Lower Plasma Glucose Levels Research Articles

Hepatic lipidosis in transition buffaloes in relation to back fat thickness, hemato-biochemical and mineral profile

The study invoved 140 buffaloes, 125 (87.41%) with ultrasonography (USG) features of normal liver and 18 (12.58%) with features of hepatic lipidosis (HL). Among the later 7 had grade I, 6 grade II and 5 grade III USG features of HL. The grouping of animals according to transition stage and evaluation of body condition score (BCS) showed that buffaloes with moderate to severe HL lost BCS from Far off dry (FOD) to fresh stage by more than one (1.0) increment whereas, healthy buffaloes lost BCS from FOD to fresh stage by less than 0.5 increment. Significantly low levels of haemoglobin, packed cell volume and total erythrocyte count was observed in buffaloes with severe HL. Significantly low levels of total plasma protein, glucose, calcium, potassium, copper and zinc along with increased levels of plasma urea nitrogen, beta hydroxyl butyric acid, non esterified fatty acid, aspartate amino transferase, alanine amino transferase, gamma glutamyl transferase, lactate dehydrogenase and Glutamic dehydrogenase were observed in buffaloes with HL. A strong positive association exists between the severity of BCS and back fat thickness (BFT) reduction and occurrence of HL in transition buffaloes.

Administration of Selenium Decreases Lipid Peroxidation and Increases Vascular Endothelial Growth Factor in Streptozotocin Induced Diabetes Mellitus.

The imbalance in oxidant/antioxidant status plays a pivotal role in diabetes mellitus (DM). Selenium is a integral component of the antioxidant enzyme glutathione peroxidase. Se treatment induces angiogenesis and improves endothelial function through increased expression of vascular endothelial growth factor (VEGF). The aim of this study is to investigate the effect of selenium on oxidative stress, VEGF, and endothelin 1 (ET1) in a DM rat model. We performed an experimental animal study with 64 adult male Wistar-Albino rats. Rats were divided into the following groups (n=8): control (C)7, C21, C+sodium selenite (Se)7, and C+Se21 (control rats), and DM7, DM21, DM+Se7, and DM+Se21 (diabetic rats). Diabetes was induced by 2-deoxy-2-(3-methyl-3-nitrosoureido)- D-glucopyranose [streptozotocin (STZ)]. Three weeks after STZ, DM+Se7 rats received intraperitoneal (i.p.) injections of 0.4 mg/kg Se for 7 days. The DM+Se21 rats received these injections for 21 days. The same dose/duration of Se was administered to the C+Se7 and C+Se21 groups. The remaining rats (C7, C21, DM7, DM21) received physiologic saline injections for 7 or 21 days. Ferric reducing antioxidant power (FRAP), malondialdehyde (MDA), advanced oxidation protein products (AOPP), and endothelial function markers (VEGF and ET1) in plasma samples were measured. Diabetic rats (DM7 and DM21) had significantly increased plasma FRAP (P=0.002, P=0.001), AOPP (P=0.024, P=0.01), MDA (P=0.004, P=0.001), and ET1 (P=0.028, P=0.003) levels compared with C7 and C21 control rats. VEGF (P=0.02, P=0.01) significantly decreased in DM7 and DM21 diabetic rats compared with their controls (C7, C21). Se administration reversed the increased MDA and decreased VEGF levels, and lowered plasma glucose levels in the DM+Se7 and DM+Se21 diabetic groups compared with diabetic rats (DM7, DM21). We observed positive correlations between FRAP-AOPP (r=0.460), FRAP-ET1 (r=0.510), AOPP-MDA (r=0.270), and AOPP-ET1 (r=0.407), and a negative correlation between MDA-VEGF (r=-0.314). We observed accentuated oxidative stress and impaired endothelial function in diabetes. Se treatment reduced lipid peroxidation and hyperglycemia. Se probably improved endothelial dysfunction in diabetic rats because of the increased VEGF levels.

Low plasma glucose limits glucose metabolism by RBCs and heart in some species of teleosts.

