Intravenous Injection Of Glucose Research Articles

Does Incretin Agonism Have Sustainable Efficacy?

Recent clinical trials using synthetic incretin hormones, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have demonstrated that these treatments ameliorated many complications related to obesity, emphasizing the significant impact of body weight on overall health. Incretins are enteroendocrine hormones secreted by gut endothelial cells triggered by nutrient ingestion. The phenomenon that oral ingestion of glucose elicits a much higher insulin secretion than intra-venous injection of equimolar glucose is known as the incretin effect. This also alludes to the thesis that food intake is the root cause of insulin resistance. Synthetic GLP-1 and GIP agonists have demonstrated unprecedented glucoregulation and body weight reduction. Also, randomized trials have shown their ability to prevent complications of obesity, including development of diabetes from prediabetes, reducing cardiovascular disease risks and renal complications in diabetic patients. Moreover, the benefits of these agonists persist among the patients who are already on metformin or insulin. The ultimate question is "Are these benefits of incretin agonism sustainable?" Chronic agonism of pancreatic β-cells may decrease the number of receptors and cause β-cell exhaustion, leading to β-cell failure. Unfortunately, the long-term effects of these drugs are unknown at the present because the longest duration in randomized trials is 3 years. Additionally, manipulation of the neurohormonal axis to control satiety and food intake may hinder the long-term sustainability of these treatments. In this review, we will discuss the incretins' mechanism of action, challenges, and future directions. We will briefly review other molecules involved in glucose homeostasis such as amylin and glucagon. Amylin is co-expressed with insulin from the pancreas β-cells but does not have insulinotropic function. Amylin suppresses glucagon secretion, slowing gastric emptying and suppressing the reward center in the central nervous system, leading to weight loss. However, amylin can self-aggregate and cause serious cytotoxicity and may cause β-cell apoptosis. Glucagon is secreted by pancreatic α-cells and participates in glucose homeostasis in a glucose-dependent manner. In hypoglycemia, glucagon increases the blood glucose level by glycogenolysis and gluconeogenesis and inhibits glycogenesis in the liver. Several triple agonists, in combination with dual incretins and glucagon, are being developed.

Preliminary Observations of the Loke Microdialysis in an Experimental Pig Model: Are We Ready for Continuous Monitoring of Brain Energy Metabolism?

Brain energy metabolism is often disturbed after acute brain injuries. Current neuromonitoring methods with cerebral microdialysis (CMD) are based on intermittent measurements (1-4 times/h), but such a low frequency could miss transient but important events. The solution may be the recently developed Loke microdialysis (MD), which provides high-frequency data of glucose and lactate. Before clinical implementation, the reliability and stability of Loke remain to be determined in vivo. The purpose of this study was to validate Loke MD in relation to the standard intermittent CMD method. Four pigs aged 2-3 months were included. They received two adjacent CMD catheters, one for standard intermittent assessments and one for continuous (Loke MD) assessments of glucose and lactate. The standard CMD was measured every 15 min. Continuous Loke MD was sampled every 2-3 s and was averaged over corresponding 15-min intervals for the statistical comparisons with standard CMD. Intravenous glucose injections and intracranial hypertension by inflation of an intracranial epidural balloon were performed to induce variations in intracranial pressure, cerebral perfusion pressure, and systemic and cerebral glucose and lactate levels. In a linear mixed-effect model of standard CMD glucose(mM), there was a fixed effect value (± standard error [SE]) at 0.94 ± 0.07 (p < 0.001) for Loke MD glucose(mM), with an intercept at - 0.19 ± 0.15 (p = 0.20). The model showed a conditional R2 at 0.81 and a marginal R2 at 0.72. In a linear mixed-effect model of standard CMD lactate(mM), there was a fixed effect value (± SE) at 0.41 ± 0.16 (p = 0.01) for Loke MD lactate(mM), with an intercept at 0.33 ± 0.21 (p = 0.25). The model showed a conditional R2 at 0.47 and marginal R2 at 0.17. The established standard CMD glucose thresholds may be used as for Loke MD with some caution, but this should be avoided for lactate.

