The potential of Myrmecodia pendans in preventing complications of diabetes mellitus as an antidiabetic and antihyperlipidemic agent.

Background: Hyperglycemia in diabetes mellitus (DM) can lead to dyslipidemia, which is a risk factor for macrovascular complications such as heart disease and stroke. Aside from administering antidiabetic medications, DM treatment can also be achieved through the use of natural components, such as Myrmecodia pendans, commonly known as the ant nest plant (ANP). Aim: This study aimed to investigate the impact of administering the ANP on the lipid profile of Wistar rats. Methods: A group of 20 rats was divided into two categories: 6 rats served as healthy controls (H), while the remaining 14 rats were subjected to a high-lipid diet and streptozotocin to generate a model of type 2 diabetes mellitus (T2DM). The diabetic rats were divided into two groups: the DM group consisted of rats that did not receive any treatment, while the ANP group was administered the herb orally. Results: The results revealed significant variations in triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels among the three groups (p < 0.05). The post hoc test revealed disparities in triglyceride and LDL between those in the DM group and the ANP group (p < 0.05). Conclusion: Myrmecodia pendans demonstrated the ability to decrease triglyceride and LDL, while increasing HDL levels in rats with T2DM.

Incretin therapy in feline diabetes mellitus - A review of the current state of research.

Incretin hormones potentiate the glucose-induced insulin secretion following enteral nutrient intake. The best characterised incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) which are produced in and secreted from the gut in response to nutrient ingestion. The property of incretins to enhance endogenous insulin secretion only at elevated blood glucose levels makes them interesting therapeutics for type 2 diabetes mellitus with a better safety profile than exogenous insulin. While incretin therapeutics (especially GLP-1 agonists, and more recently also GLP-1 / GIP dual agonists and other drugs that influence the incretin metabolism (e.g., dipeptidyl peptidase-4 (DPP-4) inhibitors)) are already widely used treatment options for human type 2 diabetes, these drugs are not yet approved for the therapy of feline diabetes mellitus. This review provides an introduction to incretins and feline diabetes mellitus in general and summarises the current study situation on incretins as therapeutics for feline diabetes mellitus to assess their possible future potential in feline medicine. Studies to date on the use of GLP-1 receptor agonists (GLP-1RA) in healthy cats largely confirm their insulinotropic effect known from other species. In diabetic cats, GLP-1RAs appear to significantly reduce glycaemic variability (GV, an indicator for the quality of glycaemic control), which is important for the management of the disease and prevention of long-term complications. However, for widespread use in feline diabetes mellitus, further studies are required that include larger numbers of diabetic cats, and that consider and test a possible need for dose adjustments to overweight and diabetic cats. Also evaluation of the outcome of GLP-1RA monotherapy will be neceessary.

Drosophila melanogaster as a model organism for diabetes II treatment by the ethyl acetate fraction of Atriplex halimus L.

Type 2 diabetes (T2D) is the most common metabolic disorder. The undesirable effects of synthetic drugs demand a search for safe antidiabetic agents. This study aimed to assess the antidiabetic activity of different fractions of Atriplex halimus (petroleum ether 60-80, methylene chloride, ethyl acetate, and n-butanol) using Drosophila melanogaster larvae. Titers of total glucose and trehalose, as well as larval weight, were measured and compared with those of control and diabetic larvae. The expression of Drosophila insulin-like peptides (DILP2 and DILP3) and adipokinetic hormone (AKH) was evaluated. The results revealed a significant increase in total glucose, trehalose, and a decrease in body weight in the larvae fed a high-sugar diet compared with those in the control. When larvae fed diets containing the tested fractions, the total glucose and trehalose decreased to the control level, and the body weight increased. DILP2, DILP3, and AKH exhibited significant decreases upon treatment with A. halimus ethyl acetate. Metabolomic profiling of the ethyl acetate fraction of A. halimus revealed the presence of flavonoids and flavonoid glycosides. After docking screening to predict the most powerful moiety, we discovered that flavonoid glycosides (especially eriodictyol-7-O-neohesperidoside) have a greater affinity for the pocket than the other moieties. The results indicated the therapeutic activity of the A. halimus ethyl acetate fraction against induced T2D in Drosophila larvae. The antidiabetic activity may be attributed to flavonoids, which are the main components of the A. halimus ethyl acetate fraction.

