scholarly journals A Two-Week Insulin Infusion in Intrauterine Growth Restricted Fetal Sheep at 75% Gestation Increases Skeletal Myoblast Replication but Did Not Restore Muscle Mass or Increase Fiber Number

2021 ◽  
Vol 12 ◽  
Author(s):  
Eileen I. Chang ◽  
Byron Hetrick ◽  
Stephanie R. Wesolowski ◽  
Carrie E. McCurdy ◽  
Paul J. Rozance ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Insulin Infusion ◽  
Feedback Inhibition ◽  
Cell Mass ◽  
Β Cell ◽  
Fetal Sheep ◽  
Intrauterine Growth ◽  
Arterial Blood ◽  
Myoblast Proliferation ◽  
Fiber Number

Intrauterine growth restricted (IUGR) fetuses are born with lower skeletal muscle mass, fewer proliferating myoblasts, and fewer myofibers compared to normally growing fetuses. Plasma concentrations of insulin, a myogenic growth factor, are lower in IUGR fetuses. We hypothesized that a two-week insulin infusion at 75% gestation would increase myoblast proliferation and fiber number in IUGR fetal sheep. Catheterized control fetuses received saline (CON-S, n=6), and the IUGR fetuses received either saline (IUGR-S, n=7) or insulin (IUGR-I, 0.014 ± 0.001 units/kg/hr, n=11) for 14 days. Fetal arterial blood gases and plasma amino acid levels were measured. Fetal skeletal muscles (biceps femoris, BF; and flexor digitorum superficialis, FDS) and pancreases were collected at necropsy (126 ± 2 dGA) for immunochemistry analysis, real-time qPCR, or flow cytometry. Insulin concentrations in IUGR-I and IUGR-S were lower vs. CON-S (P ≤ 0.05, group). Fetal arterial PaO2, O2 content, and glucose concentrations were lower in IUGR-I vs. CON-S (P ≤ 0.01) throughout the infusion period. IGF-1 concentrations tended to be higher in IUGR-I vs. IUGR-S (P=0.06), but both were lower vs. CON-S (P ≤ 0.0001, group). More myoblasts were in S/G2 cell cycle stage in IUGR-I vs. both IUGR-S and CON-S (145% and 113%, respectively, P ≤ 0.01). IUGR-I FDS muscle weighed 40% less and had 40% lower fiber number vs. CON-S (P ≤ 0.05) but were not different from IUGR-S. Myonuclear number per fiber and the mRNA expression levels of muscle regulatory factors were not different between groups. While the pancreatic β-cell mass was lower in both IUGR-I and IUGR-S compared to CON-S, the IUGR groups were not different from each other indicating that feedback inhibition by endogenous insulin did not reduce β-cell mass. A two-week insulin infusion at 75% gestation promoted myoblast proliferation in the IUGR fetus but did not increase fiber or myonuclear number. Myoblasts in the IUGR fetus retain the capacity to proliferate in response to mitogenic stimuli, but intrinsic defects in the fetal myoblast by 75% gestation may limit the capacity to restore fiber number.

scholarly journals Increased fetal insulin concentrations for one week fail to improve insulin secretion or β-cell mass in fetal sheep with chronically reduced glucose supply

2013 ◽  
Vol 304 (1) ◽  
pp. R50-R58 ◽  
Author(s):  
Jinny R. Lavezzi ◽  
Stephanie R. Thorn ◽  
Meghan C. O'Meara ◽  
Dan LoTurco ◽  
Laura D. Brown ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Infusion ◽  
Cell Mass ◽  
Placental Insufficiency ◽  
Late Gestation ◽  
Β Cell ◽  
Fetal Sheep ◽  
Maternal Undernutrition ◽  
Pregnant Sheep ◽  
Glucose Supply

Maternal undernutrition during pregnancy and placental insufficiency are characterized by impaired development of fetal pancreatic β-cells. Prolonged reduced glucose supply to the fetus is a feature of both. It is unknown if reduced glucose supply, independent of other complications of maternal undernutrition and placental insufficiency, would cause similar β-cell defects. Therefore, we measured fetal insulin secretion and β-cell mass following prolonged reduced fetal glucose supply in sheep. We also tested whether restoring physiological insulin concentrations would correct any β-cell defects. Pregnant sheep received either a direct saline infusion (CON = control, n = 5) or an insulin infusion (HG = hypoglycemic, n = 5) for 8 wk in late gestation (75 to 134 days) to decrease maternal glucose concentrations and reduce fetal glucose supply. A separate group of HG fetuses also received a direct fetal insulin infusion for the final week of the study with a dextrose infusion to prevent a further fall in glucose concentration [hypoglycemic + insulin (HG+I), n = 4]. Maximum glucose-stimulated insulin concentrations were 45% lower in HG fetuses compared with CON fetuses. β-Cell, pancreatic, and fetal mass were 50%, 37%, and 40% lower in HG compared with CON fetuses, respectively ( P < 0.05). Insulin secretion and β-cell mass did not improve in the HG+I fetuses. These results indicate that chronically reduced fetal glucose supply is sufficient to reduce pancreatic insulin secretion in response to glucose, primarily due to reduced pancreatic and β-cell mass, and is not correctable with insulin.