Oral glucose gel in the prevention of neonatal hypoglycemia: A systematic review and meta-analysis.

Neonatal hypoglycemia (NH) is the most prevalent metabolic disorder in neonates and glucose gel in oral solution is a relatively new treatment option for NH. We aimed to determine whether oral glucose gel can prevent NH. We conducted an open literature search using PubMed, Embase, Cochrane Library, and Web of Science. We used relative risk as the statistical data, expressed each outcome effect as a 95% confidence interval, and conducted a heterogeneity test. If heterogeneity statistics indicated that I2 was ≥ 50%, the random effects model analysis was used; otherwise, the fixed effects model analysis was conducted, and sensitivity analyses were conducted for all outcomes. In this review, we included a total of 10 studies involving 4801 neonates. Meta-analysis revealed that there were no significant differences between the preventive oral glucose gel group and the control group in terms of blood glucose concentration, glucose concentration 30 minutes after the first breastfeeding, length of stay, Bayley-III composite score, subsequent need for intravenous injection of glucose, 24-hour glucose > 50 mg/dL, separation from mother for treatment of hypoglycemia/admitted to neonatal intensive care unit for hypoglycemia, normoglycemia after 1 to 2 treatments, or normoglycemia after more than 2 treatments, breastfeeding at discharge, delayed feeding, neurosensory impairment, parental satisfaction, developmental delay, and seizure. The subsequent intake was significantly lower in the glucose gel group compared to the control group. The use of oral glucose gel as a preventative measure may not reduce the incidence of NH. In order to assess the efficacy of glucose gel in preventing NH, a more high-quality, large-sample, and rigorously designed randomized controlled trial is required.

Cardiovascular Response to Intravenous Glucose Injection during Hemodialysis with Assessment of Entropy Alterations.

The quality of autonomic blood pressure (BP) control can be assessed by the entropy of serial BP data. The aim of this study was to evaluate the effect of hemodialysis (HD) and glucose infusion (GI) on amplitude aware permutation entropy (AAPE) of hemodynamic variables during HD in chronic kidney disease patients with and without type-2 diabetes mellitus (DM). Twenty-one patients without DM (NDO) and ten with DM were studied. Thirty minutes after the start of HD, a 40% glucose solution was administered. Hemodynamic data were extracted from continuous recordings using the Portapres® system. AAPE decreased during HD in all patients and all hemodynamic signals with the exception of AAPE of mean and diastolic BP in DM patients. GI led to an increase in AAPE for cardiac output in all patients, while AAPE for heart rate and ejection time increased only in DM studies, and AAPE for systolic, diastolic, and mean arterial pressure, as well as total peripheral resistance, increased only in NDO patients. The reduction in entropy during HD indicates impaired autonomic control in response to external perturbations. This state is partially reversed by the infusion of glucose with differences in central and peripheral responsiveness in DM and NDO patients.

The Glucose Sensitivity of Insulin Secretion-Lessons from In Vivo and In Vitro Studies in Mice.

This study explored the relationship between the glucose dose and insulin response from beta cells in vivo and in vitro in mice. Glucose was administered intravenously at different dose levels (from 0 to 0.75 g/kg) in anesthetized C57BL/6J mice, and the glucose and insulin concentrations were determined in samples taken after 50 min. Furthermore, freshly isolated mouse islets were incubated for 60 min in the presence of different concentrations of glucose (from 2.8 to 22.2 mmol/L) and insulin levels were analyzed in the medium. It was found that insulin levels increased after an intravenous injection of glucose with the maximal increase seen after 0.35 g/kg with no further increase after 0.5 or 0.75 g/kg. The acute increase in insulin levels (during the first 5 min) and the maximum glucose level (achieved after 1 min) showed a curvilinear relation with the half-maximal increase in insulin levels achieved at 11.4 mmol/L glucose and the maximal increase in insulin levels at 22.0 mmol/L glucose. In vitro, there was also a curvilinear relation between glucose concentrations and insulin secretion. Half maximal increase in insulin concentrations was achieved at 12.5 mmol/L glucose and the maximal increase in insulin concentrations was achieved at 21.5 mmol/L. Based on these data, we concluded that the glucose-insulin relation was curvilinear both in vivo and in vitro in mice with similar characteristics in relation to which glucose levels that achieve half-maximal and maximal increases in insulin secretion. Besides the new knowledge of knowing these relations, the results have consequences on how to design studies on insulin secretion to obtain the most information.