Effect of postbiotic Lactiplantibacillus plantarum LRCC5314 supplemented in powdered milk on type 2 diabetes in mice.

Type 2 diabetes (T2D) is a chronic multifactorial disease characterized by a combination of insulin resistance and impaired glucose regulation. The alleviative effects of probiotics on T2D have been widely studied. However, studies on the effects of postbiotics, known as inactivated probiotics, on dairy products are limited. This study aimed to evaluate the effectiveness of postbiotic Lactiplantibacillus plantarum LRCC5314 in milk powder (MP-LRCC5314) in a stress-induced T2D (stress-T2D) mouse model. Compared with probiotic MP-LRCC5314, postbiotic MP-LRCC5314 significantly influenced stress-T2D-related factors. The administration of heat-killed MP-LRCC5314 reduced corticosterone levels, increased short-chain fatty acid production by modulating gut microbiota, and regulated immune response, glucose metabolism, stress-T2D-related biomarkers in the brain, gut, and adipose tissues, as well as glucose and insulin sensitivity. In addition, heat-killed MP-LRCC5314 treatment led to a decrease in pro-inflammatory cytokine levels and an increase in anti-inflammatory cytokine levels. Overall, these findings suggest that adding postbiotic MP-LRCC5314 to milk powder could serve as a potential supplement for stress-T2D mitigation.

An analysis of risk factors for spontaneously occurring type 2 diabetes mellitus in rhesus macaques (Macaca mulatta).

BACKGROUND: Type 2 Diabetes Mellitus (T2D) is a chronic disease with a high prevalence worldwide. Human literature suggests factors beyond well-known risk factors (e.g., age, body mass index) for T2D: cytomegalovirus serostatus, season of birth, maternal age, birth weight, and depression. Nothing is known, however, about whether these variables are influential in primate models of T2D. METHODS: Using a retrospective methodology, we identified 22 cases of spontaneously occurring T2D among rhesus monkeys at our facility. A control sample of n = 1199 was identified. RESULTS: Animals born to mothers that were ≤5.5 years of age, and animals that showed heightened Activity and Emotionality in response to brief separation in infancy, had a greater risk for development of T2D in adulthood. CONCLUSIONS: Knowledge of additional risk factors for T2D could help colony managers better identify at-risk animals and enable diabetes researchers to select animals that might be more responsive to their manipulations.

Short-term glycemic variability in non-diabetic, non-obese dogs assessed by common glycemic variability indices.

Glycemic variability (GV) refers to swings in blood glucose levels and is an emerging measure of glycemic control in clinical practice. It is associated with micro- and macrovascular complications and poor clinical outcomes in diabetic humans. Although an integral part of patient assessment in human patients, it is to a large extent neglected in insulin-treated diabetic dogs. This prospective pilot study was performed to describe canine within-day GV in non-diabetic dogs with the aim to provide a basis for the interpretation of daily glucose profiles, and to promote GV as an accessible tool for future studies in veterinary medicine. Interstitial glucose concentrations of ten non-diabetic, non-obese beagles were continuously measured over a 48-h period using a flash glucose monitoring system. GV was assessed using the common indices MAGE (mean amplitude of glycemic excursion), GVP (Glycemic variability percentage) and CV (coefficient of variation). A total of 2260 sensor measurements were obtained, ranging from 3.7 mmol/L (67 mg/dL) to 8.5 mmol/L (153 mg/dL). Glucose profiles suggested a meal-dependent circadian rhythmicity with small but significant surges during the feeding periods. No differences in GV indices were observed between day and night periods (p > 0.05). The MAGE (mmol/L), GVP (%) and CV (%) were 0.86 (± 0.19), 7.37 (± 1.65), 6.72 (± 0.89) on day one, and 0.83 (± 0.18), 6.95 (± 1.52), 6.72 (± 1.53) on day two, respectively. The results of this study suggest that GV is low in non-diabetic dogs and that glucose concentrations are kept within narrow ranges.

Development of a requirement for exogenous insulin treatment in dogs with hyperglycemia.

