Reduced Plasma Glucose Levels Research Articles

Abstract 373: Mineralocorticoid Receptor and Rhoa/rho Kinase Contribute to Vascular Dysfunction in Obese Db/db Mice

Increasing evidence indicates that adipose tissue modulates vascular function. Our previous studies demonstrated that adipocytes secrete aldosterone. We hypothesized that adipocyte-releasing factors induce vascular dysfunction through mineralocorticoid receptor (MR)-dependent mechanisms. This study explored the small G protein RhoA/Rho kinase as a pathway linking aldosterone/MR and the paracrine effects of adipose tissue in the vasculature, since the activation of this pathway regulates vascular contraction. Diabetic obese mice (db/db) and their control counterparts (db/+) were treated with MR antagonist (MRA) (K canrenoate, 30mg/Kg/day, S.C., 4 weeks) or RhoA/Rho kinase inhibitor, fasudil (30 mg/Kg/day, S.C., 3 weeks). Blood pressure levels were similar between groups. Fasudil, but not MRA, reduced plasma glucose levels in db/db mice (db/+:12.3±6; db/db: 30.1±3; MRA-treated db/db: 32.5±2; fasudil treated db/db: 17.1±2; mmoL/mL). Arteries from db/db mice displayed reduced relaxation to 10 - 5 M acetycholine (Ach; db/+:79.4±3.9% vs db/db: 14.3±3.1%). Arteries from MRA-treated db/db mice exposed to fat conditioned medium (FCM) had improved responses to Ach (MRA-treated db/db: 28.3±1.9% vs MRA-treated db/db +FCM: 42.8±4.3%). Increased norepinephrine (NE)-induced contraction was observed in db/db mice in endothelium-denuded arteries (10 -5 M NE; db/+: 1.5 ± 0.1 vs db/db: 2.2 ± 0.1; mN/mm). NE responses were reduced in MRA-treated db/db mice (1.7±0.1 mN/mm) or fasudil (1.6±0.2 mN/mm). Vascular calcium sensitivity was similar between depolarized arteries from db/+ and db/db. Fasudil treatment reduced calcium-induced contraction in both groups with greater effect in db/db mice (5 mmol/L CaCl 2 ; db/+: 73 % vs db/db: 57 %). MR blockade did not affect vascular RhoA/Rho kinase activity (RhoA membrane to cytosol translocation) in db/db mice. Our data suggest that in db/db mice: MR and RhoA/Rho kinase signaling contribute to adipose modulation of vascular/contraction. While MR plays a role in vascular relaxation, RhoA/Rho kinase signalling is important in contractile dysfunction, adipocyte secretion, and glucose metabolism - processes that may contribute to cardiovascular injury in obesity-associated diabetes.

Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled by Established Basal Insulin

OBJECTIVETo examine the efficacy and safety of adding the once-daily glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide to established basal insulin therapy alone or together with metformin, in people with type 2 diabetes and elevated glycated hemoglobin (HbA1c).RESEARCH DESIGN AND METHODSWe conducted a double-blind, parallel-group, placebo-controlled trial. Patients (n = 495) with established basal insulin therapy but inadequate glycemic control were randomized to add lixisenatide 20 μg or placebo for 24 weeks. Basal insulin dosage was unchanged except to limit hypoglycemia. HbA1c reduction from baseline was the primary end point.RESULTSMean duration of diabetes was 12.5 years, duration of insulin use was 3.1 years, insulin dosage was 55 units/day, and baseline HbA1c was 8.4%. With lixisenatide, the placebo-corrected change of HbA1c from baseline was –0.4% (95% CI –0.6 to –0.2; P = 0.0002), and mean HbA1c at end point was 7.8%. HbA1c <7.0% (53 mmol/mol) was attained by more lixisenatide (28%) than placebo (12%; P < 0.0001) participants. Lixisenatide reduced plasma glucose levels after a standardized breakfast (placebo-corrected reduction, –3.8 mmol/L; P < 0.0001); seven-point glucose profiles showed a reduction persisting through the day. Reductions in body weight (placebo corrected, –1.3 kg; P < 0.0001) and insulin dosage (–3.7 units/day; P = 0.012) were greater with lixisenatide. Main adverse events (AEs) with lixisenatide were gastrointestinal. Symptomatic hypoglycemia was 28% for lixisenatide and 22% for placebo; 4 of 328 subjects (1.2%) had severe hypoglycemia with lixisenatide vs. 0 of 167 with placebo.CONCLUSIONSBy improving HbA1c and postprandial hyperglycemia without weight gain in type 2 diabetes with inadequate glycemic control despite stable basal insulin, lixisenatide may provide an alternative to rapid-acting insulin or other treatment options.