The effects of Zinc-Methionine on glucose metabolism and insulin resistance during late pregnancy in ewes

This study investigated the effects of dietary supplements of Zinc-Methionine (Zn-Met) on the zinc concentration of the blood and indices such as insulin resistance and glucose tolerance in late-pregnancy ewes to provide a practical solution to prevent metabolic diseases associated with energy status. In this research, 18 Makouei pregnant ewes were selected and randomized into 3 experimental groups: Group 1: Basal diet containing 10.3 mg Zn/kgDM and no zinc supplementation = CTR (Control); Group 2: Basal diet supplemented with low-dose zinc equivalent to the pregnancy requirements (30 mg Zn/kgDM) = LZN; Group 3: Basal diet supplemented with high-dose zinc (300 mg Zn/kgDM) = HZN. Blood samples for insulin resistance and glucose tolerance indices were collected according to standard methods. The results of this study indicated that supplementation of high-dose Zn-Met decreased (P < 0.05) blood glucose and tended (P < 0.1) to reduce the beta-hydroxybutyrate (BHB) concentrations. After intravenous injection of glucose and insulin, none of the glucose tolerance and insulin resistance indices were significant among groups (P > 0.05). However, the intravenous glucose tolerance test (IGTT) showed that the area under the curve (AUC) of serum glucose in the HZN group was numerically lower than that of the LZN and CTR groups. Furthermore, the numerically higher clearance rate (CR) of glucose and more negative glucose AUC following intravenous administration of insulin in Zinc-supplemented groups suggested that the ewes had greater insulin response than control group. The results showed a decrease in blood glucose concentration due to higher zinc intake after insulin injection and supported the evidence for improving insulin sensitivity. In addition, our results showed that ewes receiving zinc supplementation experienced a more favorable state of BHB or NEFA values. In conclusion, Zn-Met supplementation was found to have promising effects in improving energy metabolism in late pregnant ewes. However, further studies are needed to understand the mechanisms involved in regulating lipolysis and energy metabolism.

Systemic delivery of targeted nanotherapeutic reverses angiotensin II-induced abdominal aortic aneurysms in mice

Abdominal aortic aneurysm (AAA) disease causes dilation of the aorta, leading to aortic rupture and death if not treated early. It is the 14th leading cause of death in the U.S. and 10th leading cause of death in men over age 55, affecting thousands of patients. Despite the prevalence of AAA, no safe and efficient pharmacotherapies exist for patients. The deterioration of the elastic lamina in the aneurysmal wall is a consistent feature of AAAs, making it an ideal target for delivering drugs to the AAA site. In this research, we conjugated nanoparticles with an elastin antibody that only targets degraded elastin while sparing healthy elastin. After induction of aneurysm by 4-week infusion of angiotensin II (Ang II), two biweekly intravenous injections of pentagalloyl glucose (PGG)-loaded nanoparticles conjugated with elastin antibody delivered the drug to the aneurysm site. We show that targeted delivery of PGG could reverse the aortic dilation, ameliorate the inflammation, restore the elastic lamina, and improve the mechanical properties of the aorta at the AAA site. Therefore, simple iv therapy of PGG loaded nanoparticles can be an effective treatment option for early to middle stage aneurysms to reverse disease progression and return the aorta to normal homeostasis.

