Clearance Rate Of Glucose Research Articles

The Effect of a Vegetarian vs Conventional Hypocaloric Diabetic Diet on Thigh Adipose Tissue Distribution in Subjects with Type 2 Diabetes: A Randomized Study

ABSTRACTObjective: The aim of our study was to compare the effects of a vegetarian and a conventional diet on thigh adipose tissue distribution in subjects with type 2 diabetes (T2D).Methods: Seventy-four subjects with T2D were randomly assigned to either follow a vegetarian diet (V, n = 37) or a control group who followed an isocaloric conventional anti-diabetic diet (C, n = 37). Both diets were calorie restricted (−500 kcal/day). To measure insulin sensitivity, the hyperinsulinemic (1 mU.kg−1.min−1) isoglycemic clamp was conducted. β-Cell function was assessed using a mathematical model after a test meal. Magnetic resonance imaging of the thigh was performed. All subjects were examined at 0, 3, and 6 months. Statistical analyses were performed using repeated measures analysis of variance and a multivariate regression model.Results: Greater reduction was observed in total leg area in V (−13.6 cm2 [95% confidence interval [CI], −14.2 to −12.9] in V vs −9.9 cm2 [95% CI, −10.6 to −9.2] in C; Gxt p < 0.001). The reduction in subcutaneous fat was comparable in response to both diets (Gxt, p = 0.64). Subfascial fat was reduced only in response to a vegetarian diet (−0.82 [95% CI, −1.13 to −0.55] cm2 in V vs −0.44 [95% CI, −0.78 to +0.02] cm2 in C; Gxt, p = 0.04). The reduction in intramuscular fat tended to be greater in response to a vegetarian diet (−1.78 [95% CI, −2.26 to −1.27] cm2 in V vs −0.57 [95% CI, −1.06 to −0.09] cm2 in C; Gxt, p = 0.12). Changes in subcutaneous and subfascial fat correlated with changes in glycated hemoglobin (HbA1c), fasting plasma glucose, and β-cell insulin sensitivity. After adjustment for changes in body mass index (BMI), correlations remained significant for changes in fasting plasma glucose and β-cell insulin sensitivity and with changes in triglycerides.Conclusions: Our data indicate the importance of both subcutaneous and subfascial fat in relationship to glucose and lipid metabolism.Abbreviations: BMI , body mass index; C , control group; FPG , fasting plasma glucose; Gxt , interaction between group and time; HbA1c , glycated hemoglobin; MCR , metabolic clearance rate of glucose; OPLS , orthogonal projections to latent structure; T2D , type 2 diabetes; V , vegetarian group

Short term elevation in dietary protein intake does not worsen insulin resistance or lipids in older adults with metabolic syndrome: a randomized-controlled trial

BackgroundThere is a great deal of controversy as to whether higher protein intake improves or worsens insulin sensitivity in humans. The purpose of the study was to determine the influence of a short-term elevation in dietary protein on hepatic and peripheral insulin sensitivity in twelve older subjects (51–70 yrs) with metabolic syndrome.MethodsIndividuals were randomly assigned to one of the dietary groups: recommended protein intake (RPI, 10% of daily calorie intake) or elevated protein intake (EPI, 20% of daily calorie intake) for 4 weeks. Prior to and immediately following the dietary intervention, subjects were studied with primed continuous infusion of [6,6-2H2]glucose and [1-13C]glucose dissolved in drink during the dual tracer oral glucose tolerance test (DT OGTT) to determine hepatic and peripheral insulin sensitivity. Plasma lipids were measured pre- and post-dietary intervention.ResultsIn both intervention groups: 1) hepatic insulin sensitivity as assessed by the endogenous glucose rate of appearance (glucose Ra), 2) peripheral insulin sensitivity as assessed by the metabolic clearance rate of glucose normalized to plasma glucose concentration (MCR) and/or the rate of glucose utilization (Rd) or 3) glucose/insulin AUC were unaffected by the diets. Moreover, fasting lipid was not affected by RPI or EPI.ConclusionOur findings suggest that a short-term elevation in EPI with correspondingly higher branched chain amino acid (BCAA) contents has no detrimental impact on hepatic and peripheral insulin sensitivity or plasma lipid parameters in older adults with metabolic syndrome.Trial registrationClinicalTrials.gov Identifier: NCT02885935; This trial was registered retrospectively (Study start date, April 01, 2013, date of registration, August 26, 2016).

Decreased basal hepatic glucose uptake in impaired fasting glucose.

