Animal Models Of Diabetes Research Articles

Oxidative Stress and Histomorphometric Remodeling: Two Key Intestinal Features of Type 2 Diabetes in Goto–Kakizaki Rats

Gastrointestinal complications of diabetes are often overlooked, despite affecting up to 75% of patients. This study innovatively explores local glutathione levels and morphometric changes in the gut of Goto–Kakizaki (GK) rats, a type 2 diabetes animal model. Segments of the intestine, cecum, and colon were collected for histopathological analysis and glutathione quantification. A significant increase in the total thickness of the intestinal wall of GK rats was observed, particularly in the duodenum (1089.02 ± 39.19 vs. 864.19 ± 37.17 µm), ileum (726.29 ± 24.75 vs. 498.76 ± 16.86 µm), cecum (642.24 ± 34.15 vs. 500.97 ± 28.81 µm), and distal colon (1211.81 ± 51.32 vs. 831.71 ± 53.2 µm). Additionally, diabetic rats exhibited thickening of the muscular layers in all segments, except for the duodenum, which was also the only portion where the number of smooth muscle cells did not decrease. Moreover, myenteric neuronal density was lower in GK rats, suggesting neurological loss. Total glutathione levels were lower in all intestinal segments of diabetic rats (except duodenum), and the reduced/oxidized glutathione ratio (GSH/GSSG) was significantly decreased in GK rats, indicating increased oxidative stress. These findings strongly indicate that GK rats undergo significant intestinal remodeling, notable shifts in neuronal populations, and heightened oxidative stress—factors that likely contribute to the functional gastrointestinal alterations seen in diabetic patients.

Systematic Review and Meta-Analysis of Sclerocarya birrea on Metabolic Disorders: Evidence from Preclinical Studies

Background/Objectives: Metabolic disorders, including diabetes, obesity, and cardiovascular diseases, are significant global health issues. Nutraceuticals, such as Sclerocarya birrea (SB), known for its high polyphenol content, are increasingly explored for managing these conditions. This study aims to evaluate the antihyperglycemic, hypolipidemic, and antihypertensive effects of SB in animal models to understand its potential as a natural intervention for metabolic diseases. Methods: A systematic review and meta-analysis were conducted according to PRISMA guidelines. Searches across databases like PubMed, Web of Science, Embase, and Scopus identified studies using SB in animal models of metabolic disorders. Inclusion criteria were studies with SB intervention, control groups, and quantitative measures of metabolic parameters. The study was registered with INPLASY (INPLASY2024100031). Results: The meta-analysis revealed that SB significantly reduces blood glucose levels in diabetic animal models. Acute administration of SB showed a pooled standardized mean difference (SMD) of −7.13 (95% CI: −11.44 to −2.83) at 1 h and −9.75 (95% CI: −15.92 to −3.59) at 2–4 h post-administration. Chronic administration indicated a non-significant reduction in glucose levels (SMD: −5.69, 95% CI: −16.38 to 5.01). Conclusions: SB appears to have the potential for reducing blood glucose levels and may offer benefits for other cardiometabolic risk factors, including lipid profiles and oxidative stress. However, variability in the results underscores the need for further research, including standardized animal studies and clinical trials, to confirm these effects and clarify the mechanisms by which SB may impact metabolic disorders.

Application of Integrated Optical Density in Evaluating Insulin Expression in the Endocrine Pancreas During Chronic Ethanol Exposure and β-Carotene Supplementation: A Novel Approach Utilizing Artificial Intelligence

