Long term administration of thiamine disulfide improves FOXO1/PEPCK pathway in liver to reduce insulin resistance in type 1 diabetes rat model.

OBJECTIVE: The main objective of this study was to find if thiamine disulfide (TD) lowers blood glucose level and improves insulin resistance (IR) in liver and muscle in rats with chronic type 1 diabetes (T1DM) using euglycemic-hyperinsulinemic clamp technique. METHODS: A total of fifty male Wistar rats were assigned to five groups consisted of: non-diabetic control (NDC), diabetic control (DC), diabetic treated with thiamine disulfide (D-TD), diabetic treated with insulin (D-insulin), and diabetic treated with both TD and insulin (D-insulin+TD). Diabetes was induced by a 60 mg/kg dose of streptozotocin. Blood glucose levels, pyruvate tolerance test (PTT), intraperitoneal glucose tolerance test (IPGTT), levels of glycosylated hemoglobin (HbA1c), glucose infusion rate (GIR), liver and serum lipid profiles, liver glycogen stores, liver enzymes ([ALT], [AST]), and serum calcium and magnesium levels. were evaluated. Additionally, gene expression levels of phosphoenolpyruvate carboxykinase (Pepck), forkhead box O1 (Foxo1), and glucose transporter type 4 (Glut4) were assessed in liver and skeletal muscle tissues. RESULTS: Blood glucose level was reduced by TD treatment. In addition, TyG index, HOMA-IR, serum and liver lipid profiles, HbA1c levels, and expressions of Foxo1 and Pepck genes were decreased significantly (P<0.05) in all the treated groups. However, TD did not influence Glut4 gene expression, but GIR as a critical index of IR were 5.0±0.26, 0.29±0.002, 1.5±0.07, 0.9±0.1 and 1.3±0.1 mg.min-1Kg-1 in NDC, DC, D-TD, D-insulin and D-insulin+TD respectively. CONCLUSIONS: TD improved IR in the liver primarily by suppressing gluconeogenic pathways, implying the potential use of TD as a therapeutic agent in diabetes.

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.

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.

Magnesium Supplementation Affects the Expression of Sirtuin1, Tumor Protein P53 and Endothelial Nitric Oxide Synthase Genes in Patients with Atherosclerosis: A Double-Blind, Randomized, Placebo-Controlled Trial.

Magnesium seems to play a role in improving cardiovascular function, but its exact mechanism is unknown. In this study, we hypothesized that magnesium could modulate the expression of genes involved in atherosclerosis. The aim of the present investigation was to evaluate the effect of magnesium sulfate on the expression of sirtuin1 (SIRT1), tumor protein p53 (TP53), and endothelial nitric oxide synthase (eNOS) genes in patients with atherosclerosis. This study was a placebo-controlled double-blind randomized clinical trial on 56 patients with angiographically proven atherosclerosis. Participants were randomly divided into two groups receiving 300 mg/day magnesium sulfate (n = 29) and placebo (n = 27) for three months (following up every month). Fasting blood samples were taken before and after the intervention and total RNA was extracted and used to evaluate the expression level of SIRT1, TP53, and eNOS genes by Real-Time PCR. The expression of eNOS gene was significantly increased (P < 0.0001) and the expression of TP53 gene was decreased (P = 0.02) in the magnesium sulfate group compared to the placebo group. But SIRT1 gene expression was not significantly different between the two groups. Our findings demonstrate that magnesium sulfate supplementation may have a protective role against the progression of atherosclerosis through upregulation of eNOS and downregulation of TP53 gene. Trial registration: This present clinical trial has been registered in the Iranian Registry of Clinical Trials (IRCT) with the registration code of "IRCT20151028024756N3", https://www.irct.ir/trial/29097?revision=114102. Registered on 16 December 2019.

The Therapeutic Effects of Magnesium in Insulin Secretion and Insulin Resistance.

