Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect: A possible role of SGLT2 in mesangial cells.

Several clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on diabetic nephropathy. The underlying mechanisms are not fully understood. We found that administration of canagliflozin at a low dose (0.01 mg/kg/day) did not affect either blood glucose levels or glycosuria, but it improved albuminuria and mesangial expansion in db/db mice to a similar extent as at a high dose (3.0 mg/kg/day) that lowered blood glucose levels. This indicated the existence of a tubular SGLT2-independent reno-protective mechanism. Here we focused on the potential role of SGLT2 in mesangial cells (MCs). Western blot analysis revealed the expression of SGLT2 in cultured mouse MCs. Exposure of MCs to high glucose levels for 72 h significantly increased the expression of SGLT2. Canagliflozin or ipragliflozin (both 100 nM) treatment inhibited glucose consumption in the medium under high-glucose conditions but not under normal-glucose conditions. Furthermore, canagliflozin inhibited high-glucose-induced activation of the protein kinase C (PKC)-NAD(P)H oxidase pathway and increases in reactive oxygen species (ROS) production. Thus, the inhibition of mesangial SGLT2 may cause an inhibition of PKC activation and ROS overproduction in diabetic nephropathy, and this may at least in part account for the reno-protective effect of SGLT2 inhibitors.

Glycosuria medicated with ipragliflozin and nifedipine or ipragliflozin and candesartan: a case report.

INTRODUCTION: Animal studies have reported that treatment with angiotensin II receptor blockers reduced kidney sodium-dependent glucose cotransporter expression. We therefore hypothesized that patients with hypertension treated with an angiotensin II receptor blocker (candesartan) would probably have an increased response to sodium-dependent glucose cotransporter inhibitor therapy (ipragliflozin) compared with patients treated with alternative hypertensive medications such as calcium channel blockers (nifedipine). Although sodium-dependent glucose cotransporter inhibitor (ipragliflozin) is a new anti-diabetic medicine, the clinical efficacy in the Japanese population has not been fully evaluated. We compared the combined effect of angiotensin II receptor blocker candesartan plus ipragliflozin with nifedipine plus ipragliflozin therapy and found that the combination of candesartan plus ipragliflozin was more effective in increasing glycosuria and lowering plasma glucose. CASE PRESENTATION: A 57-year-old Japanese man with essential hypertension was treated with candesartan. Candesartan was switched to nifedipine for the initial 10 days of an observation period and 5 days later he was started on ipragliflozin (day 6 of nifedipine treatment) with nifedipine for the next 5 days. Thereafter (from day 11 to day 20), candesartan was started instead of nifedipine and ipragliflozin was continued. In the last 5 days ipragliflozin was stopped and he was treated with candesartan alone. Neither nifedipine alone (0.038+/-0.004) nor candesartan alone (0.048+/-0.006) produce any trace amount of glycosuria. However, the extent of glycosuria under ipragliflozin with candesartan treatment (37.5+/-8.45) was significantly greater than that of ipragliflozin with nifedipine (23.75+/-0.35; P<0.05). CONCLUSION: Candesartan demonstrated additive actions with ipragliflozin to increase glycosuria compared to ipragliflozin with nifedipine treatment.

Inhibition of the intestinal sodium-coupled glucose transporter 1 (SGLT1) by extracts and polyphenols from apple reduces postprandial blood glucose levels in mice and humans.

SCOPE: There is a growing interest in food constituents that could reduce intestinal glucose absorption to prevent overshooting plasma glucose and insulin levels in patients with prediabetes and diabetes mellitus type 2. METHODS AND RESULTS: We here demonstrate that an extract and individual polyphenols from apple diminish sodium-coupled glucose transporter 1 (SGLT1) mediated glucose uptake in vitro and in vivo. Inhibition of transport of sugars by SGLT1 was shown in Xenopus oocytes and in mice jejunal segments. Strongest inhibition was observed for phlorizin with IC50 values for transport inhibition of 0.46 ± 0.19 and 4.1 ± 0.6 µM in oocytes and intestinal segments, respectively. An oral glucose tolerance test performed in volunteers with prior administration of the apple extract reduced venous blood glucose and plasma insulin levels, similar to findings obtained in C57BL/6N mice. Analysis of human urine samples revealed that the extract increased modestly renal glucose loss that is most likely a result of inhibition of renal glucose reabsorption by phloretin derivatives found in plasma of the volunteers. CONCLUSION: Although the apple extract substantially decreased intestinal glucose absorption in all test systems, the finding that there are systemic effects that relate to inhibition of glucose transport processes beyond the intestine addresses safety issues that need further exploitation.