Background: β-carotene is an essential antioxidant, providing protection against type 2 diabetes mellitus, cardiovascular illnesses, obesity, and metabolic syndrome. This study investigates the impact of β-carotene on biochemical parameters and pancreatic insulin expression in mice exposed to ethanol. Methods: Thirty-six C57BL/6 mice (Mus musculus) were divided into six groups: 1. C (control), 2. LA (3% alcohol dose), 3. MA (7% alcohol dose), 4. B (0.52 mg/kg body weight/day β-carotene), 5. LA+B (3% alcohol dose + 0.52 mg/kg body weight/day β-carotene), and 6. MA+B (7% alcohol dose plus 0.52 mg/kg body weight/day β-carotene). After 28 days, the animals were euthanized for serum and pancreatic tissue collection. Biochemical analysis and pancreatic insulin expression were performed. One-way ANOVA was used. Results: The B, LA+B, and MA+B groups improved insulin levels and decreased HOMA-β versus the C group, with the LA+B and MA+B groups also showing lower ADH and ALDH levels than their nonsupplemented counterparts (p < 0.05). The B, LA+B, and MA+B groups showed a greater β-cell mass area compared to the unsupplemented groups. Additionally, the LA+B and MA+B groups demonstrated significantly increased β-cell area and integrated optical density compared to the LA and MA groups, respectively (p < 0.001). Conclusions: In mice, β-cell loss led to increased glucose release due to decreased insulin levels. β-carotene appeared to mitigate ethanol’s impact on these cells, resulting in reduced insulin degradation when integrated optical density was used. These findings suggest that antioxidant supplementation may be beneficial in treating ethanol-induced type 2 diabetes in animal models.

Establishing a Female Animal Model of Prediabetes Using a High-Carbohydrate, High-Fat Diet

Prediabetes is a condition that often precedes the onset of type 2 diabetes and is characterized by moderate levels of insulin resistance. This condition is well established in male animal models for diabetes; however, few female models exist. There is accumulating evidence that sex variations affect the pathogenesis, treatment, and consequences of numerous diseases, such as type 2 diabetes. Therefore, we sought to develop a diet-induced prediabetic female animal model to better understand prediabetes development and its effects in females. Female Sprague Dawley rats were randomly allocated to one of two groups: the standard diet (SD) group fed a standard diet with normal drinking water, and the high-carbohydrate, high-fat (HCHF) group fed a high-carbohydrate and high-fat diet with drinking water supplemented with fructose. During induction, we measured food intake, body weight, body mass index (BMI), and oral glucose tolerance response (OGT). After the induction period, biochemical analyses were conducted to assess the levels of plasma leptin, ghrelin, insulin, and glycated hemoglobin (HbA1c). Glycogen concentrations were quantified in the liver and skeletal muscles. The HCHF diet-fed group presented higher body weight gain, food intake, and BMI levels, which were accompanied by elevated plasma insulin, ghrelin, and liver and skeletal muscle glycogen levels compared to the SD-fed group. In the HCHF diet-fed group, the HOMA-IR was above 1.9, suggesting the presence of moderate levels of insulin resistance. The OGT response was significantly higher in the HCHF-fed group versus the SD-fed group, suggesting impaired glucose tolerance, thus displaying the signs and symptoms of prediabetes. The HCHF diet with fructose led to the induction of prediabetes in female Sprague Dawley rats. This model could be used to investigate and outline the pathophysiological complications associated with prediabetes in females as a result of the prolonged ingestion of a high carbohydrate, high-fat diet with fructose. The development of this model could also serve as an effort to further bridge the gap regarding the inclusion of females in biomedical research, thus providing advancements in deriving better, specified treatment strategies for women.

Uninephrectomy and sodium-glucose cotransporter 2 inhibitor administration delay the onset of hyperglycemia.

The kidneys are essential for glucose homeostasis, as they perform gluconeogenesis, utilize glucose, and reabsorb glucose. Reabsorption is performed by SGLT2, which is responsible for about 90%. However, little is known about how renal glucose handling is altered in patients with chronic kidney disease (CKD). SGLT2 inhibitors have demonstrated efficacy in suppressing CKD progression in clinical trials, but their mechanisms are not fully understood. Therefore, this study aimed to evaluate how each uninephrectomy (UNx) and SGLT2 inhibitor affects blood glucose concentrations and SGLTs dynamics in rats with type 2 diabetes mellitus. Male rats were divided into four treatment groups: sham + placebo, sham + dapagliflozin, UNx + placebo, and UNx + dapagliflozin. There were few group differences in food intake or body weight, but blood glucose concentrations continued to rise in the sham + placebo, whereas this rise was delayed for several weeks in the UNx + placebo, and largely suppressed by dapagliflozin. SGLT2 mRNA expression was significantly lower in the UNx group, but SGLT1 mRNA expression did not significantly differ. Dapagliflozin did not alter SGLT1 or SGLT2 mRNA expression. In animal models of diabetes, renal glucose reabsorption appears likely to be a major contributor to the development of hyperglycemia.