Within teleosts there is a species range in plasma glucose levels from undetectable to 20mM. At low plasma glucose levels the gradient from the extracellular to the intracellular space is decreased. The impact of this on glucose metabolism by RBCs and heart from species with different steady state levels of plasma glucose (Atlantic cod ~5mM; Atlantic salmon ~5mM, cunner ~1mM, lumpfish <1mM; short-horned sculpin <1mM) is the subject of this review. Under normoxia, at physiological levels of extracellular glucose, RBCs and heart produce lactate although the contribution of anaerobic metabolism to ATP production is small. Sustained lactate production from extracellular glucose appears to be the primary fate of extracellular glucose. In many cases, glycogen is not mobilized and the rate of glucose metabolism=two times the rate of lactate production. As such, alternative metabolic sources are required to fuel oxidative metabolism. Under hypoxia, hearts from Atlantic cod and rainbow trout increase rates of both glucose metabolism and lactate production, partially supported by glycogen reserves. But in lumpfish and short-horned sculpin hearts there is no change in rates of glucose metabolism. The most likely explanation is that glucose uptake is compromised in lumpfish and short-horned sculpin hearts due to a low diffusion gradient. Under these conditions rates of lactate production are well below that of Atlantic cod or rainbow trout. Energy demand must be reduced under hypoxia in lumpfish and short-horned sculpin hearts in order to maintain ATP balance.

Adult Nesidioblastosis With Hypoglycemia Mimicking an Insulinoma: A Challenging Case

Introduction: Nesidioblastosis is the primary cause of persistent hyperinsulinemic hypoglycemia in infants but it is a rare entity for the adults. Nesidioblastosis is defined as an increase of pancreatic beta cells in number and in size. Case Presentation: We describe a rare case of nesidioblastosis with positive endoscopic ultrasonography result mimicking an insulinoma. A 35-year-old female patient had hypoglycemic episodes with high insulin level. Her investigation revealed low venous plasma glucose, high insulin and C-peptide level with positive 72-hour fasting test suggestive of hyperinsulinemic hypoglycemia. Abdominal computed tomography did not show any mass lesion. Endoscopic ultrasonography revealed a mass lesion sized as 1 cm in diameter in the pancreas. But, insulinoma like lesion couldn't be found intra-operatively. It was decided to perform distal pancreatectomy. After distal pancreatectomy, nesidioblastosis was diagnosed histopathologically. The patient was free from her symptoms after surgery. Conclusion: This case illustrates difficulties and limitations of imaging modalities and false positive result of EUS in a case of nesidioblastosis. When there is no insulinoma like lesion during operation, operation should be performed as gradient guided pancreatectomy by the way of selective arterial calcium injection test.

Metabolic, Reproductive, and Neurologic Abnormalities in Agpat1-Null Mice.

Defects in the biosynthesis of phospholipids and neutral lipids are associated with cell membrane dysfunction, disrupted energy metabolism, and diseases including lipodystrophy. In these pathways, the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) enzymes transfer a fatty acid to the sn-2 carbon of sn-1-acylglycerol-3-phosphate (lysophosphatidic acid) to form sn-1, 2-acylglycerol-3-phosphate [phosphatidic acid (PA)]. PA is a precursor for key phospholipids and diacylglycerol. AGPAT1 and AGPAT2 are highly homologous isoenzymes that are both expressed in adipocytes. Genetic defects in AGPAT2 cause congenital generalized lipodystrophy, indicating that AGPAT1 cannot compensate for loss of AGPAT2 in adipocytes. To further explore the physiology of AGPAT1, we characterized a loss-of-function mouse model (Agpat1-/-). The majority of Agpat1-/- mice died before weaning and had low body weight and low plasma glucose levels, independent of plasma insulin and glucagon levels, with reduced percentage of body fat but not generalized lipodystrophy. These mice also had decreased hepatic messenger RNA expression of Igf-1 and Foxo1, suggesting a decrease in gluconeogenesis. In male mice, sperm development was impaired, with a late meiotic arrest near the onset of round spermatid production, and gonadotropins were elevated. Female mice showed oligoanovulation yet retained responsiveness to gonadotropins. Agpat1-/- mice also demonstrated abnormal hippocampal neuron development and developed audiogenic seizures. In summary, Agpat1-/- mice developed widespread disturbances of metabolism, sperm development, and neurologic function resulting from disrupted phospholipid homeostasis. AGPAT1 appears to serve important functions in the physiology of multiple organ systems. The Agpat1-deficient mouse provides an important model in which to study the contribution of phospholipid and triacylglycerol synthesis to physiology and diseases.