BACKGROUND: It has been suggested that overt diabetes mellitus in dogs be defined based on a persistent fasting blood glucose concentration (BGC) >144 mg/dL. OBJECTIVE: Determine the number of dogs with randomly identified hyperglycemia without insulin-treated diabetes mellitus (ITDM) that later develop a need for exogenous insulin treatment. ANIMALS: A total of 1318 dogs examined at a university teaching hospital without ITDM and with randomly identified hyperglycemia. METHODS: Retrospective longitudinal study. Hyperglycemia was defined as randomly identified BGC above >112 mg/dL, moderate hyperglycemia as BGC >144 mg/dL but <200 mg/dL and pronounced hyperglycemia as BGC ≥200 mg/dL. Dogs were defined as having ITDM if they were treated with insulin. Follow-up was attempted 7 to 12 years after hyperglycemia was documented to determine if over time dogs developed a need for exogenous insulin treatment. RESULTS: Twenty-nine of 824 dogs (3.5%) with hyperglycemia and follow-up information developed ITDM, including 3/824 dogs (0.4%) with moderate hyperglycemia, and 2/824 dogs (0.2%) with pronounced hyperglycemia. Most dogs with hyperglycemia that developed ITDM (24/29, 83%) had BGC ≤144 mg/dL. Among dogs that eventually developed a need for exogenous insulin treatment, no association was found between the degree of hyperglycemia and the time interval between documentation of hyperglycemia and diagnosis of ITDM. Logistic regression determined that BGC is not significantly associated with ITDM. CONCLUSIONS AND CLINICAL IMPORTANCE: Most dogs with randomly identified hyperglycemia did not develop a need for exogenous insulin treatment. Other criteria could be required to augment the definition of overt DM in non-insulin treated dogs.

Insulin release from isolated cat islets of Langerhans.

Feline diabetes mellitus is a common endocrine disease with increasing prevalence. It shows similarities with human type 2 diabetes and is characterized by insulin resistance and deficient insulin secretion. Moreover, cats and humans belong to the very few species that form amyloid depositions in the pancreatic islets. However, little is known about cat islet function and no studies have addressed insulin secretion from isolated islets ex vivo. The aim of this study was to establish a protocol for isolation of islets of Langerhans from pancreata of cats euthanized due to disease, and to evaluate insulin secretion responses to various physiological and pharmacological stimuli. Collagenase digestion of pancreatic tissue from 13 non-diabetic cats and two cats with diabetic ketoacidosis yielded individual islets surrounded by a layer of exocrine tissue that was reduced after two days in culture. Histological examination showed islet amyloid in pancreatic biopsies from most non-diabetic and in one diabetic cat. Islets from non-diabetic cats cultured at 5.5 mM glucose responded with increased insulin secretion to 16.7 mM glucose, 30 mM K+ and 20 µM of the sulfonylurea glipizide (2-3 times basal secretion at 3 mM glucose). The glucagon-like peptide-1 receptor agonist exendin-4 (100 nM) had no effect under basal conditions but potentiated glucose-triggered insulin release. Only one of nine islet batches from diabetic cats released detectable amounts of insulin, which was enhanced by exendin-4. Culture of islets from non-diabetic cats at 25 mM glucose impaired secretion both in response to glucose and K+ depolarization. In conclusion, we describe a procedure for isolation of islets from cat pancreas biopsies and demonstrate that isolated cat islets secrete insulin in response to glucose and antidiabetic drugs. The study provides a basis for future ex vivo studies of islet function relevant to the understanding of the pathophysiology and treatment of feline diabetes.

Diabetes mellitus drug discovery: insights into targeting feline and human amylin with small molecules.

BACKGROUND: Type 2 diabetes (T2D) is a health concern for both humans and cats, with cases rising over the past decade. Around 70% of patients from either species exhibit pancreatic aggregates of islet amyloid polypeptide (IAPP), a protein that proves toxic upon misfolding. These misfolded protein aggregates congregate in the islets of Langerhans of the pancreas, diminishing the capability of ß-cells to produce insulin and further perpetuating disease. OBJECTIVE: Our team's drug discovery program is investigating newly synthesized compounds that could diminish aggregates of both human and feline IAPP, potentially disrupting the progression of T2D. MATERIAL AND METHODS: We prepared 24 compounds derived from diaryl urea, as ureas have previously demonstrated great potential at reducing accumulations of misfolded proteins. Biophysical methods were employed to analyze the anti-aggregation activity of these compounds at inhibiting and/or disrupting IAPP fibril formation in vitro. RESULTS: The results demonstrate that compounds 12 and 24 were most effective at reducing the fibrillization and aggregation of both human and feline IAPP. When compared with the control for each experiment, samples treated with either compound 12 or 24 exhibited fewer accumulations of amyloid-like fibrils. CONCLUSION: Urea-based compounds, such as compounds 12 and 24, may prove crucial in future pre-clinical studies in the search for therapeutics for T2D.