This research aimed to define the pathophysiological defects responsible for the elevated fasting plasma glucose (FPG) concentration and excessive rise in post-load plasma glucose observed in individuals with impaired fasting glucose (IFG). We used tracer techniques to quantify basal splanchnic (primarily hepatic) glucose uptake and glucose fluxes following glucose ingestion in individuals with normal glucose tolerance (NGT; n=10) and IFG (n=10). Individuals with IFG had a comparable basal rate of hepatic glucose production to those with NGT (15.2±0.2 vs 18.0±0.8μmolmin-1[kg lean body mass (LBM)]-1; p=0.09). However, they had a significantly reduced glucose clearance rate during the fasting state compared with NGT (2.64±0.11 vs 3.62±0.20ml min-1[kgLBM]-1; p<0.01). The difference between the basal rate of glucose appearance measured with [3-3H]glucose and [1-14C]glucose, which represent basal splanchnic glucose uptake, was significantly reduced in IFG compared with NGT (1.39±0.28 vs 3.16±0.44μmolmin-1[kgLBM]-1; p=0.02). Following glucose ingestion, the total amount of exogenous glucose that appeared in the systemic circulation was not significantly different between groups. However, suppression of endogenous glucose production (EGP) was markedly impaired in individuals with IFG. These results demonstrate that decreased tissue (liver) glucose uptake, not enhanced EGP, is the cause for elevated FPG concentration in individuals with IFG, while the excessive rise in plasma glucose concentration following a glucose load in these individuals is the result of impaired suppression of hepatic glucose production.

Metabolic Profiling Reveals Differences in Plasma Concentrations of Arabinose and Xylose after Consumption of Fiber-Rich Pasta and Wheat Bread with Differential Rates of Systemic Appearance of Exogenous Glucose in Healthy Men

BackgroundThe consumption of products rich in cereal fiber and with a low glycemic index is implicated in a lower risk of metabolic diseases. Previously, we showed that the consumption of fiber-rich pasta compared with bread resulted in a lower rate of appearance of exogenous glucose and a lower glucose clearance rate quantified with a dual-isotope technique, which was in accordance with a lower insulin and glucose-dependent insulinotropic polypeptide response. ObjectiveTo gain more insight into the acute metabolic consequences of the consumption of products resulting in differential glucose kinetics, postprandial metabolic profiles were determined. MethodsIn a crossover study, 9 healthy men [mean ± SEM age: 21 ± 0.5 y; mean ± SEM body mass index (kg/m2): 22 ± 0.5] consumed wheat bread (132 g) and fresh pasta (119 g uncooked) enriched with wheat bran (10%) meals. A total of 134 different metabolites in postprandial plasma samples (at −5, 30, 60, 90, 120, and 180 min) were quantified by using a gas chromatography–mass spectrometry–based metabolomics approach (secondary outcomes). Two-factor ANOVA and advanced multivariate statistical analysis (partial least squares) were applied to detect differences between both food products. ResultsForty-two different postprandial metabolite profiles were identified, primarily representing pathways related to protein and energy metabolism, which were on average 8% and 7% lower after the men consumed pasta rather than bread, whereas concentrations of arabinose and xylose were 58% and 53% higher, respectively. Arabinose and xylose are derived from arabinoxylans, which are important components of wheat bran. The higher bioavailability of arabinose and xylose after pasta intake coincided with a lower rate of appearance of glucose and amino acids. We speculate that this higher bioavailability is due to higher degradation of arabinoxylans by small intestinal microbiota, facilitated by the higher viscosity of arabinoxylans after pasta intake than after bread intake. ConclusionsThis study suggests that wheat bran, depending on the method of processing, can increase the viscosity of the meal bolus in the small intestine and interfere with macronutrient absorption in healthy men, thereby influencing postprandial glucose and insulin responses. This trial was registered at www.controlled-trials.com as ISRCTN42106325.

Effects of chromium supplementation on physiology, feed intake, and insulin related metabolism in growing pigs subjected to heat stress.

