The effects of aerobic exercise on liver function, insulin resistance, and lipid profiles in prediabetic and type 2 diabetic mice.

BACKGROUND AND AIMS: The purpose of the current study was to evaluate the expression of gluconeogenesis and insulin resistance key genes; including insulin receptor substrate 1 (Irs1), a serine/threonine protein kinase (Akt), forkhead box class-O 1 (FoxO1) and phosphoenolpyruvate carboxykinase (Pepck) genes, and lipid profiles following either a standard or a high-fat diet (HFD) and either an aerobic exercise or non-exercise intervention in prediabetic and type 2 diabetic (T2DM) mice. METHODS: 24 male mice were randomly assigned to two groups fed with a normal diet (ND) or a HFD for 12 weeks. The mice in each group were again randomly assigned to two groups to create four groups in total: 1. Prediabetes-exercised (Prediabetes-Exe), 2. Prediabetes-non exercised (Prediabetes-Non exe), 3. Healthy-exercised (Healthy-Exe), and 4. Healthy-non exercised (Healthy-Non exe). Eighteen additional male mice were fed with the HFD for 8 weeks, after which streptozotocin (STZ) was administered. The mice were then fed the HFD for an additional 4 weeks. These T2DM mice were then randomly divided into two groups: 1. Diabetes-exercised (Diabetic-Exe), and 2. Diabetes-Non exe. The three Exe groups all exercised on a treadmill for 8 weeks for 5 sessions/week. After the last training session, liver tissue was extracted, and the expression of Irs1, Akt, FoxO1, and Pepck genes was measured using real time quantitative Polymerase chain reaction tests. Lipid profiles were measured in serum and in the liver. RESULTS: The expression of both Irs1 and Akt was significantly increased in the Healthy-Exe, Prediabetes-Exe, and Diabetes-Exe groups as compared to the Healthy-Non exe, Prediabetes-Non exe, and Diabetes-Non exe groups (p < 0.001). Additionally, the expression of FoxO1 (p < 0.05) and Pepck (p < 0.001) decreased significantly in the Prediabetes-Exe, and Diabetes-Exe groups as compared to the Prediabetes-non exe, and Diabetes-Non exe groups. Aerobic exercise did not lead to reductions in FoxO1 or Pepck expression in the Healthy-Exe mice. CONCLUSIONS: Eight weeks of aerobic exercise (5 sessions/week) significantly increased the expression of key genes that are important for maintaining glucose homeostasis and improving insulin resistance (Irs1 and Akt), and decreased expression of genes that are important for decreasing gluconeogenesis in the liver (FoxO1 and Pepck) in healthy, prediabetic, and T2DM mice. The lipid profiles improved in healthy, prediabetic, and T2DM mice.

Psychometric evaluation of Persian version of medical artificial intelligence readiness scale for medical students.

BACKGROUND: Artificial intelligence's advancement in medicine and its worldwide implementation will be one of the main elements of medical education in the coming years. This study aimed to translate and psychometric evaluation of the Persian version of the medical artificial intelligence readiness scale for medical students. METHODS: The questionnaire was translated according to a backward-forward translation procedure. Reliability was assessed by calculating Cronbach's alpha coefficient. Confirmatory Factor Analysis was conducted on 302 medical students. Content validity was evaluated using the Content Validity Index and Content Validity Ratio. RESULTS: The Cronbach's alpha coefficient for the whole scale was found to be 0.94. The Content Validity Index was 0.92 and the Content Validity Ratio was 0.75. Confirmatory factor analysis revealed a fair fit for four factors: cognition, ability, vision, and ethics. CONCLUSION: The Persian version of the medical artificial intelligence readiness scale for medical students consisting of four factors including cognition, ability, vision, and ethics appears to be an almost valid and reliable instrument for the evaluation of medical artificial intelligence readiness.

Changes in Protease-Activated Receptor and Trypsin-1 Expression Are Involved in the Therapeutic Effect of Mg2+ Supplementation in Type 2 Diabetes-Induced Gastric Injury in Male Adult Rats.