Diminished β-cell replication contributes to reduced β-cell mass in fetal sheep with intrauterine growth restriction

2005 ◽  
Vol 288 (5) ◽  
pp. R1297-R1305 ◽  
Author(s):  
Sean W. Limesand ◽  
Jan Jensen ◽  
John C. Hutton ◽  
William W. Hay
Keyword(s):  
Intrauterine Growth Restriction ◽  
Cell Mass ◽  
Later Life ◽  
Growth Restriction ◽  
Pancreatic Β Cell ◽  
Cell Replication ◽  
Β Cells ◽  
Β Cell ◽  
Fetal Sheep ◽  
Intrauterine Growth

Human fetuses with severe intrauterine growth restriction (IUGR) have less pancreatic endocrine tissue and exhibit β-cell dysfunction, which may limit β-cell function in later life and contribute to their increased incidence of noninsulin-dependent diabetes mellitus. Three factors, replication, apoptosis, and neoformation, contribute to fetal β-cell mass. We studied an ovine model of IUGR to understand whether nutrient deficits lead to decreased rates of fetal pancreatic β-cell replication, increased rates of apoptosis, or lower rates of differentiation. At 90% of term gestation, IUGR fetal and pancreatic weights were 58% and 59% less than pair-fed control, respectively. We identified a selective impairment of β-cell mass compared with other pancreatic cell types in IUGR fetuses. Insulin and insulin mRNA contents were less than other pancreatic endocrine hormones in IUGR fetuses, as were pancreatic insulin positive area (42%) and β-cell mass (76%). Pancreatic β-cell apoptosis was not different between treatments. β-cell capacity for cell cycling, determined by proliferating cell nuclear antigen (PCNA) immunostaining, was not different between treatment groups. However, the percentage of β-cells actually undergoing mitosis was 72% lower in IUGR fetuses. These results indicate that in utero nutrient deficits decrease the population of pancreatic β-cells by lengthening G1, S, and G2 stages of interphase and decreasing mitosis near term. Diminished β-cell mass in IUGR infants at birth, if not adequately compensated for after birth, may contribute to insufficient insulin production in later life and, thus, a predisposition to noninsulin-dependent diabetes.

scholarly journals Pulsatile hyperglycemia increases insulin secretion but not pancreatic β-cell mass in intrauterine growth-restricted fetal sheep

2018 ◽  
Vol 9 (5) ◽  
pp. 492-499 ◽  
Author(s):  
B. H. Boehmer ◽  
L. D. Brown ◽  
S. R. Wesolowski ◽  
W. W. Hay ◽  
P. J. Rozance
Keyword(s):  
Insulin Secretion ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Fetal Sheep ◽  
Square Wave ◽  
Cell Numbers ◽  
Intrauterine Growth ◽  
Hyperglycemic Clamp

AbstractImpaired β-cell development and insulin secretion are characteristic of intrauterine growth-restricted (IUGR) fetuses. In normally grown late gestation fetal sheep pancreatic β-cell numbers and insulin secretion are increased by 7–10 days of pulsatile hyperglycemia (PHG). Our objective was to determine if IUGR fetal sheep β-cell numbers and insulin secretion could also be increased by PHG or if IUGR fetal β-cells do not have the capacity to respond to PHG. Following chronic placental insufficiency producing IUGR in twin gestation pregnancies (n=7), fetuses were administered a PHG infusion, consisting of 60 min, high rate, pulsed infusions of dextrose three times a day with an additional continuous, low-rate infusion of dextrose to prevent a decrease in glucose concentrations between the pulses or a control saline infusion. PHG fetuses were compared with their twin IUGR fetus, which received a saline infusion for 7 days. The pulsed glucose infusion increased fetal arterial glucose concentrations an average of 83% during the infusion. Following the 7-day infusion, a square-wave fetal hyperglycemic clamp was performed in both groups to measure insulin secretion. The rate of increase in fetal insulin concentrations during the first 20 min of a square-wave hyperglycemic clamp was 44% faster in the PHG fetuses compared with saline fetuses (P<0.05). There were no differences in islet size, the insulin+ area of the pancreas and of the islets, and β-cell mass between groups (P>0.23). Chronic PHG increases early phase insulin secretion in response to acute hyperglycemia, indicating that IUGR fetal β-cells are functionally responsive to chronic PHG.