Improving insulin sensitivity may reduce impacts of heat stress (HS) in pigs by facilitating heat dissipation. Chromium (Cr) has been reported to improve insulin sensitivity in pigs. Therefore, the aim of this experiment was to investigate whether Cr supplementation can mitigate HS in growing pigs. Thirty-six gilts were randomly assigned to 2 diets containing 0 (control) or 400 ppb Cr. After 14 d the supplemented pigs were allocated to either 8 d thermoneutral (20°C constant; TN) or cyclic HS (35°C, 0900 h to 1700 h) conditions and continued their respective diet (n = 9 per group). Growth performance was recorded during the 14-d supplementation period. The physiological responses to HS were monitored by measuring respiration rate, rectal temperature, blood gas chemistry, and feed intake during thermal exposure. Kinetics of plasma glucose, insulin and NEFA were studied by intravenous glucose tolerance test (IVGTT) on d 8 of thermal treatment. Results showed Cr alleviated the HS-increased rectal temperature (P < 0.05) and respiration rate (P < 0.01) at 1300 h and 1600 h during thermal exposure. However, Cr did not mitigate the reduction in average daily feed intake which was reduced by 35% during HS or the HS-induced respiratory alkalosis. Chromium tended to increase average daily gain (0.86 vs. 0.95 kg, P = 0.070) during the 14-d supplementation under TN conditions before thermal exposure, which might be associated with the potential of Cr in improving overall insulin sensitivity, as evidenced by a reduced insulin resistance index calculated by Homeostatic Model Assessment (HOMA-IR; 0.65 vs. 0.51, P = 0.013) and a tendency of reduced fasting plasma insulin concentration (1.97 vs. 1.67 μU/mL, P = 0.094). Heat stress decreased the acute insulin releasing rate (P = 0.012) and consequently slowed glucose clearance rate (P = 0.035) during IVGTT. Besides, HS enlarged the values of area under the curve of NEFA during IVGTT (P < 0.01), indicating a reduced lipid mobilization. In conclusion, HS reduced insulin response to IVGTT. Chromium supplementation exhibited a potential in improving insulin sensitivity and mitigating HS symptoms in growing pigs.

Responses of plasma glucose and nonesterified fatty acids to intravenous insulin tolerance tests in dairy cows during a 670-day lactation

The metabolic response of dairy cows undergoing an extended lactation to an insulin tolerance test (ITT) was investigated. Twelve multiparous Holstein-Friesian cows that calved in late winter in a pasture-based system were managed for a 670-d lactation by delaying rebreeding. Four 5-wk experimental periods commenced at approximately 73, 217, 422, and 520 d in milk (DIM). Cows were offered a diet of perennial ryegrass (73 and 422 DIM) or pasture hay and silage (217 and 520 DIM) supplemented with 1 kg dry matter (DM) of grain (control; CON) or 6 kg DM of grain (GRN). Daily energy intake was approximately 160 and 215 MJ of metabolizable energy/cow for CON and GRN, respectively. At all other times, cows were managed as a single herd and grazed pasture supplemented with grain to an estimated daily intake of 180 MJ of metabolizable energy/cow. Cows were fitted with a jugular catheter during the final week of each experimental period. An ITT using 0.12 IU of insulin/kg of body weight (BW) was conducted on each cow at approximately 100, 250, 460, and 560 DIM. Cows in the GRN treatment had greater milk yield, milk solids yield, and BW than cows in the CON treatment. Within treatment, individual cow responses to the ITT were highly variable. Plasma glucose and nonesterified fatty acid (NEFA) concentrations declined at all stages of lactation. The clearance rate of plasma glucose was slower before 300 DIM than after 300 DIM, which indicates greater inhibition of hepatic glucose synthesis and uptake of glucose by insulin-dependent tissues later in the lactation. The clearance rate, area under the curve, and recovery of plasma NEFA were greatest at 100 DIM, indicating greater responsiveness to the antilipolytic effect of insulin in early lactation, but also greater lipolytic responsiveness. The variation in response to the ITT was mostly a result of DIM rather than diet. However, the plasma NEFA response showed interactions between diet and DIM, indicating that energy intake may affect tissue responses to insulin. The responsiveness of peripheral tissues to insulin, primarily adipose tissue, changed throughout a 670-d lactation and contributed to a greater proportion of nutrients being partitioned to body reserves at the expense of milk yield as lactation progressed. Both stage of lactation and dietary intake have a role in the determination of whole-body and peripheral tissue responses to insulin; however, the exact mechanisms in control of this are unclear.

