Tissue specific responses that constrain glucose oxidation and increase lactate production with the severity of hypoxemia in fetal sheep

2021 ◽  
Author(s):  
Amanda K. Jones ◽  
Dong Wang ◽  
David Goldstrohm ◽  
Laura D Brown ◽  
Paul J. Rozance ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Beta Cell ◽  
Glucose Oxidation ◽  
Glucose Utilization ◽  
Lactate Production ◽  
Late Gestation ◽  
Whole Body ◽  
Fetal Sheep ◽  
Oxidation Rates ◽  
Lactate And Pyruvate

Fetal hypoxemia decreases insulin and increases cortisol and norepinephrine concentrations and may restrict growth by decreasing glucose utilization and altering substrate oxidation. Specifically, we hypothesized that hypoxemia would decrease fetal glucose oxidation and increase lactate and pyruvate production. We tested this by measuring whole-body glucose oxidation and lactate production, and molecular pathways in liver, muscle, adipose, and pancreas tissues of fetuses exposed to maternal hypoxemia for 9 days (HOX) compared with control fetal sheep (CON) in late gestation. Fetuses with more severe hypoxemia had lower whole-body glucose oxidation rates, and HOX fetuses had increased lactate production from glucose. In muscle and adipose tissue, expression of the glucose transporter GLUT4 was decreased. In muscle, pyruvate kinase (PKM) and lactate dehydrogenase B (LDHB) expression was decreased. In adipose tissue, LDHA and lactate transporter (MCT1) expression was increased. In liver, there was decreased gene expression of PKLR and MPC2 and phosphorylation of PDH, and increased LDHA gene and protein abundance. LDH activity, however, was decreased only in HOX skeletal muscle. There were no differences in basal insulin signaling across tissues, nor differences in pancreatic tissue insulin content, beta cell area, or genes regulating beta cell function. Collectively, these results demonstrate coordinated metabolic responses across tissues in the hypoxemic fetus that limit glucose oxidation and increase lactate and pyruvate production. These responses may be mediated by hypoxemia induced endocrine responses including increased norepinephrine and cortisol, which inhibit pancreatic insulin secretion resulting in lower insulin concentrations and decreased stimulation of glucose utilization.

scholarly journals Exogenous amino acids suppress glucose oxidation and potentiate hepatic glucose production in late gestation fetal sheep

2017 ◽  
Vol 312 (5) ◽  
pp. R654-R663 ◽  
Author(s):  
Laura D. Brown ◽  
Jaden R. Kohn ◽  
Paul J. Rozance ◽  
William W. Hay ◽  
Stephanie R. Wesolowski
Keyword(s):  
Glucose Oxidation ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Oxidation Rates ◽  
Carbon Supply ◽  
Hepatic Glucose ◽  
Arterial Plasma ◽  
Branched Chain

Acute amino acid (AA) infusion increases AA oxidation rates in normal late gestation fetal sheep. Because the fetal oxygen consumption rate does not change with increased AA oxidation, we hypothesized that AA infusion would suppress glucose oxidation pathways and that the additional carbon supply from AA would activate hepatic glucose production. To test this, late gestation fetal sheep were infused intravenously for 3 h with saline or exogenous AA (AA). Glucose tracer metabolic studies were performed and skeletal muscle and liver tissues samples were collected. AA infusion increased fetal arterial plasma branched chain AA, cortisol, and glucagon concentrations. Fetal glucose utilization rates were similar between basal and AA periods, yet the fraction of glucose oxidized and the glucose oxidation rate were decreased by 40% in the AA period. AA infusion increased expression of PDK4, an inhibitor of glucose oxidation, nearly twofold in muscle and liver. In liver, AA infusion tended to increase PCK1 gluconeogenic gene and PCK1 correlated with plasma cortisol concentrations. AA infusion also increased liver mRNA expression of the lactate transporter gene ( MCT1), protein expression of GLUT2 and LDHA, and phosphorylation of AMPK, 4EBP1, and S6 proteins. In isolated fetal hepatocytes, AA supplementation increased glucose production and PCK1, LDHA, and MCT1 gene expression. These results demonstrate that AA infusion into fetal sheep competitively suppresses glucose oxidation and potentiates hepatic glucose production. These metabolic patterns support flexibility in fetal metabolism in response to increased nutrient substrate supply while maintaining a relatively stable rate of oxidative metabolism.