Antidiabetic activity of Passiflora incarnata Linn. in streptozotocin-induced diabetes in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The present study was designed to investigate the hypoglycemic and hypolipidemic properties of Passiflora incarnata Linn. leaves which are widely used as traditional treatment for diabetes mellitus. MATERIALS AND METHODS: The methanolic extracts of leaves of Passiflora incarnata were administered orally (100 and 200 mg/kg, for 15 days) to streptozotocin-induced diabetic mice. Hypoglycemic effects, oral glucose tolerance test, change in body weight and lipid profile of diabetic mice treated with methanolic extracts were assessed and compared with normal, diabetic control and standard drug treated mice. Histological examination during 15 days of treatment was also carried out. RESULTS: Methanolic extract (200 mg/kg) produced a significant reduction in fasting blood glucose level in streptozotocin-induced diabetic mice. Significant differences were also observed in urine glucose level, oral glucose tolerance test, serum lipid profile and body weight of methanolic extract treated diabetic mice, when compared with diabetic, normal and standard drug treated mice. Histopathological studies of the pancreas showed comparable regeneration of the cells by extract which were earlier necrosed by streptozotocin. CONCLUSION: Methanolic extract of Passiflora incarnata exhibit significant anti-hyperglycemic and hypolipidemic activities in streptozotocin-induced diabetes in mice.

Curcumin suppresses increased bone resorption by inhibiting osteoclastogenesis in rats with streptozotocin-induced diabetes.

Curcumin is a potent inhibitor of the transcription factor activator protein-1 which plays an essential role in osteoclastogenesis. However, the effects of curcumin on bone metabolism have not been clarified in vivo. We reported herein the inhibitory effects of curcumin on the stimulated osteoclastic activity in insulin-dependent diabetes mellitus using rats with streptozotocin-induced diabetes. A dietary supplement of curcumin reversed the increase in levels of activity and mRNA of tartrate-resistant acid phosphatase (TRAP) and cathepsin K to control values. A histochemical analysis showed that the increase in TRAP-positive cells in the distal femur of the diabetic rats was reduced to the control level by the supplement. These results suggested that curcumin reduced diabetes-stimulated bone resorptive activity and the number of osteoclasts. When bone marrow cells were cultured with macrophage colony stimulating factor and receptor activator NF-kappaB ligand (RANKL), the increased activity to form TRAP-positive multinucleated cells and the increased levels of mRNA and protein of c-fos and c-jun in the cultured cells from diabetic rats decreased to control levels in the curcumin-supplemented rats. Similarly, the increased expression of c-fos and c-jun in the distal femur of the diabetic rats was significantly reduced by the supplement. These results suggested that curcumin suppressed the increased bone resorptive activity through the prevention of osteoclastogenesis associated with inhibition of the expression of c-fos and c-jun in the diabetic rats.

Antihyperglycaemic and antihyperlipidaemic effects of Nymphaea stellata in alloxan-induced diabetic rats.