Insulin resistance (IR) is a chronic pathological condition that is related to reduce the rates of glucose uptake, especially in the liver, muscle, and adipose tissue as target tissues. Metabolic syndrome and type 2 diabetes mellitus can occur following progression of the disease. The majority of prior research has applied that some cations such as magnesium (Mg2+) have important physiological role in insulin metabolism. Mg2+ is the fourth most abundant mineral in the human body that gets involved as a cofactor of various enzymes in several metabolic events, such as carbohydrate oxidation, and it has a fundamental role in glucose transporting mechanism of the cell membrane. This cation has numerous duties in the human body such as regulation of insulin secretion in pancreatic beta-cells and phosphorylation of the insulin receptors in target cells and also gets involved in other downstream signal kinases as intracellular cation. On this basis, intracellular Mg2+ balancing is vital for adequate carbohydrate metabolism. This paper summarizes the present knowledge about the therapeutic effects of Mg2+ in reducing IR in liver, muscle, and pancreases with different mechanisms. For this, the search was performed in Google Scholar, PubMed, Scopus, and Web of Science by insulin resistance, skeletal muscle, liver, pancreases, magnesium, Mg2+, and inflammation keywords.

The role of pancreas to improve hyperglycemia in STZ-induced diabetic rats by thiamine disulfide.

BACKGROUND: The present study investigated the effect of thiamine disulfide (TD) on the pancreas in terms of hyperglycemia improvement and insulin sensitivity increase in diabetic male rats. We also aimed to study the function of Pdx1 (pancreatic and duodenal homeobox 1) and Glut2 (glucose transporter 2) genes in pancreatic tissue. METHODS: Type 1 diabetes was induced through injection of 60 mg/kg streptozotocin (STZ). The diabetic rats were divided into four groups, namely diabetic control (DC), diabetic treated with thiamine disulfide (D-TD), diabetic treated with insulin (D-insulin), and diabetic treated with TD and insulin (D-insulin+TD). The non-diabetic (NDC) and diabetic groups received a normal diet (14 weeks). Blood glucose level and body weight were measured weekly; insulin tolerance test (ITT) and glucagon tolerance test (GTT) were performed in the last month of the study. The level of serum insulin and glucagon were measured monthly and a hyperglycemic clamp (Insulin Infusion rate (IIR)) was done for all the groups. Pancreas tissue was isolated so that Pdx1and Glut2 genes expression could be measured. RESULTS: We observed that TD therapy decreased blood glucose level, ITT, and serum glucagon levels in comparison with those of the DC group; it also increased serum insulin levels, IIR, and expression of Pdx1 and Glut2 genes in comparison with those of the DC group. CONCLUSION: Administration of TD could improve hyperglycemia in type 1 diabetic animals through improved pancreas function. Therefore, not only does TD have a significant effect on controlling and reducing hyperglycemia in diabetes, but it also has the potential to decrease the dose of insulin administration.

Combination Therapy with GABA and MgSO4 Improves Insulin Sensitivity in Type 2 Diabetic Rat.

BACKGROUND: Gamma-aminobutyric acid (GABA) and magnesium sulfate (MgSO4) play a crucial role in glycemic control. Therefore, we studied the effect of combination therapy with GABA and MgSO4 to improve insulin sensitivity in diabetes induced by streptozotocin as well as high-fat diet in a diabetic rat model. Design and Methods. Forty randomly selected rats were assigned to four groups: nondiabetic control group was fed the normal diet, insulin-resistant diabetic rat model was induced by streptozotocin and high-fat diet, GABA + MgSO4 group received GABA and MgSO4, and insulin group was treated with insulin. Body weight, abdominal fat, blood glucose, serum insulin, and glucagon concentration were measured. The glucose clamp technique, glucose tolerance test, and insulin tolerance test were performed to study insulin sensitivity. Also, the expressions of glucose 6 phosphatase, glucagon receptor, and phosphoenolpyruvate carboxykinase genes in liver were assessed for the gluconeogenesis pathway. Protein translocation and glucose transporter 4 (Glut4) genes expression in muscle were also assessed. RESULTS: Combination of GABA + MgSO4 or insulin therapy enhanced insulin level, glycemic control, glucose and insulin tolerance test, some enzymes expression in the gluconeogenesis pathway, body fat, body weight, and glucagon receptor in diabetic rats. Moreover, an increase was observed in protein and gene expression of Glut4. Insulin sensitivity in combination therapy was more than the insulin group. CONCLUSIONS: GABA and MgSO4 enhanced insulin sensitivity via increasing Glut4 and reducing the gluconeogenesis enzyme and glucagon receptor gene expressions.