Abstract 278: PGC1α Activation Corrects Cardiac Dysfunction Caused by Anti-diabetic Dual-PPARα/γ Therapy

Peroxisome proliferator-activated receptor (PPAR) agonists are used in metabolic diseases. PPARα agonists target hyperlipidemia and PPARγ agonists correct hyperglycemia. Dual PPARα/γ agonists were developed to combine the benefits in type 2 diabetes patients. Despite their beneficial effect, PPARα/γ agonists caused cardiac dysfunction. We studied the mechanisms that underlie this toxic effect aiming to improve a failed therapy. Wild type mice were fed with chow and high fat diets containing Tesaglitazar (TESA) a dual PPARα/γ agonist for 6 weeks. Although, TESA lowered plasma triglyceride and glucose levels compared to controls, 2D-echo revealed severe cardiac dysfunction. Assessment of the expression of cardiac fatty acid metabolism genes that are regulated by PPARs showed that mRNA and protein levels of PPARγ-coactivator (PGC1α), a regulator of mitochondrial biogenesis, had the most profound reduction. Furthermore, we observed increased acetylation of PGC1α levels, which indicates lower activation and lower mitochondrial respiration. We then examined the mechanisms that underlie lower expression of PGC1α upon activation of PPARα and PPARγ. Thus, we administered C57BL/6 mice with both single PPARα and PPARγ agonists (WY14643 and rosiglitazone). This treatment reproduced the reduction in PGC1α expression that we observed with TESA. Moreover, mitochondria abundance was lower. Luciferase promoter analysis in a human cardiomyocyte cell line showed that PPARα and PPARγ compete for binding on PPAR elements of the human Pgc1a promoter, as well as that PPARα binding compromises PPARγ-mediated activation of the Pgc1α promoter. Aiming to decipher the mechanism via which dual PPARα/γ activation increases acetylation and thus inhibits PGC1α, we measured cardiac protein levels of the deacetylase sirtuin 1 (SIRT1), which were lower in primary cardiomyocytes from TESA-treated mice. We then treated mice with diet containing TESA and Resveratrol (RSV), which stimulates SIRT1. RSV attenuated TESA-driven cardiac dysfunction and corrected mitochondrial respiratory rates in primary cardiomyocytes. We propose that SIRT1-mediated activation of PGC1α blunts the cardiotoxic effect of dual PPARα/γ agonists and improves their therapeutic potential.

IMPACT OF APOE GENOTYPE ON THE SEX-DIFFERENTIATED BIOENERGETIC TRAJECTORIES AND AD RISKS IN AGING MOUSE BRAINS

Age, APOE4 genotype, and female sex are top risk factors for AD. Our previous studies demonstrated that the bioenergetic shifts occurring in the perimenopausal female brain could contribute to an increased AD risk in women. We also observed substantial sex disparities in brain bioenergetic trajectories in normal aging mice. The goal of this study is to determine the sex differences in the impact of APOE genotype on AD at-risk phenotypes during brain aging. Female and male, APOE3- and APOE4 targeted replacement (TR) mice were assessed for: (a) bioenergetic-, inflammatory-, and AD pathology-related gene expression in hippocampus followed by bioinformatic analysis, and (b) key metabolic parameters in the periphery. Functional assessments are undergoing, including: (a) FDG-microPET for cerebral glucose metabolism, (b) brain mitochondrial function, and (c) glucose tolerance test for peripheral metabolism. Gene expression analyses revealed that female APOE4 mice at pre-menopause age (6-month old) exhibited a significantly different bioenergetic profile relative to APOE3 controls: APOE4 mice showed a higher expression of genes involved in mitochondrial oxidative phosphorylation, mitochondrial membrane transport, and mitochondrial fusion. These changes in female APOE4 brains could represent an adaptive response to deficits in brain glucose availability and a shift in energy fuels from glucose to ketone bodies and glucose. This hypothesis is further supported by: (a) APOE4 mice had lower levels of plasma glucose in both sexes while the higher levels of ketone bodies and triglycerides were only seen in the females; (b) both APOE3 and APOE4 females had lower peripheral glucose levels and higher ketone body levels than their genotype-matched male counterparts, indicating a potential earlier shift in bioenergetic fuel usage in females. These findings suggest that APOE4 genotype interacts with the age-related decline in glucose metabolism and the bioenergetic shift to alternative fuels, particularly in females. Outcomes of this study will provide mechanistic details of the APOE4 genetic burden on the sex-differentiated bioenergetic fluctuation during aging and its contribution to higher AD risks in women. This work was supported by NIA 5P01AG026572 to RDB and Alzheimer's Association SAGA-17–419459 to RDB.

