Differential timing for programming of glucose homoeostasis, sensitivity to insulin and blood pressure by in utero exposure to dexamethasone in sheep

2000 ◽  
Vol 98 (5) ◽  
pp. 553-560 ◽  
Author(s):  
Kathryn L. GATFORD ◽  
E. Marelyn WINTOUR ◽  
Miles J. DE BLASIO ◽  
Julie A. OWENS ◽  
Miodrag DODIC
Keyword(s):  
Amino Acid ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Acid Metabolism ◽  
Area Under The Curve ◽  
Whole Body ◽  
Acid Uptake ◽  
Critical Periods ◽  
Fetal Sheep ◽  
Increased Risk

Numerous epidemiological studies have related an increased risk of adult-onset cardiovascular and metabolic disease to an adverse intra-uterine environment at critical periods. We have shown that fetal sheep exposed to dexamethasone for only 2 days at 27 days of gestation (term ≈ 150 days) became hypertensive adults, whereas those exposed at 64 days of gestation remained normotensive, as did controls. In the same sheep, now nearly 5 years old, we performed glucose tolerance tests and hyperinsulinaemic euglycaemic clamps to study the insulin sensitivity of glucose, amino acid and non-esterified fatty acid metabolism. Glucose tolerance, calculated as the area under the curve, after intravenous administration of bolus glucose and insulin secretion in response to a glucose challenge were not altered in any group. There were no significant differences in the insulin sensitivity of net whole-body glucose or amino acid uptake. However, suppression of lipolysis by insulin, measured as the proportional decrease in the circulating concentration of non-esterified fatty acids during the hyperinsulinaemic clamp, was 69±1.2% at steady-state plasma insulin levels (≈ 1000 m-units/l) in the group exposed to dexamethasone at 27 days of gestation, but only 50.8±6.5% in the controls (P < 0.05). In the group exposed to dexamethasone at 64 days of gestation, the decrease was 66.4±5.1%, which did not reach significance compared with the controls (P = 0.10). Thus brief dexamethasone exposure during early gestation programmed hypertension independently of insulin resistance of glucose or amino acid metabolism; however, it did lead to increased insulin sensitivity of the inhibition of lipolysis, which may increase susceptibility to the development of obesity postnatally.

scholarly journals Role of the foregut in the early improvement in glucose tolerance and insulin sensitivity following Roux-en-Y gastric bypass surgery

2011 ◽  
Vol 300 (5) ◽  
pp. G795-G802 ◽  
Author(s):  
Erik N. Hansen ◽  
Robyn A. Tamboli ◽  
James M. Isbell ◽  
Jabbar Saliba ◽  
Julia P. Dunn ◽  
...  
Keyword(s):  
Gastric Bypass ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Area Under The Curve ◽  
Whole Body ◽  
Sensitivity Index ◽  
Mixed Meal ◽  
Early Improvement ◽  
Delivery Route ◽  
Over Time

Bypass of the foregut following Roux-en-Y gastric bypass (RYGB) surgery results in altered nutrient absorption, which is proposed to underlie the improvement in glucose tolerance and insulin sensitivity. We conducted a prospective crossover study in which a mixed meal was delivered orally before RYGB (gastric) and both orally (jejunal) and by gastrostomy tube (gastric) postoperatively (1 and 6 wk) in nine subjects. Glucose, insulin, and incretin responses were measured, and whole-body insulin sensitivity was estimated with the insulin sensitivity index composite. RYGB resulted in an improved glucose, insulin, and glucagon-like peptide-1 (GLP-1) area under the curve (AUC) in the first 6 wk postoperatively (all P ≤ 0.018); there was no effect of delivery route (all P ≥ 0.632) or route × time interaction (all P ≥ 0.084). The glucose-dependent insulinotropic polypeptide (GIP) AUC was unchanged after RYGB ( P = 0.819); however, GIP levels peaked earlier after RYGB with jejunal delivery. The ratio of insulin AUC to GLP-1 and GIP AUC decreased after surgery ( P =.001 and 0.061, respectively) without an effect of delivery route over time (both P ≥ 0.646). Insulin sensitivity improved post-RYGB ( P = 0.001) with no difference between the gastric and jejunal delivery of the mixed meal over time ( P = 0.819). These data suggest that exclusion of nutrients from the foregut with RYGB does not improve glucose tolerance or insulin sensitivity. However, changes in the foregut response post-RYGB due to lack of nutrient exposure cannot be excluded. Our findings suggest that foregut bypass may alter the incretin response by enhanced nutrient delivery to the hindgut.