Effect of hyperinsulinemia on amino acid utilization and oxidation independent of glucose metabolism in the ovine fetus

2006 ◽  
Vol 291 (6) ◽  
pp. E1333-E1340 ◽  
Author(s):  
Laura D. Brown ◽  
William W. Hay
Keyword(s):  
Amino Acid ◽  
Glucose Metabolism ◽  
Oxidation Rate ◽  
Glucose Oxidation ◽  
Glucose Utilization ◽  
Control Period ◽  
Fetal Sheep ◽  
Leucine Oxidation ◽  
Oxidation Rates ◽  
C Value

We studied the effect of acute hyperinsulinemia on amino acid (AA) utilization and oxidation rates independent of insulin-enhanced glucose metabolism in fetal sheep. Metabolic studies were conducted in each fetus ( n = 11) under three experimental periods. After control period (C) study, a fetal hyperinsulinemic-euglycemic-euaminoacidemic (HI-euG-euAA) clamp was established, followed by a hyperinsulinemic-hypoglycemic-euaminoacidemic (HI-hypoG-euAA) clamp to decrease glucose metabolic rates toward C values. Infusions of 3H20, l-[1-13C]leucine, and [14C(U)]glucose were administered to measure blood flow, leucine oxidation, and fetal glucose uptake, utilization, and oxidation in each period. Fetal glucose utilization rate increased 1.7-fold with hyperinsulinemia (C 5.8 ± 0.8 mg·kg−1·min−1, HI-euG-euAA 10 ± 1.3 mg·kg−1·min−1, P < 0.0001), returning to rates not different from C with hypoglycemia (HI-hypoG-euAA 7.1 ± 0.9 mg·kg−1·min−1 vs. C value, P = 0.15). Fetal glucose oxidation rate increased 1.7-fold with hyperinsulinemia (C 3.1 ± 0.2 mg·kg−1·min−1, HI-euG-euAA 5.4 ± 0.4 mg·kg−1·min−1, P < 0.0001) and decreased to near control rates with hypoglycemia (4.0 ± 0.3 HI-hypoG-euAA vs. C value, P = 0.006). AA utilization rates increased with hyperinsulinemia for all essential and most nonessential AAs ( P < 0.001) and did not change when insulin-induced increases in glucose utilization returned to control rates. Leucine oxidation rate increased 1.7-fold with hyperinsulinemia (C 1.0 ± 0.3 μmol·min−1·kg−1, HI-euG-euAA 1.7 ± 0.3 μmol·min−1·kg−1, P < 0.002) and did not change when glucose oxidation rate was decreased with hypoglycemia. These results demonstrate that, in fetal sheep, insulin promotes AA utilization and oxidation independent of its simultaneous effects on glucose metabolism. In acute hyperinsulinemic conditions, AA oxidation does not change when insulin-induced glucose utilization is prevented.

scholarly journals Importance of lactate dehydrogenase for the regulation of glycolytic flux and insulin secretion in insulin-producing cells

2000 ◽  
Vol 352 (2) ◽  
pp. 373-380 ◽  
Author(s):  
Oscar ALCAZAR ◽  
Markus TIEDGE ◽  
Sigurd LENZEN
Keyword(s):  
Insulin Secretion ◽  
Lactate Dehydrogenase ◽  
Oxidation Rate ◽  
Glucose Oxidation ◽  
Glucose Utilization ◽  
Lactate Production ◽  
Glycolytic Flux ◽  
Oxidation Rates ◽  
Insulin Producing Cells ◽  
Insulin Secreting Cells