Short communication: Limitations of glucose tolerance tests in the assessment of peripheral tissue insulin sensitivity during pregnancy and lactation in dairy heifers

The aim of the present study was to point at the limitations of glucose tolerance tests (GTT) to assess peripheral tissue insulin sensitivity in dairy heifers in different physiological states (pregnancy and lactation). Intravenous GTT were performed in 5 nonpregnant, nonlactating heifers, 5 heifers at the end of pregnancy (12-7 d before calving), and 5 lactating primiparous cows (11-14 d after calving). Glucose and insulin concentrations were determined and area under the curve (AUC) and clearance rate of glucose and insulin were calculated. Additionally, data were analyzed using the minimal model to derive the insulin sensitivity parameter (Si). Basal glucose and insulin concentrations were greater in the nonpregnant, nonlactating heifers. Clearance rate of glucose and Si were lowest, whereas the AUC for glucose was greatest in the nonpregnant, nonlactating heifers. Insulin concentrations during the GTT were greater for the nonpregnant, nonlactating heifers. Results from the GTT in pregnant heifers and lactating primiparous cows are biased by the fact that a large part of the glucose disappearance during an intravenous GTT occurs independently of insulin by the pregnant uterus or the lactating mammary gland. As such, greater AUC of glucose, lower clearance rate of glucose, or lower Si derived from GTT performed in nonpregnant, nonlactating dairy heifers in the present study might indicate decreased peripheral tissue insulin sensitivity of the glucose metabolism or decreased insulin-independent glucose disappearance. Based on the results from a GTT, it is impossible to discriminate between both metabolic pathways. It can be concluded that parameters derived from GTT are not suited to compare peripheral tissue insulin sensitivity of the glucose metabolism between dairy heifers in different physiological states due to the large variation in insulin secretion and the substantial difference in insulin-independent glucose disposal associated with these physiological states.

High-Fat-Diet-Induced Deficits in Dopamine Terminal Function Are Reversed by Restoring Insulin Signaling.

Systemically released insulin crosses the blood-brain barrier and binds to insulin receptors on several neural cell types, including dopaminergic neurons. Insulin has been shown to decrease dopamine neuron firing in the ventral tegmental area (VTA), but potentiate release and reuptake at dopamine terminals in the nucleus accumbens (NAc). Here we show that prolonged consumption of a high fat diet blocks insulin's effects in the NAc, but insulin's effects are restored by inhibiting protein tyrosine phosphatase 1B, which supports insulin receptor signaling. Mice fed a high fat diet (60% kcals from fat) displayed significantly higher fasting blood glucose 160 mg/dL, compared to 101 mg/dL for control-diet-fed mice, and high-fat-diet-fed mice showed reduced blood glucose clearance after an intraperitoneal glucose tolerance test. Using fast scan cyclic voltammetry to measure electrically evoked dopamine in brain slices containing the NAc core, high-fat-diet-fed mice exhibited slower dopamine reuptake compared to control-diet-fed mice (2.2 ± 0.1 and 2.67 ± 0.15 μM/s, respectively). Moreover, glucose clearance rate was negatively correlated with Vmax. Insulin (10 nM to 1 μM) dose dependently increased reuptake rates in control-diet-fed mice compared with in the high-fat-diet group; however, the small molecule insulin receptor sensitizing agent, TCS 401 (300 nM), restored reuptake in high-fat-diet-fed mice to control-diet levels, and a small molecule inhibitor of the insulin receptor, BMS 536924 (300 nM), attenuated reuptake, similar to high-fat-diet-fed mice. These data show that a high-fat diet impairs dopamine reuptake by attenuating insulin signaling at dopamine terminals.

Effects of concentrate type and chromium propionate on insulin sensitivity, productive and reproductive parameters of lactating dairy cows consuming excessive energy