Plasma Glucose Level Is Predictive of Serum Ammonia Level After Retrograde Occlusion of Portosystemic Shunts.

The purpose of this study was to evaluate predictors of reduction in ammonia levels by occlusion of portosystemic shunts (PSS) in patients with cirrhosis. Forty-eight patients with cirrhosis (21 women, 27 men; mean age, 67.8 years) with PSS underwent balloon-occluded retrograde transvenous obliteration (BRTO) at one institution between February 2008 and June 2014. The causes of cirrhosis were hepatitis B in one case, hepatitis C in 20 cases, alcohol in 15 cases, nonalcoholic steatohepatitis in eight cases, and other conditions in four cases. The Child-Pugh classes were A in 24 cases, B in 23 cases, and C in one case. The indication for BRTO was gastric varices in 40 cases and hepatic encephalopathy in eight cases. Testing was conducted before and 1 month after the procedure. Statistical analyses were performed to identify predictors of a clinically significant decline in ammonia levels after BRTO. Occlusion of PSS resulted in a clinically significant decrease in ammonia levels accompanied by increased portal venous flow and improved Child-Pugh score. Univariate analyses showed that a reduction in ammonia levels due to BRTO was significantly related to lower plasma glucose levels, higher RBC counts, and higher hemoglobin concentration before the treatment. Furthermore, multivariate logistic regression identified preoperative plasma glucose level as the strongest independent predictor of a significant ammonia reduction in response to BRTO. In addition, although BRTO resulted in significantly declined ammonia levels in patients with normal glucose tolerance before the procedure, ammonia levels were not significantly decreased after shunt occlusion in patients with diabetes mellitus or impaired glucose tolerance before BRTO, according to 75-g oral glucose tolerance test results. Preoperative plasma glucose level is a useful predictor of clinically significant ammonia reduction resulting from occlusion of PSS in patients with cirrhosis. Even if PSS are present, control of blood ammonia levels by BRTO alone may be difficult in patients with glucose intolerance.

Harnessing basic and clinic tools to evaluate SGLT2 inhibitor nephrotoxicity.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of medications that target the transporter that reabsorbs ~90% of glucose in the S1 segment of the proximal convoluted tubule. As a result, SGLT2 inhibition increases urinary glucose excretion, effectively lowering plasma glucose levels. In addition to reducing hemoglobin A1c levels, these drugs also lower body weight, blood pressure, and uric acid levels in Type 2 diabetes mellitus (T2DM) patients. Importantly, empagliflozin has been observed to slow progression of kidney disease and reduce dialysis requirements in T2DM patients. However, the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) has collected over 100 cases of acute kidney injury (AKI) for canagloflozin and dapagliflozin since their approval. Of the 101 patients, 96 required hospitalization, 22 required intensive care unit admission, and 15 underwent hemodialysis. The FDA now requires that AKI be listed as a potential side effect of the SGLT2 inhibitors along with cautious prescription of these drugs with other medications, such as renin-angiotensin-system antagonists, diuretics, and NSAIDs. It is unclear, however, whether this FAERS reported "AKI" actually represents structural kidney injury, as randomized, controlled trials of these drugs do not describe AKI as an adverse event despite coprescription with RAS blockers and diuretics. As a result of this FDA warning, diabetic patients with early-stage CKD may not be prescribed an SGLT2 inhibitor for fear of AKI. Thus, it is imperative to ascertain whether the reported AKI represents true structural kidney injury or a functional decline in glomerular filtration rate. We propose using readily available clinical tools with experimental biomarkers of kidney injury and kidney-on-a-chip technology to resolve this question and provide solid evidence about the AKI risk of these drugs for healthcare providers.