The role of lactate dehydrogenase (LDH) in the generation of the metabolic signal for insulin secretion was studied after stable overexpression in INS-1 and RINm5F insulin-producing cells. INS-1 cells with a 25-fold overexpression of LDH-A, the highest level achieved, showed a 20–30% decrease in the glucose oxidation rate at glucose concentrations above 5mM when compared with control cells, whereas values were unchanged at lower glucose concentrations. Lactate release increased in parallel with a decrease in the glucose oxidation rate. However, the INS-1 cell glucose-induced insulin secretory response, together with the rate of glucose utilization, were not significantly affected by LDH-A overexpression. Despite 3-fold overexpression of LDH-A in glucose-unresponsive RINm5F cells, there was no change in insulin secretion, glucose metabolism or lactate production in these cells. Exogenously added pyruvate and lactate potentiated glucose-stimulated insulin secretion in INS-1 cells, an effect that was abolished after LDH-A overexpression. Both compounds significantly decreased glucose oxidation rates in control cells. After overexpression of LDH-A in INS-1 cells, the effects of pyruvate and lactate on glucose oxidation were diminished. On the other hand, after LDH-A overexpression, both glycolytic metabolites decreased the glucose utilization rate at 5mM glucose. The present data suggest that the level of LDH expression in insulin-secreting cells is critical for correct channelling of pyruvate towards mitochondrial metabolism. Interestingly, glucokinase-mediated glycolytic flux was decreased after LDH-A overexpression. Thus preferential channelling of glucose towards aerobic metabolism by glucokinase may be determined, at least in part, by the low level of constitutive expression of LDH-A in pancreatic β-cells. In conclusion, the level of LDH expression in insulin-secreting cells is an important determinant of the physiological insulin-secretory capacity, and also determines how pyruvate and lactate affect insulin secretion.

Metabolic Effects of Acute Hyperketonaemia in Man before and during An Hyperinsulinaemic Euglycaemic Clamp

1994 ◽  
Vol 86 (6) ◽  
pp. 677-687 ◽  
Author(s):  
J. Webber ◽  
E. Simpson ◽  
H. Parkin ◽  
I. A. MacDonald
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Glucose Oxidation ◽  
Respiratory Exchange Ratio ◽  
Saline Infusion ◽  
Metabolic Effects ◽  
Whole Body ◽  
Glucose Storage ◽  
Adipose Tissue Lipolysis ◽  
Subcutaneous Abdominal Adipose Tissue

1. The effects of acutely raising blood ketone body levels to those seen after 72 h of starvation were examined in 10 subjects after an overnight fast. Metabolic rate and respiratory exchange ratio were measured with indirect calorimetry before and during an insulin—glucose clamp. Arteriovenous differences were measured across forearm and subcutaneous abdominal adipose tissue. 2. In response to the clamp the respiratory exchange ratio rose from 0.82 to 0.83 during 3-hydroxybutyrate infusion and from 0.83 to 0.94 during control (saline) infusion (P < 0.001). 3. Forearm glucose uptake at the end of the clamp was 4.02 ± 0.95 (3-hydroxybutyrate infusion) and 7.09 ± 1.24 mmol min−1 100 ml−1 forearm (saline infusion). Whole body glucose uptake at the end of the clamp was 72.8 ± 7.9 (3-hydroxybutyrate infusion) and 51.0 ± 3.0 (saline infusion) mmol min−1 kg−1 body weight−1. 4. 3-Hydroxybutyrate infusion reduced the baseline abdominal venous—arterialized venous glycerol difference from 84 ± 28 to 25 ± 12 mmol/l and the non-esterified fatty acid difference from 0.60 ± 0.17 to 0.02 ± 0.09 mmol/l (P < 0.05 versus saline infusion). 5. Hyperketonaemia reduces adipose tissue lipolysis and decreases insulin-mediated forearm glucose uptake. Hyperketonaemia appears to prevent insulin-stimulated glucose oxidation, but does not reduce insulin-mediated glucose storage.

