objective of the study was to combine the 3-amino-4-(2,4,5- trifluorophenyl) butyric acid and menthol to develop a new candidate drug molecule that can be used as a hypoglycemic drug in type II diabetes. In this study, the molecular structure of 3-amino-4-(2,4,5-trifluorophenyl) butyric acid in sitagliptin was modified by replacing pyrazine imidazole with menthol. The structure of the target compound was characterized by nuclear magnetic resonance (NMR). The anti-diabetic activity of BHF in N000180 BKS.Cg-Dock7m+/ +Leprdb/Nju mice with spontaneous diabetes was preliminarily studied. A potential multi-target drug molecule, 3-amino-4-(2,4,5-trifluorophenyl) butyrate (BHF), was synthesized by combining 3-amino-4-(2,4,5-trifluorophenyl) butyric acid and menthol. BHF is suitable for hyperglycemic mice and has a significant hypoglycemic effect; the low dose of 10 mg/kg-1 started to be effective, and the high dose of 40 mg/kg-1 was more effective than the positive drug metformin. In this study, BHF has been synthesized and presented significant antidiabetic activities.

EVALUATION OF ANTI-DIABETIC ACTIVITY OF METHANOLIC EXTRACT FROM THE FRUIT PEEL OF ATALANTIA MONOPHYLLA (LINN.) IN ALLOXAN INDUCED DIABETIC MICE

Objective: Atlantia monophylla is an indigenous medicinal plant, with a folk reputation as hypoglycemic agent throughout India. Considerable research has shown that plants rich in flavonoids content with anti-oxidant potential are known to be bioactive for the management of diabetes mellitus (DM). In the present investigation, hypoglycemic activity of aqueous fruit peel extract of A. monophylla was evaluated using alloxan-induced hyperglycemic mice. Methods: Aqueous extract of the fruit peel of A. monophylla (AEAM) was subjected to preliminary phytochemical screening and acute oral toxicity study as per Organization for Economic Cooperation and Development guidelines 425. AEAM was evaluated for hypoglycemic activity, Alloxan induced DM in mice, oral glucose tolerance test in fasted mice. In vitro α- amylase inhibitory in albino mice method was employed for evaluation of hypoglycemic activity. Results: All of the mice in each group had their blood glucose levels measured both before and after the treatments on fasting animals. The extract was given at doses of 200 mg/kg and 400 mg/kg body weight, or 100 mg/kg body weight of the conventional antidiabetic medication Metformin. A glucometer was used to measure the blood glucose level. After 1 h, 2 h, and 4 h, the extract-treated diabetic mice had a substantial (p≤0.05) drop in blood glucose levels. The hypoglycemic action was similar to that of the medication Metformin used as a benchmark. Conclusion: The results of this study indicate that AEAM has strong hypoglycemic properties. One such method might include the activation of insulin receptors and subsequent release of insulin once β cells are stimulated. The hypoglycemic effect of the plant could be achieved through increasing insulin release from the pancreas.