scholarly journals Characterization of glucose-insulin responsiveness and impact of fetal number and sex difference on insulin response in the sheep fetus

2011 ◽  
Vol 300 (5) ◽  
pp. E817-E823 ◽  
Author(s):  
Alice S. Green ◽  
Antoni R. Macko ◽  
Paul J. Rozance ◽  
Dustin T. Yates ◽  
Xiaochuan Chen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Sex Difference ◽  
Cell Mass ◽  
Insulin Response ◽  
Β Cell ◽  
Fetal Sheep ◽  
Square Wave ◽  
Hyperglycemic Clamp ◽  
Insulin Responsiveness ◽  
Sheep Fetus

GSIS is often measured in the sheep fetus by a square-wave hyperglycemic clamp, but maximal β-cell responsiveness and effects of fetal number and sex difference have not been fully evaluated. We determined the dose-response curve for GSIS in fetal sheep (0.9 of gestation) by increasing plasma glucose from euglycemia in a stepwise fashion. The glucose-insulin response was best fit by curvilinear third-order polynomial equations for singletons ( y = 0.018 x3 − 0.26 x2 + 1.2 x − 0.64) and twins ( y = −0.012 x3 + 0.043 x2 + 0.40 x − 0.16). In singles, maximal insulin secretion was achieved at 3.4 ± 0.2 mmol/l glucose but began to plateau after 2.4 ± 0.2 mmol/l glucose (90% of maximum), whereas the maximum for twins was reached at 4.8 ± 0.4 mmol/l glucose. In twin ( n = 18) and singleton ( n = 49) fetuses, GSIS was determined with a square-wave hyperglycemic clamp >2.4 mmol/l glucose. Twins had a lower basal glucose concentration, and plasma insulin concentrations were 59 ( P < 0.01) and 43% ( P < 0.05) lower in twins than singletons during the euglycemic and hyperglycemic periods, respectively. The basal glucose/insulin ratio was approximately doubled in twins vs. singles ( P < 0.001), indicating greater insulin sensitivity. In a separate cohort of fetuses, twins ( n = 8) had lower body weight ( P < 0.05) and β-cell mass ( P < 0.01) than singleton fetuses ( n = 7) as a result of smaller pancreata ( P < 0.01) and a positive correlation ( P < 0.05) between insulin immunopositive area and fetal weight ( P < 0.05). No effects of sex difference on GSIS or β-cell mass were observed. These findings indicate that insulin secretion is less responsive to physiological glucose concentrations in twins, due in part to less β-cell mass.

Prevention of hypoinsulinemia modifies catecholamine effects in fetal sheep

2000 ◽  
Vol 278 (5) ◽  
pp. R1171-R1181 ◽  
Author(s):  
John M. Bassett ◽  
Clifford Hanson
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Insulin Secretion ◽  
Metabolic Activity ◽  
Plasma Glucose ◽  
Insulin Infusion ◽  
Prolonged Infusion ◽  
Fetal Sheep ◽  
Intravenous Insulin ◽  
Arterial Blood

Increased epinephrine (Epi) and norepinephrine (NE) production plays an important role in fetal adaptation to reduced oxygen and/or nutrient availability, inhibiting insulin secretion and slowing growth to support more essential processes. To assess the importance of hypoinsulinemia for the efficacy of catecholamines, normoinsulinemia was restored by intravenous insulin infusion (0.18 mU ⋅ kg− 1 ⋅ min− 1) during prolonged infusion of either Epi (0.25–0.35 μg ⋅ kg− 1 ⋅ min− 1for 12 days, n = 7) or NE (0.5–0.7 μg ⋅ kg− 1 ⋅ min− 1for 7 days, n = 6) into normoxemic fetuses in twin-pregnant ewes, from 125–127 days of gestation. Insulin infusion for 8 days during Epi infusion or for 4 days during NE infusion decreased arterial blood pressure, O2 content, and plasma glucose, but increased heart rate significantly (all P <0.05), despite continuation of Epi or NE infusion. Cessation of insulin infusion reversed these changes. Estimated growth of fetuses infused with insulin during Epi or NE infusion (55 ± 13.9 and 83 ± 15.2 g/day) did not differ significantly from that of untreated controls (72 ± 15.4 g/day, n = 6). Growth of selected muscles and hindlimb bones was not altered either. Restoration of normoinsulinemia evidently counteracts the redistribution of metabolic activity and decreased anabolism brought about by Epi or NE in the fetus. Inhibition of insulin secretion by Epi and NE, therefore, appears essential for the efficacy of catecholamine action in the fetus.