Anemic Hypoxemia Reduces Myoblast Proliferation and Muscle Growth in Late Gestation Fetal Sheep

2021 ◽  
Author(s):  
Paul J. Rozance ◽  
Stephanie R Wesolowski ◽  
Sonnet S. Jonker ◽  
Laura D Brown
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Muscle Growth ◽  
Late Gestation ◽  
Whole Body ◽  
Myoblast Differentiation ◽  
Fetal Sheep ◽  
Body Protein ◽  
Skeletal Muscle Growth ◽  
Myoblast Proliferation

Fetal skeletal muscle growth requires myoblast proliferation, differentiation, and fusion into myofibers in addition to protein accretion for fiber hypertrophy. Oxygen is an important regulator of this process. Therefore, we hypothesized that fetal anemic hypoxemia would inhibit skeletal muscle growth. Studies were performed in late gestation fetal sheep that were bled to anemic, and therefore hypoxemic, conditions beginning at ~125 days of gestation (term = 148 days) for 9 ± 0 days (n=19) and compared to control fetuses (n=16). A metabolic study was performed on gestational day ~134 to measure fetal protein kinetic rates. Myoblast proliferation and myofiber area were determined in biceps femoris (BF), tibialis anterior (TA), and flexor digitorum superficialis (FDS) muscles. mRNA expression of muscle regulatory factors was determined in BF. Fetal arterial hematocrit and oxygen content were 28% and 52% lower, respectively, in anemic fetuses. Fetal weight and whole-body protein synthesis, breakdown, and accretion rates were not different between groups. Hindlimb length, however, was 7% shorter in anemic fetuses. TA and FDS muscles weighed less and FDS myofiber area was smaller in anemic fetuses compared to controls. The percentage of Pax7+ myoblasts that expressed Ki67 was lower in BF and tended to be lower in FDS from anemic fetuses indicating reduced myoblast proliferation. There was less MYOD and MYF6 mRNA expression in anemic vs. control BF consistent with reduced myoblast differentiation. These results indicate that fetal anemic hypoxemia reduced muscle growth. We speculate that fetal muscle growth may be improved by strategies that increase oxygen availability.

scholarly journals Limited capacity for glucose oxidation in fetal sheep with intrauterine growth restriction

2015 ◽  
Vol 309 (8) ◽  
pp. R920-R928 ◽  
Author(s):  
Laura D. Brown ◽  
Paul J. Rozance ◽  
Jennifer L. Bruce ◽  
Jacob E. Friedman ◽  
William W. Hay ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Glucose Oxidation ◽  
Fetal Liver ◽  
Lactate Production ◽  
Glucose Production ◽  
Limited Capacity ◽  
Fetal Sheep ◽  
Intrauterine Growth ◽  
Insulin Clamp

Intrauterine growth-restricted (IUGR) fetal sheep, produced by placental insufficiency, have lower oxygen concentrations, higher lactate concentrations, and increased hepatic glucose production that is resistant to suppression by insulin. We hypothesized that increased lactate production in the IUGR fetus results from reduced glucose oxidation, during basal and maximal insulin-stimulated conditions, and is used to support glucose production. To test this, studies were performed in late-gestation control (CON) and IUGR fetal sheep under basal and hyperinsulinemic-clamp conditions. The basal glucose oxidation rate was similar and increased by 30–40% during insulin clamp in CON and IUGR fetuses ( P < 0.005). However, the fraction of glucose oxidized was 15% lower in IUGR fetuses during basal and insulin-clamp periods ( P = 0.05). IUGR fetuses also had four-fold higher lactate concentrations ( P < 0.001) and lower lactate uptake rates ( P < 0.05). In IUGR fetal muscle and liver, mRNA expression of pyruvate dehydrogenase kinase ( PDK4), an inhibitor of glucose oxidation, was increased over fourfold. In IUGR fetal liver, but not skeletal muscle, mRNA expression of lactate dehydrogenase A ( LDHA) was increased nearly fivefold. Hepatic expression of the gluconeogenic genes, phosphoenolpyruvate carboxykinase ( PCK)1, and PCK2, was correlated with expression of PDK4 and LDHA. Collectively, these in vivo and tissue data support limited capacity for glucose oxidation in the IUGR fetus via increased PDK4 in skeletal muscle and liver. We speculate that lactate production also is increased, which may supply carbon for glucose production in the IUGR fetal liver.