8433 Elucidation of the Molecular Basis of Human and Mouse Pancreatic β-Cell Senescence Induced by Hyperglycemia

Abstract Disclosure: K. Iwasaki: None. P. Carapeto: None. C. Aguayo-Mazzucato: None. Background and AIM: Senescent cells accumulate with age and contribute to the development of chronic diseases, including Type 2 Diabetes (T2D). Whereas senescence is an important pathogenic mechanism in diabetes, the role of hyperglycemia as a metabolic driver of pancreatic β-cells has not been clarified. The aim of this study is to elucidate the molecular basis of hyperglycemia-induced pancreatic β-cell senescence using human and rodent islets. Methods: 1) Human islets were cultured for 2 weeks in 20.2 mM high (HG) or 2.8mM low glucose (LG), and analyzed by qPCR and glucose-responsive insulin secretion (GSIS) to explore the molecular basis of senescence in ex vivo. To test the effects of senescent cell removal, senolytics Dasatinib (1μM) and Quercetin (20μM) (DQ) were used. 2) To evaluate the effects of hyperglycemia in vivo, we transplanted mouse and human islets under the kidney capsule of normoglycemic (NG) or streptozocin-induced hyperglycemic (Stz-Db) immunodeficient mice for two weeks. Graft function was evaluated by intraperitoneal glucose tolerance test and cellular identity using qPCR or immunohistochemistry. DQ (5mg/kg/day + 50mg/kg/day) was used to evaluate the effects of removing senescent cells in transplantation (Tx). To investigate the effect of specific removal of p16-positive senescent β-cells in transplanted islets, INK-ATTAC mice islets (p16Ink4a-mediated apoptosis by targeted activation of caspases) were transplanted into Stz-Db and treated with BB homodimer (BB) to remove p16+ cells or vehicle. Results: (1) Human islets from 5 healthy donors cultured in HG had an increased senescence index (mean of senescence markers p16, p21 and HMGB1 mRNA) when compared to LG islets (p<0.05) and lost glucose responsiveness as evaluated by ex vivo GSIS compared to LG (p<0.05). 2) Human islets (1000IEQ) were transplanted to Stz-Db or NG mice. In Stz-Db graft, P21 mRNA significantly increased with decreased expression of β-cell genes when compared to NG. Stz-Db mice treated with DQ (Db-DQ) for 5 days after Tx, significantly decreased expression of senescence index (p<0.05) and increased in β-cell index (mean of β-cell hallmark genes) (p<0.05) at mRNA levels. Stz-Db mice transplanted with INK-ATTAC mice islets had lower fed glucose levels, decreased p16 mRNA, increased expression β-cell hallmark genes and improved insulin secretion ex vivo after removal of p16+ cells. Conclusion: Sustained exposure of human islets to hyperglycemia induced cellular senescence, leading to pancreatic β-cell dysfunction and loss of cellular identity. Furthermore, elimination of senescent cells may protect pancreatic β-cells from hyperglycemia-induced functional decline, which may have potential clinical application in both Type 1 Diabetes and T2D. Presentation: 6/2/2024

Diminished light sensitivities of ON alpha retinal ganglion cells observed in a mouse model of hyperglycemia

This study aimed to investigate potential functional changes in retinal ganglion cells (RGCs) in a mouse model of hyperglycemia and explore possible therapeutic approaches. Hyperglycemia resembling type 1 diabetes mellitus (DM) was induced in C57BL/6 mice through intraperitoneal injection of streptozotocin (STZ). Blood glucose levels were confirmed to be elevated after 1 week and 4 weeks of injection. Mice with blood glucose levels above 350 mg/mL after 4 weeks of one-dose STZ injection were considered hyperglycemic. The light sensitivity of ON alpha (α) retinal ganglion cells (RGCs), not OFF αRGCs, was reduced in the hyperglycemic mouse model. The number of apoptotic cells, RGCs, and amacrine cells (ACs) remained unaffected at this stage. Similarly, the eletroretinogram (ERG) and optokinetic test results showed no significant differences. The application of picrotoxin (PTX) to block GABA receptors could increase the light sensitivity of ON αRGCs by 1 log unit in hyperglycemic mice. The results show that ON αRGCs may be more susceptible to microenvironmental changes caused by hyperglycemia than OFF αRGCs. This decline in light sensitivity may occur before cell apoptosis during the early stages of the hyperglycemic mouse model but has the potential to be reversed.

Disruption of immune responses by type 1 diabetes exacerbates SARS-CoV-2 mediated lung injury.

COVID-19 commonly presents as pneumonia, with those most severely affected progressing to respiratory failure. Patient responses to SARS-CoV-2 infection are varied, with comorbidities acting as major contributors to varied outcomes. Focusing on one such major comorbidity, we assessed whether pharmacological induction of type 1 diabetes mellitus (T1DM) would increase the severity of lung injury in a murine model of COVID-19 pneumonia utilizing wild-type mice infected with mouse-adapted SARS-CoV-2. Hyperglycemic mice exhibited increased weight loss and reduced blood oxygen saturation in comparison with their euglycemic counterparts, suggesting that these animals indeed experienced more severe lung injury. Transcriptomic analysis revealed a significant impairment of the adaptive immune response in the lungs of diabetic mice compared with those of control. To expand the limited options available for tissue analysis due to biosafety restrictions, we also employed a new technique to digest highly fixed tissue into a single-cell suspension, originally designed for scRNA-Seq, which we then adapted for flow cytometric analysis. Flow immunophenotyping and scRNA-Seq confirmed impaired recruitment of T-cells into the lungs of T1DM animals. In addition, scRNA-Seq revealed a distinct, highly inflammatory macrophage profile in the diabetic cohort that correlates with the more severe infection these mice experienced clinically, allowing insight into a possible mechanism for this phenomenon. Recognizing the near certainty that respiratory viruses will continue to present significant public health concerns for the foreseeable future, our study provides key insights into how T1DM results in a much more severe infection and identifies possible targets to ameliorate comorbidity-associated severe disease.NEW & NOTEWORTHY We define the exacerbating effects of type 1 diabetes mellitus (T1DM) on COVID-19 pneumonia severity in mice. Hyperglycemic mice experienced increased weight loss and reduced oxygen saturation. Transcriptomic analysis revealed impaired immune responses in diabetic mice, while flow cytometry and single-cell RNA sequencing confirmed reduced T-cell recruitment and an inflammatory macrophage profile. In addition, we introduced a novel technique for tissue analysis, enabling flow cytometric analysis on highly fixed tissue samples.