This experiment compared insulin sensitivity parameters, milk production and reproductive outcomes in lactating dairy cows consuming excessive energy, and receiving in a 2×2 factorial arrangement design: (1) concentrate based on ground corn (CRN; n=13) or citrus pulp (PLP; n=13), and (2) supplemented (n=14) or not (n=12) with 2.5 g/day of chromium (Cr)-propionate. During the experiment (day 0 to 182), 26 multiparous, non-pregnant, lactating Gir×Holstein cows (initial days in milk=80±2) were offered corn silage for ad libitum consumption, and individually received concentrate formulated to allow diets to provide 160% of their daily requirements of net energy for lactation. Cow BW and body condition score (BCS) were recorded weekly. Milk production was recorded daily and milk samples collected weekly. Blood samples were collected weekly before the morning concentrate feeding. Glucose tolerance tests (GTT; 0.5 g of glucose/kg of BW) were performed on days −3, 60, 120 and 180. Follicle aspiration for in vitro embryo production was performed via transvaginal ovum pick-up on days −1, 82 and 162. No treatment differences were detected (P⩾0.25) for BW and BCS change during the experiment. Within weekly blood samples, concentrations of serum insulin and glucose, as well as insulin : glucose ratio were similar among treatments (P⩾0.19), whereas CRN had less (P<0.01) non-esterified fatty acid concentrations compared with PLP (0.177 v. 0.215 mmol/l; SEM=0.009). During the GTT, no treatment differences were detected (P⩾0.16) for serum glucose concentration, glucose clearance rate, glucose half-life and insulin : glucose ratio. Serum insulin concentrations were less (P=0.04) in CRN supplemented with Cr-propionate compared with non-supplemented CRN (8.2 v. 13.5 µIU/ml, respectively; SEM=1.7), whereas Cr-propionate supplementation did not impact (P=0.70) serum insulin within PLP cows. Milk production, milk fat and solid concentrations were similar (P⩾0.48) between treatments. However, CRN had greater (P<0.01) milk protein concentration compared with PLP (3.54% v. 3.14%, respectively; SEM=0.08). No treatment differences were detected (P⩾0.35) on number of viable oocytes collected and embryos produced within each aspiration. In summary, feeding a citrus pulp-based concentrate to lactating dairy cows consuming excessive energy did not improve insulin sensitivity, milk production and reproductive outcomes, whereas Cr-propionate supplementation only enhanced insulin sensitivity in cows receiving a corn-based concentrate during a GTT.

Characterization of Metabolic Status in Nonhuman Primates with the Intravenous Glucose Tolerance Test.

The intravenous glucose tolerance test (IVGTT) plays a key role in the characterization of glucose homeostasis. When taken together with serum biochemical profiles, inclusive of blood glucose levels in both the fed and fasted state, HbA1c, insulin levels, clinical history of diet, body composition, and body weight status, an assessment of normal and abnormal glycemic control can be made. Interpretation of an IVGTT is done through measurement of changes in glucose and insulin levels over time in relation to the dextrose challenge. Critical components to be considered are: peak glucose and insulin levels reached in relation to T0 (end of glucose infusion), the glucose clearance rate K derived from the slope of rapid glucose clearance in the first 20 min (T1 to T20), the time to return to glucose baseline, and the area under the curve (AUC). These IVGTT measures will show characteristic changes as glucose homeostasis moves from a healthy to a diseased metabolic state5. Herein we will describe the characterization of nonhuman primates (Rhesus and Cynomolgus macaques), which are the most relevant animal model of Type II diabetes (T2D) in humans and the IVGTT and clinical profiles of these animals from a lean healthy, to obese dysmetabolic, and T2D state 8, 10, 11.

Insulin sensitivity predictions in individuals with obesity and type II diabetes mellitus using mathematical model of the insulin signal transduction pathway.

Mathematical modeling approaches have been commonly used in complex signaling pathway studies such as the insulin signal transduction pathway. Our expanded mathematical model of the insulin signal transduction pathway was previously shown to effectively predict glucose clearance rates using mRNA levels of key components of the pathway in a mouse model. In this study, we re-optimized and applied our expanded model to study insulin sensitivity in other species and tissues (human skeletal muscle) with altered protein activities of insulin signal transduction pathway components. The model has now been optimized to predict the effect of short term exercise on insulin sensitivity for human test subjects with obesity or type II diabetes mellitus. A comparison between our extended model and the original model showed that our model better simulates the GLUT4 translocation events of the insulin signal transduction pathway and glucose uptake as a clinically relevant model output. Results from our extended model correlate with O'Gorman's published in-vivo results. This study demonstrates the ability to adapt this model to study insulin sensitivity to many biological systems (human skeletal muscle and mouse liver) with minimal changes in the model parameters.

Validation of different measures of insulin sensitivity of glucose metabolism in dairy cows using the hyperinsulinemic euglycemic clamp test as the gold standard