Hypertriglyceridemia in equines with refractory hyperinsulinemia treated with SGLT2 inhibitors.

Background: Sodium-Glucose CoTransporter-2 (SGLT2) inhibitors, the -flozin group of drugs, which block glucose reuptake in the renal proximal tubule, are being increasingly used off-label to treat horses with refractory hyperinsulinemia. After 2 years of use by animals in our group, a horse on canagliflozin was incidentally noted to be hyperlipemic. Case Description: We have been following a cohort of equines (n = 20) treated with SGLT2 inhibitors due to refractory hyperinsulinemia. The animals are owned by members of the Equine Cushing's and Insulin Resistance Group and treated by their attending veterinarians. The index case was a 23 years old gelding with a 2 years history of recurring laminitis that began canagliflozin therapy to control hyperinsulinemia which was no longer responsive to metformin. Between 6 and 10 weeks post start of therapy, significant weight loss was noticed. Two days later he was hospitalized with colic symptoms and hyperlipemia but was bright, alert, and eating well throughout. Canagliflozin was discontinued and triglycerides returned to normal reference values within 10 days. A subsequent study of 19 other horses on SGLT2 inhibitors revealed varying degrees of hypertriglyceridemia, all asymptomatic. Conclusion: While this class of drugs holds great promise for cases of refractory hyperinsulinemia and laminitis that do not respond to diet or metformin therapy, hypertriglyceridemia is a potential side effect. In our experience, animals remained asymptomatic and eating well. Further study of hypertriglyceridemia in horses on SGLT2 inhibitors and the possible mitigating effect of diet is indicated. To our knowledge, this is the first report of hypertriglyceridemia with canagliflozin treatment in equines.

Pathophysiology of Prediabetes, Diabetes, and Diabetic Remission in Cats.

Diabetes mellitus (DM) has a heterogenous cause, and the exact pathogenesis differs between patients. Most diabetic cats have a cause similar to human type 2 DM but, in some, DM is associated with underlying conditions, such as hypersomatotropism, hyperadrenocorticism, or administration of diabetogenic drugs. Predisposing factors for feline DM include obesity, reduced physical activity, male sex, and increasing age. Gluco(lipo)toxicity and genetic predisposition also likely play roles in pathogenesis. Prediabetes cannot be accurately diagnosed in cats at the current time. Diabetic cats can enter remission, but relapses are common, as these cats might have ongoing, abnormal glucose homeostasis.

Insulin Therapy in Small Animals, Part 3: Dogs.

Insulin therapy should ideally mimic a basal-bolus pattern. Lente, NPH, NPH/regular mixes, PZI, glargine U100, and detemir are intermediate-acting formulations that are administered twice daily in dogs. To minimize hypoglycemia, intermediate-acting insulin protocols are usually geared towards alleviating (but not eliminating) clinical signs. Insulin glargine U300 and insulin degludec meet the criteria for an effective and safe basal insulin in dogs. In most dogs, good control of clinical signs is achieved when using a basal insulin alone. In a small minority, bolus insulin at the time of at least one meal per day may be added to optimize glycemic control.

Insulin Therapy in Small Animals, Part 2: Cats.

No insulin formulation should be considered best by default for management of feline diabetes. Rather, the choice of insulin formulation should be tailored to the specific clinical situation. In most cats that have some residual beta cell function, administering only a basal insulin might lead to complete normalization of blood glucose concentrations. Basal insulin requirements are constant throughout the day. Therefore, for an insulin formulation to be effective and safe as a basal insulin, its action should be roughly the same every hour of the day. At present, only insulin glargine U300 approaches this definition in cats.

Insulin Therapy in Small Animals, Part 1: General Principles.