Purpose: Gastric inflammation is common and usually severe in patients with type 2 diabetes mellitus (T2DM). Evidence suggests protease-activated receptors (PARs) are a link between inflammation and gastrointestinal dysfunction. Given that magnesium (Mg2+) deficiency is a highly prevalent condition in T2DM patients, we assessed the therapeutic role of Mg2+ on the factors involved in gastric inflammation in T2DM. Methods: A rat model of T2DM gastropathy was established using a long-term high-fat diet + a low dose of streptozocin. Twenty-four rats were divided into control, T2DM , T2DM + insulin (positive control), and T2DM + Mg2+ groups. At the end of 2-month therapies, changes in the expression of gastric trypsin-1, PAR1, PAR2, PAR3, PI3K/Akt, and COX-2 proteins were measured by western blot. Hematoxylin and eosin and Masson's trichrome staining were used to detect gastric mucosal injury and fibrosis. Results: The expression of trypsin-1, PAR1, PAR2, PAR3, and COX-2 increased in diabetes, and Mg2+/insulin treatment strongly decreased their expression. The PI3K/p-Akt significantly decreased in T2DM, and treatment with Mg2+/insulin improved PI3K in T2DM rats. Staining of the gastric antrum tissue of the insulin/Mg2+-treated T2DM rats showed a significantly minimal mucosal and fibrotic injury compared with those of rats from the T2DM group. Conclusion: Mg2+ supplement, comparable to insulin, via decreasing PARs expression, mitigating COX-2 activity, and decreasing collagen deposition could exert a potent gastroprotective effect against inflammation, ulcer, and fibrotic development in T2DM patients.

Impact of magnesium sulfate therapy in improvement of renal functions in high fat diet-induced diabetic rats and their offspring.

The role of magnesium sulfate (MgSO4) administration to prevent diabetic nephropathy (DN) by reducing insulin resistance (IR) and the relationship of this action with gender and the expression of NOX4 and ICAM1 genes in the parents and their offspring were studied. Males and females rat, and their pups were used. Type 2 diabetes induced by high-fat diet (HFD) administration and a low dose of streptozotocin. Animals were divided into the: non-treated diabetic (DC), the diabetic group received insulin (Ins), and the diabetic group received MgSO4. Two groups of parents received just a normal diet (NDC). Following each set of parents for 16 weeks and their pups for 4 months, while eating normally. We assessed the amount of water consumed, urine volume, and blood glucose level. The levels of glucose, albumin, and creatinine in the urine were also measured, as well as the amounts of sodium, albumin, and creatinine in the serum. Calculations were made for glomerular filtration rate (GFR) and the excretion rates of Na and glucose fractions (FE Na and FE G, respectively). The hyperinsulinemic-euglycemic clamp was done. NOX4 and ICAM1 gene expressions in the kidney were also measured. MgSO4 or insulin therapy decreased blood glucose, IR, and improved GFR, FE Na, and FE G in both parents and their offspring compared to D group. MgSO4 improved NOX4 and ICAM1 gene expressions in the parents and their offspring compared to D group. Our results indicated that MgSO4 could reduce blood glucose levels and insulin resistance, and it could improve kidney function.

Long-term GABA administration improves FNDC5, TFAM, and UCP3 mRNA expressions in the skeletal muscle and serum irisin levels in chronic type 2 diabetic rats.

In this study, we aimed to investigate whether the anti-diabetic effects of γ-aminobutyric acid (GABA) and insulin can be mediated through the regulation of gene expression related to irisin production and mitochondrial biogenesis in type 2 diabetic mellitus (T2DM) rats. Four groups (n = 6) were used in this study: control, T2DM, T2DM + insulin, and T2DM + GABA groups. After T2DM induction for 3 months (high-fat diet + 35 mg/kg streptozotocin) and treatment with GABA or insulin for 3 months, circulating levels of FBG, triglyceride, LDL, Ox-LDL, and insulin as well as hepatic and serum irisin levels were measured. The mRNA expressions of fibronectin type III domain-containing protein 5 (FNDC5), mitochondrial transcription factor A (TFAM), and mitochondrial uncoupling protein 3 (UCP3) were also evaluated in the skeletal muscle of all groups. GABA therapy improved the FBG and insulin levels in diabetic rats. Insulin treatment significantly reduced FBG and failed to maintain glucose close to the control level. Insulin or GABA therapy significantly decreased the levels of LDL, Ox-LDL, and HOMA-IR index. Circulating irisin levels were markedly decreased in insulin-treated group, while irisin levels did not show significant changes in GABA-treated group compared with control group. GABA or insulin therapy increased mRNA expressions of TFAM and UCP3 in diabetic rats. GABA therapy also led to a significant increase in FNDC5 mRNA. Our findings suggest that the anti-diabetic effect of GABA may be mediated, in part, by a decrease in Ox-LDL levels and an increase in the levels of irisin as well as FNDC5, TFAM, and UCP3 gene expression in T2DM rats.

Beneficial effects of MgSO4 on TFAM, UPC3 and FNDC5 mRNA expressions in skeletal muscle of type 2 diabetic rats: a possible mechanism to improve insulin resistance.

