Oral Glucose Administration Research Articles

HYPOGLYCEMIC EFFECT OF OLIVE MILL WASTEWATER IN MICE INVOLVES THE SGLT-1 TRANSPORTER

<p><strong>Objective: </strong>Olive mill wastewater (OMWW) is a by-product of olive oil production and contains biologically active compounds. The aim of this study was to investigate the effect of OMWW on intestinal glucose absorption in mice, a target for treating diabetes.</p><p><strong>Methods: </strong>The effect oral administration of OMWW on mice glycemia was evaluated<em> </em>by oral glucose tolerance tests (OGTT), and mice jejunal mucosal strips were mounted in Ussing chambers to evaluate the activity of sodium-dependent glucose transporter (SGLT-1). Western blot analysis was performed to study SGLT-1 and protein kinase C (PKC) at the brush border membranes (BBM) of mice jejunal mucosa.</p><p><strong>Results: </strong>We found that the raised glycemia in mice in response to oral glucose administration (OGTT) was decreased in presence of OMWW, being highly effective at 4 g/kg of body weight. Further, OMWW inhibited glucose induced short-circuit current (Isc) in mice jejunal, which is a marker of SGLT-1 activity. The effect was rapid, with maximal inhibition of 80 % versus control. Also, OMWW induced a strong decrease of SGLT-1 protein (60%) as well as PKC (30%), a key effector protein in BBM of mice jejunal mucosa in response to glucose.</p><p><strong>Conclusion: </strong>Our results suggest that OMWW<em> </em>may be beneficial for diabetes through its novel hypoglycemic effect by acting on the PKC-SGLT-1 axis.</p>

Nonsuppressed Glucagon After Glucose Challenge as a Potential Predictor for Glucose Tolerance.

Glucagon levels are classically suppressed after glucose challenge. It is still not clear as to whether a lack of suppression contributes to hyperglycemia and thus to the development of diabetes. We investigated the association of postchallenge change in glucagon during oral glucose tolerance tests (OGTTs), hypothesizing that higher postchallenge glucagon levels are observed in subjects with impaired glucose tolerance (IGT). Glucagon levels were measured during OGTT in a total of 4,194 individuals without diabetes in three large European cohorts. Longitudinal changes in glucagon suppression were investigated in 50 participants undergoing a lifestyle intervention. Only 66-79% of participants showed suppression of glucagon at 120 min (fold change glucagon120/0 <1) during OGTT, whereas 21-34% presented with increasing glucagon levels (fold change glucagon120/0 ≥1). Participants with nonsuppressed glucagon120 had a lower risk of IGT in all cohorts (odds ratio 0.44-0.53, P < 0.01). They were also leaner and more insulin sensitive and had lower liver fat contents. In the longitudinal study, an increase of fold change glucagon120/0 was associated with an improvement in insulin sensitivity (P = 0.003). We characterize nonsuppressed glucagon120 during the OGTT. Lower glucagon suppression after oral glucose administration is associated with a metabolically healthier phenotype, suggesting that it is not an adverse phenomenon.

Mice with Deletion of Neuromedin B Receptor Exhibit Decreased Oral Glucose-Stimulated Insulin Release.