Antidepressant Effects of Mitragyna Speciosa Korth Extract on Diabetic Rats

Background: Diabetes mellitus is most common associated with neurological complications, including depressive symptoms, so this study investigated whether mitragyna may provide benefits in reducing depressive symptoms in animal models of diabetes. This study aims to evaluate the effect of mitragyna as a potential antidepressant agent in animal models of diabetes mellitus using the Force Swimming Test (FST). Methods: In this study, diabetes mellitus rats were induced by administering streptozotocin and then divided into four groups: control group (Control), Group Diabetes (DM), Mitragyna treatment group (DM+EMS 15mg) and (DM+EMS 30mg). After the treatment period, the rats were then tested with the FST, which is used to measure immobility behavior which can be used as an indicator of depressive symptoms. Results: The results showed that the treatment group that received mitragyna showed shorter immobility times compared to the control group (P<0.01), indicating an increased active response in facing FST stressors. Conclusion: These results indicate that mitragyna has potential as an antidepressant agent in reducing depressive symptoms in rats models of diabetes mellitus.

Fermented Moringa oleifera seed-cassava inclusion improves protein and selected biochemical indices in alloxan-induced diabetes in animal model

Despite the availability of many pharmacological interventions for diabetes management, current evidence shows an alarming rising trend in the occurrence of undesirable complications, confirming that other complementary approaches are required. This study evaluated the nutraceutical properties of fermented Moringa oleifera seed-Cassava (FMOC) inclusion on selected biochemical parameters in rats induced with diabetes. Portions of cassava was substituted with moringa seed at 100:0 (control), 80:20 (not fermented:T1), 80:20 (fermented;T2) and 70:30% (fermented:T3). Fermentation was achieved using a starter culture containing Lactic acid bacteria for 36 h. Thirty-six (36) male albino rats were randomly divided into six groups (n=6/group). Groups B-F were rendered diabetic using alloxan (150 mg/kg. bw; IP) while group A served as the normal control. The effects of FMOC on proximate and selected biochemical indices of diabetic rats were evaluated. Results showed that protein increased significantly (p<0.05) (2.43}0.1 to 20.44} 02 g/100g) in the fermented sample as against non fermented control. All test diets (especially T2) counteracted the diabetic effects in rats by lowering (P<0.05) the elevated serum levels of glucose (249.0 to 105.6 mg/dl), Cholesterol (6.73 to 4.13mmol/L), TAG (2.43 to 1.99mmo/L), LDL (3.72 to 2.66mmol/L), Urea (35.3 to 23.2mmol/L) and malondialdehyde (2.34 to 1.29mg/dl) compared with diabetic group. It also improved (P<0.05) glutathione (2.69-3.76mg/dl) and catalase enzyme activity (1.52-2.90 U/mg). No significant effect was recorded for HDL (P>0.05). Histological outcomes of pancreas corroborated these findings. A food–based approach incorporating fermented M. oleifera seed could be considered an effective strategy to manage the complications that might arise from diabetes.

Protective Potential of Cicerbita alpina Leaf Extract on Metabolic Disorders and Oxidative Stress in Model Animals.

Metabolic disorders (MDs) include disease states such as diabetes mellitus, obesity, dyslipidemia, hyperuricemia, etc., affecting about 30% of the planet's population. The purpose of the present study was to investigate the protective potential of Cicerbita alpina leaf extract (ECA) against chemically induced type 2 diabetes in Wistar rats. Additionally, some biochemical parameters in the blood serum and liver, as well as histopathological investigation, were also performed. Quantitative analysis of the major compounds in the used extract was performed using ultrahigh-performance liquid chromatography-diode array detection (UHPLC-DAD) analyses using the external standard method. C. alpina extract revealed a beneficial effect on MDs, lowering blood sugar levels and MDA quantity in the liver, increasing the reduced glutathione level, and increasing antioxidant enzyme activity. Cichoric acid (CA) (91.93 mg/g dry extract (de) ± 4.64 mg/g de) was found to be the dominant compound in the extract, followed by caftaric (11.36 ± 2.10 mg/g de), and chlorogenic acid (CGA) (9.25 ± 0.05 mg/g de). In conclusion, C. alpina leaf extract (ECA) is rich in caffeoyltartaric and caffeoylquinic acids and provides beneficial effects on the diabetic animal model.