Insulin as an early treatment for type 2 diabetes: ORIGIN or end of an old question?

The Emerging Risk Factors Collaboration (1) has recently confirmed that type 2 diabetes remains associated with substantial premature mortality. Compared with nondiabetic individuals, those with diabetes have a hazard ratio (HR) of 1.80 (95% CI 1.71–1.90) for death from any cause, 1.25 (1.19–1.31) for death from cancer, 2.32 (2.11–2.56) for death from vascular causes, and 1.73 (1.62–1.85) for death from other causes. As is apparent, the greater risk is owing to cardiovascular (CV) disease, which accounts for >60% of the years of life lost because of diabetes. Although this increase in CV risk is largely attributable to the coexistence of multiple metabolic and hemodynamic disorders, elevation of plasma glucose levels remains strongly associated with increased CV morbidity and mortality (2–4). In support of a potential direct effect of plasma glucose elevation is the association between fasting plasma glucose levels >100 mg/dL (5.6 mmol/L) and vascular death (1). Since this a near-linear association (1,5) it has been postulated that reduction of plasma glucose levels should exert a positive impact on CV morbidity and mortality. In the UK Prospective Diabetes Study (UKPDS), improvement of glycemic control was associated with a 16% reduction in the risk of myocardial infarction without achieving statistical significance ( P < 0.052) (6). Glycemic control in that seminal trial was, however, relatively unsuccessful. Though intensively treated patients achieved an average A1C of 7%, a progressive worsening in glycemic control occurred after the initial improvement. A more aggressive and successful approach was adopted in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) (7) and Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) (8) trials and Veterans Affairs Diabetes Trial (VADT) (9). In all these three large studies, glycemic control was achieved (A1C 6.5–7.0%) and maintained over a substantial period of …

Effects of Sitagliptin May Depend on Clinical and Laboratory Data at the Baseline

We have previously reported that the 6-month sitagliptin treatment significantly reduced HbA1c, body weight in Japanese patients with type 2 diabetes [1]. We also found a negative correlation between changes in body weight and body mass index (BMI) at baseline, and also reported a negative correlation between changes in HbA1c and HbA1c levels at baseline [1]. Kubota A et al reported that the 12 weeks-sitagliptin treatment significantly decreased HbA1c, serum total cholesterol and postprandial triglyceride levels, systolic blood pressure and diastolic blood pressure, and also increased serum creatinine [2]. However, we could not observe significant differences in systolic and diastolic blood pressure, and serum lipid levels, and estimated glomerular filtration rate (e-GFR) between before and after the sitagliptin treatment [1]. The mean ± SD of age (63.3 ± 11.5) in the study by Kubota A et al was younger than that (64.0 ± 14.0) in our study [1, 2]. Aging influences pharmacokinetics and pharmacodynamics. To understand how age influences effects of sitaglitpin, we analyzed data by dividing subjects studied into patients who are 75 years old or older (the elderly group, n = 54) and patients who are 74 years old or younger (the young group, n = 166). Age ranged from 22 to 74 years old and from 75 to 91 years old, and 83 and 32 female patients were included in the young group and the elderly group, respectively. The mean ± SD of age and BMI were 58.0 ± 12.0 years old and 27.0 ± 5.4 kg/m2, and 81.0 ± 5.0 years old and 23.2 ± 4.0 kg/m2 in the young group and the elderly group, respectively. In the young group, sitagliptin significantly reduced plasma glucose levels in addition to reduction in body weight and HbA1c which were observed in the previous study (Table 1) [1]. In the elderly group, sitaglitpin significantly reduced HbA1c, however, did not show a significant reduction of body weight which was observed in the previous study (Table 2) [1]. Differences in changes in clinical and biochemical data after 6 month-use of sitagliptin between the young group and the elderly group were shown in Table 3. Sitagliptin showed greater decrease of body weight, systolic blood pressure, plasma glucose and HbA1c, and also showed smaller decrease of serum levels of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, and e-GFR in the young group as compared with the elderly group. In conclusion, our previous study and present study demonstrated that effects of sitagliptin may depend on clinical data such as age and BMI and laboratory data such as HbA1c at the baseline.