Neuromedin B (NB) and gastrin-releasing peptide (GRP) are bombesin-like peptides, found in the gastrointestinal tube and pancreas, among other tissues. Consistent data proposed that GRP stimulates insulin secretion, acting directly in pancreatic cells or in the release of gastrointestinal hormones that are incretins. However, the role of NB remains unclear. We examined the glucose homeostasis in mice with deletion of NB receptor (NBR-KO). Female NBR-KO exhibited similar fasting basal glucose with lower insulinemia (48.4%) and lower homeostasis model assessment of insulin resistance index (50.5%) than wild type (WT). Additionally, they were more tolerant to oral glucose, demonstrated by a decrease in the area under the glucose curve (18%). In addition, 15 min after an oral glucose load, female and male NBR-KO showed lower insulin serum levels (45.6 and 26.8%, respectively) than WT, even though blood glucose rose to similar levels in both groups. Single injection of NB, one hour before the oral glucose administration, tended to induce higher serum insulin in WT (28.9%, p=0.3), however the same did not occur in NBR-KO. They showed no changes in fasting insulin content in pancreatic islets by immunohistochemistry, however, the fasting serum levels of glucagon-like peptide, a potent incretin, exhibited a strong trend to reduction (40%, p=0.07). Collectively, mice with deletion of NB receptor have lower insulinemia, especially in response to oral glucose, and females also exhibited a better glucose tolerance, suggesting the involvement of NB and its receptor in regulation of insulin secretion induced by incretins, and also, in insulin sensitivity.

Abstract PR277

Background & Objectives: Newborns are often sedated during MRI but sedation itself creates adverse events and the management is more challenging in the MR environment (1). We describe our initial experience with oral 30% glucose administration through a teat during MRI for imaging of newborns. Materials & Methods: Nineteen newborns were assessed retrospectively after institutional research and ethics committee approval. 0.5-1 mL 30% glucose solution was administered orally. The motionless and sleepiness of newborns were evaluated after suckling. If the target conditions was not achieved, 0.5-1 mL increments of glucose was added. After 2 consecutive oral glucose administration the newborns who did not keep motionless or asleep and had motion artefacts were sedated with midazolam. The routine blood glucose level measurement of the newborns after imaging procedures in the ICU was performed for each patient. Results: Fifteen of 19 newborns quietened, kept motionless and slept during the procedure with administration of oral 30% glucose solution. However, 4 of 19 newborns did not keep motionless or asleep after 2 additional dosages of 30% glucose for induction and were needed further sedation. Conclusion: Majority of newborns completed MRI examination with oral 30% glucose administration without a need for sedation. Thereby, we recommend and support the integration of this safe and reliable technique into routine practice for newborns during MRI.

Evaluation of Postprandial To Fasting Insulin Ratio as a Biochemical Marker of Insulin Resistance in Obese Indian Children

Background:Insulin resistance in childhood obesity is a well recognised and worrisome complication. Reliable measurements of insulin resistance require invasive or multiple sampling procedures or complex mathematical calculations which are difficult to practice in routine office practice. Objective:This observational study was aimed to evaluate a simple ratio of 120 minute post glucose load (OGTT) insulin to fasting insulin for diagnosis of insulin resistance in obese children having clinical markers of insulin resistance and with a HOMA-IR value suggestive of insulin resistance for age and sex. Methods:Forty Eight obese children and adolescents (35 girls and 34 boys; mean age 10.19 ± 4.23 years and mean BMI 26.17± 3.76) were included in the study. All participants underwent an OGTT. Blood samples were obtained 0 and 120 minutes after oral glucose administration for glucose and insulin measurements, and 2 separate groups were studied in both pubertal and pre-pubertal age group, according to the presence or absence of insulin resistance as per the standard HOMA-IR cut-offs. The ratio of 120 minute and fasting insulin, measurements was termed as insulin resistance Index (Ri) and was calculated for both pre-pubertal and pubertal children with insulin resistance. The accuracy of this measurement in measuring Insulin Resistance and the optimal insulin resistance index (Ri) for diagnosis of insulin resistance was established with a receiver operating characteristic (ROC) curve. Results:The area under the curve for pre-pubertal children was 0.7(close to upper left) and yielded a sensitivity of 76% and specificity of 70% at Ri value of 4.7. The value of positive likelihood ratio comes at 2.53, pretest probability of 0.61, pretest odds of 1.56, post-test odds of 3.95 and post-test probability of 0.78. However ROC plot had area under the curve of only 0.3 in pubertal children (close to bottom right). Conclusion:Ri is a sensitive and specific test for calculation of insulin resistance in pre pubertal children but not accurate in pubertal children.