ROS exhaustion reverses the effects of hyperbaric oxygen on hemorrhagic transformation through reactivating microglia in post-stroke hyperglycemic mice

Acute ischemic stroke (AIS) is a major global health concern due to its high mortality and disability rates. Hemorrhagic transformation, a common complication of AIS, leads to poor prognosis yet lacks effective treatments. Preclinical studies indicate that hyperbaric oxygen (HBO) treatment within 12 h of AIS onset alleviates ischemia/reperfusion injuries, including hemorrhagic transformation. However, clinical trials have yielded conflicting results, suggesting some underlying mechanisms remain unclear. In this study, we confirmed that HBO treatments beginning within 1 h post reperfusion significantly alleviated the haemorrhage and neurological deficits in hyperglycemic transient middle cerebral arterial occlusion (tMCAO) mice, partly due to the inhibition of the NLRP3 inflammasome-mediated pro-inflammatory response in microglia. Notably, reactive oxygen species (ROS) mediate the anti-inflammatory and protective effect of early HBO treatment, as edaravone and N-Acetyl-l-Cysteine (NAC), two commonly used antioxidants, reversed the suppressive effect of HBO treatment on NLRP3 inflammasome-mediated inflammation in microglia. Furthermore, NAC countered the protective effect of early HBO treatment in tMCAO mice with hyperglycemia. These findings support that early HBO treatment is a promising intervention for AIS, however, caution is warranted when combining antioxidants with HBO treatment. Further assessments are needed to clarify the role of antioxidants in HBO therapy for AIS.

Hyperglycemia sensitizes female mice to stress-induced depressive-like behavior in an inflammation-independent manner

BackgroundDepression is a multifaceted disorder that represents one of the most common causes of disability. The risk for developing depression is increased in women and among individuals with chronic diseases. For example, individuals in the United States with diabetes mellitus (DM) are at a twofold increased risk of developing depression compared to the general population and approximately one-quarter of women with diabetes have comorbid depression. The neurobiological mechanisms underlying this association between diabetes and depression is not fully understood and is particularly under-investigated in female models. We sought to explore the role of neuroinflammation in diabetes-induced depression in a female mouse model of hyperglycemia. MethodsTo this end, we utilized female C57BL/6 J mice to (1) characterize the depressive-like symptoms in response to 75 mg/kg/day dose of streptozotocin (STZ) over 5 days, a dose reported to induce hyperglycemia in female mice (n=20), (2) determine if female hyperglycemic mice are sensitized to unpredictable chronic mild stress (UCMS)-induced depressive-like behavior and neuroinflammation (n=28), and (3) investigate if female hyperglycemic mice are primed to respond to a subthreshold dose of lipopolysaccharide (LPS), an acute inflammatory challenge (n=21). ResultsOur results demonstrate that female mice exhibit robust hyperglycemia but limited evidence of depressive-like behavior in response to 75 mg/kg STZ. Additionally, we observe that healthy female mice have limited response to our stress protocol; however, hyperglycemic mice display increased stress-sensitivity as indicated by increased immobility in the forced swim test. While STZ mice show evidence of mild neuroinflammation, this effect was blunted by stress. Further, STZ mice failed to display a sensitization to inflammation-induced depressive-like behavior. ConclusionWe interpret this data to indicate that while STZ-induced hyperglycemia does increase vulnerability to stress-induced depressive-like behavior, this effect is not a consequence of neuroinflammatory priming. Future studies will seek to better understand the mechanisms underlying this sensitization.