Atrial tachycardia causes hydrops in fetal lambs

1990 ◽  
Vol 258 (4) ◽  
pp. H1159-H1163
Author(s):  
A. L. Gest ◽  
T. N. Hansen ◽  
A. A. Moise ◽  
C. J. Hartley
Keyword(s):  
Plasma Protein ◽  
Protein Concentration ◽  
Venous Pressure ◽  
Cell Mass ◽  
Turnover Time ◽  
Base Line ◽  
Albumin Concentration ◽  
Edema Formation ◽  
Fetal Sheep ◽  
Arterial Blood

The purpose of this project was to study mechanisms responsible for edema formation in fetuses with hydrops. We produced hydrops fetalis in 28 fetal sheep [gestational age of 125 +/- 5 days (mean +/- SD)] by pacing their atria at 300-320 beats/min for 68 +/- 40 (SD) h. All fetuses developed peripheral edema and ascites [volume of ascitic fluid was 134 +/- 75 (SD) ml; total protein concentration was 3.10 +/- 0.6 (SD) g/dl, and total albumin concentration was 1.68 +/- 0.3 (SD) g/dl]. Pacing did not affect aortic pressure but increased venous pressure from 4 +/- 1 to 8 +/- 1 (SE) Torr. Pacing did not affect pH, arterial partial pressure of O2 (PaO2), or Na+ but increased PaCO2 from 53 +/- 1 to 55 +/- 1 (SE) Torr and K+ from 3.9 +/- 0.1 to 4.3 +/- 0.1 (SE) meq/l. Hematocrit increased from 29 +/- 1 to 32 +/- 1 (SE)% acutely with pacing but returned to base line by the last day of the experiment. Plasma protein concentration decreased slightly from 3.7 +/- 0.1 to 3.5 +/- 0.1 (SE) g/dl by the last day of the experiment; plasma albumin concentration did not change. Plasma volume decreased acutely from 271 +/- 19 to 238 +/- 16 (SE) ml and then remained decreased throughout the experiment. Red blood cell mass and the turnover time for albumin were not affected by pacing. We found no consistent relationship between edema formation and changes in arterial blood gas tensions, plasma protein concentrations, or the turnover time for albumin.2

Glucocorticoids impair fetal β-cell development in rats

2001 ◽  
Vol 281 (3) ◽  
pp. E592-E599 ◽  
Author(s):  
B. Blondeau ◽  
J. Lesage ◽  
P. Czernichow ◽  
J. P. Dupouy ◽  
B. Bréant
Keyword(s):  
Glucose Intolerance ◽  
Growth Retardation ◽  
Potential Role ◽  
Cell Mass ◽  
Cell Development ◽  
Insulin Content ◽  
Β Cell ◽  
Intrauterine Growth ◽  
Negative Role

In rats, poor fetal growth due to maternal food restriction during pregnancy is associated with decreased β-cell mass at birth and glucose intolerance in adulthood. Overexposure to glucocorticoids in utero can induce intrauterine growth retardation in humans and animals and subsequent glucose intolerance in rodents. The aims of this study were to investigate whether glucocorticoid overexposure mediates the effect of undernutrition on β-cell mass and to study their potential role in normally nourished rats. Undernutrition significantly increased maternal and fetal corticosterone levels. Twenty-one-day-old fetuses with undernutrition showed growth retardation and decreased pancreatic insulin content; adrenalectomy and subcutaneous corticosterone implants in their dams prevented the maternal corticosterone increase and restored fetal β-cell mass. In fetuses with normal nutrition, fetal corticosterone levels were negatively correlated to fetal weight and insulin content; fetal β-cell mass increased from 355 ± 48 μg in sham to 516 ± 160 μg after maternal adrenalectomy; inhibition of steroid production by metyrapone induced a further increase to 757 ± 125 μg. Our data support the new concept of a negative role of glucocorticoids in fetal β-cell development.

scholarly journals Adrenal Demedullation and Oxygen Supplementation Independently Increase Glucose-Stimulated Insulin Concentrations in Fetal Sheep With Intrauterine Growth Restriction