MRI abnormality of the bilateral middle cerebellar peduncles and long‐term follow‐up in hypoglycemic encephalopathy: A case report

AbstractA 32‐year‐old woman had a medical history of a hypoglycemic attack. One year later, she had a second hypoglycemic attack. She could move her limbs after an intravenous glucose injection, but communication difficulty and cerebellar ataxia remained. We found brain MRI abnormalities in the bilateral middle cerebellar peduncles and internal capsule. The patient was diagnosed with insulinoma. High‐intensity MRI fluid‐attenuated inversion recovery at the bilateral middle cerebellar peduncles remained on the 45th day, but it disappeared after 1.7 years from the second attack. Consciousness improved, but cerebellar ataxia remained. The patient was able to walk without a cane following rehabilitation. There are few case reports of MRI abnormalities in the bilateral middle cerebellar peduncles in hypoglycemic encephalopathy. This case showed that infratentorial lesions, such as those in the middle cerebellar peduncles, might be observed on MRI in hypoglycemic encephalopathy that MRI abnormalities might disappear at long‐term follow‐up.

The Relationship between Insulin Resistance and Type II Ketosis in Dairy Cows

Background: Cows in perinatal period are prone to ketosis, characterized by increased ketone bodies and decreased blood sugar. Study found that cows with type II ketosis had higher blood glucose levels. This type of ketosis exhibits insulin resistance and impaired glucose tolerance that are similar to type 2 diabetes. The purpose of this study was to investigate the role of insulin resistance(IR) in type II ketosis in dairy cows.Materials, Methods &amp; Results: In one intensive cattle farm, eight cows with ketosis and eight healthy cows that were 14-21 days postpartum were selected. The plasma of experimental dairy cows was collected and tested for the concentration of glucose concentration. Glucose tolerance of blood glucose levels in 120 min was used as the cut-off point to divide the dairy cows into three groups: the abnormal glucose tolerance ketosis group (TH), the normal glucose tolerance ketosis (TL), and the healthy control group. Simultaneously, the indexes of plasma liver function, oxidative stress, and insulin resistance were detected. The results showed that after intravenous glucose injection, there was no significant difference in blood glucose concentration between the TL and control group, while the blood glucose levels in the TH group were always higher than in the other two groups. The insulin sensitivity index (RQUICKI) value was significantly lower in the TH group than in the other two groups. Liver function abnormalities in the TH group were more severe than in the TL and control group. Oxidative stress was higher in the TH group than in the TL and control groups.Discussion: Postpartum dairy cows, with high lactation, consume large amounts of sugar, resulting in a lower blood sugar, and the postnatal dry matter intake peak is later than the peak lactation, which further decreases blood sugar and leads to a negative energy balance in cows. Such ketosis is associated with NEB caused by hypoglycemia, However, a survey of blood glucose concentration in cows with ketosis shows that ketosis can still occur in cows with high blood sugar levels. The pathogenesis of hyperglycemic ketosis is still unclear. Insulin Resistance (IR) refers to tissue sensitivity to insulin decreases, compensatory Islet beta cells secreting insulin thus producing hyperinsulinemia. AST is a typical indicator of liver damage, plasma AST levels in Group TH were significantly higher than the other two groups.The RQUICKI is a key indicator determining whether the body has developed insulin resistance. the plasma insulin sensitivity index of group TH was significantly lower than Group TL and C. BHBA levels in serum is the gold standard for the diagnosis of cow ketosis.The concentration of NEFA and BHBA in the blood is a sign of negative energy balance. The concentration of BHBA and NEFA in the TH group was significantly higher than in the group C, and the concentration of BHBA was higher than the critical value of ketosis. SOD is a metal antioxidant enzyme and its level are key indicators in measuring the removal of oxidizing substances. T-AOC is a measuring indicator for total antioxidant function. The reduction of SOD and T-AOC concentrations in the TH group indicated that the antioxidant capacity of ketone cows with abnormal glucose tolerance was reduced. The above results show that the TH group is severely impaired in liver function, and has a disorder of glucose metabolism, abnormal glucose tolerance and hyperinsulinemi, which also have severe IR. Moreover, the antioxidant capacity of the TH cows with ketosis declined, the body was in a state of oxidative stress. Thus, the occurrence of ketosis in some cows is related to a glucose utilization disorder caused by insulin resistance, and abnormal liver function and oxidative stress are the causes of insulin resistance.