Stigmast-4-en-3-one from Euonymus alatus (Thunb.) Siebold. improves diabetic retinopathy and angiogenesis mediated by glucocorticoids receptor

Ethnopharmacological relevanceEuonymus alatus (Thunb.) Siebold. (EA), a traditional Chinese medicine, is widely used in the treatment of diabetes. Our group has previously found that EA could treat diabetic retinopathy (DR) and stigmast-4-en-3-one (Numbered E6) is the active substance responsible for inhibiting angiogenesis in vitro by EA. However, the effects and mechanisms of E6 in the treatment of DR is still unknown. Aim of the studyThe aim of this study was to investigate the effects and mechanisms of E6 in EA on DR. Additionally, a comparison was made between the effects of E6 and triamcinolone acetonide (TA), as well as the side effects of E6 and dexamethasone. Materials and methodsOcular affinity assessment and pharmacokinetic parameter prediction were conducted to evaluate the potential of E6 to treat DR. Retinal endothelial cells were used to investigate the in vitro inhibitory effect of E6 on vascular proliferation. Additionally, chicken embryos, zebrafish, and mice were used to investigate the in vivo anti-vascular proliferation effect of E6. Finally, diabetic mice were used to investigate whether E6 improves diabetic retinopathy and to compare its efficacy with that of TA. We then used network pharmacology to study the targets of E6 and performed molecular docking; followed by immunofluorescence experiments, ELISA, Western blot, and tube formation experiments to further investigate its mechanism. Finally, we compared the side effects of E6 with those of dexamethasone. ResultsE6 was found to have an affinity for the eye and to inhibit vascular proliferation both in vivo and in vitro. Moreover, E6 was found to be more efficacious than TA in the treatment of DR. Molecular docking experiments predicted that the glucocorticoid receptor (GR) is a potential target of E6, and immunofluorescence analyses confirmed that E6 upregulated the expression of the GR in the retina of hyperglycemic mice. In addition, western blotting results and tube formation experiments showed that E6 also attenuated angiogenesis by inhibiting the Hippo and VEGF pathways. Finally, by comparing the effects of E6 and dexamethasone on glucose regulation and osteoporosis, E6 was found to have fewer side effects. ConclusionsE6 is a highly effective drug for the treatment of DR, superior to TA and with fewer side effects than dexamethasone. Its mechanism involves the activation of glucocorticoid receptor and inhibition of Hippo and VEGF pathways to alleviate angiogenesis and inflammation. This study is the first to investigate the role and mechanism of E6 in improving DR. The findings suggest that E6 has unique advantages in the treatment of DR.

Dietary L-arabinose-induced gut dysbiosis exacerbates Salmonella infection outcome.

The gut microbiota is essential for providing colonization resistance against pathogens. Dietary sugars markedly shift the composition of the intestinal microbiota and alter host susceptibility to enteric infections. Here, we demonstrate the effect of L-arabinose on bacterial infection by using a mouse infection model with Salmonella enterica serovar Typhimurium (S. Tm). In the presence of microbiota, L-arabinose induces a dramatic expansion of Enterobacteriaceae, thereby decreasing the microbiota diversity and causing more severe systemic infection. However, L-arabinose supplementation does not alter the disease progression of Salmonella infection in a microbiota-depleted mouse model. More importantly, short-term supplementation of L-arabinose fails to exert anti-diabetic effects in Salmonella-infected hyperglycemia mice and still promotes infection. Overall, our work reveals that a high intake of dietary L-arabinose supports a bloom of Enterobacteriaceae in Salmonella-infected gut, further accelerating the process of systemic infection.IMPORTANCEL-arabinose is a promising natural sweetener and food additive for the regulation of hyperglycemia. Since diabetic subjects are more susceptible to infections, the safety of dietary L-arabinose in diabetic patients experiencing infection remains a concern. Our findings reveal that L-arabinose exacerbates Salmonella infection outcome by inducing gut microbiota dysbiosis in mice. High dietary intake of L-arabinose may be deleterious for diabetic individuals undergoing infection.