Biokinetics of 13C in the human body after oral administration of 13C-labeled glucose as an index for the biokinetics of 14C

The retention of 13C in the human body after oral administration of 13C-labeled glucose was studied in three healthy volunteer subjects to estimate the 50 year cumulative body burden for 13C as an index of the committed dose of the radioisotope 14C. After administration of 13C-labeled glucose, the volunteers ingested controlled diets with a fixed number of calories for 112 d. Samples of breath and urine were collected up to 112 d after administration. Samples of feces were collected up to 14 d after administration. Hair samples were obtained at 119 d after administration and analyzed as a representative index of the rate of excretion of organic 13C via pathways such as skin cell exfoliation and mucus secretion. All samples were analyzed for 13C/12C atomic ratio to determine the rate of excretion via each pathway. We then constructed a metabolic model with a total of four pathways (breath, urine, feces, and other) comprising seven compartments. We determined the values of the biokinetic parameters in the model by using the obtained excretion data. From 74% to 94% of the 13C administered was excreted in breath, whereas <2% was excreted in urine and feces. In the other pathway, the excretion rate constant in the compartment with the longest residence time stretched to hundreds of days but the rate constant for each subject was not statistically significant (P value > 0.1). In addition, the dataset for one of the three subjects was markedly different from those of the other two. When we estimated the 50 year cumulative body burden for 13C by using our model and we included non-statistically significant parameters, a considerable cumulative body burden was found in the compartments excreting to the other pathway. Although our results on the cumulative body burden of 13C from orally administered carbon as glucose were inconclusive, we found that the compartments excreting to the other pathway had a markedly long residence time and therefore should be studied further to clarify the fate of carbon in the human body. In addition to excreta, data for serum and blood cell samples were also collected from the subjects to examine the metabolism of 13C in human body.

Rice (Oryza sativa japonica) Albumin Suppresses the Elevation of Blood Glucose and Plasma Insulin Levels after Oral Glucose Loading.

The suppressive effect of rice albumin (RA) of 16 kDa on elevation of blood glucose level after oral loading of starch or glucose and its possible mechanism were examined. RA suppressed the increase in blood glucose levels in both the oral starch tolerance test and the oral glucose tolerance test. The blood glucose concentrations 15 min after the oral administration of starch were 144 ± 6 mg/dL for control group and 127 ± 4 mg/dL for RA 200 mg/kg BW group, while those after the oral administration of glucose were 157 ± 7 mg/dL for control group and 137 ± 4 mg/dL for RA 200 mg/kg BW group. However, in the intraperitoneal glucose tolerance test, no significant differences in blood glucose level were observed between RA and the control groups, indicating that RA suppresses the glucose absorption from the small intestine. However, RA did not inhibit the activity of mammalian α-amylase. RA was hydrolyzed to an indigestible high-molecular-weight peptide (HMP) of 14 kDa and low-molecular-weight peptides by pepsin and pancreatin. Furthermore, RA suppressed the glucose diffusion rate through a semipermeable membrane like dietary fibers in vitro. Therefore, the indigestible HMP may adsorb glucose and suppress its absorption from the small intestine.

L-Cysteine enhances nutrient absorption via a cystathionine-β-synthase-derived H2 S pathway in rodent jejunum.