scholarly journals Effect of IGF-I on serine metabolism in fetal sheep

2000 ◽  
Vol 165 (2) ◽  
pp. 261-269 ◽  
Author(s):  
EC Jensen ◽  
P van Zijl ◽  
PC Evans ◽  
JE Harding
Keyword(s):  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Amino Acid Uptake ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Acid Uptake ◽  
Amino Acid Synthesis ◽  
Fetal Sheep ◽  
Igf I

Acute infusion of IGF-I to the fetus has been shown to inhibit amino acid oxidation and appears to increase fetoplacental amino acid uptake. This study was designed to investigate further the effects of IGF-I on fetal amino acid metabolism. Radiolabeled serine was used to test the hypothesis that fetal IGF-I infusion enhances serine uptake into the fetus and/or placenta and inhibits serine oxidation. Eight fetal sheep were studied at 127 days of gestation before and during a 4-h infusion of IGF-I (50 microg/h per kg). During the infusion there was no change in uptake of serine or its oxidation by fetus or placenta. However, both uptake and oxidation of serine and glycine decreased in the fetal carcass. There was also a decrease in fetal blood serine and glycine concentrations which could indicate a decrease in protein breakdown, although reduced amino acid synthesis cannot be excluded. Thus IGF-I appeared to influence the distribution of these amino acids as oxidative substrates between different fetal tissues. In addition, fetal IGF-I infusion increased the conversion of serine to glycine which is likely to have increased the availability of one-carbon groups for biosynthesis. Our data provide further evidence that IGF-I plays a role in the regulation of fetoplacental amino acid metabolism.

scholarly journals No difference in exogenous carbohydrate oxidation during exercise in children with and without impaired glucose tolerance

2016 ◽  
Vol 121 (3) ◽  
pp. 724-729 ◽  
Author(s):  
Lisa Chu ◽  
Katherine M. Morrison ◽  
Michael C. Riddell ◽  
Sandeep Raha ◽  
Brian W. Timmons
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Area Under The Curve ◽  
Tolerance Test ◽  
Normal Glucose Tolerance ◽  
Whole Body ◽  
Oral Glucose ◽  
Insulin Resistant ◽  
Glucose Levels

The capacity to match carbohydrate (CHO) utilization with availability is impaired in insulin-resistant, obese adults at rest. Understanding exogenous carbohydrate (CHOexo) oxidation during exercise and its association to insulin resistance (IR) is important, especially in children at risk for type 2 diabetes. Our objective was to examine the oxidative efficiency of CHOexo during exercise in obese children with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). Children attended two visits and were identified as NGT ( n = 22) or IGT ( n = 12) based on 2-h oral glucose tolerance test (OGTT) glucose levels of <7.8 mmol/l or ≥7.8 mmol/l, respectively. Anthropometry, body composition, and aerobic fitness (V̇o2max) were assessed. Insulin and glucose at baseline, 30, 60, 90, and 120 min during the OGTT were used to calculate measures of insulin sensitivity. On a separate day, a 13C-enriched CHO drink was ingested before exercise (3 × 20 min bouts) at 45% V̇o2max. Breath measurements were collected to calculate CHOexo oxidative efficiency. CHOexo oxidative efficiency during exercise was similar in IGT (17.0 ± 3.6%) compared with NGT (17.1 ± 4.4%) ( P = 0.90) despite lower whole body insulin sensitivity in IGT at rest ( P = 0.02). Area under the curve for insulin (AUCins) measured at rest during the OGTT was greater in IGT compared with NGT ( P = 0.04). The ability of skeletal muscle to utilize CHOexo was not impaired during exercise in children with IGT.

scholarly journals Betamethasone-exposed preterm birth does not impair insulin action in adult sheep

2017 ◽  
Vol 232 (2) ◽  
pp. 175-187 ◽  
Author(s):  
R De Matteo ◽  
D J Hodgson ◽  
T Bianco-Miotto ◽  
V Nguyen ◽  
J A Owens ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Preterm Birth ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Cell Mass ◽  
Whole Body ◽  
Intravenous Glucose ◽  
Adult Sheep ◽  
Insulin Signalling Pathway ◽  
Increased Risk