7574 Diabetes Stem Cells: A Common Target for Abnormal Insulin Secretion and Insulin Resistance

Abstract Disclosure: H. Kojima: None. M. Katagi: None. J. Okano: None. T. Nakagawa: None. Diabetes is based on chronic inflammation and cannot be cured using only drugs that lower blood glucose levels. A culprit was lurking there that was hindering healing. We discovered abnormal hematopoietic stem cells that caused persistent chronic inflammation in the bone marrow of diabetic model animals. The real culprit is born after several days of hyperglycemia, never dies, and each time glycemic control deteriorates, it moves its progeny in large numbers throughout the body, fusing with unique cells in various organs and producing TNF-α from the organ cells. We have named these worst stem cells, which resemble cancer stem cells, "diabetes stem cells," and attempted to induce complete remission in diabetic model animals by eliminating them with drugs. In this study, we used streptozotocin (STZ)-induced insulin-deficient diabetes model mice. "Diabetes stem cells" were included in the CD106-positive short-term hematopoietic stem cell fraction, in which progenitor cells that play an important role in the regeneration of the thymus and peripheral tissues, and were characterized by abnormal expression of proinsulin and TNF-α. Furthermore, like cancer cells, the expression of histone deacetylases (HDACs) increased, and once the cells were born, they would not disappear. Therefore, we aimed to eliminate diabetes by administering an HDAC inhibitor and subcutaneously injecting insulin pellets to temporarily correct blood glucose levels. We treated diabetic mice with HDAC inhibitor for 8 weeks, along with several weeks of insulin therapy. Insulin aims to prevent the formation of new abnormal cells in the bone marrow and to prevent the inhibition of pancreatic islet wasting due to the forced insulin secretion caused by hyperglycemia. The combination therapy allowed the beta cells to regenerate and produce enough insulin to normalize blood glucose levels and maintain them even after treatment was discontinued. It also solved the mystery of how the abnormal cell population evades attacks from the T cells. In STZ diabetes, the supply of normal CD106-positive progenitor cells from the bone marrow for thymic regeneration was completely blocked, resulting in marked thymic atrophy. As a result, the thymus, which had lost its progenitor cells, was unable to establish an immune surveillance system to eliminate mutated cells throughout the body. In other words, the combination therapy completely broke the vicious cycle caused by atrophies in both the islet and the thymus. Moreover, when the thymus was surgically removed along with the adventitia to prevent regeneration, diabetes remission was completely inhibited, supporting the importance of thymic normalization. Diabetes is a hematopoietic stem cell disease accompanied by thymic dysfunction, and the removal of "diabetes stem cells" paves the way for the cure of diabetes. Presentation: 6/2/2024

Gut microbiota and metabolomic profile changes play critical roles in tacrolimus-induced diabetes in rats.

Hyperglycemia is one of the adverse effects of tacrolimus (TAC), but the underlying mechanism is not fully identified. We used multi-omics analysis to evaluate the changes in the gut microbiota and metabolic profile of rats with TAC-induced diabetes. To establish a diabetic animal model, Sprague Dawley rats were divided randomly into two groups. Those in the TAC group received intraperitoneal injections of TAC (3 mg/kg) for 8 weeks, and those in the CON group served as the control. 16S rRNA sequencing was used to analyze fecal microbiota. The metabolites of the two groups were detected and analyzed by nontargeted and targeted metabolomics, including amino acids (AAs), bile acids (BAs), and short-chain fatty acids (SCFAs). The rats treated with TAC exhibited hyperglycemia as well as changes in the gut microbiota and metabolites. Specifically, their gut microbiota had significantly higher abundances of Escherichia-Shigella, Enterococcus, and Allobaculum, and significantly lower abundances of Ruminococcus, Akkermansia, and Roseburia. In addition, they had significantly reduced serum levels of AAs including asparagine, aspartic acid, glutamic acid, and methionine. With respect to BAs, they had significantly higher serum levels of taurocholic acid (TCA), and glycochenodeoxycholic acid (GCDCA), but significantly lower levels of taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA). There were no differences in the levels of SCFAs between the two groups. Correlations existed among glucose metabolism indexes (fasting blood glucose and fasting insulin), gut microbiota (Ruminococcus and Akkermansia), and metabolites (glutamic acid, hydroxyproline, GCDCA, TDCA, and TUDCA). Both AAs and BAs may play crucial roles as signaling molecules in the regulation of TAC-induced diabetes.