Bioactive polyphenols in kinkéliba tea (Combretum micranthum) and their glucose-lowering activities

Herbal tea kinkéliba prepared from the leaves of Combretum micranthum has been widely consumed in West African countries for its flavor, nutritional and medicinal properties. Under bio-guided screening, the kinkéliba leaves were chemically investigated using various chromatographic and spectrometric methods that led to the identification of thirteen different flavonoid compounds. Further biological tests illustrated that the identified compounds may have synergistic effects to decrease the expression of phosphoenolpyruvate carboxykinase (PEPCK) mRNA and glucose production in an H4IIE hepatoma cell line, indicating its potential use for insulin-resistant diabetes treatment. Further in vivo study on C57BL/6J mice indicates that kinkéliba can lower plasma glucose levels in a dose-dependent manner without significant weight loss and toxicity. The ethyl acetate extract in rich of flavonoids could also increase the glucose tolerance (GT) after seven weeks' administrations. Both in vitro and in vivo experiments support a potential new application of kinkéliba leaves as an anti-diabetes agent.

Association of the polymorphism in NUCB2 gene and the risk of type 2 diabetes

BackgroundNesfatin-1, originating from its precursor protein called nucleobindin 2 (NUCB2), plays an important role in glucose metabolism and diabetes. The aim of this study is to examine the association of the c.1012C>G (rs757081) polymorphism of NUCB2 gene with the presence of T2DM.MethodsThis study was performed in a population of 396 patients with T2DM and 196 healthy subjects. The c.1012C>G polymorphism of NUCB2 gene was determined using polymerase chain reaction and sequencing method.ResultsT2DM patients showed lower CG and GG genotype, as well as G allele frequencies compared with healthy subjects. Logistic regression analysis showed that c.1012C>G polymorphism was associated with a decreased risk of developing T2DM. In addition, GG genotype of NUCB2 was significantly correlated with lower levels of body mass index and fasting plasma glucose in patients with T2DM.ConclusionsThe c.1012C>G polymorphism of NUCB2 is associated with the decreased risk of developing T2DM in Chinese Han population.

Sodium-glucose Cotransporter 2 Inhibitors (SGLT2i): Their Role in Cardiometabolic Risk Management.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel category of oral antidiabetic drugs that inhibit renal glucose reabsorption and increase renal glucose excretion, thus lowering plasma glucose levels. This unique mechanism of SGLT2i action is insulin independent, thus improving glycemic control without promoting hypoglycemia in the absence of exogenously administered insulin. The present narrative review addresses the putative associations between SGLT2i and several cardiovascular (CV) and microvascular risk factors, as well as their effects on cardiac and renal function. SGLT2i improve several CV risk factors, including fasting and postprandial plasma glucose levels, lipids, blood pressure, body weight, serum uric acid and arterial stiffness. These drugs may also favorably modulate cardiac and renal function via their effects on inflammation, oxidative stress, diuresis, fluid and sodium retention, myocardial function, vascular resistance and 'fuel' metabolism. In the EMPA-REG OUTCOME study, the first published large CV outcome SGLT2i trial, empagliflozin significantly reduced the primary composite outcome (i.e. CV death, nonfatal myocardial infarction or stroke) and all-cause death as well as hospitalization for heart failure. In addition, empagliflozin was associated with a slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care in patients at high CV risk. Multiple metabolic benefits may account for the positive clinical outcomes in the EMPA-REG OUTCOME study. Ongoing CV outcome trials involving other SGLT2i will help establish whether the reported CV and microvascular risk benefits are compound-specific or drug class effects.

Effects of nutritional history on stress response in gibel carp (Carassius auratus gibelio) and largemouth bass (Micropterus salmoides).