Cortisol has no effect on prolactin receptor (PRLR) abundance in brown adipose tissue (BAT) in late gestation fetal sheep

2001 ◽  
Vol 29 (1) ◽  
pp. A39-A39
Author(s):  
S. Pearce ◽  
H. Budge ◽  
A. Forhead ◽  
A. Fowden ◽  
P. Ingleton ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Prolactin Receptor ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Brown Adipose

scholarly journals Lactate production is the major metabolic fate of glucose in splenocytes and is altered in spontaneously diabetic BB rats

1990 ◽  
Vol 272 (2) ◽  
pp. 445-452 ◽  
Author(s):  
C J Field ◽  
G Wu ◽  
M D Métroz-Dayer ◽  
M Montambault ◽  
E B Marliss
Keyword(s):  
Glucose Utilization ◽  
Lactate Production ◽  
Resting Cells ◽  
Metabolic Fate ◽  
Con A ◽  
Normal Cells ◽  
Immunological Activation ◽  
Proliferation Of Lymphocytes ◽  
Lactate And Pyruvate

Enhanced glucose metabolism is necessary to support the activation and proliferation of lymphocytes. To define further quantitatively the metabolic fates of glucose and assess glucose utilization both in normal cells and in an autoimmune disease with abnormal lymphocytes, [U-14C]glucose conversion into 14CO2 and the production of lactate and pyruvate were measured in splenocytes. Cells from non-diabetes-prone (BBn) and spontaneously diabetic (BBd) rats were studied both freshly isolated ‘resting’ and cultured for 96 h with and without concanavalin A (Con A) stimulation. (1) Lactate was confirmed to be the major end product in both freshly isolated (53% of utilized glucose) and unstimulated cultured (62% of utilized glucose) cells from BBn animals studied at (2-8) x 10(6) cells/ml concentration. The use of concentrations from 10 x 10(6) to 300 x 10(6) cells/ml resulted in progressively less lactate production per 10(6) splenocytes. (2) Cells from BBd animals after stimulation with Con A incorporated less [3H]thymidine and produced significantly less lactate (155 +/- 14 versus 305 +/- 24 nmol/2 h per 10(6) cells) than did BBn cells (P less than 0.05). (3) However, more lactate (101 +/- 8 versus 78 +/- 6 nmol/5 h per 10(6) cells) was produced by ‘resting’ cells from BBd animals compared with BBn (P less than 0.03), and this difference was sustained after 4 days in culture. (4) Significantly greater amounts of pyruvate were produced by BBd than by BBn cells, particularly when stimulated with Con A, suggesting an alteration in the availability of reducing equivalents in BBd cells. (5) These results are consistent with prior metabolic as well as immunological ‘activation’ of cells in vivo in the BB diabetic animals.

scholarly journals Enhanced glycogen metabolism in adipose tissue decreases triglyceride mobilization

2010 ◽  
Vol 299 (1) ◽  
pp. E117-E125 ◽  
Author(s):  
Kathleen R. Markan ◽  
Michael J. Jurczak ◽  
Margaret B. Allison ◽  
Honggang Ye ◽  
Maria M. Sutanto ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipid Metabolism ◽  
Lactate Production ◽  
Transgenic Animals ◽  
Whole Body ◽  
Nonesterified Fatty Acids ◽  
Transgenic Mouse Line ◽  
Whole Body Metabolism