962-P: Continuous Glucose Monitor Readings Lag Interstitial Glucose by Several Minutes

Objective: Continuous glucose monitor (CGM) measured glucose lags blood glucose by several minutes, and this delay is usually attributed to the latency of interstitial fluid. However, independent findings suggest that interstitial glucose dispersion is near-immediate. This study seeks to determine the physiological locus of CGM latency. Methods: Current was measured at 1 Hz in Dexcom G4 CGMs using a CHI 1440 potentiostat. CGMs were exposed to varying glucose levels in vitro to define sensor kinetics. Next, CGMs were implanted in mice, and sensor vs. blood glucose responses were measured following an intravenous glucose challenge. Finally, dispersion of a fluorescent glucose analogue (2-NBDG) into the CGM micro-environment was observed in vivo using intravital microscopy. Tissue deposited on sensors and non-CGM implanted subcutaneous fat were then collected for histological analysis. Results: The CGM time constant in vitro was 51±3 seconds. In vivo, CGMs took 24±7 minutes to reach a local maximum in maximum current following intravenous injection of glucose. 2-NBDG took 21±7 minutes to reach maximum fluorescence near the sensor, vs. 6±6 minutes in subcutaneous fat (p=0.0011). Collagen was increased in sensor deposits relative to non-CGM implanted subcutaneous fat (p=0.0018), and collagen content was correlated with 2-NBDG latency (R=0.96, p=0.0004). Conclusions: Interstitial glucose responds to changes in blood glucose within seconds, whereas the glucose levels seen by a CGM are delayed by several minutes due to fibrous encapsulation. A CGM that avoids encapsulation could approximate real-time blood glucose measurements. Additionally, these data raise the possibility that fibrosis underlies insulin resistance by creating a biophysical impediment to the interstitial dispersion of glucose. Disclosure P.M. McClatchey: None. E.S. McClain: None. I.M. Williams: None. J.M. Gregory: Consultant; Self; InClinica. D. Cliffel: None. D. Wasserman: None. Funding National Institutes of Health (DK059637, DK054902, DK050277, T32DK101003, F32DK120104); American Heart Association

SP564Double product in relation to body mass index, insulin resistance and hemodynamic response after intravenous glucose injection in patients with different glucose tolerance during hemodialysis

SP564Double product in relation to body mass index, insulin resistance and hemodynamic response after intravenous glucose injection in patients with different glucose tolerance during hemodialysis

Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia.

Glomerular hyperfiltration is common in early diabetes and is considered a risk factor for later diabetic nephropathy. We propose that sodium-glucose cotransporter 1 (SGLT1) senses increases in luminal glucose at the macula densa, enhancing generation of neuronal nitric oxide synthase 1 (NOS1)-dependent nitric oxide (NO) in the macula densa and blunting the tubuloglomerular feedback (TGF) response, thereby promoting the rise in GFR. We used microperfusion, micropuncture, and renal clearance of FITC-inulin to examine the effects of tubular glucose on NO generation at the macula densa, TGF, and GFR in wild-type and macula densa-specific NOS1 knockout mice. Acute intravenous injection of glucose induced hyperglycemia and glucosuria with increased GFR in mice. We found that tubular glucose blunts the TGF response in vivo and in vitro and stimulates NO generation at the macula densa. We also showed that SGLT1 is expressed at the macula densa; in the presence of tubular glucose, SGLT1 inhibits TGF and NO generation, but this action is blocked when the SGLT1 inhibitor KGA-2727 is present. In addition, we demonstrated that glucose increases NOS1 expression and NOS1 phosphorylation at Ser1417 in mouse renal cortex and cultured human kidney tissue. In macula densa-specific NOS1 knockout mice, glucose had no effect on NO generation, TGF, and GFR. We identified a novel mechanism of acute hyperglycemia-induced hyperfiltration wherein increases in luminal glucose at the macula densa upregulate the expression and activity of NOS1 via SGLT1, blunting the TGF response and promoting glomerular hyperfiltration.