The stress response of omnivorous gibel carp (Carassius auratus gibelio) and carnivorous largemouth bass (Micropterus salmoides) with different nutritional history were evaluated. A 2×2 layout, including two fish species (gibel carp or largemouth bass) and two nutritional history (fasted or fed to satiation for four weeks), was used. After feeding or fasting, the fishes were subjected to an acute handling. Fasting resulted in decrease of plasma glucose level and liver glycogen content of gibel carp and largemouth bass. After handling stress, plasma levels of cortisol, glucose and lactate of gibel carp and largemouth bass increased, regardless the fasted fish or fed fish. During the period from 0h to 24h post-stress, the fasted gibel carp exhibited lower plasma cortisol and glucose levels, brain and liver glycogen contents, and liver phosphoenolpyruvate carboxykinase (PEPCK) activity compared with the fed counterpart. The plasma glucose level, brain glucose level, brain and liver glycogen contents were lower, while the liver PEPCK and hexokinase (HK) activities were higher, in the faster largemouth bass than the fed counterpart. This study indicates that nutritional history can influence stress response of gibel carp and largemouth bass, and the stress response is less severe in the fasted fish relative to the fed counterpart. This study also reveals that gibel carp and largemouth bass may have different strategies in response to fasting and acute handling stress.

Dapagliflozin improves insulin resistance and glucose intolerance in a novel transgenic rat model of chronic glucose overproduction and glucose toxicity.

To determine whether the excretion of glucose improves insulin resistance, impaired insulin secretion or both. Appropriate methods were used to assess insulin sensitivity (euglycaemic-hyperinsulinaemic clamp) and insulin secretion (hyperglycaemic clamp) in insulin-resistant and hyperglycaemic phosphoenolpyruvate carboxykinase (PEPCK) transgenic rats after treatment with the sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin. In 14-week-old rats with hyperglycaemia, insulin resistance and glucose intolerance, 6 weeks of dapagliflozin treatment resulted in lower weight gain, plasma glucose and insulin levels, and improved glucose tolerance, associated with enhanced insulin sensitivity (rate of glucose disappearance: 51.6 ± 2.3 vs 110.6 ± 3.9 µmol/min/kg; P < .005) and glucose uptake in muscle (0.9 ± 0.1 vs 1.7 ± 0.3 µmol/min/100 g; P < .05) and fat (0.23 ± 0.04 vs 0.55 ± 0.10 µmol/min/100 g, P < .05). Additionally, adipose tissue GLUT4 protein levels were increased (0.78 ± 0.05 vs 1.20 ± 0.09 arbitrary units; P < .05), adipocyte count was higher (221.4 ± 17.7 vs 302.3 ± 21.7 per mm2 fat area; P < .05) and adipocyte size was reduced (4631.8 ± 351.5 vs 3397.6 ± 229.4 µm2 , P < .05). There was no improvement, however, in insulin secretion. To determine whether earlier intervention is necessary, 5-week-old PEPCK transgenic rats were treated with dapagliflozin for 9 weeks and insulin secretion assessed. Dapagliflozin resulted in improved plasma glucose and insulin levels, and lower weight gain but, again, insulin secretion was not improved. In this transgenic model of low-grade chronic hyperglycaemia, SGLT2 inhibitor treatment resulted in reduced blood glucose and insulin levels and enhanced glucose tolerance, associated with improved muscle and fat insulin resistance but not improved insulin secretory function.

Effect of dietary polyphenol-rich grape seed on growth performance, antioxidant capacity and ileal microflora in broiler chicks.