Prevention of Chronic Diabetic Neuropathy and Diabetes-Associated Cognitive Impairment Using Medicinal Herbs (Cassia Angustifolia and Nigella Sativa).

Nodal regions, areas of intensive contact between Schwann cells and axons, may be exceptionally vulnerable to diabetes-induced changes because they are exposed to and impacted by the metabolic implications of diabetes. Insulin receptors, glucose transporters, Na+ and K+ channels, and mitochondria are abundant in nodes, all of which have been linked to the development and progression of Diabetic Peripheral Neuropathy (DPN) and Type 1 Diabetes Mellitus (T1DM)-associated cognitive impairment. Our study aimed to evaluate if the administration of Nigella sativa (NS) and Cassia angustifolia (CA) prevented diabetes-associated nervous system deficits in hyperglycemic mice. We developed T1DM mice through Streptozotocin (STZ) injections and validated the elevations in blood glucose levels. NS and CA were administered immediately upon the induction of diabetes. Behavioral analysis, histopathological evaluations, and assessment of molecular biomarkers (NR2A, MPZ, NfL) were performed to assess neuropathy and cognitive impairment. Improvements in memory, myelin loss, and the expression of synaptic proteins, even with the retention of hyperglycemia, were evident in the mice who were given a dose of herbal products upon the detection of hyperglycemia. NS was more beneficial in preventing memory impairments, demyelination, and synaptic dysfunction. The findings indicate that including these herbs in the diets of diabetic as well as pre-diabetic patients can reduce complications associated with T1DM, notably diabetic peripheral neuropathy and cognitive deficits associated with T1DM.

Prevotella copri alleviates hyperglycemia and regulates gut microbiota and metabolic profiles in mice.

As a core member of the human intestinal ecosystem, Prevotelal copri has been associated with glucose metabolic homeostasis in previous studies. However, these results have often been derived from metagenomic studies, and the experimental studies have been based solely on the type of strain DSM 18205T. Therefore, more experimental evidence from additional isolates is needed to validate the results according to their high genomic heterogeneity. In this study, we isolated different branches of strains and demonstrated that P. copri could improve the metabolic profile of hyperglycemic mice by modulating microbial activity. This finding supports the causal contribution of P. copri in host glucose metabolism.

Enhancing Spermatozoa Quality and Spermatogenic Cell in Hyperglycemic Mice (Mus musculus L.) with Sambung Nyawa (Gynura procumbens) and Mahagany (Swietenia mahagoni jacq) extracts, Alone and in Combination

This study aimed to investigate the effect of the ethanol extract of sambung nyawa (Gynura procumbens) leaves, mahogany (Swietenia mahagoni jacq) seeds, and their combination on the motility, viability, morphology, and concentration of spermatozoa, spermatogonia, spermatocytes, and spermatids in hyperglycemic mice induced with 10% dextrose. A total of 48 male mice were used as experimental animals, and the extracts were administered orally for 35 days. On day 36, spermatozoa and testicular tissues were collected for analysis. The results showed that the extracts at various doses had the potential to reduce blood glucose levels and improve the motility, viability, morphology, and concentration of spermatozoa and germ cells in hyperglycemic mice. Result:The combination of sambung nyawa leaves and mahogany seeds at a dose of 150:150 mg/kg BW was found to be the most effective in reducing blood sugar levels and improving sperm parameters. Therefore, these extracts have the potential to be used as alternative herbal ingredients with similar effects to metformin in reducing diabetes and improving fertility.

Efficacy of Human Recombinant Growth Hormone in Females of a Non-Obese Hyperglycemic Mouse Model after Birth with Low Birth Weight.

We examined whether the administration of growth hormone (GH) improves insulin resistance in females of a non-obese hyperglycemic mouse model after birth with low birth weight (LBW), given that GH is known to increase muscle mass. The intrauterine Ischemia group underwent uterine artery occlusion for 15 min on day 16.5 of gestation. At 4 weeks of age, female mice in the Ischemia group were divided into the GH-treated (Ischemia-GH) and non-GH-treated (Ischemia) groups. At 8 weeks of age, the glucose metabolism, muscle pathology, and metabolome of liver were assessed. The insulin resistance index improved in the Ischemia-GH group compared with the Ischemia group (p = 0.034). The percentage of type 1 muscle fibers was higher in the Ischemia-GH group than the Ischemia group (p < 0.001); the muscle fiber type was altered by GH. In the liver, oxidative stress factors were reduced, and ATP production was increased in the Ischemia-GH group compared to the Ischemia group (p = 0.014), indicating the improved mitochondrial function of liver. GH administration is effective in improving insulin resistance by increasing the content of type 1 muscle fibers and improving mitochondrial function of liver in our non-obese hyperglycemic mouse model after birth with LBW.