SEDDS of gliclazide: Preparation and characterization by in-vitro, ex-vivo and in-vivo techniques

In the study, self emulsifying drug delivery system (SEDDS) of gliclazide, a poorly soluble drug, was developed and evaluated by in-vitro, ex-vivo and in-vivo techniques. Oil and surfactant were screened out according to their solubilizing capacity. Among the tested components Transcutol HP and Tween-80 showed good solubilizing capacity. These two components were used in different ratios to prepare gliclazide SEDDS. The SEDDS formulations were transparent and clear. Droplet size of the emulsion was determined by Laser Diffraction Technology of Malvern. Formulation F1 containing 1:1 (m/m) mixture of Transcutol HP/Tween-80 showed minimum mean droplet size (50.959μm). In-vitro drug release from F1 was higher (99% within 20min) than other formulations. The developed SEDDS was also evaluated for ex-vivo permeability profile by using chicken intestinal sac. Formulation F1 showed optimal drug diffusion. In-vivo performance of SEDDS was evaluated in albino mice using plasma glucose level as a pharmacodynamic marker parameter. The test formulation (F1) showed significant reduction in plasma glucose level, after oral administration. So SEDDS may be an alternative technique for the oral administration of gliclazide.

Effects of Gmelina arborea extract on experimentally induced diabetes

ObjectiveTo study the effects of aqueous extract of Gmelina arborea bark on normoglycemic levels and streptozotocin (STZ) induced diabetes in rats. MethodsAfter single administration of the aqueous extract, plasma glucose level was determined up to 6 h. In subacute study, the aqueous extract was administered for 28 d and plasma glucose level was determined weekly. The diabetes was induced in rats by the intraperitoneal injection of STZ at a dose of 55 mg/kg body weight. The diabetic animals were divided into four groups containing six in each: Group I diabetic control, Group II and III treated with the aqueous extract respectively at a dose of 250 and 500 mg/kg body weight once daily and Group IV treated with glibenclamide at a dose of 0.6 mg/kg body weight once daily. In acute study, the aqueous extract and glibenclamide were administered orally to rats. Plasma glucose levels were determined at 30, 60, 120, 240 and 360 min after the administration of the test samples. To study subacute effects, test samples (the aqueous extract and glibenclamide) were administered for 28 d consecutively. The effects of each test sample on plasma glucose level, body weight as well as food and water intake were also monitored weekly. The oral glucose tolerance test and biochemical indicators were estimated on day 28. ResultsThe aqueous extract did not significantly decrease the plasma glucose level in the normoglycemic rats as shown by the acute and subacute assays. However, after oral administration of the aqueous extract, the plasma glucose level was significantly (P<0.001) decreased in the diabetic rats in the acute study. The long-term administration of the aqueous extract significantly (P<0.001) reduced plasma glucose levels of the diabetic rats. Additionally, the aqueous extract also reduced loss of body weight and significantly decreased food and water intake in the diabetic animals. Nevertheless, no effects on biochemical indicators were observed at the selected doses. ConclusionsThe aqueous extract of Gmelina arborea bark had antihyperglycemic activity against STZ induced diabetes in rats, after single and subacute oral administration. Moreover, it did not show significant glucose lowering effect in normoglycemic rats.