BACKGROUND: Hypomagnesemia has been associated with development of type 2 diabetes mellitus (T2DM) and its complications. Irisin has beneficial effects on glucose uptake and improves hepatic glucose and lipid metabolism. In this study, we aimed to evaluate the effects of long-term treatment of MgSO4 and insulin on insulin resistance, dyslipidemia, serum and hepatic irisin levels, skeletal muscle gene expression of fibronectin type III domain-containing protein 5 (FNDC5), mitochondrial transcription factor A (TFAM) and mitochondrial uncoupling protein 3 (UCP3) in T2DM rats. METHODS AND RESULTS: Twenty-four rats were divided into four groups: Control group, diabetic control (DC) using a high-fat diet + streptozotocin, insulin-treated diabetic group (DC + Ins), MgSO4-treated diabetic group (DC + Mg). At the end of therapies, serum concentrations of FBG, TG, insulin, Ox-LDL, along with serum and hepatic irisin levels were measured. FNDC5, TFAM, and UCP3 mRNA expressions were measured in the skeletal muscle by Real-time PCR. In comparison with DC group, MgSO4 therapy resulted in decreased FBG, TG, Ox-LDL, improved serum insulin and irisin levels, and increased mRNA expressions of FNDC5, UCP3 and TFAM. Insulin therapy significantly decreased FBG, Ox-LDL, FNDC5 and serum irisin levels compared with the control group. While, insulin therapy markedly increased TFAM and UCP3 compared with the DC group. CONCLUSIONS: In conclusion, MgSO4 can improve insulin resistance and hyperlipidemia partly through decreasing Ox-LDL, increasing serum irisin levels as well as increasing FNDC5, TFAM, and UCP3 mRNA expressions in T2DM rats. These findings can be considered in the management of diabetes treatment.

Insulin resistance and the role of gamma-aminobutyric acid.

Insulin resistance (IR) is mentioned to be a disorder in insulin ability in insulin-target tissues. Skeletal muscle (SkM) and liver function are more affected by IR than other insulin target cells. SkM is the main site for the consumption of ingested glucose. An effective treatment for IR has two properties: An inhibition of ß-cell death and a promotion of ß-cell replication. Gamma-aminobutyric acid (GABA) can improve beta-cell mass and function. Multiple studies have shown that GABA decreases IR probably via increase in glucose transporter 4 (GLUT4) gene expression and prevention of gluconeogenesis pathway in the liver. This review focused on the general aspects of IR in skeletal muscle (SkM), liver; the cellular mechanism(s) lead to the development of IR in these organs, and the role of GABA to reduce insulin resistance.

Magnesium sulfate improves insulin resistance in high fat diet induced diabetic parents and their offspring.

In the present study, first, the role of high-fat diet (HFD) in insulin resistance (IR) in offspring with diabetic and non-diabetic parents, and then the effect of magnesium sulfate (Mg) administration on improved IR in HFD diabetic parents, and their offspring were investigated. Induction of diabetes was carried out by eating HFD and a low dose of streptozotocin (STZ). Diabetic rats were divided into three groups: diabetic control (DC), insulin, and Mg-treated (Mg). The non-diabetic control (NDC) group received a normal diet. Their offspring were fed on a regular diet for four months. Blood glucose and body weight of all animals were measured weekly, and IPGTT, urine volume, and water intake were measured monthly. In both parents and their offspring, the hyperinsulinemic euglycemic clamp was conducted, and blood samples were obtained. In all groups, the expression of IRS1, Akt and GLUT4 genes in muscle was measured. The HFD-fed rats exhibited a significant increase in blood glucose, body weight and IPGTT. In diabetic parents and their offspring, Mg or insulin therapy lowered blood glucose, IPGTT, and HbA1c relative to the DC group. They also increased GIR in parents and their offspring. Compared to the DC group, the expression of IRS1, Akt and GLUT4 genes was increased in both parents. Mg had positive effects on the expression of IRS1, Akt and GLUT4 genes in Mg treated offspring and reduced IR in them. As a result, magnesium may have beneficial effects on IR by increasing the expression of IRS1, Akt and GLUT4 genes.

Gamma-aminobutyric acid attenuates insulin resistance in type 2 diabetic patients and reduces the risk of insulin resistance in their offspring.