Pharmacokinetic behaviors of ligustrazine after single- and multiple-dose intravenous Shenxiong glucose injection in rats by high-performance liquid chromatography.

Shenxiong glucose injection (SXG) is a traditional Chinese medicine that is used for cardio-cerebral vascular diseases on the national essential drug list of China. To date, a comprehensive knowledge concerning the pharmacokinetic profile of SXG-related components, especially following multiple dosing, is still lacking. This study was designed to investigate the pharmacokinetics and tissue distribution of ligustrazine after single- and multiple-dose intravenous administration of SXG in rats. A simple HPLC method was developed for the determination of ligustrazine in biological samples. The pharmacokinetic profiles of ligustrazine in rats were linear after both single- and multiple-dose intravenous administration of SXG, with a half-life of approximately 35min. Ligustrazine was readily distributed in highly perfused organs and almost eliminated from organs after 90min of SXG injection. The AUC0-t and C0 of ligustrazine after SXG injection (18ml/kg, equal to 9.0mg/kg ligustrazine) were increased significantly compared to those of single ligustrazine administration (9.0mg/kg), indicating that the pharmacokinetics of ligustrazine in the SXG were affected by other ingredients. This study provided first evidence for the pharmacokinetic characteristics of ligustrazine after both single and multiple-dose SXG in rats, which would be helpful for its clinical application.

Hyperpolarized [1-13 C] pyruvate as a possible diagnostic tool in liver disease.

Introduction of hyperpolarized magnetic resonance in preclinical studies and lately translation to patients provides new detailed in vivo information of metabolic flux in organs. Hyperpolarized magnetic resonance based on 13C enriched pyruvate is performed without ionizing radiation and allows quantification of the pyruvate conversion products: alanine, lactate and bicarbonate in real time. Thus, this methodology has a promising potential for in vivo monitoring of energetic alterations in hepatic diseases. Using 13C pyruvate, we investigated the metabolism in the porcine liver before and after intravenous injection of glucose. The overall mean lactate to pyruvate ratio increased significantly after the injection of glucose whereas the bicarbonate to pyruvate ratio was unaffected, representative of the levels of pyruvate entering the tricarboxylic acid cycle. Similarly, alanine to pyruvate ratio did not change. The increased lactate to pyruvate ratio over time showed an exponential correlation with insulin, glucagon and free fatty acids. Together, these data, obtained by hyperpolarized 13C magnetic resonance spectroscopy and by blood sampling, indicate a hepatic metabolic shift in glucose utilization following a glucose challenge. Our findings demonstrate the capacity of hyperpolarized 13C magnetic resonance spectroscopy for quantifying hepatic substrate metabolism in accordance with well‐known physiological processes. When combined with concentration of blood insulin, glucagon and free fatty acids in the blood, the results indicate the potential of hyperpolarized magnetic resonance spectroscopy as a future clinical method for quantification of hepatic substrate metabolism.

In vivo monitoring of intracellular Ca2+ dynamics in the pancreatic β-cells of zebrafish embryos

ABSTRACTAssessing the response of pancreatic islet cells to glucose stimulation is important for understanding β-cell function. Zebrafish are a promising model for studies of metabolism in general, including stimulus-secretion coupling in the pancreas. We used transgenic zebrafish embryos expressing a genetically-encoded Ca2+ sensor in pancreatic β-cells to monitor a key step in glucose induced insulin secretion; the elevations of intracellular [Ca2+]i. In vivo and ex vivo analyses of [Ca2+]i demonstrate that β-cell responsiveness to glucose is well established in late embryogenesis and that embryonic β-cells also respond to free fatty acid and amino acid challenges. In vivo imaging of whole embryos further shows that indirect glucose administration, for example by yolk injection, results in a slow and asynchronous induction of β-cell [Ca2+]i responses, while intravenous glucose injections cause immediate and islet-wide synchronized [Ca2+]i fluctuations. Finally, we demonstrate that embryos with disrupted mutation of the CaV1.2 channel gene cacna1c are hyperglycemic and that this phenotype is associated with glucose-independent [Ca2+]i fluctuation in β-cells. The data reveal a novel central role of cacna1c in β-cell specific stimulus-secretion coupling in zebrafish and demonstrate that the novel approach we propose – to monitor the [Ca2+]i dynamics in embryonic β-cells in vivo – will help to expand the understanding of β-cell physiological functions in healthy and diseased states.

