Activation of renal CSE/H2S pathway by alpha-lipoic acid protects against histological and functional changes in the diabetic kidney.

INTRODUCTION: We previously reported that alpha-lipoic acid (ALA) supplementation protects against progression of diabetic kidney disease (DKD). In this study, we aim to investigate whether the mechanism of renal protection by ALA involves renal cystathionine γ-lyase/hydrogen sulfide (CSE/H2S) system in type 2 diabetes mellitus (T2DM). METHODS: Thirty-seven male Sprague-Dawley rats underwent 12 h of overnight fasting. To induce T2DM, 30 of these rats received intraperitoneal administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). T2DM rats then received either oral administration of ALA (60 mg/kg/day) or intraperitoneal administration of 40 mg/kg/day DL-propargylglycine (PAG, a CSE inhibitor) or both for 6 weeks after which rats were sacrificed and samples collected for analysis. Untreated diabetic and non-diabetic rats served as diabetic and healthy controls respectively. RESULTS: T2DM was characterized by reduced pancreatic ß-cell function and hyperglycemia. Histologically, untreated diabetic rats showed significantly damaged pancreatic islets, glomerular and tubular injury, with elevated levels of renal function markers compared to healthy control rats (p < 0.001). These pathological changes worsened significantly following PAG administration (p < 0.05). While some renal protection was observed in ALA+PAG rats, ALA administration in untreated diabetic rats provided superior protection comparable to healthy control rats, with improved antioxidant status, lipid profile and reduced inflammation. Mechanistically, ALA significantly activated renal CSE/H2S system in diabetic rats, which was markedly suppressed in PAG-treated rats (p < 0.001). CONCLUSION: Our data suggest that ALA protects against DKD development and progression by activating renal CSE/H2S pathway. Hence, CSE/H2S pathway may represent a therapeutic target in the treatment or prevention of DKD in diabetic patients.

Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-ß/Smad Pathway.

Background: Diabetic cardiomyopathy (DCM) is a major long-term complication of diabetes mellitus, accounting for over 20% of annual mortality rate of diabetic patients globally. Although several existing anti-diabetic drugs have improved glycemic status in diabetic patients, prevalence of DCM is still high. This study investigates cardiac effect of alpha-lipoic acid (ALA) supplementation of anti-diabetic therapy in experimental DCM. Methods: Following 12 h of overnight fasting, 44 male Sprague Dawley rats were randomly assigned to two groups of healthy control (n = 7) and diabetic (n = 37) groups, and fasting blood glucose was measured. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal (i.p.) administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). After confirmation of T2DM on day 3, diabetic rats received monotherapies with ALA (60 mg/kg; n = 7), gliclazide (15 mg/kg; n = 7), ramipril (10 mg/kg; n = 7) or combination of the three drugs (n = 7) for 6 weeks while untreated diabetic rats received distilled water and were used as diabetic control (n = 9). Rats were then sacrificed, and blood, pancreas and heart tissues were harvested for analyses using standard methods. Results: T2DM induction caused pancreatic islet destruction, hyperglycemia, weight loss, high relative heart weight, and development of DCM, which was characterized by myocardial degeneration and vacuolation, cardiac fibrosis, elevated cardiac damage markers (plasma and cardiac creatine kinase-myocardial band, brain natriuretic peptide and cardiac troponin I). Triple combination therapy of ALA, gliclazide and ramipril preserved islet structure, maintained body weight and blood glucose level, and prevented DCM development compared to diabetic control (p < 0.001). In addition, the combination therapy markedly reduced plasma levels of inflammatory markers (IL-1ß, IL-6 and TNF-α), plasma and cardiac tissue malondialdehyde, triglycerides and total cholesterol while significantly increasing cardiac glutathione and superoxide dismutase activity and high-density lipoprotein-cholesterol compared to diabetic control (p < 0.001). Mechanistically, induction of T2DM upregulated cardiac expression of TGF-ß1, phosphorylated Smad2 and Smad3 proteins, which were downregulated following triple combination therapy (p < 0.001). Conclusion: Triple combination therapy of ALA, gliclazide and ramipril prevented DCM development by inhibiting TGF-ß1/Smad pathway. Our findings can be extrapolated to the human heart, which would provide effective additional pharmacological therapy against DCM in T2DM patients.

Effect of Metaswitch® dietary supplement on anthropometric parameters, serum lipids, glucose level, oxidative stress and in vivo antioxidant properties in high fat diet-induced overweight Sprague Dawley rats.

PURPOSE: Obesity and overweight are metabolic disorders associated with oxidative stress, and risk factors for many chronic diseases. We sought to investigate the effects of Metaswitch dietary supplement on weight gain and associated acute metabolic alterations in a high-fat diet-induced overweight rat model. METHODS: Female Sprague Dawley (SD) rats were put into 6 groups. Control groups were fed normal (NCD) or high-fat diet (HFD). Treatment groups on HFD receieved 3 different daily doses of Metaswitch for 3 weeks. Another group on HFD received Slimrite® (phenylpropanolamine), a standard drug. Rats on HFD also received cyproheptadine to stimulate appetite. Food consumption and anthropometric parameters were determined weekly. Serum lipids, glucose level, hepatic lipid peroxidation, and antioxidant activity were used to assess overweight in rats. RESULTS: Food intake remained relatively constant among groups. Rats on HFD had significantly increased body weight compared to rats fed NCD. Metaswitch significantly prevented weight gain; this effect was greater or similar to rats administered Slimrite, but was not dose-dependant. No significant changes occurred in the levels of serum lipids and glucose among the groups. However, serum triglyceride (TG) was significantly increased. The TG/HDL-C ratio revealed significant metabolic alterations which was prevented by Metaswitch. Catalase activity was significantly decreased in the HFD untreated group but was restored in Metaswitch-treated groups. CONCLUSIONS: A 3-week HFD regimen with cyproheptadine supplementation in female SD rats resulted in a significant increase in body weight and acute metabolic alterations. The aforementioned changes were found to have been prevented with the administration of Metaswitch.