Understanding the pharmacology of insulin and how it relates to the pathophysiology of diabetes can lead to better clinical outcomes. No insulin formulation should be considered "best" by default. Insulin suspensions (NPH, NPH/regular mixes, lente, and PZI) as well as insulin glargine U100 and detemir are intermediate-acting formulations that are administered twice daily. For a formulation to be an effective and safe basal insulin, its action should be roughly the same every hour of the day. Currently, only insulin glargine U300 and insulin degludec meet this standard in dogs, whereas in cats, insulin glargine U300 is the closest option.

The Future of Diabetes Therapies: New Insulins and Insulin Delivery Systems, Glucagon-Like Peptide 1 Analogs, Sodium-Glucose Cotransporter Type 2 Inhibitors, and Beta Cell Replacement Therapy.

As the prevalence of diabetes mellitus increases, so too does the number of available treatment modalities. Many diabetic therapies available in human medicine or on the horizon could hold promise in the management of small animal diabetes. However, it is important to consider how species differences in pathophysiology, management practices and goals, and lifestyle may affect the translation of such treatment modalities for veterinary use. This review article aimed to familiarize veterinarians with the more promising novel diabetic therapies and explore their possible applications in the treatment of canine and feline diabetes mellitus.

Etiology and Pathophysiology of Diabetes Mellitus in Dogs.

Canine diabetes results from a wide spectrum of clinical pathophysiological processes that cause a similar set of clinical signs. Various causes of insulin deficiency and beta cell loss, insulin resistance, or both characterize the disease, with genetics and environment playing a role. Understanding the genetic and molecular causes of beta cell loss will provide future opportunities for precision medicine, both from a therapeutic and preventative perspective. This review presents current knowledge of the etiology and pathophysiology of canine diabetes, including the importance of disease classification. Examples of potential targets for future precision medicine-based approaches to therapy are discussed.

Purification and characterization of the dipeptidyl peptidase-IV inhibitory peptides from eel (Anguilla rostrata) scraps enzymatic hydrolysate for the treatment of type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a serious threat to human health. Owing to the action of dipeptidyl peptidase-IV (DPP-IV), the half-life of entero-insulin hormone after secretion is extremely short, causing insufficient insulin secretion in diabetic patients. Dipeptidyl peptidase-IV inhibitors can be used as a new treatment for T2DM. In this study, the proteins of eel (Anguilla rostrata) scraps hydrolyzed using Protamex protease (EPHs) were found to have strong DPP-IV inhibitory activity. The study also provided research ideas for the development and utilization of A. rostrata scraps. RESULTS: The median inhibition concentration (IC50 ) value of EPHs was 5.455 ± 0.24 mg mL-1 . The peptide fractions with the highest DPP-IV inhibitory activity were sequentially separated by ultrafiltration, gel filtration chromatography (GFC), and reversed-phase high performance liquid chromatography (RP-HPLC) in a continuous hierarchical manner and analyzed using matrix-assisted laser desorption/ionization time-of-flight/ time-of-flight mass spectrometry/mass spectrometry (MALDI-TOF/TOF MS/MS). Three peptides that revealed significant inhibitory activity were screened among the identified sequences, with sequences of Phe-Pro-Arg (IC50  = 62.14 ± 1.47 µM), Tyr-Pro-Pro-Ser-Phe-Ser (IC50  = 102.65 ± 4.57 µM), and Tyr-Pro-Tyr-Pro-Ala-Ser (IC50  = 68.30 ± 3.85 µM). Molecular docking simulations revealed that their inhibitory effect was mainly due to the formation of hydrogen bonds with amino acid residues in the active sites of DPP-IV. Analysis of the inhibition patterns of the synthetic peptides displayed that Phe-Pro-Arg and Tyr-Pro-Pro-Ser-Phe-Ser displayed competitive inhibition, whereas Tyr-Pro-Tyr-Pro-Ala-Ser showed mixed competitive/non-competitive inhibition. CONCLUSIONS: The protein hydrolysates isolated from eel scraps are potential functional food ingredients for the treatment of T2DM. © 2023 Society of Chemical Industry.

Low serum creatinine, a surrogate marker of muscle mass, correlates with insulin sensitivity in nonhuman primates.