Maternal Western diet during gestation and lactation modifies adult offspring's cognitive and hedonic brain processes, behavior, and metabolism in Yucatan minipigs.

This study explores the long-term effects of exposure to a maternal Western diet (WD) vs. standard diet (SD) in the Yucatan minipig, on the adult progeny at lean status ( n = 32), and then overweight status. We investigated eating behavior, cognitive abilities, brain basal glucose metabolism, dopamine transporter availability, microbiota activity, blood lipids, and glucose tolerance. Although both groups demonstrated similar cognitive abilities in a holeboard test, WD pigs expressed a higher stress level than did SD pigs (immobility, P < 0.05) and lower performance in an alley maze ( P = 0.06). WD pigs demonstrated lower dopamine transporter binding potential in the hippocampus and parahippocampal cortex ( P < 0.05 for both), as well as a trend in putamen ( P = 0.07), associated with lower basal brain activity in the prefrontal cortex and nucleus accumbens ( P < 0.05) compared with lean SD pigs. Lean WD pigs demonstrated a lower glucose tolerance than did SD animals (higher glucose peak, P < 0.05) and a tendency to a higher incremental area under the curve of insulin from 0 to 30 minutes after intravenous glucose injection ( P < 0.1). Both groups developed glucose intolerance with overweight, but WD animals were less impacted than SD animals. These results demonstrate that maternal diet shaped the offspring's brain functions and cognitive responses long term, even after being fed a balanced diet from weaning, but behavioral effects were only revealed in WD pigs under anxiogenic situation; however, WD animals seemed to cope better with the obesogenic diet from a metabolic standpoint.-Gautier, Y., Luneau, I., Coquery, N., Meurice, P., Malbert, C.-H., Guerin, S., Kemp, B., Bolhuis, J. E., Clouard, C., Le Huërou-Luron, I., Blat, S., Val-Laillet, D. Maternal Western diet during gestation and lactation modifies adult offspring's cognitive and hedonic brain processes, behavior, and metabolism in Yucatan minipigs.

Impacts of pre- and postnatal nutrition on glucagon regulation and hepatic signalling in sheep.

To evaluate the long-term impacts of early-life nutritional manipulations on glucagon secretion and hepatic signalling, thirty-six twin-pregnant ewes during their last trimester were exposed to NORM (fulfilling 100% of daily energy/protein requirements), HIGH (fulfilling 150/110% of daily energy/protein requirements) or LOW (50% of NORM) diets. Twin lambs were assigned after birth to a moderate (CONV) or high-carbohydrate high-fat (HCHF) diet until 6 months. Then, responses in plasma glucagon concentrations and glucagon ratios relative to previously reported values for insulin, glucose and lactate were determined after intravenous bolus injections of glucose or propionate (fed and 2-day fasting state). Hepatic mRNA expressions of glucagon receptor (GCGR), glucose-6-phosphatase (G6PC), phosphoenolpyruvate carboxykinase (PEPCK) and fructose 1,6-biphosphatase (FBP) were also determined in a sub group of autopsied lambs. Expression of GCGR and all three enzymes were supressed by prenatal LOW compared to NORM (except PEPCK) and HIGH (except FBP) nutrition. The postnatal HCHF diet reduced plasma glucagon responses to propionate and hepatic mRNA expression of all genes. In response to propionate, insulin/glucagon ratio was decreased (fasted state), but lactate/glucagon and glucose/glucagon increased in HCHF compared to CONV lambs. In conclusion, prenatal undernutrition and postnatal overnutrition had similar long-term implications and reduced hepatic glucagon signalling. Glucagon secretory responses to propionate were, however, not related to the prenatal nutrition history, but negatively affected by the postnatal obesogenic diet. The pancreatic α-cell compared to β-cells may thus be less sensitive towards late gestation malnutrition, whereas hepatic glucagon signalling appears to be a target of prenatal programming.