Hydrogen sulphide (H2 S) is generated endogenously from L-cysteine (L-Cys) by the enzymes cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). In addition, L-Cys is commonly used as a precursor in the food and pharmaceutical industries. The aim of the present study is to determine whether L-Cys regulates intestinal nutrient transport. To that end, the presence of CBS and CSE in the jejunum epithelium was assessed by immunohistochemistry, Western blotting and the methylene blue assay. In addition, in vivo L-Cys (100 mg/kg, administered immediately after the glucose load) significantly increased blood glucose levels 30 min after the oral administration of glucose to mice. This effect of L-Cys was completely blocked by amino-oxyacetic acid (AOA; 50 mg/kg; administered at the same time as L-Cys) an inhibitor of CBS. Measurements of the short-circuit current (Isc) in the rat jejunum epithelium revealed that L-Cys (1 mmol/L; 6 min before the administration of L-alanine) enhances Na(+)-coupled L-alanine or glucose transport, and that this effect is inhibited by AOA (1 mmol/L;10 min before the administration of L-Cys), but not D,L-propargylglycine (PAG;1 mmol/L; 10 min before the administration of L-Cys), a CSE inhibitor. Notably, L-Cys-evoked enhancement of nutrient transport was alleviated by glibenclamide (Gli;0.1 mmol/L; 10 min before the administration of L-Cys), a K(+) channel blocker. Together, the data indicate that L-Cys enhances jejunal nutrient transport, suggesting a new approach to future treatment of nutrition-related maladies, including a range of serious health consequences linked to undernutrition.

Intraocular Pressure Changes During Oral Glucose Tolerance Tests in Diabetic and Non-diabetic Individuals.

Hyperglycaemia in diabetic patients may lead to elevated intraocular pressure. Different reasons have been suggested in previous studies to explain the increase in intraocular pressure. The purpose of the present study was to investigate the change in intraocular pressure during oral glucose tolerance tests in diabetic and non-diabetic subjects. 51 individuals who fulfilled the inclusion criteria of the study and were scheduled for oral glucose tolerances tests based on the recommendations of World Health Organization (WHO) underwent clinical examinations. Biochemical parameters associated with metabolic syndrome, insulin resistance (HOMA-IR) and systolic and diastolic blood pressure were also measured. A complete ophthalmologic examination was performed before the test. During the test, intraocular pressure was measured twice in the fasting state and at the first and second hours after oral glucose administration using rebound tonometry (ICARE). The mean age of the 51 patients was 46.19±9.13 years. The participants were categorized as non-diabetic (n: 24) and diabetic (n: 27). The baseline glucose levels were higher in the diabetic patients (p<0.001). The first-hour intraocular pressures (IOP1-0) changes in the right eye were significant in the diabetic and non-diabetic participants, and the first-hour intraocular pressure changes in the left eye (IOP1-0l) in the diabetic group were significant (p=0.017, p=0.017, p<0.001, respectively). The relation between diabetes mellitus and glaucoma has been addressed in many studies, but no clear underlying mechanisms have been identified. In our study of diabetic and non-diabetic individuals, hyperglycaemia during an oral glucose tolerance test was found to be positively related to intraocular pressure, which suggests that hyperglycaemia may represent a possible mechanism by which elevated IOP occurs.

The inactivation of extracellular signal-regulated kinase by glucagon-like peptide-1 contributes to neuroprotection against oxidative stress

Glucagon-like peptide-1 (GLP-1), an insulinotropic peptide secreted from enteroendocrine cells, has been known to have a neuroprotective effect. However, it is not fully understood the intracellular mediator of GLP-1 signaling in neuronal cells. In the present study, we examined the change in intracellular signaling of cortical neurons after GLP-1 application and luminal glucose stimulation in vitro and in vivo. GLP-1 receptor was highly expressed in cultured cortical neurons and brain tissues including the prefrontal cortex and hippocampus. The activation of GLP-1 receptor (5min) significantly decreased levels of phosphorylated extracellular signal-regulated kinase (pERK), which is involved in neuronal cell survival and death, in cultured cortical neurons. Oral glucose administration also rapidly reduced pERK levels in the prefrontal cortex, while intraperitoneal glucose injection did not show such an effect. Further, GLP-1 attenuated hydrogen peroxide-induced cell death and hyperactivity of ERK in cultured cortical neurons. It is possible that increased GLP-1 by luminal glucose stimulation affects cortical system including the maintenance of neuronal cell survival.

Hypoglycemic Activity of Aqueous Root Bark Extract Zanthoxylum chalybeum in Alloxan-Induced Diabetic Rats.