Preterm birth is associated with increased risk of type 2 diabetes (T2D) in adulthood; however, the underlying mechanisms are poorly understood. We therefore investigated the effect of preterm birth at ~0.9 of term after antenatal maternal betamethasone on insulin sensitivity, secretion and key determinants in adulthood, in a clinically relevant animal model. Glucose tolerance and insulin secretion (intravenous glucose tolerance test) and whole-body insulin sensitivity (hyperinsulinaemic euglycaemic clamp) were measured and tissue collected in young adult sheep (14 months old) after epostane-induced preterm (9M, 7F) or term delivery (11M, 6F). Glucose tolerance and disposition, insulin secretion, β-cell mass and insulin sensitivity did not differ between term and preterm sheep. Hepatic PRKAG2 expression was greater in preterm than in term males (P = 0.028), but did not differ between preterm and term females. In skeletal muscle, SLC2A4 (P = 0.019), PRKAA2 (P = 0.021) and PRKAG2 (P = 0.049) expression was greater in preterm than in term overall and in males, while INSR (P = 0.047) and AKT2 (P = 0.043) expression was greater in preterm than in term males only. Hepatic PRKAG2 expression correlated positively with whole-body insulin sensitivity in males only. Thus, preterm birth at 0.9 of term after betamethasone does not impair insulin sensitivity or secretion in adult sheep, and has sex-specific effects on gene expression of the insulin signalling pathway. Hence, the increased risk of T2D in preterm humans may be due to factors that initiate preterm delivery or in early neonatal exposures, rather than preterm birth per se.

scholarly journals Observational study of thrombosis and bleeding in COVID-19 VV ECMO patients

2021 ◽  
pp. 039139882198906
Author(s):  
Brianda Ripoll ◽  
Antonio Rubino ◽  
Martin Besser ◽  
Chinmay Patvardhan ◽  
William Thomas ◽  
...  
Keyword(s):  
Intensive Care ◽  
Ct Scan ◽  
Thrombotic Event ◽  
Area Under The Curve ◽  
Whole Body ◽  
Bleeding Events ◽  
Heparin Resistance ◽  
Increased Risk ◽  
Thrombotic Complications ◽  
Clinically Significant

Introduction: COVID-19 has been associated with increased risk of thrombosis, heparin resistance and coagulopathy in critically ill patients admitted to intensive care. We report the incidence of thrombotic and bleeding events in a single center cohort of 30 consecutive patients with COVID-19 supported by veno-venous extracorporeal oxygenation (ECMO) and who had a whole body Computed Tomography Scanner (CT) on admission. Methodology: All patients were initially admitted to other hospitals and later assessed and retrieved by our ECMO team. ECMO was initiated in the referral center and all patients admitted through our CT scan before settling in our intensive care unit. Clinical management was guided by our institutional ECMO guidelines, established since 2011 and applied to at least 40 patients every year. Results: We diagnosed a thrombotic event in 13 patients on the initial CT scan. Two of these 13 patients subsequently developed further thrombotic complications. Five of those 13 patients had a subsequent clinically significant major bleeding. In addition, two patients presented with isolated intracranial bleeds. Of the 11 patients who did not have baseline thrombotic events, one had a subsequent oropharyngeal hemorrhage. When analyzed by ROC analysis, the area under the curve for % time in intended anticoagulation range did not predict thrombosis or bleeding during the ECMO run (0.36 (95% CI 0.10–0.62); and 0.51 (95% CI 0.25–0.78); respectively). Conclusion: We observed a high prevalence of VTE and a significant number of hemorrhages in these severely ill patients with COVID-19 requiring veno-venous ECMO support.

scholarly journals Interactive effects of aging and aerobic capacity on energy metabolism–related metabolites of serum, skeletal muscle, and white adipose tissue

GeroScience ◽  
2021 ◽  
Author(s):  
Haihui Zhuang ◽  
Sira Karvinen ◽  
Timo Törmäkangas ◽  
Xiaobo Zhang ◽  
Xiaowei Ojanen ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Amino Acid ◽  
White Adipose Tissue ◽  
Aerobic Capacity ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Disease Risk ◽  
Whole Body ◽  
Whole Body Metabolism