Increased insulin clearance in mice with double deletion of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors.

To establish whether incretin hormones affect insulin clearance, the aim of this study was to assess insulin clearance in mice with genetic deletion of receptors for both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), so called double incretin receptor knockout mice (DIRKO). DIRKO ( n = 31) and wild-type (WT) C57BL6J mice ( n = 45) were intravenously injected with d-glucose (0.35 g/kg). Blood was sampled for 50 min and assayed for glucose, insulin, and C-peptide. Data were modeled to calculate insulin clearance; C-peptide kinetics was established after human C-peptide injection. Assessment of C-peptide kinetics revealed that C-peptide clearance was 1.66 ± 0.10 10-3 1/min. After intravenous glucose administration, insulin clearance during first phase insulin secretion was markedly higher in DIRKO than in WT mice (0.68 ± 0.06 10-3 l/min in DIRKO mice vs. 0.54 ± 0.03 10-3 1/min in WT mice, P = 0.02). In contrast, there was no difference between the two groups in insulin clearance during second phase insulin secretion ( P = 0.18). In conclusion, this study evaluated C-peptide kinetics in the mouse and exploited a mathematical model to estimate insulin clearance. Results showed that DIRKO mice have higher insulin clearance than WT mice, following intravenous injection of glucose. This suggests that incretin hormones reduce insulin clearance at physiological, nonstimulated levels.

Post-prandial decrease in plasma growth hormone levels is not related to the increase in plasma insulin levels in goats.

ObjectiveIn the present study, we examined whether the post-prandial reduction in plasma growth hormone (GH) levels is related to the increase in plasma insulin levels in ruminants.MethodsWe performed two experiments: intravenous bolus injection of insulin (0.2 IU/kg body weight) or glucose (1.0 mmol/kg body weight) was administered to increase the plasma insulin levels in male Shiba goats.ResultsIn the insulin injection experiment, significant (p<0.05) increase in GH concentrations was observed, 15 to 20 min after the injection; it was accompanied with a significant (p<0.01) increase in cortisol concentrations at 45 to 90 min, when compared to the concentrations in the saline-injected controls. The glucose injection significantly (p<0.05) increased the plasma GH concentration at 20 to 45 min; this was not accompanied by significantly higher cortisol concentrations than were observed for the saline-injected control. Hypoglycemia induced by the insulin injection, which causes the excitation of the adrenal cortex, might be involved in the increase in insulin levels.ConclusionBased on these results, we conclude that post-prandial increases in plasma insulin or glucose levels do not induce a decrease in GH concentration after feeding in the ruminants.

Response to Intravenous Glucose-Tolerance Test and Risk of Cancer: A Long-Term Prospective Cohort Study

BackgroundImpaired glucose regulation, measured with an oral glucose-tolerance test, has been associated with the risk of cancer. Here, we explored whether the response to an intravenous glucose-tolerance test (IVGTT) is associated with the risk of cancer. MethodsA cohort of 945 healthy men, aged 40–59years in 1972–75, was followed for 40years. An IVGTT was performed at baseline. Blood samples for glucose determinations were drawn immediately before glucose injection and thereafter every 10min for 1h. Associations were assessed with incidence rate ratios (IRR) and Cox models. FindingsCancer incidence was higher among men with 10-min glucose levels below the median than in men with levels above the median (IRR: 1.5, 95% CI: 1.2–1.9). This association remained significant after adjusting for relevant confounders (HR: 1.6, 95% CI: 1.3–2.1) and when excluding the first 10years of follow-up to minimize the possibility of reverse causality (HR: 1.5, 95% CI: 1.2–2.0). InterpretationHealthy middle-aged males that responded to an intravenous glucose injection with rapid glucose elimination during the first phase had an elevated risk of cancer during 40years of follow-up. First phase response to a glucose load might be related to cancer development.