Embryos from Prepubertal Hyperglycemic Female Mice Respond Differentially to Oxygen Tension In Vitro.

Reduced oxygen during embryo culture in human ART prevents embryo oxidative stress. Oxidative stress is also the major mechanism by which maternal diabetes impairs embryonic development. This study employed induced hyperglycemia prepubertal mice to mimic childhood diabetes to understand the effects of varying oxygen tension during in vitro embryonic development. The oocytes were fertilized and cultured at low (≈5%) oxygen (LOT) or atmospheric (≈20%) oxygen tension (HOT) for up to 96 h. Embryo development, apoptosis in blastocysts, inner cell mass (ICM) outgrowth proliferation, and Hif1α expression were assessed. Though the oocyte quality and meiotic spindle were not affected, the fertilization rate (94.86 ± 1.18 vs. 85.17 ± 2.81), blastocyst rate (80.92 ± 2.92 vs. 69.32 ± 2.54), and ICM proliferation ability (51.04 ± 9.22 vs. 17.08 ± 3.05) of the hyperglycemic embryos were significantly higher in the LOT compared to the HOT group. On the other hand, blastocysts from the hyperglycemic group, cultured at HOT, had a 1.5-fold increase in apoptotic cells compared to the control and lower Hif1α transcripts in ICM outgrowths compared to the LOT. Increased susceptibility of embryos from hyperglycemic mice to higher oxygen tension warrants the need to individualize the conditions for embryo culture systems in ART clinics, particularly when an endogenous maternal pathology affects the ovarian environment.

PIEZO1 as a new target for hyperglycemic stress-induced neuropathic injury: The potential therapeutic role of bezafibrate

Hyperglycemic stress can directly lead to neuronal damage. The mechanosensitive ion channel PIEZO1 can be activated in response to hyperglycemia, but its role in hyperglycemic neurotoxicity is unclear. The role of PIEZO1 in hyperglycemic neurotoxicity was explored by constructing a hyperglycemic mouse model and a high-glucose HT22 cell model. The results showed that PIEZO1 was significantly upregulated in response to high glucose stress. In vitro experiments have shown that high glucose stress induces changes in neuronal cell morphology and membrane tension, a key mechanism for PIEZO1 activation. In addition, high glucose stress upregulates serum/glucocorticoid-regulated kinase-1 (SGK1) and activates PIEZO1 through the Ca2+ pool and store-operated calcium entry (SOCE). PIEZO1-mediated Ca2+ influx further enhances SGK1 and SOCE, inducing intracellular Ca2+ peaks in neurons. PIEZO1 mediated intracellular Ca2+ elevation leads to calcium/calmodulin-dependent protein kinase 2α (CaMK2α) overactivation, which promotes oxidative stress and apoptosis signalling through p-CaMK2α/ERK/CREB and ox-CaMK2α/MAPK p38/NFκB p65 pathways, subsequently inducing synaptic damage and cognitive impairment in mice. The intron miR-107 of pantothenic kinase 1 (PANK1) is highly expressed in the brain and has been found to target PIEZO1 and SGK1. The PANK1 receptor is activated by peroxisome proliferator-activated receptor α (PPARα), an activator known to upregulate miR-107 levels in the brain. The clinically used lipid-lowering drug bezafibrate, a known PPARα activator, may upregulate miR-107 through the PPARɑ/PANK1 pathway, thereby inhibiting PIEZO1 and improving hyperglycemia-induced neuronal cell damage. This study provides a new idea for the pathogenesis and drug treatment of hyperglycemic neurotoxicity and diabetes-related cognitive dysfunction.

Hyperglycemia enhances brain susceptibility to lipopolysaccharide-induced neuroinflammation via astrocyte reprogramming.