Diabetic Kidney Disease: Contribution of Phenyl Sulfate Derived from Dietary Tyrosine upon Gut Microbiota Catabolism.

Deranged gut microbiota can release increased levels of uremic toxins leading to exacerbated kidney injury. In diabetic kidney disease (DKD), phenyl sulfate (PS) derived from tyrosine catabolism by gut microbiota has been demonstrated to be both an early diagnostic marker and a therapeutic target. In this perspective article, we summarize PS generation pathways and recent findings on PS and kidney injury in DKD. Increasing evidence has shown that the underlying mechanisms of PS-induced kidney injury mainly involve oxidative stress, redox imbalance, and mitochondrial dysfunction, which all may be targeted to attenuate PS-induced kidney injury. For future research directions, we think that a deeper understanding of the pathogenic role of PS in kidney injury using a variety of diabetic animal models should be investigated. Moreover, we also suggest beneficial approaches that could be used to mitigate the deleterious effect of PS on the kidney. These approaches include caloric restriction, tyrosine restriction, and administration of ketogenic drugs, ketogenic diets or natural products; all of which should be conducted under obese and diabetic conditions.

Quercus infectoria Gall Ethanolic Extract Accelerates Wound Healing through Attenuating Inflammation and Oxidative Injuries in Skin Fibroblasts.

Quercus infectoria Olivier (Fagaceae) nutgall, a traditional Asian medicine, is renowned for its efficacy in treating wounds and skin disorders. Although the gall extract has shown promising results in accelerating wound healing in diabetic animal models, its mechanisms, particularly the effects on redox balance, remain poorly understood. This study aims to investigate the effects and mechanisms of Q. infectoria gall ethanolic extract (QIG) on wound healing in fibroblasts, with a specific emphasis on its modulation of oxidative stress. Hydrogen peroxide (H2O2)-treated L929 cells were used as an in vitro model of oxidation-damaged fibroblasts. QIG exhibited potent antioxidant activity with 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), and ferric reducing antioxidant power (FRAP) assay values of 305.43 ± 7.48, 508.94 ± 15.12, and 442.08 ± 9.41 µM Trolox equivalents (TE)/µg, respectively. Elevated H2O2 levels significantly reduced L929 cell viability, with a 50% lethal concentration of 1.03 mM. QIG mitigated H2O2-induced cytotoxicity in a dose-dependent manner, showing protective effects in pre-, post-, and co-treatment scenarios. QIG significantly reduced H2O2-induced intracellular reactive oxygen species production and inflammation-related gene expression (p < 0.05). Additionally, at 25 µg/mL, QIG remarkably improved wound closure in H2O2-treated L929 cells by approximately 9.4 times compared with the H2O2 treatment alone (p < 0.05). These findings suggest QIG has potential therapeutic applications in wound healing, mediated through the regulation of oxidative stress and inflammatory response.

Impact of Bitter Gourd (Momordica charantia) Hypoglycemic Formulation on Biochemical Parameters in Alloxan-induced Diabetic Albino Rats