The aim of the present research was to compare different measures of insulin sensitivity in dairy cows at the end of the dry period. To do so, 10 clinically healthy dairy cows with a varying body condition score were selected. By performing hyperinsulinemic euglycemic clamp (HEC) tests, we previously demonstrated a negative association between the insulin sensitivity and insulin responsiveness of glucose metabolism and the body condition score of these animals. In the same animals, other measures of insulin sensitivity were determined and the correlation with the HEC test, which is considered as the gold standard, was calculated. Measures derived from the intravenous glucose tolerance test (IVGTT) are based on the disappearance of glucose after an intravenous glucose bolus. Glucose concentrations during the IVGTT were used to calculate the area under the curve of glucose and the clearance rate of glucose. In addition, glucose and insulin data from the IVGTT were fitted in the minimal model to derive the insulin sensitivity parameter, Si. Based on blood samples taken before the start of the IVGTT, basal concentrations of glucose, insulin, NEFA, and β-hydroxybutyrate were determined and used to calculate surrogate indices for insulin sensitivity, such as the homeostasis model of insulin resistance, the quantitative insulin sensitivity check index, the revised quantitative insulin sensitivity check index and the revised quantitative insulin sensitivity check index including β-hydroxybutyrate. Correlation analysis revealed no association between the results obtained by the HEC test and any of the surrogate indices for insulin sensitivity. For the measures derived from the IVGTT, the area under the curve for the first 60 min of the test and the Si derived from the minimal model demonstrated good correlation with the gold standard.

Ethylenedisalicylic Acid Derivatives as Dual Inhibitors of PTP1B and IKKβ and their Antiobesity and Antidiabetic Effects in Mice

Ethylenedisalicylic acid (EDSA) was developed as a novel scaffold for dual inhibitors of protein tyrosine phosphatase (PTP) 1B and IkB kinase β (IKKβ). EDSA is a modified version of methylenedisalicylic acid (MDSA) and contains two salicylate moieties connected by an ethylene moiety. In this study, derivatives of EDSA were synthesized and their inhibitory potencies against PTP1B and IKKβ were investigated. Many of these derivatives exhibited half‐maximal inhibitory concentrations (IC50s) in the low micromolar range. The metabolic effects of ESA4 , 7, and 8 were further examined in a mouse model system. ESA4 and ESA8 significantly suppressed diet‐induced weight gain, whereas ESA7 had a marginal effect. ESA4 , 7, and 8 also lowered fasting glucose levels and accelerated glucose clearance rates after glucose injection. These observations indicate that EDSA scaffold‐based compounds are promising candidates for the treatment of obesity and diabetes.

Long‐Term Effects of Early‐Life Exposure to Olanzapine

An increasing number of children and young adults are prescribed antipsychotic medications, such as olanzapine, which is known to cause excessive weight gain and other metabolic issues. This has raised concerns of long‐term complications such as obesity, diabetes and heart disease. We propose to use fish oil, with known triglyceride lowering effects and potential anti‐obesity properties, to counteract obesity and other metabolic complications associated with antipsychotic drugs. Hence, we designed this project to test the effects of olanzapine and fish oil, individually or in combination in mice fed high fat diets. Specifically, male C57BL/6J mice (N=32) were given plain cookie dough or cookie dough with olanzapine (3 and then 6 mg/kg/day) from postnatal day (PND) 35 to 63. Mice were maintained on a high fat (HF)‐high sucrose (HS) diet, with or without fish oil (FO) supplementation, resulting in four groups of mice (n=8 per group): HF‐HS, HF‐HS with olanzapine, HF‐HS‐FO, and HF‐HS‐FO with olanzapine. Body weight and food consumption were measured daily. Glucose and insulin tolerance were assessed in adulthood (≥ PND 90). Mice exposed to FO and olanzapine had lower body weights compared to HF‐HS diet alone, despite equivalent amounts of food consumed between the groups. Glucose clearance rates were higher in the HF‐HS with olanzapine and FO supplementation group compared to HF‐HS fed mice. In conclusion, the results demonstrated long‐lasting effects of early‐life exposure to olanzapine on body weight and metabolism that were comparable to fish oil effects. Gene expression analyses of genes related to lipid metabolism, obesity, and diabetes, as well as triglyceride content in the liver are currently underway to determine the mechanisms mediating long‐term effects of olanzapine on body weight and liver metabolism.Support or Funding InformationTexas Tech University Presidential Cluster Hire Tier 2 and Obesity Research Cluster Pilot and Feasibility Award