Background. Medicinal plants offer cheaper and safer treatment options to current diabetic drugs. The present study evaluated the effect of aqueous root bark extract of Zanthoxylum chalybeum on oral glucose tolerance and pancreas histopathology in alloxanized rats. Method. Diabetes was induced in rats by administration of alloxan monohydrate. Root extract of Z. chalybeum was administered to rats at 200 and 400 mg/kg BW daily for 28 days. Blood glucose was measured by glucometer and pancreatic histopathology evaluated microscopically. Results. Initial increase was observed in blood glucose of the rats after oral administration of glucose from time zero. Two hours after treatment with Z. chalybeum, a significant reduction in blood glucose was observed within treatment groups (p < 0.05) compared to 0.5 hr and 1 hr. There was no significant difference between treatment group receiving 400mg/Kg BW extract and the normal groups (p = 0.27), implying that the former group recovered and were able to regulate their blood sugar, possibly via uptake of glucose into cells. The reversal in pancreatic histopathology further supports the protective effect of Z. chalybeum extract towards diabetic damage. Conclusion. Extract of Z. chalybeum is effective in controlling blood glucose in diabetes and protecting pancreatic tissues from diabetic damage.

Interaction of Peptide Transporter 1 With d-Glucose and l-Glutamic Acid; Possible Involvement of Taste Receptors

We investigated the influence of sweet and umami (savory) tastants on the intestinal absorption of cephalexin (CEX), a substrate of peptide transporter 1 (PEPT1, SLC15A1) in rats. After oral administration of glucose or mannitol to rats, CEX was administered together with a second dose of glucose or mannitol. Western blot analysis indicated that expression of PEPT1 in rat jejunum membrane was decreased by glucose, compared to mannitol. Furthermore, the maximum plasma concentration (Cmax) of orally administered CEX was reduced by glucose compared to mannitol. The effect of glucose was diminished by nifedipine, a l-type Ca2+ channel blocker. We also found that Cmax of orally administered CEX was reduced by treatment with l-glutamic acid, compared to d-glutamic acid. Thus, excessive intake of glucose and l-glutamic acid may impair oral absorption of PEPT1 substrates.

Effects of D-allulose on glucose metabolism after the administration of sugar or food in healthy dogs.

D-allulose is a C-3 epimer of D-fructose and has recently been investigated for its hypoglycemic effects. In the present study, the effects of D-allulose on glucose metabolism were evaluated in healthy dogs administrated sugar or food. The oral administrations of D-allulose decreased plasma glucose concentrations after oral glucose or maltose administration, with a diminished plasma insulin rise. The glucose suppressive effect of D-allulose was also observed after intravenous glucose administrations without increase in plasma insulin concentration. In contrast, D-allulose showed no effect on plasma glucose and insulin concentrations after feeding. The present results suggest that D-allulose administration may be beneficial in dogs with impaired glucose tolerance. Further studies investigating the therapeutic efficacy of D-allulose in diabetic dogs are required.

The incretin effect in critically ill patients: a case-control study.