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.

GABA administration improves liver function and insulin resistance in offspring of type 2 diabetic rats.

This study investigated the role of GABA in attenuating liver insulin resistance (IR) in type 2 diabetes parents and reducing its risk in their descendants' liver. Both sexes' rats were divided into four groups of non-diabetic control, diabetic control (DC), GABA-treated (GABA), and insulin-treated (Ins). The study duration lasted for six months and the young animals followed for four months. Consequently, hyperinsulinemic-euglycemic clamp was performed for all animals. Apart from insulin tolerance test (ITT), serum and liver lipid profile were measured in all groups. Glycogen levels, expression of Foxo1, Irs2, Akt2, and Pepck genes in the liver were assessed for all groups. Overall, GABA improved ITT, increased liver glycogen levels and decreased lipid profile, blood glucose level, and HbA1c in parents and their offspring in compared to the DC group. GIR also increased in both parents and their offspring by GABA. Moreover, the expression of Foxo1, Irs2, Akt2, and Pepck genes improved in GABA-treated parents and their descendants in compared to DC group. Results indicated that GABA reduced liver IR in both parents and their offspring via affecting their liver insulin signaling and gluconeogenesis pathways.

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.

Magnesium Sulfate Improves Some Risk Factors for Atherosclerosis in Patients Suffering from One or Two Coronary Artery Diseases: A Double-blind Clinical Trial Study.

PURPOSE: Given the beneficial effect of MgSO4 on the cardiovascular system, this study was designed to investigate the effect of MgSO4 administration on suppressing some atherosclerotic risk factors in moderate coronary artery disease patients with one or two atherosclerotic vessels. PATIENTS AND METHODS: In a randomized double-blind placebo-controlled clinical trial study, 64 patients with moderate coronary artery disease (55-69% stenosis) were selected according to angiography findings. Patients were divided into four groups including patients with one or two atherosclerotic vessels treated with MgSO4 (Mg-treated-VR1, Mg-treated-VR2, respectively), placebo treated patients with one or two atherosclerotic vessels (Control-VR1, Control-VR2, respectively). The patients received either placebo or MgSO4 supplement capsule containing 300 mg MgSO4 for six months on a daily basis. ESR, Ca/Mg ratio, urine Mg level, serum Mg, fibrinogen, homocysteine, uric acid, Na, K, Ca, CRP, T3, T4, TSH, BUN, and Cr concentrations were measured at baseline and every three months. RESULTS: Serum T3, Ca, K, homocysteine, CRP, and Mg concentrations were significantly improved in Mg-treated groups compared to placebo groups. CONCLUSION: The results of this study showed that despite the slight change in serum magnesium level, oral administration of MgSO4for six months could slightly reduce the serum levels of some inflammatory and vascular factors in moderate coronary artery disease patients.

Magnesium Sulfate Administration in Moderate Coronary Artery Disease Patients Improves Atherosclerotic Risk Factors: A Double-Blind Clinical Trial Study.

Magnesium (Mg) deficiency is known to promote vascular and cardiac dysfunctions such as atherosclerosis. This study investigated the effect of oral MgSO4 therapy to improve lipid profile and serum oxidized LDL level and its receptor (LOX1) in moderate coronary atherosclerotic patients. In this randomized double-blind placebo-controlled clinical trial study, 64 patients with moderate coronary artery disease were selected according to angiography findings. Participants were divided into 2 groups including Mg-treated (n = 32) and placebo (n = 32) The patients received either placebo or MgSO4 supplement capsule, containing 300 mg MgSO4 for 6 months on a daily basis. Lipid profile, HbA1c, 2h postprandial (2hpp) blood glucose, fasting blood sugar, serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), oxidized low-density lipoprotein, and lectin-like ox-LDL receptor 1 (LOX1) concentrations were measured at baseline and every 3 months. HbA1c, serum LOX1, and oxidized low-density lipoprotein concentrations were significantly lower in the Mg-treated group than the placebo group 3 months after MgSO4 administration. 2hpp, serum low-density lipoprotein cholesterol, SGPT, SGOT levels, and HbA1c levels significantly improved in the Mg-treated group compared with the placebo-received group. Overall, the results of this study showed that magnesium treatment improved some of the major risk factors of atherosclerosis. According to the results of liver function tests (SGOT and SGPT), magnesium therapy seems to be safe in patients with moderate atherosclerotic plaque. Therefore, it is suggested that magnesium to be used along with other atherosclerosis control drugs.