AbstractAerobic capacity is a strong predictor of longevity. With aging, aerobic capacity decreases concomitantly with changes in whole body metabolism leading to increased disease risk. To address the role of aerobic capacity, aging, and their interaction on metabolism, we utilized rat models selectively bred for low and high intrinsic aerobic capacity (LCRs/HCRs) and compared the metabolomics of serum, muscle, and white adipose tissue (WAT) at two time points: Young rats were sacrificed at 9 months of age, and old rats were sacrificed at 21 months of age. Targeted and semi-quantitative metabolomics analysis was performed on the ultra-pressure liquid chromatography tandem mass spectrometry (UPLC-MS) platform. The effects of aerobic capacity, aging, and their interaction were studied via regression analysis. Our results showed that high aerobic capacity is associated with an accumulation of isovalerylcarnitine in muscle and serum at rest, which is likely due to more efficient leucine catabolism in muscle. With aging, several amino acids were downregulated in muscle, indicating more efficient amino acid metabolism, whereas in WAT less efficient amino acid metabolism and decreased mitochondrial β-oxidation were observed. Our results further revealed that high aerobic capacity and aging interactively affect lipid metabolism in muscle and WAT, possibly combating unfavorable aging-related changes in whole body metabolism. Our results highlight the significant role of WAT metabolism for healthy aging.

scholarly journals Prolonged amino acid infusion into intrauterine growth-restricted fetal sheep increases leucine oxidation rates

2018 ◽  
Vol 315 (6) ◽  
pp. E1143-E1153 ◽  
Author(s):  
Sandra G. Wai ◽  
Paul J. Rozance ◽  
Stephanie R. Wesolowski ◽  
William W. Hay ◽  
Laura D. Brown
Keyword(s):  
Amino Acid ◽  
Amino Acid Uptake ◽  
Acid Uptake ◽  
Fetal Sheep ◽  
Acid Infusion ◽  
Amino Acid Infusion ◽  
Intrauterine Growth ◽  
Leucine Oxidation ◽  
Fetal Plasma ◽  
Oxidation Rates

Overcoming impaired growth in an intrauterine growth-restricted (IUGR) fetus has potential to improve neonatal morbidity, long-term growth, and metabolic health outcomes. The extent to which fetal anabolic capacity persists as the IUGR condition progresses is not known. We subjected fetal sheep to chronic placental insufficiency and tested whether prolonged amino acid infusion would increase protein accretion in these IUGR fetuses. IUGR fetal sheep were infused for 10 days with either mixed amino acids providing ~2 g·kg−1·day−1 (IUGR-AA) or saline (IUGR-Sal) during late gestation. At the end of the infusion, fetal plasma leucine, isoleucine, lysine, methionine, and arginine concentrations were higher in the IUGR-AA than IUGR-Sal group ( P < 0.05). Fetal plasma glucose, oxygen, insulin, IGF-1, cortisol, and norepinephrine concentrations were similar between IUGR groups, but glucagon concentrations were fourfold higher in the IUGR-AA group ( P < 0.05). Net umbilical amino acid uptake rate did not differ between IUGR groups; thus the total amino acid delivery rate (net umbilical amino acid uptake + infusion rate) was higher in the IUGR-AA than IUGR-Sal group (30 ± 4 vs. 19 ± 1 μmol·kg−1·min−1, P < 0.05). Net umbilical glucose, lactate, and oxygen uptake rates were similar between IUGR groups. Fetal leucine oxidation rate, measured using a leucine tracer, was higher in the IUGR-AA than IUGR-Sal group (2.5 ± 0.3 vs. 1.7 ± 0.3 μmol·kg−1·min−1, P < 0.05). Fetal protein accretion rate was not statistically different between the IUGR groups (1.6 ± 0.4 and 0.8 ± 0.3 μmol·kg−1·min−1 in IUGR-AA and IUGR-Sal, respectively) due to variability in response to amino acids. Prolonged amino acid infusion into IUGR fetal sheep increased leucine oxidation rates with variable anabolic response.