ANTIDIABETIC ACTIVITY OF JATROPHA GOSSYPIFOLIA LINN ROOT EXTRACTS IN ALLOXAN INDUCED DIABETIC MICE

Diabetes is most common endocrine disease which exists globally and interests about 6 % of the world population. The recommen dation of W . H . O . about diabetes has led to a rise in investigation of medicinal plants for hypoglycemic agents. D ecoction prepared from roots of Jatropha gossypifolia Linn is used in the treatment of diabetes and its associated complications. The aim of this study was to evaluate the hypoglycemic effect of successive extracts of the roots of the plant in comparison to metfor min. Petroleum ether (60 - 80°C), chloroform, methanol and aqueous extracts (250 and 500 mg/kg body weight) were orally administered to alloxan - induced diabetic mice for 7 days. Change in body weight and plasma glucose levels were estimated after the treatme nt. Methanol extract exhibited significant reduction in plasma glucose level as compared to diabetic control, followed by aqueous extract. Chloroform and petroleum ether extracts were comparatively less active. The results confirm the folklore use of the plant in management of diabetes.

Hyperglycemic Emergencies in Adults

Hyperglycemic Emergencies in Adults

Modulatory effect of green tea extract on hepatic key enzymes of glucose metabolism in streptozotocin and high fat diet induced diabetic rats

The study was undertaken to evaluate the antidiabetic effect of green tea extract on carbohydrate metabolic key enzymes in control and streptozotocin high fat diet -induced diabetic rats. The daily oral treatment of green tea extract (300mg/kg body weight) to diabetic rats for 30 days resulted in a significant reduction in the levels of plasma glucose, glycosylated hemoglobin (HbA1c) and increase in the levels of insulin and hemoglobin. The altered activities of the key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase in liver of diabetic rats were significantly reverted to near normal levels by the administration of green tea extract. Further, green tea extract administration to diabetic rats improved muscle and hepatic glycogen content suggesting the antihyperglycemic potential of green tea extract in diabetic rats. The obtained results were compared with metformin, a standard oral hypoglycemic drug. Thus, this study indicates that the administration of green tea extract to diabetic rats resulted in alterations in the metabolism of glucose with subsequent reduction in plasma glucose levels.

Effects of liraglutide on postprandial insulin and glucagon responses in Japanese patients with type 2 diabetes

This study assessed the endocrine pancreatic responses to liraglutide (0.9 mg once a day) during normal living conditions in Japanese patients with type 2 diabetes. The study included 14 hospitalized patients with type 2 diabetes. Meal tests were performed after improvement of glycemic control achieved by two weeks of multiple insulin injection therapy and after approximately two weeks of liraglutide treatment. Continuous glucose monitoring was performed to compare daily variation in glycemic control between multiple insulin injection therapy and liraglutide treatment. Liraglutide reduced plasma glucose levels after the test meals (60–180 min; p<0.05), as a result of significant increases in insulin secretion (0–180 min; p<0.05) and decreases in the incremental ratio of plasma glucagon (15–60 min; p<0.05). Continuous glucose monitoring showed that liraglutide treatment was also associated with a decrease in glucose variability. We also demonstrated that optimal glycemic control seen as a reduction in 24-h mean glucose levels and variability was obtained only with liraglutide monotherapy. In conclusion, liraglutide treatment increases insulin secretion and suppresses glucagon secretion in Japanese patients with type 2 diabetes under normal living conditions. The main therapeutic advantages of liraglutide are its use as monotherapy and its ability to decrease glucose variability.