Introduction: Diabetes mellitus is a widespread endocrine disorder that leads to chronic hyperglycemia, posing significant health challenges globally. Effective management of blood glucose levels remains a critical goal in diabetes treatment. Recent studies have highlighted the potential of natural products in diabetes management. Momordica charantia, commonly known as bitter gourd, has been traditionally used for its purported hypoglycemic effects. This study aims to evaluate the efficacy of a methanolic extract of Momordica charantia in reducing blood glucose levels in an animal model of diabetes and compare its effectiveness to a standard antidiabetic medication, Glizid-M. Materials and Methods: The study utilized alloxan-induced diabetic albino rats to assess the hypoglycemic effects of the methanolic extract of Momordica charantia. Diabetic rats were divided into groups and administered varying doses of the extract: 150 mg/kg, 300 mg/kg, and 600 mg/kg. A control group received Glizid-M, and a baseline group received no treatment. Blood glucose levels were monitored at regular intervals to evaluate the efficacy of the extract in managing hyperglycemia. Results and Discussion: The administration of the methanolic extract of Momordica charantia resulted in a dose-dependent reduction in blood glucose levels. Among the tested dosages, the 600 mg/kg dose demonstrated a statistically significant decrease in blood glucose compared to the lower doses of 150 mg/kg and 300 mg/kg. The 600 mg/kg dosage showed comparable efficacy to the standard antidiabetic drug, Glizid-M, indicating a strong hypoglycemic effect. The results of this study suggest that Momordica charantia has a potent hypoglycemic effect, with its efficacy increasing with dosage. The significant reduction in blood glucose levels at the highest dosage implies that the extract may influence glucose metabolism effectively. The dose-dependent response highlights the importance of optimizing dosage for maximum therapeutic benefit. Comparison with Glizid-M further supports the potential of Momordica charantia as a viable alternative or complementary therapy in diabetes management. Conclusion: This study provides scientific validation for the use of Momordica charantia methanolic extract as a therapeutic agent for diabetes management. The observed dose-dependent reduction in blood glucose levels suggests its potential as an effective natural remedy for controlling hyperglycemia. Further research is warranted to explore the underlying mechanisms and long-term efficacy of this extract in diabetes treatment.

In-silico, in-vitro and in-vivo Biological Activities of Flavonoids for the Management of Type 2 Diabetes.

In spite of the fact that many medicinal plants have been truly utilized for the management of diabetes all through the world, very few of them have been reported scientifically. Recently, a diverse variety of animal models have been established to better understand the pathophysiology of diabetes mellitus, and new medications to treat the condition have been introduced in the market. Flavonoids are naturally occurring substances that can be found in plants and various foods and may have health benefits in the treatment of neuropathic pain. Flavonoids have also been shown to have an anti-inflammatory impact that is significant to neuropathic pain, as indicated by a decrease in several pro-inflammatory mediators such TNF-, NF-B IL-6, and IL-1. Flavonoids appear to be a viable novel therapy option for macrovasular complications in preclinical models; however, human clinical data is still inadequate. Recently, several in silico, in-vitro and in-vivo aproaches were made to evaluate mechanisms associated with the pathogenesis of diabetes in a better way. Screening of natural antidiabetic agents from plant sources can be analysed by utilizing advanced in-vitro techniques and animal models. Natural compounds, mostly derived from plants, have been studied in diabetes models generated by chemical agents in the majority of research. The aim of this work was to review the available in silico, in-vitro and animal models of diabetes for screening of natural antidiabetic agents. This review contributes to the scientist's design of new methodologies for the development of novel therapeutic agents having potential antihyperglycemic activity.

A Review of Animal Models for Studying Bone Health in Type-2 Diabetes Mellitus (T2DM) and Obesity.

Preclinical research on diabetes and obesity has been carried out in various animal models over the years. These animal models are developed from genetic manipulation that affects their body metabolism, chemical-induced procedures, diet alteration/modifications, or combinations of the aforementioned approaches. The diabetic and obesity animal models have allowed researchers to not only study the pathological aspect of the diseases but also enable them to screen and explore potential therapeutic compounds. Besides several widely known complications such as macrovascular diseases, diabetic neuropathy, nephropathy and retinopathy, type 2 diabetes mellitus is also known to affect bone health. There is also evidence to suggest obesity affects bone health. Therefore, continuous research needs to be conducted to find a remedy or solution to this matter. Previous literature reported evidence of bone loss in animal models of diabetes and obesity. These findings, as highlighted in this review, further augment the suggestion of an inter-relationship between diabetes, obesity and bone loss.

Growth Differentiation Factor -15 (GDF-15) Levels in Diabetic Conditions: Animal Model

Diabetes mellitus (DM) is a disease characterized by increased blood sugar levels, consisting of Diabetes Mellitus type I (DMT1) and Diabetes Mellitus type II (DMT2). Chronic increases in blood glucose levels will cause oxidative stress through the accumulation of Reactive Oxygen Species (ROS). Oxidative stress will induce the secretion of pro- and anti-inflammatory mediators, including Growth Differentiation Factor-15 (GDF-15). GDF-15 levels can be used to predict the risk and progression of DM disease. In exploring diabetes, several studies were carried out on experimental animal models of diabetes, both T1DM and 2DMT models. This research is an experimental study with a Pre and Post-Test Control Group Design approach using rat animals divided into four groups (I=Control group; II=Alloxan group; III=Streptozotocin group and IV=Streptozotocin and high fat diet group) with the aim of to see the levels of Growth Differentiation Factor-15 (GDF-15) in diabetic animal model. Based on this research, there was an increase in levels of Growth Differentiation Factor-15 (GDF-15) before and after diabetic animal model in the Streptozotocin group P value 0.010; and Streptozotocin with a High Fat Diet group with P value of 0.043 (significance value P &lt; 0.05).