Neural Modulation of Liver Function to Regulate Lipid and Glucose Metabolism

Mammalian blood glucose concentrations are maintained within well‐defined biological limits despite considerable fluctuations in the rate at which glucose is obtained from food and utilized by tissues. Of all homeostatic mechanisms, maintenance of blood glucose levels is finely regulated, and one in which the liver and the central nervous system play a prominent role. The liver can add or remove glucose from circulating blood in accordance with the demands of the body, which are transmitted by both hormonal and neural messaging. The hormonal messaging system is well understood, unlike the neural messaging system. Hormonal messaging is mediated by the pancreatic hormones insulin and glucagon, which have opposite effects on blood glucose levels. In contrast, the neural messaging system is controlled via two pathways innervating the liver ‐ one sympathetic and one parasympathetic, both originating from hypothalamic areas. Previous studies have shown that electrical stimulation of these hypothalamic nuclei can lead to rapid changes in blood glucose levels. Additional studies have also shown that electrical stimulation of peripheral nerves innervating the liver can lead to changes in hepatic output, however the limitations associated with neural control of glucose and lipid levels is unclear. Here we take an interdisciplinary approach to characterizing the use of electrical stimulation to control hepatic glucose and lipid metabolism. Using electrical stimulation, we demonstrate and characterize the ability to modulate both sympathetic and parasympathetic activity to the liver, enabling modulation of the glucose clearance rate assessed via oral glucose tolerances tests. Furthermore, we demonstrate how electrical stimulation can modulate lipid metabolism as a function of frequency, amplitude, and location of stimulation.Support or Funding InformationThis work is funded by the GlaxoSmithKline Bioelectronics Initiative.

Difference in postprandial GLP-1 response despite similar glucose kinetics after consumption of wheat breads with different particle size in healthy men

PurposeUnderlying mechanisms of the beneficial health effects of low glycemic index starchy foods are not fully elucidated yet. We varied the wheat particle size to obtain fiber-rich breads with a high and low glycemic response and investigated the differences in postprandial glucose kinetics and metabolic response after their consumption.MethodsTen healthy male volunteers participated in a randomized, crossover study, consuming 13C-enriched breads with different structures; a control bread (CB) made from wheat flour combined with wheat bran, and a kernel bread (KB) where 85 % of flour was substituted with broken wheat kernels. The structure of the breads was characterized extensively. The use of stable isotopes enabled calculation of glucose kinetics: rate of appearance of exogenous glucose, endogenous glucose production, and glucose clearance rate. Additionally, postprandial plasma concentrations of glucose, insulin, glucagon, incretins, cholecystokinin, and bile acids were analyzed.ResultsDespite the attempt to obtain a bread with a low glycemic response by replacing flour by broken kernels, the glycemic response and glucose kinetics were quite similar after consumption of CB and KB. Interestingly, the glucagon-like peptide-1 (GLP-1) response was much lower after KB compared to CB (iAUC, P < 0.005). A clear postprandial increase in plasma conjugated bile acids was observed after both meals.ConclusionsSubstitution of 85 % wheat flour by broken kernels in bread did not result in a difference in glucose response and kinetics, but in a pronounced difference in GLP-1 response. Thus, changing the processing conditions of wheat for baking bread can influence the metabolic response beyond glycemia and may therefore influence health.

Effect of Methanolic Extract of Passiflora foetida on Glucose Kinetics in Alloxan-induced Diabetic Mice

Background: This study investigated the hypoglycemic potential of methanolic extract of Passiflora foetida (PF) in alloxan-induced diabetic albino mice. Diabetes is a metabolic disease characterized with high blood sugar levels over a prolonged period. Discovery of a new drug will greatly reduce the mortality and morbidity associated with the disease. Methods: Diabetes was induced in albino mice by administration of 150 mg/kg body weight (b.w.) alloxan. Different concentrations of the methanolic extract of PF was prepared and administered orally to groups of alloxan-induced diabetic mice. Blood glucose was determined at different time points over 4 hrs. Results: The extract reduced blood glucose levels in diabetic mice significantly (P<0.001) and the kinetic parameters such as, area under glucose concentration time curve (AUC 0-4hG ) (P<0.05), glucose mean residence time (MRT G), glucose t 1/2G were significantly lower (<0.05) in PF treated groups when compared with the control groups. The rate of glucose clearance (CL G) was high in the group treated with the extract. Conclusion: The results of this study indicate presence of hypoglycemic constituent in the plant. Original Research Article

Equine hyperinsulinemia: investigation of the enteroinsular axis during insulin dysregulation.