더위지기 추출물이 당뇨 흰쥐의 혈당과 항산화 효소 활성도에 미치는 영향

This study was undertaken to evaluate the antihyperglycemic, antilipid peroxidative, and antioxidant effects of the ethanol extracts of Artemisia iwayomogi (Ai) in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in Sprague-Dawley rats with a single intravenous injection (45 mg/kg b.w.) of STZ. The diabetic rats were then randomized to the diabetic and Ai extract therapy groups which were treated with Ai extract at doses of 1, 2, and 3 g/kg b.w./day, respectively, for 14 days. Oral administration of Ai (2 g/kg b.w.) significantly decreased their intake of food. Dosage of 2 g/kg of the extract significantly decreased blood glucose levels in the glucose level in diabetic rats after 4 day, there was no significant difference observed at 1 and 3 g/kg. A dose of 2 or 3 g/kg of the Ai extract significantly reduced plasma glucose levels in STZ-induced hyperglycemic rats at 7 days. The hypoglycemic effect of Ai at a dose of 2 g/kg was significantly more effective than that of STZ-control. The effect was more pronounced in 2 g/kg than 1 g and 3 g/kg. A significant reduction in triglycerides (TG) and free fatty acids (FFA), and a significant increase in liver glycogen were observed in treated diabetic rats at doses of 2 g/kg after 14 days of treatment. Administration of Ai extracts to diabetic rats showed a significant decrease in liver malondialdehyde (MDA) levels. The activity of superoxide dismutase (SOD) was significantly increased in the 3 g extract-supplemented groups. The activities of glutathione peroxidase (GSH-px) and catalase (CAT) were significantly increased in the 1 g and 3 g extract-supplemented groups. Ai extract significantly increased glutathione-S transferase (GST) activity in a dose-dependent manner compared with treatment in STZ-control rats. Our result supports the fact that the administration of Ai extract is able to reduce hyperglycemia and hyperlipidemia risk, and also reduce the oxidative stress in diabetic rats.

Hydrodynamic-based delivery of PTP1B shRNA reduces plasma glucose levels in diabetic mice

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling which is overexpressed in the liver of diabetic animals. The aims of this study were to generate liver-specific PTP1B knockout mice using a PTP1B‑short hairpin RNA (shRNA) plasmid and to investigate the effect of PTP1B inhibition on plasma glucose levels in streptozotocin-induced diabetic mice. We first validated the hydrodynamic tail vein injection in mice using a vector carrying the luciferase gene. Expression of the PTP1B gene was quantified by real-time PCR. The level of phosphorylated Akt was examined by western blot analysis. The injection of the plasmid containing firefly luciferase revealed that the highest transfer of the vector into the liver was obtained 24h after the injection of 20µg plasmid. The injection of PTP1B-shRNA, but not the scrambled shRNA plasmid, resulted in a reduction in PTP1B expression levels by up to 84% in the liver of the diabetic mice. Plasma glucose levels following the injection of PTP1B-shRNA remained significantly lower in the diabetic mice for 5days. In addition, mice receiving PTP1B-shRNA in the basal and insulin-stimulated states had higher levels of Akt phosphorylation in the liver cells compared with mice that were injected with the scrambled sequence (35 and 60%, respectively; p<0.01). Furthermore, PTP1B overexpression was observed in the muscle, liver, adipose, heart and kidney tissues of the diabetic mice. The data from this study demonstrate that PTP1B inhibition may be a promising approach for lowering plasma glucose levels in diabetic patients. However, further studies using non-viral carriers are required to deliver the plasmid safely into the liver.