Adipose tissue is a primary site for lipid storage containing trace amounts of glycogen. However, refeeding after a prolonged partial fast produces a marked transient spike in adipose glycogen, which dissipates in coordination with the initiation of lipid resynthesis. To further study the potential interplay between glycogen and lipid metabolism in adipose tissue, the aP2-PTG transgenic mouse line was utilized since it contains a 100- to 400-fold elevation of adipocyte glycogen levels that are mobilized upon fasting. To determine the fate of the released glucose 1-phosphate, a series of metabolic measurements were made. Basal and isoproterenol-stimulated lactate production in vitro was significantly increased in adipose tissue from transgenic animals. In parallel, basal and isoproterenol-induced release of nonesterified fatty acids (NEFAs) was significantly reduced in transgenic adipose tissue vs. control. Interestingly, glycerol release was unchanged between the genotypes, suggesting that enhanced triglyceride resynthesis was occurring in the transgenic tissue. Qualitatively similar results for NEFA and glycerol levels between wild-type and transgenic animals were obtained in vivo during fasting. Additionally, the physiological upregulation of the phospho enolpyruvate carboxykinase cytosolic isoform (PEPCK-C) expression in adipose upon fasting was significantly blunted in transgenic mice. No changes in whole body metabolism were detected through indirect calorimetry. Yet weight loss following a weight gain/loss protocol was significantly impeded in the transgenic animals, indicating a further impairment in triglyceride mobilization. Cumulatively, these results support the notion that the adipocyte possesses a set point for glycogen, which is altered in response to nutritional cues, enabling the coordination of adipose glycogen turnover with lipid metabolism.

Chronic activation of PPARα is detrimental to cardiac recovery after ischemia

2006 ◽  
Vol 290 (1) ◽  
pp. H87-H95 ◽  
Author(s):  
Nandakumar Sambandam ◽  
Dominique Morabito ◽  
Cory Wagg ◽  
Brian N. Finck ◽  
Daniel P. Kelly ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Glucose Oxidation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
High Fatty Acid ◽  
Whole Body ◽  
Cardiac Recovery ◽  
Oxidation Rates ◽  
Cardiac Power ◽  
Chronic Activation

High fatty acid oxidation (FAO) rates contribute to ischemia-reperfusion injury of the myocardium. Because peroxisome proliferator-activated receptor (PPAR)α regulates transcription of several FAO enzymes in the heart, we examined the response of mice with cardiac-restricted overexpression of PPARα (MHC-PPARα) or whole body PPARα deletion including the heart (PPARα−/−) to myocardial ischemia-reperfusion injury. Isolated working hearts from MHC-PPARα and nontransgenic (NTG) littermates were subjected to no-flow global ischemia followed by reperfusion. MHC-PPARα hearts had significantly higher FAO rates during aerobic and postischemic reperfusion (aerobic 1,479 ± 171 vs. 699 ± 117, reperfusion 1,062 ± 214 vs. 601 ± 70 nmol·g dry wt−1·min−1; P < 0.05) and significantly lower glucose oxidation rates compared with NTG hearts (aerobic 225 ± 36 vs. 1,563 ± 165, reperfusion 402 ± 54 vs. 1,758 ± 165 nmol·g dry wt−1·min−1; P < 0.05). In hearts from PPARα−/− mice, FAO was significantly lower during aerobic and reperfusion (aerobic 235 ± 36 vs. 442 ± 75, reperfusion 205 ± 25 vs. 346 ± 38 nmol·g dry wt−1·min−1; P < 0.05) whereas glucose oxidation was significantly higher compared with wild-type (WT) hearts (aerobic 2,491 ± 631 vs. 901 ± 119, reperfusion 2,690 ± 562 vs. 1,315 ± 172 nmol·g dry wt−1·min−1; P < 0.05). Increased FAO rates in MHC-PPARα hearts were associated with a markedly lower recovery of cardiac power (45 ± 9% vs. 71 ± 6% of preischemic levels in NTG hearts; P < 0.05). In contrast, the percent recovery of cardiac power of PPARα−/− hearts was not significantly different from that of WT hearts (80 ± 8% vs. 75 ± 9%). This study demonstrates that chronic activation of PPARα is detrimental to the cardiac recovery during reperfusion after ischemia.

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