Characterization of MSCs expressing islet neogenesis associated protein (INGAP): INGAP secretion and cell survival in vitro and in vivo

Mesenchymal stem/stromal cells (MSCs) are emerging as a new therapy for diabetes. Here we investigate the properties of MSCs engineered to express Islet Neogenesis Associated Protein (INGAP) previously shown to reverse diabetes in animal models and evaluate their potential for anti-diabetic applications in mice. Mouse bone marrow-derived MSCs retrovirally transduced to co-express INGAP, Firefly Luciferase and EGFP (INGAP-MSCs), were characterized in vitro and implanted intraperitoneally (IP) into non-diabetic and diabetic C57BL/6 mice (Streptozotocin model) and tracked by live bioluminescence imaging (BLI). Distribution and survival of IP injected INGAP-MSCs differed between diabetic and non-diabetic mice, with a rapid clearance of cells in the latter, and a stronger retention (up to 4 weeks) in diabetic mice concurring with homing towards the pancreas. Interestingly, INGAP-MSCs inhibited the progression of hyperglycemia starting at day 3 and lasting for the entire 6 weeks of the study. Pursuing greater retention, we investigated the survival of INGAP-MSCs in hydrogel matrices. When mixed with Matrigel™ and injected subcutaneously into non-diabetic mice, INGAP-MSCs remained in the implant up to 16 weeks. In vitro tests in three matrices (Matrigel™, Type I Collagen and VitroGel®-MSC) demonstrated that INGAP-MSCs survive and secrete INGAP, with best results at the density of 1–2 x 106 cells/mL. However, all matrices induced spontaneous adipogenic differentiation of INGAP-MSCs in vitro and in vivo, which requires further investigation of its potential impact on MSC therapeutic properties. In summary, based on their ability to stop the rise in hyperglycemia in STZ-treated mice, INGAP-MSCs are a promising therapeutic tool against diabetes but require further research to improve cell delivery and survival.

Downregulation of tRF-Cys-GCA-029 by hyperglycemia promotes tumorigenesis and glycolysis of diabetic breast cancer through upregulating PRKCG translation

BackgroundDiabetes mellitus (DM) affects up to one-third of breast cancer (BC) patients. Patients with co-existing BC and DM (BC-DM) have worsened BC prognosis. Nevertheless, the molecular mechanisms orchestrating BC-DM prognosis remain poorly understood. tRNA-derived fragments (tRFs) have been shown to regulate cancer progression. However, the biological role of tRFs in BC-DM has not been explored.MethodstRF levels in tumor tissues and cells were detected by tRF sequencing and qRT-PCR. The effects of tRF on BC cell malignancy were assessed under euglycemic and hyperglycemic conditions in vitro. Metabolic changes were assessed by lactate, pyruvate, and extracellular acidification rate (ECAR) assays. Diabetic animal model was used to evaluate the impacts of tRF on BC tumor growth. RNA-sequencing (RNA-seq), qRT-PCR, Western blot, polysome profiling, luciferase reporter assay, and rescue experiments were performed to explore the regulatory mechanisms of tRF in BC-DM.ResultsWe identified that tRF-Cys-GCA-029 was downregulated in BC-DM tissues and under hyperglycemia conditions in BC cells. Functionally, downregulation of tRF-Cys-GCA-029 promoted BC cell proliferation and migration in a glucose level-dependent manner. tRF-Cys-GCA-029 knockdown also enhanced glycolysis metabolism in BC cells, indicated by increasing lactate/pyruvate production and ECAR levels. Notably, injection of tRF-Cys-GCA-029 mimic significantly suppressed BC tumor growth in diabetic-mice. Mechanistically, tRF-Cys-GCA-029 regulated BC cell malignancy and glycolysis via interacting with PRKCG in two ways: binding to the coding sequence (CDS) of PRKCG mRNA to regulate its transcription and altering polysomal PRKCG mRNA expression to modify its translation.ConclusionsHyperglycemia-downregulated tRF-Cys-GCA-029 enhances the malignancy and glycolysis of BC cells. tRF-Cys-GCA-029-PRKCG-glycolysis axis may be a potential therapeutic target against BC-DM.Graphical

Diabetes mellitus, hearing loss, and therapeutic interventions: A systematic review of insights from preclinical animal models.