Response of hepatic lipid and glucose metabolism to a mixture or single fatty acids: Possible presence of fatty acid-sensing mechanisms

To assess the hypothesis that an acute dietary fatty acid (FA) supply may improve glucose tolerance in rainbow trout, we orally administered fish with fish oil (FO; 10mL.kg−1, one time), which were then subjected to a glucose tolerance test and sampled 6h after injection. Parameters related to glucose and lipid metabolism were then assessed. The results suggest that when both nutrients were administered at the same time, an increased potential for lipogenesis occurred concomitantly with a lower level of glycaemia. In a second experiment we administered intraperitoneally a single FA present in the FO mixture such as oleic acid (60 or 300μg.kg−1) whereas octanoic acid (60 or 300μg.kg−1) was used as negative control (absent from the FO). However, the effects of both FA were similar in reducing the potential of lipid synthesis and oxidation, and in enhancing the potential of glucose synthesis and glycogenesis. Differences found between FO and single FA administration show that response to FA was dependent on the treatment (mixture vs. single FA) but also comply with the idea that an interaction between FA and glucose rather than FA alone are in the origin of the results reported. The administration of individual FA such as oleic and octanoic acid failed in enhancing lipogenesis and reducing plasma glucose levels and thus in explaining results obtained with FO. However, results provide evidence that FA even provided at a low dose play a key role in the regulation of several putative components of a FA sensing system present in rainbow trout liver.

Abstract 221: Renoprotective Effects of SGLT2 Inhibitor, Luseogliflozin, on the Progression of Diabetic Nephropathy in T2DN Rats

This study examined the effect of long term control of hyperglycemia with a new selective SGLT2 inhibitor, luseogliflozin (TS-071), given alone and in combination with lisinopril on the development of renal injury in a rat model of type 2 diabetic nephropathy (T2DN). Chronic treatment of 14-month old T2DN rats with luseogliflozin (10 mg/Kg/day) reduced plasma glucose levels from 285.7±17.7 mg/dL to 161.7±5.5 mg/dL and HbA1c from 8.9±0.4% to 6.4±0.2% in 17-month old T2DN rats but it had no effect on mean arterial pressure (MAP). Chronic treatment with lisinopril (10 mg/Kg/day) markedly reduced MAP (113.0±4.6 mmHg) compared with 17-month old T2DN rats (140.0±4.1 mmHg) but it had no effect on plasma glucose levels. Combination therapy with luseogliflozin and lisinopril significantly reduced MAP (92.9±4.0 mmHg) more than that seen in lisinopril treated rats. The kidneys of T2DN rats exhibited marked focal glomerulosclerosis with a glomerular injury score of 3.1±0.1 on a 0-4 scale and renal cortical fibrosis of 27.9±0.9%. Control of hyperglycemia with luseogliflozin reduced the glomerular injury score (2.6±0.1) and the renal cortical fibrosis (20.8±0.8%). Reducing blood pressure with lisinopril also reduced the glomerular injury score (2.5±0.1) but not the renal cortical fibrosis (29.0±1.5%). Combination therapy with luseogliflozin and lisinopril markedly reduced the glomerular injury score (2.0±0.1) and the renal cortical fibrosis (15.6±1.0%) more than either drug alone. GFR decreased from 0.44±0.04 to 0.29±0.03 mL/min/g- kwt and RBF decreased from 2.7±0.2 to 2.2±0.2 mL/min/g-kwt in T2DN rats over the course of this study. Chronic treatment of luseogliflozin or lisinopril prevented the decrease of GFR (0.44±0.05 and 0.54±0.05 mL/min/g-kwt) and RBF (3.2±0.2 and 6.7±1.1 mL/min/g-kwt). These results suggest that strict control of blood glucose with the luseogliflozin slows the progression of diabetic nephropathy and combination therapy with luseogliflozin and lisinopril is more effective at lowering blood pressure and is more renoprotective than administration of lisinopril alone.