INTRODUCTION: This study aims to investigate Nymphaea stellata (N. stellata) flower extract for antihyperglycaemic and antihyperlipidaemic effects in diabetic rats induced by alloxan. Its effect was compared with that of glibenclamide, a reference antidiabetic drug. METHODS: Diabetic animals were randomly divided into five groups and treated orally with different doses (200, 300 and 400 mg/kg body weight) of flower extract once a day for 30 days. The body weight of each animal was determined, to assess any possible weight gain or loss in experimental animals compared with control groups. On the 31st day, those administered 300 mg/kg of N. stellata flower showed more promising results with regard to fasting blood glucose (FBG), plasma insulin levels, haemoglobin counts, urine sugar levels, food intake, water intake, urea and protein when compared to those treated with other doses. Therefore, 300 mg/kg dose was used for further biochemical studies. Total lipids (TL), total cholesterol (TC), triglycerides (TG), phospholipids, free fatty acids (FFA), low density lipoproteins (LDL), very low density lipoproteins (VLDL), atherogenic index (AI) and high density lipoproteins (HDL) levels, on normal and diabetic rats treated with the dose of 300 mg/kg, were evaluated. RESULTS: The flower extract shows a significant (p-value is less than 0.001) reduction in levels of FBG, water intake, food intake, urine sugar, blood urea, TL, TC, TG, FFA, phospholipids, LDL, VLDL and AI. It also shows a significant increase in body weight, plasma insulin, protein, haemoglobin and HDL levels. CONCLUSION: Our results suggest that N. stellata flower extract exhibit antihyperglycaemic as well as antihyperlipidaemic effects on alloxan-induced diabetic rats.

Antihyperglycemic effect of umbelliferone in streptozotocin-diabetic rats.

The present study was designed to investigate the antihyperglycemic effect of Umbelliferone (UMB) in normal and streptozotocin (STZ)-diabetic rats. Diabetes was induced in adult male albino rats of the Wistar strain, weighing 180-200 g, by administration of STZ (40 mg/kg of body weight) intraperitoneally. Diabetic rats showed an increase in levels of blood glucose and glycosylated hemoglobin (HbA(1c)) and activities of gluconeogenic enzymes such as glucose-6-phosphatase and fructose-1,6-bisphosphatase, and a decrease in levels of plasma insulin, hemoglobin (Hb), and liver glycogen and activities of glucokinase and glucose-6-phosphate dehydrogenase. Intraperitoneal administration of UMB (10, 20, and 30 mg/kg of body weight) and glibenclamide (600 micro g/kg of body weight) in 10% dimethyl sulfoxide dissolved in water, for 45 days, produced significantly decreased levels of blood glucose and HbA(1c) and activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase, while elevating levels of plasma insulin, Hb, and liver glycogen and activities of glucokinase and glucose-6-phosphate dehydrogenase to near normal levels in STZ-diabetic rats when compared with normal control rats. Normal rats treated with UMB (30 mg/kg of body weight) also showed a significant effect on glycemic control. Thus, our results show that UMB at 30 mg/kg of body weight possesses a promising antihyperglycemic effect that is comparable with glibenclamide.

Hypoglycemic and antidiabetic effect of ethanolic extract of leaves of Annona squamosa L. in experimental animals.

The ethanolic extract of Annona squamosa L. (Annonaceae) leaves was administered orally at different doses to normal as well as streptozotocin (STZ)-induced diabetic rats and alloxan-induced diabetic rabbits. The dose of 350 mg/kg body weight (bw) reduced the fasting blood glucose (FBG) level by 6.0% within 1 h, whereas, the peak blood glucose at 1 h during glucose tolerance test (GTT) was reduced by 17.1% in normal rats. The same dose of ethanolic extract reduced FBG by 26.8% and improved glucose tolerance by 38.5 and 40.6% at 1 and 2 h, respectively, during GTT in alloxan-induced diabetic rabbits. In STZ-diabetic rats, a fall of 13.0% in FBG and an improvement in glucose tolerance by 37.2 and 60.6% at 1 and 2 h, respectively, was observed during GTT. The dose of 350 mg/kg bw of ethanolic extract in 10-day treatment of a group of STZ-diabetic rats produced 73.3% fall in FBG level and no sugar was observed in fasting urine. Treatment of severely-diabetic rabbits for 15 days with a dose of 350 mg/kg of extract reduce FBG by 52.7% and urine sugar by 75%. It brought about fall in the level of total cholesterol (TC) by 49.3% with increase of 30.3% in high-density lipoprotein (HDL) and decrease of 71.9 and 28.7% in low-density lipoprotein (LDL) and triglycerides (TG) levels, respectively.

Fruit of the jambolan tree (Eugenia jambolana Lam.) and experimental diabetes.