The role of gamma-aminobutyric acid (GABA) in attenuates insulin resistance (IR) in type 2 diabetic (T2D) patients and the reduction of the risk of IR in their offspring, and the function of GLUT4, IRS1 and Akt2 genes expression were investigated. T2D was induced by high fat diet and 35 mg/kg of streptozotocin. The male and female diabetic rats were then divided into three groups: CD, GABA, and insulin. NDC group received a normal diet. All the animals were studied for a six-month. Their offspring were just fed with normal diet for four months. Blood glucose was measured weekly in patients and their offspring. Intraperitoneal glucose tolerance test (IPGTT), urine volume, and water consumption in both patients and their offspring were performed monthly. The hyperinsulinemic euglycemic clamp in both patients and their offspring was done and blood sample collected to measure Hemoglobin A1c (HbA1c). IRS1, Akt and GLUT4 gene expressions in muscle were evaluated in all the groups. GABA or insulin therapy decreased blood glucose, IPGTT, and HbA1c in patients and their offspring compared to DC group. They also increased GIR in patients and their offspring. IRS1, Akt and GLUT4 gene expressions improved in both patients in comparison with DC group. GABA exerts beneficial effects on IRS1 and Akt gene expressions in GABA treated offspring. GABA therapy improved insulin resistance in diabetic patients by increasing the expression of GLUT4. It is also indirectly able to reduce insulin resistance in their offspring possibly through the increased gene expressions of IRS1 and Akt.

The Effect of Sneezing on the Reduction of Infarct Volume and the Improvement of Neurological Deficits in Male Rats.

BACKGROUND: Sneezing transiently elevates cerebral blood flow. We speculated that induced sneezing, following embolism would restore arterial flow, thereby diminishing infarct volume and improving neurological deficits. MATERIALS AND METHODS: Male rats were subjected to middle cerebral artery occlusion (MCAO) using prepared clots (embolization) and randomized into four equal groups as follows: (1) pre-MCAO-induced sneezing (PRMIS), (2) post-MCAO-induced sneezing (POMIS), and (3) pre- and POMIS (PRPOMIS) and the control group (eight rats per group). In the treatment groups, rats' sneezing episodes were induced before MCAO in PRMIS group or before regaining consciousness from surgical anesthesia in other treatment groups by cutting their whiskers during their anesthesia and subsequently inserted them into the rats' nostrils. Infarct volume was evaluated by 2, 3, 5-triphenyl tetrazolium chloride staining, and neurological deficits and brain edema were assessed by Bederson scale deficit scores 24-h post-MCAO. RESULTS: The infarct volume and brain edema reduced and neurological deficits improved in the induced sneezing groups as compared with the MCAO control group. Compared to the control group, the highest improvements in the infarct volume and neurological deficits were seen in the PRPOMIS group, and POMIS group showed the most significant differences concerning the results of both ischemic and nonischemic brain edema. The highest protective effect was observed in the central region of the MCA territory. CONCLUSIONS: The reduction in ischemia-induced brain injury, brain edema, and neurological deficits by sneezing suggest that brief episodes of acute hypertension after stroke can increase blood flow to the ischemic area and improve recovery.

TRPV1 receptor-mediated expression of Toll-like receptors 2 and 4 following permanent middle cerebral artery occlusion in rats.

OBJECTIVES: Stroke is known as a main cause of mortality and prolonged disability in adults. Both transient receptor potential V1 (TRPV1) channels and toll-like receptors (TLRs) are involved in mediating the inflammatory responses. In the present study, the effects of TRPV1 receptor activation and blockade on stroke outcome and gene expression of TLR2 and TLR4 were assessed following permanent middle cerebral artery occlusion in rats. MATERIALS AND METHODS: Eighty male Wistar rats were divided into four groups as follows: sham, vehicle, AMG9810 (TRPV1 antagonist) -treated and capsaicin (TRPV1 agonist) -treated. For Stroke induction, the middle cerebral artery was permanently occluded and then behavioral functions were evaluated 1, 3 and 7 days after stroke. RESULTS: TRPV1 antagonism significantly reduced the infarct volume compared to the stroke group. Also, neurological deficits were decreased by AMG9810 seven days after cerebral ischemia. In the ledged beam-walking test, the slip ratio was enhanced following ischemia. AMG9810 decreased this index in stroke animals. However, capsaicin improved the ratio 3 and 7 days after cerebral ischemia. Compared to the sham group, the mRNA expression of TLR2 and TLR4 was significantly increased in the stroke rats. AMG9810 Administration significantly reduced the mRNA expression of TLR2 and TLR4. However, capsaicin did not significantly affect the gene expression of TLR2 and TLR4. CONCLUSION: Our results demonstrated that TRPV1 antagonism by AMG9810 attenuates behavioral function and mRNA expression of TLR2 and TLR4. Thus, it might be useful to shed light on future therapeutic strategies for the treatment of ischemic stroke.