In this study, we examined the effect of dietary supplementation with grape seed (GS) on the performance, carcass traits, plasma biochemistry, antioxidant status and ileal microflora in broilers. Experiment diets included a control diet (without additive) and three levels of GS powder (10, 20 and 40g/kg of diet). Each diet was fed to a total of 300 one-day-old Cobb-500 chicks for 42days. The addition of 20g/kg of GS to the basal diet increased final body weight and body weight gain, improved the feed conversion ratio and did not affect feed intake. Dietary 20g GS significantly increased (p<.05) the percentage of carcass yield %, dressing % and gizzard. However, the addition of 40g/kg of GS significantly reduced the percentage of abdominal fat in the birds. Diets supplemented with GS showed the lowest content of ether extract compared with the control group (p<.05). The physical characteristics of meat and the chemical composition of DM, CP and ash were not significantly influenced by treatments. In the GS groups, plasma protein, albumin, globulin, aspartate aminotransferase and alanine aminotransferase concentrations showed no significant change compared with the control group. Broilers fed a diet supplemented with GS had lower levels of plasma glucose, total lipids, triglycerides and cholesterol compared with the control birds (p<.05). The addition of 40g of GS significantly (p<.05) enhanced the activity of reduced glutathione, catalase, superoxide dismutase, glutathione peroxidase and GST, and correlated with significantly decreased thiobarbituric acid-reactive substances levels compared with the control group. The value of ileal pH was not significantly affected by the GS levels. Broilers fed diets supplemented with GS had lower ileal Streptococcus spp. and Escherichia coli populations but higher Lactobacillus spp. populations (p<.05). No adverse effects on birds' health were detected due to the use of GS. Thus, GS could be recommended as an herbal supplement in the diet of broiler chickens to improve performance, reduce blood lipids, enhance antioxidant capacity and decrease detrimental bacteria in the ileum.

A CLINICAL STUDY ON ADVERSE DRUG REACTIONS OF COMBINATION THERAPY OF DAPAGLIFLOZIN AND METFORMIN IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS

ABSTRACTObjective: This study aimed at determination of safety and efficacy of combination therapy of dapagliflozin and metformin in the treatment of Type2 diabetes mellitus.Methods: A total of 50 patients were enrolled in the study depending on demographic parameters and clinical data of the patients. The primaryefficacy criterion was the change in glycated hemoglobin (HbA1c) after a minimum of 12 weeks of treatment. Secondary efficacy parameters wereHbA1c value after 12 weeks, fasting and 1 hrs postprandial glucose, serum insulin and triglyceride levels, after a standardized meal, all after 12 weeksof treatment. Safety and tolerability were evaluated by the incidence of adverse events reported by patients. Patient visits to the clinical center werescheduled at screening, start of the run-in period.Results: Reductions in levels of postprandial plasma glucose were observed in all the active treatment groups. The reductions in patients receivingmetformin plus dapagliflozin combination therapy were significantly greater (p&lt;0.0001). It was clear that lower postprandial plasma insulin levelsdespite higher postprandial plasma glucose levels suggest decreased β-cell function. Changes in fasting serum insulin observed from baseline to theend of treatment did not differ significantly between metformin plus dapagliflozin combination therapy and metformin monotherapy and showed noconsistent trend.Conclusion: The results from the study suggest that the combination of the drugs was effective in controlling glycemic levels and also were safe. Noserious adverse drug reactions were reported by the patients when used daily once for 6 months.Keywords: Dapagliflozin, Metformin, Postprandial and glycemic.

Improvement of glucose metabolism via mung bean protein consumption: A clinical trial of GLUCODIATM isolated mung bean protein in Japan

Background: The main component of mung bean protein, accounting for more than 80%, is 8Sα globulin. Its structure closely resembles that of soybean β-conglycinin. Thereby, the mung bean protein is expected to have similar physiological effects to those of β-conglycinin, but there is no clinical evidence for these effects.Purpose of this study: The aim of this study was to confirm the positive effects of mung bean protein (GLUCODIATM) on glucose metabolism in clinical trials.Method: This clinical study was conducted using a double-blind placebo-controlled design with 45 prediabetes patients.Results: Many of the subjects were pre-diabetes with blood glucose levels exceeding 140 mg/dL by 2-hour plasma glucose level. However, the initial mean fasting plasma glucose level was less than 100 mg/dL. Therefore, mung bean protein did not lower fasting plasma glucose levels. The test period extended from summer to autumn, and increased fasting plasma glucose levels in the placebo group were observed due to seasonal factors. However, this increase was suppressed in the test group. Similarly, the mean insulin level increased in the placebo group, but the increase was also suppressed in the test group. Among obese subjects with a high body mass index, significant increases in fasting plasma glucose and insulin levels in the placebo group were observed. In the comparison between the test and the placebo groups with the average elevation value, there was a significant difference in fasting blood glucose level and significant tendencies in insulin level and homeostatic model assessment for insulin resistance value between the two groups.Conclusion: Mung bean protein suppresses fasting plasma glucose and insulin levels. Consequently, it may have an inhibitory effect on insulin resistance, a trigger of metabolic syndrome.Key words: mung bean protein, insulin, obesity, body mass index, randomized clinical trial, seasonal variation.