Oral herbal supplement containing magnesium sulfate improve metabolic control and insulin resistance in non-diabetic overweight patients: A randomized double blind clinical trial.

Background: Magnesium deficiency plays a key role in obesity and decreases insulin sensitivity. In our previous study, significant evidence was provided for the contribution of oral Mg supplement that could improve insulin sensitivity and body weight in animal trials. The purpose of the present study was to investigate the effects of an herbal supplement containing 300 mg magnesium sulfate on lipid profile, as well as insulin resistance and secretion in overweight patients. Methods: Seventy overweight non-diabetic volunteers with Body Mass Index (BMI) >28 kg/m2 were included in a randomized double blind placebo-controlled clinical trial (ethic number HUMS REC.1394.57) and registered in Iranian Registry of Clinical Trials (IRCT2012110124756N2 with registration number 24756). They received either placebo or an herbal supplement capsule containing 300 mg magnesium sulfate (MgSO4) for 6 months on a daily basis. Metabolic control, lipid profile and magnesium status were determined at baseline and every three months. Student t-test, repeated measure ANOVA and ANCOVA were used to compare the groups. Results: There was no significant difference between groups before intervention, but daily Mg supplement for 6 months significantly improved fasting insulin level (6.71±0.11 to 6.27±0.3 three months after Mg therapy, p<0.01 vs. 6.41±0.11 in control group (5.83±0.063) six months after Mg therapy, p< 0.0001), HOMA-IR (1.52±0.03 )in control group to 1.36±0.03 after three months Mg therapy, p<0.05 vs 1.37±0.05 in control group to 1.22±0.02 six months after Mg therapy, p< 0.05), high density lipoprotein cholesterol (HDL) (43.57±0.82 in control group to 43.91±1.92 three months after Mg therapy, p<0.001vs 43.57±0.82 in control group to 46±0.88 six months after Mg therapy, <0.01), triglyceride (TG) (163.17±6.1 in control group to 141.2±5.84 six months after g therapy, p<0.05) and low density lipoprotein cholesterol (LDL) (112.62±3.41 in control group to 104.42±2.35 six months after Mg therapy, p<0.05). Conclusion: Oral herbal supplement containing MgSO4 (300 mg/day) could improve plasma insulin level, lipid profile, and insulin resistance in non-diabetic overweight volunteers.

Effect of oral magnesium sulfate administration on lectin-like oxidized low-density lipoprotein receptor-1 gene expression to prevent atherosclerosis in diabetic rat vessels.

AIMS/INTRODUCTION: The purpose of the present study was to investigate the possible effect of oral magnesium sulfate (MgSO4 ) in the reduction of atherosclerosis plaques through inhibition of lectin-like low-density lipoprotein receptor-1 (LOX-1) gene expression in diabetic vessels. MATERIALS AND METHODS: A total of 50 rats were divided into five groups, including non-diabetic control, Mg-treated non-diabetic control, chronic diabetic, Mg-treated chronic diabetic and insulin-treated chronic diabetic. The induction of diabetes was carried out by streptozotocin. The Mg-treated chronic diabetic and Mg-treated non-diabetic control groups were treated with 10 g/L of MgSO4 added to their drinking water. The insulin-treated chronic diabetic group received 2.5 U/kg of insulin twice per day. The fasting blood glucose level and bodyweight were determined weekly. Blood pressure measurement and the intraperitoneal glucose tolerance test were carried out after 16 weeks, and the plasma levels of Mg, lipid profile and oxidized low-density lipoprotein cholesterol (oxLDL) were determined. The mesenteric bed was isolated and perfused according to the McGregor method. The aorta was isolated for LOX-1 genes and proteins expression, and pathological investigation. RESULTS: MgSO4 administration improved blood pressure, sensitivity to phenylephrine, intraperitoneal glucose tolerance test, lipid profile and plasma ox-LDL level, and also lowered the blood glucose level to the normal range, and decreased LOX-1 gene and protein expressions. Insulin decreased blood pressure, sensitivity to phenylephrine, blood glucose, lipid profiles and plasma oxLDL level, but it did not decrease LOX-1 gene and protein expressions. CONCLUSIONS: The present findings suggested that MgSO4 improves blood pressure and vessel structure through decreasing oxLDL, and LOX-1 gene and protein expressions; however, insulin did not repair vessel structure, and LOX-1 gene and protein expressions.