IntroductionPatients admitted to the intensive care unit often develop hyperglycaemia, but the underlying mechanisms have not been fully described. The incretin effect is reduced in patients with type 2 diabetes. Type 2 diabetes and critical illness have phenotypical similarities, such as hyperglycaemia, insulin resistance and systemic inflammation. Previous studies have shown beneficial effects of exogenous glucagon-like peptide (GLP)-1 on glycaemia in critically ill patients, a phenomenon also seen in patients with type 2 diabetes. In this study, we hypothesised that the incretin effect, which is mediated by the incretin hormones GLP-1 and glucose-dependent insulinotropic peptide (GIP), is impaired in critically ill patients.MethodsThe incretin effect (i.e., the relative difference between the insulin response to oral and intravenous glucose administration) was investigated in a cross-sectional case–control study. Eight critically ill patients without diabetes admitted to a mixed intensive care unit and eight healthy control subjects without diabetes, matched at group level by age, sex and body mass index, were included in the study. All subjects underwent an oral glucose tolerance test (OGTT) followed by an intravenous glucose infusion (IVGI) on the next day to mimic the blood glucose profile from the OGTT. Blood glucose, serum insulin, serum C-peptide and plasma levels of GLP-1, GIP, glucagon and proinflammatory cytokines were measured intermittently. The incretin effect was calculated as the increase in insulin secretion during oral versus intravenous glucose administration in six patients. The groups were compared using either Student’s t test or a mixed model of repeated measurements.ResultsBlood glucose levels were matched between the OGTT and the IVGI in both groups. Compared with control subjects, proinflammatory cytokines, tumour necrosis factor α and interleukin 6, were higher in patients than in control subjects. The endogenous response of GIP and glucagon, but not GLP-1, to the OGTT was greater in patients. The insulin response to the OGTT did not differ between groups, whereas the insulin response to the IVGI was higher in patients. Consequently, the calculated incretin effect was lower in patients (23 vs. 57 %, p = 0.003).ConclusionsIn critically ill patients, the incretin effect was reduced. This resembles previous findings in patients with type 2 diabetes.Trial registrationClinicalTrials.gov identifier: NCT01347801. Registered on 2 May 2011.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1118-z) contains supplementary material, which is available to authorized users.

Insulin resistance and lipid profile during an oral glucose tolerance test in women with and without gestational diabetes mellitus

We aimed to compare changes in insulin levels during an oral glucose tolerance test (OGTT) between women with normal glucose tolerance (NGT) during pregnancy and those with gestational diabetes mellitus (GDM). Overall, 105 pregnant women between 24 and 28 weeks’ gestation, 50 with NGT and 55 with GDM according to NDDG standard, were enrolled into the study. The levels of fasting blood glucose, insulin, triglyceride (TG) and total cholesterol (TC) and the insulin levels, blood glucose levels at 1, 2 and 3 hours post oral glucose administration during an OGTT (5.8, 10.6, 9.2 and 8.1 mmol/L, respectively) were measured. Then, insulin resistance (IR) index was calculated. There was no significant difference in fasting, 3-h insulin levels and 3-h blood glucose levels between those with NGT and those with GDM (P > 0.05). However, 1-h and 2-h insulin levels, fasting and 1-h and 2-h blood glucose levels in women with GDM were significantly higher than those in the NGT group (P < 0.05). Fasting TC and TG levels in the GDM group were significantly higher than those with NGT (P = 0.031 and P = 0.025, respectively). Correlation analysis showed that TG and TC levels were positively correlated with homoeostasis model assessment-IR (HOMA-IR) (r = 0.67 and r = 0.78, respectively; P < 0.05). Our findings suggest that insulin sensitivity in women with GDM was significantly lower than that observed in those with NGT. Reducing IR and blood lipids in women with GDM could potentially improve maternal and foetal outcomes.

The RGD sequence present in IGFBP-2 is required for reduced glucose clearance after oral glucose administration in female transgenic mice.

Recent studies suggest that insulin-like growth factor-binding protein-2 (IGFBP-2) affects both growth and metabolism. Whereas negative growth effects are primarily due to negative interference with IGF-I, the mechanisms for metabolic interference of IGFBP-2 are less clear. As we demonstrate, overexpression of IGFBP-2 in transgenic mice is correlated with a decelerated clearance of blood glucose after oral administration. IGFBP-2 carries an integrin-binding domain (RGD motif), which has been shown to also mediate IGF-independent effects. We thus asked if higher serum levels of IGFBP-2 without an intact RGD motif would also partially block blood glucose clearance after oral glucose application. In fact, transgenic mice overexpressing mutated IGFBP-2 with higher levels of IGFBP-2 carrying an RGE motif instead of an RGD were not characterized by decelerated glucose clearance. Impaired glucose tolerance was correlated with lower levels of GLUT4 present in plasma membranes isolated from muscle tissues after glucose challenge. At the same time, activation of TBC1D1 was depressed in mice overexpressing wild-type but not mutated IGFBP-2. Although we do not have reason to assume altered activation of IGF-I receptor or PDK1/Akt activation in both models, we have identified increased levels of integrin-linked kinase and focal adhesion kinase dependent on the presence of the RGD motif. From our results we conclude that impaired glucose clearance in female IGFBP-2 transgenic mice is dependent on the presence of the RGD motif and that translocation of GLUT4 in the muscle may be regulated by IGFBP-2 via RGD-dependent mechanisms.

