Effects of Usnic Acid on Hyperglycemia and Renal Function in Streptozotocin-Induced Diabetic Rats

Background: Diabetic hyperglycemia and glomerular hyper filtration play a causative role in the progression of chronic kidney disease. Renal glucose handling via Sodium-Glucose Cotransporter (SGLT)-2 is a targetable approach and SGLT-2 inhibitors have proven therapeutic benefits in diabetic kidney disease. Usnic Acid (UA) is an active constituent of lichen species and symbiotic organism of algae and fungi, which is variously studied in folk medicine. The objective of this study was to demonstrate the beneficial effects of UA on glucose homeostasis and renal function in streptozotocin-induced diabetic Sprague-Dawley rats and to determine whether UA has an effect on regulation of SGLT that may further aid in glucoregulation and renal function. Methods: Type 1 diabetes was induced in Sprague-Dawley rats with Streptozotocin (STZ, 60mg/kg) by intraperitoneal route on day 0. Diabetic rats were treated with UA (75 mg/kg) from day 15 to 35 via oral gavage. On day 35, urine was collected and Oral Glucose Tolerance Test (OGTT) was performed. After OGTT, blood was collected through cardiac puncture and kidneys were preserved for biochemical analysis. The results are expressed as mean ± standard error of the mean for n=8 rats per study group. The data were subjected to 1-way or 2-way ANOVA with Bonferroni’s multiple comparison post hoc test using Graph Pad Prism 5 and were considered significant at p≤0.05. Results: Diabetic rats chronically treated with UA had improved hyperphagia, hyperglycemia and glucose intolerance, glomerular hyper filtration, and urinary protein excretion (p\u3c0.05). However, UA did not prevent loss of circulating insulin in diabetic rats. UA’s blood glucose lowering effect was associated with enhanced diuretic-glucosuric response and decreased protein expression of renal SGLT-1 (p\u3c0.05). While protein expression of SGLT-2 was partially increased in the diabetic kidney and it was not decreased by UA. Metabolic corrections with UA treatment occurred in parallel with reductions in uremia and improvement of renal function indices. Additionally, in diabetic rat kidney, UA treatment corrected oxidative changes. Conclusions: Based on preliminary findings we conclude that chronic treatment of UA may act in an insulin-independent manner in lowering of diabetic hyperglycemia and improvement of renal function

Diuretic, Glucosuric and Natriuretic Effect of Pantoyltaurine in Diabetic Sprague-Dawley Rats

Sodium-glucose co-transporter (SGLT) inhibitors offer a novel tool to control hyperglycemia and its complications. We present preliminary findings of pantoyltaurine, N-substituted analog of taurine, as diuretic, glucosuric and natriuretic agent in streptozotocin (60 mg/kg/mL, i.p.)-induced type 1 diabetic Sprague-Dawley rats and whether pantoyltaurine has an effect on regulation of SGLT isoforms that may further help in reducing hyperglycemia and improving renal function. After 14 days of persistent diabetes, phlorizin (0.4 g/kg/day, s.c.) or pantoyltaurine (2.4 mM/kg/day, p.o.) was administered for three weeks, days 15 - 35. As expected, diabetic rats showed persistent hyperglycemia, hyperphagia and weight loss. Pantoyltaurine and phlorizin-treated diabetic rats consumed less diet, showed significant weight loss, reduced persistent hyperglycemia as well as reduced glucose load after oral glucose tolerance test. Diuretic, glucosuric and natriuretic response of diabetic rats was enhanced by pantoyltaurine independent of renal and plasma oxidative stress, plasma insulin and renal expression of SGLT-2. Phlorizin and pantoyltaurine reduced renal expression of SGLT-1, which accounts for ≤ 10% of glucose reabsorption. However, pantoyltaurine, but not phlorizin, normalized elevated fractional excretion of urea nitrogen and clearance of blood urea nitrogen in diabetic rats, suggesting lessening effect of pantoyltaurine on uremic toxicity associated with diabetes. Collectively, our preliminary findings show that chronic treatment with pantoyltaurine may help in an insulin-independent manner to lower diabetic hyperglycemia by producing diuresis, glucosuria and natriuresis that may have translated in improvement of renal function

Bioassay-guided Isolation of the Antidiabetic Active Principle from Salvia miltiorrhiza and its Stimulatory Effects on Glucose Uptake Using 3T3-L1 Adipocytes

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by impaired insulin secretion and insulin sensitivity, which poses an imminent threat to become a worldwide epidemic according to world health organization [1-3]. Type 2 diabetes mellitus is associated with severe complications such as hypertension, dyslipidemia, microvascular and macrovascular cardiovascular diseases [4-6]. Insulin plays a regulatory role in this disease by stimulating the uptake of blood glucose into peripheral tissues through glucose transporters and the promotion of lipid biosynthesis in adipocytes [7]. Insulin resistance causes decrease in peripheral glucose disposal resulting in increased levels of blood glucose [7]. Some of the currently available antidiabetic drugs improve blood glucose levels by increasing the glucose uptake in peripheral tissues. However such drugs are associated with adverse side effects, which limit their use in diabetic patients. Therefore it is highly desirable to discover antidiabetic agents that improve blood glucose levels with minimal side effects. Salviamiltiorrhiza(Labiatae),danshen, is an annual sage mainly found inchinaand neighboring countries. The dried root and its preparations are currently being used inchinato treat patients with cardiovascular and cerebrovascular complications [8]. Many compounds have been isolated from Salviamiltiorrhizaroots, which could be classified as lipid soluble tanshinones and water-soluble phenolic acid compounds [9]. Among phenolic acids, salvianolic acid B is a major component of S.miltiorrhizaand extensive pharmacological studies have been reported for this compound. Salvianolic acid B inhibited the amyloid formation of human islet amyloid polypeptide and protects pancreatic beta cells against cytotoxicity [10]. Many authors have studied the effect of salvianolic acid B on different organ systems in animals as well as in humans. Salvianolic acid B showed beneficial and protective effect to brain from ischemia-reperfusion injury in animal studies [11]. In addition, salvianolic acid B has been shown to inhibit platelet aggregation [12] as well as cause oxidative modification of low-density lipoprotein (LDL) thereby, resulting into decreased uptake of LDL by cultured macrophages [13]. Furthermore, salvianolic acid B has been shown to stimulate the nitric oxide production of the endothelial cell [14] and inhibition of angiotensin IIinduced hyperplasia [15]. It significantly inhibited the activity of stressactivated protein (SAP) kinase [16]. Magnesium salt of salvianolic acid B has been shown to possess potent hepatoprotective activity and shows an improved effect on uremic symptoms [17,18]. An in vitro study also revealed that salvianolic acid B is an excellent scavenger for free radicals, both cation radicals and anion radicals [19]. It has been reported that salvianolic acid B has potent inhibitory effects on lipid or biomembrane peroxidation in a superoxide anion generating system [20,21]