Effect of Long-term Administration of Oral Magnesium Sulfate and Insulin to Reduce Streptozotocin-Induced Hyperglycemia in Rats: the Role of Akt2 and IRS1 Gene Expressions.

The effects of long-term oral administration of magnesium sulfate and insulin on hyperglycemia were investigated using Akt2 and IRS1 gene expression methods in streptozotocin-induced diabetic rats. Fifty rats were randomly divided into five experimental groups: 1, non-diabetic control (NDC); 2, Mg2+-treated non-diabetic control (Mg-NDC); 3, chronic diabetic (CD); 4, Mg2+-treated chronic diabetic (Mg-CD); and 5, insulin-treated chronic diabetic (Ins-CD). Streptozotocin was used to induce diabetes. The Mg-CD and Mg-NDC groups received 10 g/l of MgSO4 added to drinking water. The Ins-CD group received 2.5 U/kg of insulin twice a day. Blood glucose level and body weight were measured every week. The intraperitoneal glucose tolerance test (IPGTT) was performed after 16 weeks. MgSO4 administration improved the blood glucose level and IPGTT. It also increased Akt2 and IRS1 genes as well as protein expression. Insulin lowered the blood glucose level and increased IRS1 gene and protein expression, but did not affect Akt2 gene and protein expression. Glucose reduction after Mg therapy may be mediated, at least partially, via IRS1 and Akt2 genes and protein stimulation. In insulin-treated rats, insulin resistance was not significant due to the absence of Akt2 gene expression.

Effect of oral magnesium sulfate administration on blood glucose hemostasis via inhibition of gluconeogenesis and FOXO1 gene expression in liver and muscle in diabetic rats.

The present study was designed to investigate the possible role of Mg2+ in suppression of phosphoenolpyruvate carboxy kinase (PEPCK) enzyme via inhibition of FOXO1gene expression in liver and we also examined whether Mg contributes to decrease blood glucose in muscle via inhibiting FOXO1 gene and protein expression. Fifty rats in five groups of experiment were considered as; non-diabetic control (NDC), Mg2+-treated non-diabetic control (Mg2+-NDC), chronic diabetic (CD), Mg2+-treated chronic diabetic (Mg2+-CD), and insulin-treated chronic diabetic (Ins-CD). Streptozotocin (STZ) was used for diabetes induction. The Mg2+-CD and Mg2+-NDC groups received 10 g/l of magnesium sulfate (MgSO4) added to drinking water, and Ins-CD group received 2.5 U/kg of insulin. The blood glucose level and body weight were measured weekly. After 16 weeks, intraperitoneal glucose tolerance test (IPGTT) was done and blood samples were taken to determine the plasma levels of Mg and gastrocnemius muscle legs, and liver were isolated for both Forkhead transcription factor (FOXO1) and PEPCK enzyme genes and proteins expression. Administration of MgSO4 improved IPGTT, lowered blood glucose levels and decreased FOXO1 and PEPCK genes and proteins expression in muscle and liver, while insulin just could decrease FOXO1 gene and protein expression in the muscle. These findings illustrated that MgSO4 improved hyperglycemia via inhibition of FOXO1 gene and protein level in the muscle and liver, and it also decreased blood glucose level by prohibition of gluconeogenesis pathway in the liver. However, long time administration of insulin did not have any effect on liver.