In vivo cardiac glucose metabolism in the high-fat fed mouse: Comparison of euglycemic–hyperinsulinemic clamp derived measures of glucose uptake with a dynamic metabolomic flux profiling approach

RationaleCardiac metabolism is thought to be altered in insulin resistance and type 2 diabetes (T2D). Our understanding of the regulation of cardiac substrate metabolism and insulin sensitivity has largely been derived from ex vivo preparations which are not subject to the same metabolic regulation as in the intact heart in vivo. Studies are therefore required to examine in vivo cardiac glucose metabolism under physiologically relevant conditions. ObjectiveTo determine the temporal pattern of the development of cardiac insulin resistance and to compare with dynamic approaches to interrogate cardiac glucose and intermediary metabolism in vivo. Methods and resultsStudies were conducted to determine the evolution of cardiac insulin resistance in C57Bl/6 mice fed a high-fat diet (HFD) for between 1 and 16 weeks. Dynamic in vivo cardiac glucose metabolism was determined following oral administration of [U-13C] glucose. Hearts were collected after 15 and 60 min and flux profiling was determined by measuring 13C mass isotopomers in glycolytic and tricarboxylic acid (TCA) cycle intermediates. Cardiac insulin resistance, determined by euglycemic–hyperinsulinemic clamp, was evident after 3 weeks of HFD. Despite the presence of insulin resistance, in vivo cardiac glucose metabolism following oral glucose administration was not compromised in HFD mice. This contrasts our recent findings in skeletal muscle, where TCA cycle activity was reduced in mice fed a HFD. Similar to our report in muscle, glucose derived pyruvate entry into the TCA cycle in the heart was almost exclusively via pyruvate dehydrogenase, with pyruvate carboxylase mediated anaplerosis being negligible after oral glucose administration. ConclusionsUnder experimental conditions which closely mimic the postprandial state, the insulin resistant mouse heart retains the ability to stimulate glucose metabolism.

Saroglitazar, a novel PPARα/γ agonist with predominant PPARα activity, shows lipid-lowering and insulin-sensitizing effects in preclinical models.

Saroglitazar is a novel nonthiazolidinediones (TZD) and nonfibric acid derivative designed to act as dual regulator of lipids and glucose metabolism by activating peroxisome proliferator-activated receptors (PPAR). These studies evaluate the efficacy and safety profile of Saroglitazar in preclinical in vitro and in vivo models. The EC50 values of Saroglitazar assessed in HepG2 cells using PPAR transactivation assay for hPPARα and hPPARγ were 0.65 pmol/L and 3 nmol/L, respectively. In db/db mice, 12-day treatment with Saroglitazar (0.01–3 mg/kg per day, orally) caused dose-dependent reductions in serum triglycerides (TG), free fatty acids (FFA), and glucose. The ED50 for these effects was found to be 0.05, 0.19, and 0.19 mg/kg, respectively with highly significant (91%) reduction in serum insulin and AUC-glucose following oral glucose administration (59%) at 1 mg/kg dose. Significant reduction in serum TG (upto 90%) was also observed in Zucker fa/fa rats, Swiss albino mice, and in high fat -high cholesterol (HF-HC)-fed Golden Syrian hamsters. LDL cholesterol was significantly lowered in hApoB100/hCETP double transgenic mice and HF-HC diet fed Golden Syrian Hamsters. Hyperinsulinemic-Euglycemic clamp study in Zucker fa/fa rats demonstrated potent insulin-sensitizing activity. Saroglitazar also showed a significant decrease in SBP (22 mmHg) and increase (62.1%) in serum adiponectin levels in Zucker fa/fa rats. A 90-day repeated dose comparative study in Wistar rats and marmosets confirmed efficacy (TG lowering) potential of Saroglitazar and has indicated low risk of PPAR-associated side effects in humans. Based on efficacy and safety profile, Saroglitazar appears to have good potential as novel therapeutic agent for treatment of dyslipidemia and diabetes.