Delayed combination therapy of local brain hypothermia and decompressive craniectomy on acute stroke outcome in rat.

OBJECTIVES: Hypothermia and decompressive craniectomy (DC) have been shown to be neuroprotective. This study was designed to evaluate neuroprotective effects of delayed singular or combination of DC and local hypothermia on stroke. MATERIALS AND METHODS: Cerebral ischemia was induced in 48 Wistar rats assigned to 4 groups: control, decompressive craniectomy (DC), local hypothermia (LH), combination of hypothermia and craniectomy (HC). Infarct size and BBB disruption were measured 48 hr after ischemia insult. Neurological deficits were assessed at 24 and 48 hr after stroke by using sticky tape test, hanging-wire test and Bederson's scoring system. BBB disruption was measured by Evans blue dye leakage. RESULTS: Although infarct size was significantly reduced in LH, DC and HC groups (P<0.001), combination therapy was more neuroprotective compared to craniectomy alone (P<0.01). BBB disruption was significantly reduced in DC (P< 0.05) and LH and HC (P< 0.01).While sticky tape test (P<0.05 at 24 hr; P<0.001 at 48 hr) and hanging-wire test (P<0.05) showed better behavioral performance only in HC, Bederson test showed improved behavioral functions of both LH (P<0.05 at 24 hr and P<0.01 at 48 hr) and HC animals (P<0.01). Neurological deficits were also decreased in LH (P<0.05) or HC (P<0.05 at 24 hr; P<0.01 at 48 hr) groups compared to the DC group at the same time. CONCLUSION: Based on our data, although both delayed local hypothermia and craniectomy are protective after stoke, combination therapy of them is more neuroprotective than given alone.

Regulatory effects of chronic low-dose morphine on nitric oxide level along with baroreflex sensitivity in two-kidney one-clip hypertensive rats.

INTRODUCTION: Opiates are traditionally used for treatment of some acute heart disorders. There are only few reports on the effects of long-term treatment of cardiovascular diseases with morphine. This study aimed to investigate the effects of chronic low-dose morphine use on the cardiovascular system in two-kidney one-clip (2K1C) hypertensive rats. MATERIALS AND METHODS: Male Wistar rats were divided into two groups as the sham and 2K1C groups and each group was further subdivided into saline and morphine treatment subgroups. Blood pressure, heart rate, plasma rennin activity, serum nitric oxide concentration, and baroreflex sensitivity were measured. RESULTS: Morphine significantly attenuated systolic blood pressure, diastolic blood pressure, and mean arterial pressure in the 2K1C animals. In addition, morphine decreased plasma rennin activity in the 2K1C group. Serum concentrations of nitric oxide were also decreased, and morphine prevented the reduction of nitric oxide. The baroreflex sensitivity was also improved following morphine administration in the 2K1C group. CONCLUSIONS: According to the results presented in this study, chronic administration of low-dose morphine reduces regulated hypertension in the 2K1C rats, probably via a nitric oxide-dependent pathway.

Proinflammatory cytokines in the embolic model of cerebral ischemia in rat.

Increased levels of proinflammatory cytokines have been recorded after the onset of transient or permanent brain ischemia and are usually associated with exacerbation of ischemic injury. Embolic stroke model is more relevant to the pathophysiological situation in such patients, because the majority of ischemic injuries in humans are induced by old thrombi that originate from the heart and carotid arteries. Therefore, the aim of the present study was to investigate changes of inflammatory cytokines after embolic stroke. Rats were subjected to embolic stroke, induced by a natural old clot which was injected in Middle Cerebral Artery (MCA), or sham stroke, which the same volume of saline was injected into the MCA. At 48 h after stroke induction, the levels of 5 cytokines (IL-1α and ß, IL-6, IFN-γ and TNF-α) were determined in 500 µg of total protein using the Bio-Plex Rat Cytokine Array (BioRad), according to the manufacturer's instructions in ischemic and non-ischemic cortices. While stroke animals showed infarctions and neurological deficits, we did not observe any cerebral infarction and neurological deficits in sham-operated animals. The levels of IL-1α (p=0.000) and -ß (p =0.004), IL-6 (p =0.008), TNF-α (p =0.000) and IFN-γ (p =0.044) were significantly increased compared to sham treated animals. The findings of the present study suggest that part of ischemic injury in the embolic stroke may be mediated through the increased levels of inflammatory cytokines.