The fruit of Indian Eugenia jambolana have been shown to have therapeutic properties, but because the therapeutic potential of a plant is related to the geographic region in which the plant was grown and to the part of the plant used, we investigated Brazilian Eugenia jambolana fruit using the same preparation and experimental methods as have been used in India. The well-established metabolic cage model was used to evaluate the physiological and metabolic parameters associated with streptozotocin-induced diabetes in rats (n=10) which had been administered, by gavage, 50 mg per day of lyophilised Eugenia jambolana fruit-pulp extract for 41 days. We found that, compared to untreated controls, rats treated with the lyophilised fruit-pulp showed no observable difference in body weight, food or water intake, urine volume, glycaemia, urinary urea and glucose, hepatic glycogen, or on serum levels of total cholesterol, HDL cholesterol or triglycerides. No change was observed in the masses of epididymal or retroperitoneal adipose tissue or of soleus or extensor digitorum longus muscles. This lack of any apparent effect on the diabetes may be attributable to the regional ecosystem where the fruit was collected and/or to the severity of the induced diabetes.

Hypoglycemic effects of sesquiterpene glycosides and polyhydroxylated triterpenoids of Eriobotrya japonica.

The effects of the constituent sesquiterpene glycosides 1-3 and polyhydroxylated triterpenoids 5-6 isolated by MeOH extraction of Eriobotrya japonica were studied in genetically diabetic mice (C57BL/KS-db/db/Ola) and normoglycemic rats. The sesquiterpene glycoside 3 and the polyhydroxylated triterpenoids 5 and 6 produced a marked inhibition of glycosuria. Furthermore, 5 and 6 were able to reduce blood glucose levels in normoglycemic rats. While there are already some data reported on hypoglycemic activity of polyhydroxylated triterpenoids, there are no previous data showing hypoglycemic activity of sesquiterpene glycosides.

[Antihypertensive therapy with co-dergocrine mesilate/nifedipine in comparison with nifedipine in type II diabetes]. / Antihypertensive Therapie mit Co-Dergocrinmesilat/Nifedipin im Vergleich mit Nifedipin bei Typ-II-Diabetes.

In a randomized cross-over study the antihypertensive effects of nifedipine and the combination of co-dergocrine and nifedipine (Pontuc) respectively as well as the influence of both preparations on the glucose metabolism was tested in 22 hypertensive patients with diabetes type II over a period of 4 weeks. During treatment with the combination a significantly more pronounced blood pressure reduction was achieved compared to monotherapy with nifedipine, whereas the heart rate was significantly increased only by nifedipine. Both drugs--nifedipine and co-dergocrine/nifedipine--did not change the concentrations of glucose in the blood or urine or of HbA1.

Blood glucose concentrations and glycosuria during and after one year of acarbose therapy.

Type-I and type-II diabetics receiving antidiabetic therapy, comprising of diet, or diet plus sulphonylureas or insulin, were additionally treated with acarbose for a period of 12 months in an open, multi-centre study carried out under general practice conditions. This was followed by an observation period without acarbose. After 3 months on acarbose, the mean fasting and post-prandial blood glucose concentrations were 30 and 40 mg/dl, respectively, lower, thereafter remaining virtually unchanged up to the end of treatment. After withdrawal of acarbose the mean blood glucose values rose to their pretreatment levels, except in patients with proven poor acarbose compliance. All three treatment subgroups mentioned above showed the same pattern of glucose reduction. The mean blood glucose values of patients previously treated by dietary measures alone fell under acarbose therapy below the upper limit of normal. The percentage of glycosuric patients in the above subgroups was halved under acarbose and rose after discontinuation of acarbose approximately to the initial numbers. The number of patients with blood-glucose control classified as "good" rose fourfold during the acarbose treatment. In the course of the trial acarbose had to be discontinued due to intestinal side effects in only 5% of the patients. Frequency and intensity of the intestinal symptoms related to increased bacterial carbohydrate cleavage (flatulence, meteorism, occasionally diarrhoea), decreased during treatment. Other subjective complaints or side effects were neither reported nor could be detected objectively.