Hyperglycemia has been shown to modulate the immune response of peripheral immune cells and organs, but the impact of hyperglycemia on neuroinflammation within the brain remains elusive. In the present study, we provide evidences that streptozotocin (STZ)-induced hyperglycemic condition in mice drives a phenotypic switch of brain astrocytes to a proinflammatory state, and increases brain vulnerability to mild peripheral inflammation. In particular, we found that hyperglycemia led to a significant increase in the astrocyte proliferation as determined by flow cytometric and immunohistochemical analyses of mouse brain. The increased astrocyte proliferation by hyperglycemia was reduced by Glut1 inhibitor BAY-876. Transcriptomic analysis of isolated astrocytes from Aldh1l1CreERT2;tdTomato mice revealed that peripheral STZ injection induced astrocyte reprogramming into proliferative, and proinflammatory phenotype. Additionally, STZ-induced hyperglycemic condition significantly enhanced the infiltration of circulating myeloid cells into the brain and the disruption of blood-brain barrier in response to mild lipopolysaccharide (LPS) administration. Systemic hyperglycemia did not alter the intensity and sensitivity of peripheral inflammation in mice to LPS challenge, but increased the inflammatory potential of brain microglia. In line with findings from mouse experiments, a high-glucose environment intensified the LPS-triggered production of proinflammatory molecules in primary astrocyte cultures. Furthermore, hyperglycemic mice exhibited a significant impairment in cognitive function after mild LPS administration compared to normoglycemic mice as determined by novel object recognition and Y-maze tasks. Taken together, these results demonstrate that hyperglycemia directly induces astrocyte reprogramming towards a proliferative and proinflammatory phenotype, which potentiates mild LPS-triggered inflammation within brain parenchymal regions.

Modulation of Cardiac Sarcomeric Function in Mouse Models of Hyperglycemia

Diabetes is a major risk factor for developing heart failure (HF) and patients with diabetes and HF have worse outcomes than patients with HF alone. Given that diabetes is associated with multiple metabolic impairments, it is critical to determine the mechanisms that exacerbate and worsen cardiac outcomes. Hyperglycemia has been associated with cardiac diastolic dysfunction, which is characterized by prolonged relaxation. The specific mechanisms underlying hyperglycemia-induced diastolic dysfunction are unclear. It is known that hyperglycemia induces profound perturbations in cardiac metabolism modifying acyl-based post-translational modifications (PTMs), which are a class of PTMs that have been gaining increasing focus as modulators of non-genomic protein function. We hypothesize that hyperglycemia contributes to cardiac dysfunction by modulating acyl-based modifications on sarcomeric proteins; thereby, leading to prolonged myofilament relaxation. We evaluated sarcomeric function and specific PTMs (acetylation, crotonylation, malonylation, propionylation, and hydoxy-butyrylation) on sarcomeric proteins in two mouse models that have elevated glucose without hyperinsulinemia: mice with inducible deletion of beta islet glucokinase and mice treated with streptozotocin (STZ) induced damage of the beta islet cells. In male and female mice of both models, myofibrils isolated from the hearts of animals with hyperglycemia demonstrated prolonged sarcomeric relaxation compared to myofibrils isolated from euglycemic mice. We found that sarcomeric proteins isolated from the hearts of hyperglycemic mice from both models have decreased protein acetylation. While crotonylation, malonylation, propionylation, and hydoxy-butyrylation are not different between hyperglycemic and euglycemic mice. To determine how decreased acetylation impacts sarcomeric mechanical function, myofibrils isolated from male and female euglycemic mice were treated with histone deacetylases decrease acetylation and mechanics were assessed. We found that decreased acetylation of myofibrils leads to prolonged relaxation similar to what was observed in hyperglycemic hearts. These findings indicate that specific modifications of acyl-PTMs on sarcomeric proteins modulate sarcomeric function and may contribute to overall diastolic dysfunction observed in hyperglycemia. This work was supported by the National Institutes of Health [K01AG066845 KCW] the American Heart Association [22CDA937598 KCW] and the University of Colorado Anschutz Medical Campus Ludeman Family Center for Women’s Health and Specialized Center for Research Excellence (SCORE) pilot award [KCW], Colorado Diabetes Research Center Pilot and Feasibility Award [P30DK11607 KCW)]. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.