Compared with some other species, insulin dysregulation in equids is poorly understood. However, hyperinsulinemia causes laminitis, a significant and often lethal disease affecting the pedal bone/hoof wall attachment site. Until recently, hyperinsulinemia has been considered a counterregulatory response to insulin resistance (IR), but there is growing evidence to support a gastrointestinal etiology. Incretin hormones released from the proximal intestine, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, augment insulin secretion in several species but require investigation in horses. This study investigated peripheral and gut-derived factors impacting insulin secretion by comparing the response to intravenous (iv) and oral d-glucose. Oral and iv tests were performed in 22 ponies previously shown to be insulin dysregulated, of which only 15 were classified as IR (iv test). In a more detailed study, nine different ponies received four treatments: d-glucose orally, d-glucose iv, oats, and commercial grain mix. Insulin, glucose, and incretin concentrations were measured before and after each treatment. All nine ponies showed similar iv responses, but five were markedly hyperresponsive to oral d-glucose and four were not. Insulin responsiveness to oral d-glucose was strongly associated with blood glucose concentrations and oral glucose bioavailability, presumably driven by glucose absorption/distribution, as there was no difference in glucose clearance rates. Insulin was also positively associated with the active amide of GLP-1 following d-glucose and grain. This study has confirmed a functional enteroinsular axis in ponies that likely contributes to insulin dysregulation that may predispose them to laminitis. Moreover, iv tests for IR are not reliable predictors of the oral response to dietary nonstructural carbohydrate.

Intramyocellular lipid content in subjects with impaired fasting glucose after telmisartan treatment, a randomised cross-over trial

Ectopic lipid accumulation in skeletal muscle is associated with insulin resistance. Telmisartan improves metabolic parameters in type 2 diabetic patients. The aim of our study was to evaluate the in vivo effect of telmisartan on intramyocellular lipid content (IMCL) in subjects with impaired fasting glucose (IFG) by magnetic resonance spectroscopy (MRS). We enrolled 10 subjects with IFG in a cross-over, placebo-controlled, randomized, double-blind trial, treated with 3 weeks of telmisartan (160 mg daily) or placebo. After completing each treatment, a hyperinsulinaemic euglycaemic clamp (1 mU/kg per min; 5 mmol/l; 120 min) to assess insulin action (metabolic clearance rate of glucose, MCR) and 1H MRS of the m. tibialis anterior using a MR Scanner Siemens Vision operating at 1.5 T to evaluate IMCL content, were performed. Plasma adipokine levels were determined simultaneously. Telmisartan treatment resulted in a lower fasting plasma glucose (FPG) (p < 0.05), but insulin action was comparable to after placebo. Telmisartan did not affect IMCL content. After placebo, IMCL correlated negatively with total cholesterol (p < 0.001), MCR (p < 0.05) and adiponectin (p < 0.05) and positively with FPG (p < 0.05). After telmisartan treatment there was only a positive correlation between IMCL and TNFα (p < 0.05). IMCL content is related to parameters of glucose metabolism and insulin action in sedentary IFG subjects. A short telmisartan treatment did not affect the IMCL content despite its positive effect on FPG. The improvement in FPG was probably mediated through interference with other metabolic pathways.

Characterization of the intravenous glucose tolerance test and the combined glucose–insulin test in donkeys

Glucose–insulin dynamic challenges such as the intravenous glucose tolerance test (IVGTT) and combined glucose–insulin test (CGIT) have not been described in donkeys. The objectives of this study were (1) to characterize the IVGTT and CGIT in healthy adult donkeys, and (2) to establish normal glucose–insulin proxies. Sixteen donkeys were used and body morphometric variables obtained each. For the IVGTT, glucose (300 mg/kg) was given IV. For the CGIT, glucose (150 mg/kg) followed by recombinant insulin (0.1 IU/kg) were administered IV. Blood samples for glucose and insulin determinations were collected over 300 min.In the IVGTT the positive phase lasted 160.9 ± 13.3 min, glucose concentration peaked at 323.1 ± 9.2 mg/dL and declined at a rate of 1.28 ± 0.15 mg/dL/min. The glucose area under the curve (AUC) was 21.4 ± 1.9 × 103 mg/dL/min and the insulin AUC was 7.2 ± 0.9 × 103 µIU/mL/min. The positive phase of the CGIT curve lasted 44 ± 3 min, with a glucose clearance rate of 2.01 ± 0.18 mg/dL/min. The negative phase lasted 255.9 ± 3 min, decreasing glucose concentration at rate of −0.63 ± 0.06 mg/dL/min, and reaching a nadir (33.1 ± 3.6 mg/dL) at 118.3 ± 6.3 min. The glucose and insulin AUC values were 15.2 ± 0.9 × 103 mg/dL/min and 13.2 ± 0.9 × 103 µIU/mL/min. This is the first study characterizing CGIT and IVGTT, and glucose–insulin proxies in healthy adult donkeys. Distinct glucose dynamics, when compared with horses, support the use of species-specific protocols to assess endocrine function.