Abstract 27: Leptin Reduces Food Intake but Fails to Raise Blood Pressure In Mice With Deficiency of Insulin Receptor Substrate (IRS2) In the Entire Brain or Specifically in Pomc Neurons

Insulin receptor substrate (IRS2) is one of three major leptin receptor signaling pathways. However, its role in mediating the chronic effects of leptin on appetite, blood pressure and glucose regulation is unclear. In the present study we tested whether deletion of IRS2 in the whole brain or specifically in proopiomelanocortin (Pomc) neurons attenuates the chronic cardiovascular and metabolic responses to leptin. Mice with IRS2 deletion in the entire brain (IRS2 flox/flox /Nestin-Cre, n=7), specifically in Pomc neurons (IRS2 flox/flox /Pomc-Cre, n=7) and control IRS2 flox/flox mice (n=9) were instrumented with telemetry probes for measurement of 24-hr mean arterial pressure (MAP) and heart rate (HR) and venous catheters for saline or leptin infusions. After a 5-day control period, mice received leptin infusion (2 μg/kg/min, iv) for 7 days. Compared to IRS2 flox/flox , IRS2 flox/flox /Pomc-Cre mice had similar body weight and food intake (33±1 vs 35±1g and 3.6±0.5 vs 3.8±0.2 g/day) and higher MAP and HR (110±2 vs 102±2 mmHg and 641±9 vs 616±5 bpm). IRS2 flox/flox /Nestin-Cre mice were heavier (38±1.5 g), had increased food intake (4.5±1.0 g/day), and higher MAP and HR (108±1.5 mmHg and 659±9.0 bpm) compared to control mice. Leptin infusion for 7 days in control IRS2 flox/flox mice gradually increased MAP by 5 mmHg despite decreasing food intake by 31%. In contrast, leptin infusion did not change MAP in IRS2 flox/flox /Nestin-Cre and IRS2 flox/flox /Pomc-Cre mice. The anorexic effect of leptin, however, was not attenuated in IRS2 flox/flox /Pomc-Cre or IRS2 flox/flox /Nestin-Cre mice (-35% and -34%, respectively). In addition, deletion of IRS2 in the whole brain or Pomc neurons did not impair the ability of leptin to reduce plasma glucose levels (IRS2 flox/flox : 170±15 to 130±12; IRS2 flox/flox /Pomc-Cre: 180±20 to 150±15; IRS2 flox/flox /Nestin-Cre: 160±10 to 131±20 mg/dL) These results indicate that activation of IRS2 signaling in the CNS, and particularly in Pomc neurons, is essential for the long-term actions of leptin to raise MAP and HR but not for its anorexic or antidiabetic effects. (NHLBI-PO1HL51971/ AHA SDG5680016)

New possibility in the oral glucose lowering treatment of type 2 diabetes mellitus: sodium-glucose co-transporter-2 inhibitors

Sodium-glucose co-transporters (SGLTs) have a key role in the re-absorption of glucose in the kidneys. Therefore, inhibition of SGLTs may provide a novel therapeutic strategy for diabetes mellitus. SGLT2 inhibitors enhance renal glucose excretion by inhibiting renal glucose re-absorption and reduce plasma glucose level, as well as they decrease the body weight. Their action is insulin independent and they improve insulin resistance in diabetes mellitus. Numerous SGLT2 inhibitors have been developed and evaluated in clinical trials. Phase III trials are needed to assess the safety of SGLT2 inhibitors. Results suggest that the beneficial effects of SGLT2 inhibition might be achieved without the development of significant side effects.

Sodium dependent glucose transporter (SGLT) 1 / 2 - elucidating inhibitor SAR and selectivity using homology modelling and 3D QSAR studies