OBJECTIVES: Decreased serum creatinine levels are associated with increased risk of type 2 diabetes (T2DM) in humans, however, its association with muscle mass and insulin sensitivity have not been studied in NHPs. METHODS: Retrospective data of 229 adult NHPs were studied for association of serum creatinine levels with muscle mass and onset of T2DM. RESULTS: Serum creatinine levels were positively correlated with lean muscle mass in nondiabetic (non-DM), male and female NHPs. Aged NHPs had significantly reduced lean muscle mass and corresponding creatinine levels compared to young age groups (p < .001). Creatinine was positively correlated with insulin sensitivity in nonDM male NHPs and significant decrease in creatinine was observed in T2DM (p < .001) compared to same age group nonDM NHPs. CONCLUSIONS: The pathophysiology of T2DM in NHPs is similar to humans, low creatinine further provides utility of surrogate biomarkers of lower muscle mass and risk factor for T2DM NHPs.

Detemir improves diabetic regulation in poorly controlled diabetic dogs with concurrent diseases.

OBJECTIVE: This study evaluated the use of detemir for treating diabetic dogs with comorbidities that were poorly controlled with intermediate-acting insulins. ANIMALS: 7 insulin-treated diabetic dogs. PROCEDURES: Retrospective pilot study. Dogs were treated with detemir for at least 3 months, and glycemia was assessed by the owners at home initially 2 to 4 times daily for 6 to 8 weeks and twice daily thereafter. Clinical evaluations occurred on days 7 to 14, day 30, and then every 60 to 90 days, and dosage adjustments of detemir occurred as needed to control glycemia. RESULTS: The mean, peak, nadir, morning, and evening preinsulin daily blood glucose concentrations were significantly lower after dosing with detemir for 1, 3, or 6 months and during the last month of treatment compared to the final month of treatment with intermediate-acting insulin. Intermediate-acting insulins resulted in significantly worse glycemic control than detemir in all 3 categories of control. The odds of a biochemical hypoglycemic measurement with detemir were not significantly different compared to intermediate-acting insulins. Clinical hypoglycemia did not occur following detemir treatment. When insulin was withheld because of low morning preinsulin blood glucose concentration < 6.7 mmol/L (≤ 120 mg/dL) and dogs were fed, mean blood glucose concentration was significantly higher 1 hour later. Glucose concentrations were also significantly higher 12 hours later on days when insulin was withheld in the morning or evening for either 1 or 12 hours. CLINICAL RELEVANCE: Detemir is useful in diabetic dogs with other comorbidities and can be considered an alternative treatment in poorly controlled diabetic dogs.

Effects of gradient high-field static magnetic fields on diabetic mice.

Although 9.4 T magnetic resonance imaging (MRI) has been tested in healthy volunteers, its safety in diabetic patients is unclear. Furthermore, the effects of high static magnetic fields (SMFs), especially gradient vs. uniform fields, have not been investigated in diabetics. Here, we investigated the consequences of exposure to 1.0-9.4 T high SMFs of different gradients (>10 T/m vs. 0-10 T/m) on type 1 diabetic (T1D) and type 2 diabetic (T2D) mice. We found that 14 h of prolonged treatment of gradient (as high as 55.5 T/m) high SMFs (1.0-8.6 T) had negative effects on T1D and T2D mice, including spleen, hepatic, and renal tissue impairment and elevated glycosylated serum protein, blood glucose, inflammation, and anxiety, while 9.4 T quasi-uniform SMFs at 0-10 T/m did not induce the same effects. In regular T1D mice (blood glucose ≥16.7 mmol/L), the >10 T/m gradient high SMFs increased malondialdehyde ( P<0.01) and decreased superoxide dismutase ( P<0.05). However, in the severe T1D mice (blood glucose ≥30.0 mmol/L), the >10 T/m gradient high SMFs significantly increased tissue damage and reduced survival rate. In vitro cellular studies showed that gradient high SMFs increased cellular reactive oxygen species and apoptosis and reduced MS-1 cell number and proliferation. Therefore, this study showed that prolonged exposure to high-field (1.0-8.6 T) >10 T/m gradient SMFs (35-1 380 times higher than that of current clinical MRI) can have negative effects on diabetic mice, especially mice with severe T1D, whereas 9.4 T high SMFs at 0-10 T/m did not produce the same effects, providing important information for the future development and clinical application of SMFs, especially high-field MRI.