Vitamin A status affects the plasma parameters and regulation of hepatic genes in streptozotocin-induced diabetic rats

Vitamin A (VA) status regulates metabolism in rats. Whether VA status and availability of retinoic acid (RA) contribute to the insulin-regulated hepatic gene expression remains to be determined. Zucker lean rats with VA sufficient (VAS) or VA deficient (VAD) status were treated with streptozotocin (STZ) to induce insulin-dependent diabetes. They were treated with saline (STZ-VAS-C or STZ-VAD-C), RA (STZ-VAS-RA or STZ-VAD-RA), insulin (STZ-VAS-INS or STZ-VAD-INS), or insulin + RA (STZ-VAS-INS + RA or STZ-VAD-INS + RA) for 3 h. Insulin and insulin + RA treatments reduced tail tip blood glucose, raised plasma insulin and suppressed plasma β-hydroxybutyrate levels in both STZ-VAD and STZ-VAS rats. STZ-VAD-INS and STZ-VAD-INS + RA rats had lower plasma glucose levels than STZ-VAD-C rats had. STZ-VAD-INS and STZ-VAD-INS + RA rats had higher plasma leptin level and lower glucagon level than STZ-VAD-C rats did. Insulin treatment induced Gck, Srebp-1c and Fas and suppressed Pck1 expression levels in the liver of STZ-VAS and STZ-VAD rats. Interestingly, insulin treatment inhibited Cyp26a1 expression in STZ-VAD, but not STZ-VAS rats, whereas RA treatment induced it in both. RA treatment induced Gck expression only in STZ-VAD rats. Insulin + RA treatment further induced the Cyp26a1 and Gck expressions in STZ-VAD rats. The Srebp-1c expression levels of STZ-VAD-INS and STZ-VAD-INS + RA rats were higher than that of STZ-VAS-INS and STZ-VAS-INS + RA rats. The changes of Gck mRNA and glucokinase protein were consistent. In STZ-induced diabetic rats, VA is not required for insulin-regulated Gck, Srebp-1c, Fas and Pck1 expression. However, VA status altered responses of certain genes (Cyp26a1 and Srebp-1c) to insulin treatment.

Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode

A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding Ki and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both Gq-coupled intracellular Ca2+ flux and Gs-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.

The Relationship between Physical Activity and Plasma Glucose Level amongst Ellisras Rural Young Adult Males and Females: Ellisras Longitudinal Study.

Unhealthy lifestyle characteristics such as low physical activity (PA) and high plasma glucose levels (PGLs) may lead to the development of type 2 diabetes mellitus in adulthood. The aim of this study was to investigate (i) the level of physical activity; (ii) the prevalence of pre-diabetes and (iii) the relationship between PA and plasma glucose level in a rural Ellisras adult population aged 18 to 28 years. A total of 713 young adults (349 males and 364 females) who took part in the Ellisras Longitudinal Study participated in the study. Fasting plasma glucose levels were analysed using Accutrend glucose meters. Physical activity data was collected using a validated questionnaire. Linear regression was used to assess the relationship between PA and pre-diabetes. The prevalence of pre-diabetes was between 45.7% and 50.2% and that of physical inactivity was 67.3% and 71.0% for males and females, respectively. There was no significant (p > 0.05) relationship between PA and pre-diabetes (beta = 1.016; 95% Confidence Interval from 0.352 to 2.777). The health benefits of PA increased with the increasing frequency, duration and intensity of exercise. The prevalence of pre-diabetes was found to be very high in this population. Our results suggest that greater physical activity is associated with low plasma glucose levels.