Fatty acid-binding protein 5 regulates diet-induced obesity via GIP secretion from enteroendocrine K cells in response to fat ingestion.

Gastric inhibitory polypeptide (GIP) is an incretin released from enteroendocrine K cells in response to nutrient intake, especially fat. GIP is one of the contributing factors inducing fat accumulation that results in obesity. A recent study shows that fatty acid-binding protein 5 (FABP5) is expressed in murine K cells and is involved in fat-induced GIP secretion. We investigated the mechanism of fat-induced GIP secretion and the impact of FABP5-related GIP response on diet-induced obesity (DIO). Single oral administration of glucose and fat resulted in a 40% reduction of GIP response to fat but not to glucose in whole body FABP5-knockout (FABP5(-/-)) mice, with no change in K cell count or GIP content in K cells. In an ex vivo experiment using isolated upper small intestine, oleic acid induced only a slight increase in GIP release, which was markedly enhanced by coadministration of bile and oleic acid together with attenuated GIP response in the FABP5(-/-) sample. FABP5(-/-) mice exhibited a 24% reduction in body weight gain and body fat mass under a high-fat diet compared with wild-type (FABP5(+/+)) mice; the difference was not observed between GIP-GFP homozygous knock-in (GIP(gfp/gfp))-FABP5(+/+) mice and GIP(gfp/gfp)-FABP5(-/-) mice, in which GIP is genetically deleted. These results demonstrate that bile efficiently amplifies fat-induced GIP secretion and that FABP5 contributes to the development of DIO in a GIP-dependent manner.

Elevation in blood flow and shear rate prevents hyperglycemia-induced endothelial dysfunction in healthy subjects and those with type 2 diabetes

Hyperglycemia, commonly present after a meal, causes transient impairment in endothelial function. We examined whether increases in blood flow (BF) protect against the hyperglycemia-mediated decrease in endothelial function in healthy subjects and patients with type 2 diabetes mellitus (T2DM). Ten healthy subjects and 10 age- and sex-matched patients with T2DM underwent simultaneous bilateral assessment of brachial artery endothelial function by means of flow-mediated dilation (FMD) using high-resolution echo-Doppler. FMD was examined before and 60, 120, and 150 min after a 75-g oral glucose challenge. We unilaterally manipulated BF by heating one arm between minute 30 and minute 60. Oral glucose administration caused a statistically significant, transient increase in blood glucose in both groups (P < 0.001). Forearm skin temperature, brachial artery BF, and shear rate significantly increased in the heated arm (P < 0.001), and to a greater extent compared with the nonheated arm in both groups (interaction effect P < 0.001). The glucose load caused a transient decrease in FMD% (P < 0.05), whereas heating significantly prevented the decline (interaction effect P < 0.01). Also, when correcting for changes in diameter and shear rate, we found that the hyperglycemia-induced decrease in FMD can be prevented by local heating (P < 0.05). These effects on FMD were observed in both groups. Our data indicate that nonmetabolically driven elevation in BF and shear rate can similarly prevent the hyperglycemia-induced decline in conduit artery endothelial function in healthy volunteers and in patients with type 2 diabetes. Additional research is warranted to confirm that other interventions that increase BF and shear rate equally protect the endothelium when challenged by hyperglycemia.