Insulin sensitivity and body composition in cirrhosis: changes after TIPS

2010 ◽  
Vol 299 (2) ◽  
pp. G486-G493 ◽  
Author(s):  
Peter Holland-Fischer ◽  
Michael Festersen Nielsen ◽  
Hendrik Vilstrup ◽  
Dennis Tønner-Nielsen ◽  
Anette Mengel ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Cell Mass ◽  
Area Under The Curve ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Endogenous Glucose

Insertion of a transjugular intrahepatic porto-systemic shunt (TIPS) increases body cell mass (BCM) in patients with liver cirrhosis. The responsible mechanism is unidentified, but may involve changes in insulin sensitivity and glucose metabolism. Eleven patients with liver cirrhosis were examined before and 6 mo after a TIPS procedure with bioimpedance analyses, 2-h oral glucose tolerance tests, and two-step hyperinsulinemic euglycemic clamp with tracer-determined endogenous glucose production. After TIPS, BCM increased by 4.8 kg [confidence interval (CI): 2.7–7.3]. Fasting (f)-insulin increased from 123 ± 81 to 193 ± 124 pmol/l ( P = 0.03), whereas f-glucose was unchanged (6.0 ± 0.8 vs. 6.2 ± 1.0 mmol/l). Glucose and insulin oral glucose tolerance test area under the curve increased by 14% (CI: 7–22%) and 53% (CI: 14–90%), respectively, P < 0.05. The C-peptide-to-insulin ratio decreased by 21% (CI: 8-35%, P = 0.01). Insulin sensitivity based on glucose infusion rate (4.69 ± 1.82 vs. 4.85 ± 2.37 mg·kg−1·min−1) and glucose tracer-based rate of disappearance were unchanged (5.01 ± 1.61 vs. 4.97 ± 2.13 mg·kg−1·min−1). Despite a further increase in peripheral hyperinsulinemia, f-endogenous glucose production did not change between study days (2.01 ± 0.42 vs. 2.42 ± 0.58 mg·kg−1·min−1) and was suppressed equally by insulin (1.1 ± 0.1 vs. 1.0 ± 0.1 mg·kg−1·min−1). Insulin clearance, growth hormone, cortisol, and glucagon levels were unchanged. BCM improvement did not correlate with the measured variables. After TIPS, BCM rose, despite enhanced hyperinsulinemia and aggravated glucose intolerance, but unchanged peripheral and hepatic insulin sensitivity. This apparent discrepancy may be ascribed to shunt-related decreased insulin exposure to the liver cells. However, the anabolic effect of TIPS seems not to be related to improvements in insulin sensitivity and remains mechanistically unexplained.

Fetal hepatic and umbilical uptakes of glucogenic substrates during a glucagon-somatostatin infusion

2002 ◽  
Vol 282 (3) ◽  
pp. E542-E550 ◽  
Author(s):  
Cecilia Teng ◽  
Frederick C. Battaglia ◽  
Giacomo Meschia ◽  
Michael R. Narkewicz ◽  
Randall B. Wilkening
Keyword(s):  
Amino Acid ◽  
Acid Metabolism ◽  
Fetal Liver ◽  
Amino Acid Uptake ◽  
Hepatic Uptake ◽  
High Rate ◽  
Acid Uptake ◽  
Glucose Carbon ◽  
Ovine Fetal ◽  
Equivalent Reduction

To test the hypothesis that fetal hepatic glutamate output diverts the products of hepatic amino acid metabolism from hepatic gluconeogenesis, ovine fetal hepatic and umbilical uptakes of glucose and glucogenic substrates were measured before and during fetal glucagon-somatostatin (GS) infusion and during the combined infusion of GS, alanine, glutamine, and arginine. Before the infusions, hepatic uptake of lactate, alanine, glutamine, arginine, and other substrates was accompanied by hepatic output of pyruvate, aspartate, serine, glutamate, and ornithine. The GS infusion induced hepatic output of 1.00 ± 0.07 mol glucose carbon/mol O2 uptake, an equivalent reduction in hepatic output of pyruvate and glutamate carbon, a decrease in umbilical glucose uptake and placental uptake of fetal glutamate, an increase in hepatic alanine and arginine clearances, and a decrease in umbilical alanine, glutamine, and arginine uptakes. The latter result suggests that glucagon inhibits umbilical amino acid uptake. We conclude that fetal hepatic pyruvate and glutamate output is part of an adaptation to placental function that requires the fetal liver to maintain both a high rate of catabolism of glucogenic substrates and a low rate of gluconeogenesis.

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