Inhibiting sodium-dependent glucose transporters (SGLTs) has been proposed as a new therapy for the treatment of diabetes [1]. SGLT2 as the most prominent member of this family is mainly expressed in the kidney and responsible for the reabsorption of the vast majority of the filtered glucose. This key role in the blood glucose homeostasis makes SGLT2 a promising target which has been clearly underlined by the results of preclinical and clinical studies. Therapeutic goals of SGLT2 inhibition are reduced plasma glucose levels and weight loss. In conjunction with the therapeutic benefits fewer side effects are expected than observed with other known diabetes drugs. Potential side effects in case of SGLT2 inhibition are expected to be mediated by a lack of selectivity towards SGLT1 that is mainly expressed in the intestine and responsible for glucose- and galactose absorption from food sources. Therefore, inhibition of SGLT1 leads to glucose- and galactose malabsorption, dehydration, and diarrhoea. Consequently, any drug discovery project aiming for promising SGLT2 inhibitors has to take into account significant selectivity towards SGLT1. In order to describe the selectivity on a structural basis we extensively used molecular modelling techniques since no x-ray structural data is available for neither SGLT1 nor SGLT2. For both transporters homology models were generated using the published x-ray structure from vSGLT (PDB-code 3DH4) [2]. Structure based alignments of published SGLT2 inhibitors including selectivity data for SGLT1 were followed by 3D-QSAR studies utilizing CoMFA fields. Given a detailed analysis of the inhibitor SAR for both transporters the two structural models of SGLT1 and SGLT2 were compared leading to the identification of relevant differences and selectivity hot spots. In the future, the presented models could serve as a basis for the identification of new potent SGLT2 inhibitors that are selective towards SGLT1, too.

Efficacy of 20-OH-ecdysone on hepatic key enzymes of carbohydrate metabolism in streptozotocin induced diabetic rats

The aim of the present investigation was to evaluate the anti-diabetic activity of 20-OH-ecdysone on glucose metabolic key enzymes in control and streptozotocin induced diabetic rats. On oral administration of 20-OH-ecdysone at a dose of 5mg/kg body weight per day to diabetic rats for 30 days resulted in a significant decrease in the levels of plasma glucose, glycosylated hemoglobin (HbA1c) and an increase in the levels of insulin and hemoglobin. Administration of 20-OH-ecdysone showed significant increase in the levels of glycolytic enzyme (hexokinase) and hepatic shunt enzyme (glucose-6-phophate dehydrogenase) whereas significant decrease in the levels of gluconeogenic enzymes (glucose-6-phosphatase and fructose-1,6-bisphosphatase) in diabetic treated rats. Furthermore, protection against body weight loss of diabetic animals also observed. This study indicates that the administration of 20-OH-ecdysone to diabetic rats resulted in alterations in the metabolism of glucose with subsequent reduction in plasma glucose levels. A comparison was made between the action of 20-OH-ecdysone and antidiabetic drug-glibenclamide. The effects produced by the 20-OH-ecdysone were comparable to that of glibenclamide.

The acute effects of Montbretin A (MbA), an á‐glucosidase inhibitor, on plasma glucose levels in the Zucker Diabetic Fatty rat

Postprandial hyperglycemia is a risk factor for cardiovascular disease in diabetic patients. Acarbose and Miglitol, current therapeutic α‐glucosidase inhibitors, reduce postprandial hyperglycemia but, due to side effects, are not well tolerated. Research is ongoing to develop products that will minimize side effects and improve patient compliance. MbA, a purified glycosylated acyl flavonol, was isolated from extracts of the plant, Crocosmia crocomiflora. In vitro studies have shown MbA to be an inhibitor of both exquisite specificity and affinity for human pancreatic α‐amylase. The objective of this study was to determine if MbA was an orally effective glucose lowering agent in an animal model of type 2 diabetes. Animals were challenged with a starch load (2 g/kg) immediately followed by MbA (dose range: 0.5 to 10 mg/kg) administered by oral gavage. Plasma glucose levels were measured immediately prior to and at 30, 60, 90 and 120 minutes post‐administration. Acarbose 10 mg/kg was used as a control for glucose response. MbA prevented the starch‐induced increase in glucose levels at doses greater than 5 mg/kg. MbA (10 mg/kg) reduced plasma glucose levels by 38±3% as compared to 26±2% for acarbose in fatty treated animals. These data show that MbA was effective in lowering plasma glucose levels in vivo. Future studies will examine the chronic effects of oral MbA treatment on diabetes mellitus. Supported by CDRD and CIHR.

Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators

A series of benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strategy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identified having a suitable balance of potency and activation profile. They showed EC50 values of 28.3 and 44.8nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were also observed on these two compounds.