The aim of this systematic review article is to evaluate the relationship between diabetes mellitus (DM) and sensorineural hearing loss (SNHL) utilizing preclinical animal models. The review focused on studies assessing SNHL in diabetic animal models, elucidating the mechanisms of DM-associated SNHL, and exploring the response of diabetic animal models to noise overexposure. We also discussed studies investigating the efficacy of potential therapeutic strategies for amelioration of DM-associated SNHL in the animal models. A protocol of this systematic review was designed a priori and was registered in the PROSPERO database (registration number: CRD42023439961). We conducted a comprehensive search on PubMed, Science Direct, Web of Science, Scopus, and EMBASE databases. A minimum of three reviewers independently screened, selected, and extracted data. The risk of bias assessment of eligible studies was conducted using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tool. Following the screening of 238 studies, twelve original articles were included in this systematic review. The studies revealed that hyperglycemia significantly affects auditory function, with various pathological mechanisms contributing to DM-induced hearing impairment, including cochlear synaptopathy, microangiopathy, neuropathy, oxidative stress, mitochondrial abnormalities, and apoptosis-mediated cell death. Emerging interventions, such as Asiaticoside, Trigonelline, Chlorogenic acid, and Huotanquyu granules, demonstrated efficacy in providing otoprotection for preserving cochlear hair cells and hearing function. Our systematic review delves into the intricate relationship between DM and hearing impairment in animal models. Future research should focus on targeted therapies to enhance cochlear mitochondrial function, alleviate oxidative stress, and regulate apoptosis. The association between SNHL and social isolation as well as cognitive decline underscores the necessity for innovative therapeutic modalities addressing yet undiscovered mechanisms. Translating findings from animal models to human studies will validate these findings, offering a synergistic approach to effectively manage DM-associated co-morbidities such as hearing impairment.

Liraglutide reduces bone marrow adipogenesis by miR-150-5p/ GDF11 axis in diabetic rats

In recent years, a common-used antidiabetic drug, liraglutide, was identified with extra effects on lipid metabolism. Its effects against excessive lipid deposition in bone marrow were gained much attention but not well established. Our aim in the present study is to explore the interaction of miRNAs-mRNAs altered by liraglutide administration during bone marrow adipogenesis in diabetes. To establish the diabetic animal model, rats were treated with high fat diet (HFD) and STZ injection. We then identified the lowering effect of liraglutide on lipids metabolism in the diabetes. During this process, high-throughput sequencing and bioinformatics analyses on miRNAs extracted from bone marrow mesenchymal stem cells (BMSCs) were conducted after liraglutide administration. We then identified five differentially expressed miRNAs (miRNA-150-5p, miRNA-129-5p, miRNA-201-3p, miRNA-201-5p, and miRNA-214-5p). The expressions of the DE miRNAs were verified as temporal specific expression patterns in Day 3 and in Day 7. Among them, miRNA-150-5p expression was more stable and consistent with the sequencing data. Of interest, miR-150-5p overexpression facilitated adipogenesis of BMSCs. But this promotion was alleviated by liraglutide. The predicted target gene of miR-150-5p, GDF11, was validated to be involved in liraglutide alleviated BMSCs’ lipid accumulation in diabetes. In vitro, liraglutide increased the GDF11 expression, rescued its down-expression by siGDF11 and inhibit the adipogenesis of BMSCs cultured in high glucose medium. In vivo, liraglutide reversed the HFD-STZ induced excessive lipid droplets by up-regulation of GDF11 expression, which was discounted by agomiR-150-5p injection. Above all, liraglutide might alleviate bone marrow fat accumulation via inactivating miR-150-5p/GDF11 axis in diabetes.