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 2104-2115 ◽  
Author(s):  
Antoni R. Macko ◽  
Dustin T. Yates ◽  
Xiaochuan Chen ◽  
Leslie A. Shelton ◽  
Amy C. Kelly ◽  
...  
Keyword(s):  
Intrauterine Growth Restriction ◽  
Arterial Oxygen Tension ◽  
Placental Insufficiency ◽  
Growth Restriction ◽  
Arterial Oxygen ◽  
Plasma Norepinephrine ◽  
Β Cell ◽  
Fetal Sheep ◽  
Intrauterine Growth ◽  
Chronic Hypoxemia

Abstract In pregnancies complicated by placental insufficiency and intrauterine growth restriction (IUGR), fetal glucose and oxygen concentrations are reduced, whereas plasma norepinephrine and epinephrine concentrations are elevated throughout the final third of gestation. Here we study the effects of chronic hypoxemia and hypercatecholaminemia on β-cell function in fetal sheep with placental insufficiency-induced IUGR that is produced by maternal hyperthermia. IUGR and control fetuses underwent a sham (intact) or bilateral adrenal demedullation (AD) surgical procedure at 0.65 gestation. As expected, AD-IUGR fetuses had lower norepinephrine concentrations than intact-IUGR fetuses despite being hypoxemic and hypoglycemic. Placental insufficiency reduced fetal weights, but the severity of IUGR was less with AD. Although basal plasma insulin concentrations were lower in intact-IUGR and AD-IUGR fetuses compared with intact-controls, glucose-stimulated insulin concentrations were greater in AD-IUGR fetuses compared with intact-IUGR fetuses. Interestingly, AD-controls had lower glucose- and arginine-stimulated insulin concentrations than intact-controls, but AD-IUGR and AD-control insulin responses were not different. To investigate chronic hypoxemia in the IUGR fetus, arterial oxygen tension was increased to normal levels by increasing the maternal inspired oxygen fraction. Oxygenation of IUGR fetuses enhanced glucose-stimulated insulin concentrations 3.3-fold in intact-IUGR and 1.7-fold in AD-IUGR fetuses but did not lower norepinephrine and epinephrine concentrations. Together these findings show that chronic hypoxemia and hypercatecholaminemia have distinct but complementary roles in the suppression of β-cell responsiveness in IUGR fetuses.

scholarly journals Increased amino acid supply potentiates glucose-stimulated insulin secretion but does not increase β-cell mass in fetal sheep

2013 ◽  
Vol 304 (4) ◽  
pp. E352-E362 ◽  
Author(s):  
Monika M. Gadhia ◽  
Anne M. Maliszewski ◽  
Meghan C. O'Meara ◽  
Stephanie R. Thorn ◽  
Jinny R. Lavezzi ◽  
...  
Keyword(s):  
Amino Acids ◽  
Insulin Secretion ◽  
Amino Acid ◽  
Cell Mass ◽  
Late Gestation ◽  
Insulin Content ◽  
Acid Mixture ◽  
Β Cell ◽  
Fetal Sheep ◽  
Glucose Stimulated Insulin Secretion

Amino acids and glucose acutely stimulate fetal insulin secretion. In isolated adult pancreatic islets, amino acids potentiate glucose-stimulated insulin secretion (GSIS), but whether amino acids have this same effect in the fetus is unknown. Therefore, we tested the effects of increased fetal amino acid supply on GSIS and morphology of the pancreas. We hypothesized that increasing fetal amino acid supply would potentiate GSIS. Singleton fetal sheep received a direct intravenous infusion of an amino acid mixture (AA) or saline (CON) for 10–14 days during late gestation to target a 25–50% increase in fetal branched-chain amino acids (BCAA). Early-phase GSIS increased 150% in the AA group ( P < 0.01), and this difference was sustained for the duration of the hyperglycemic clamp (105 min) ( P < 0.05). Glucose-potentiated arginine-stimulated insulin secretion (ASIS), pancreatic insulin content, and pancreatic glucagon content were similar between groups. β-Cell mass and area were unchanged between groups. Baseline and arginine-stimulated glucagon concentrations were increased in the AA group ( P < 0.05). Pancreatic α-cell mass and area were unchanged. Fetal and pancreatic weights were similar. We conclude that a sustained increase of amino acid supply to the normally growing late-gestation fetus potentiated fetal GSIS but did not affect the morphology or insulin content of the pancreas. We speculate that increased β-cell responsiveness (insulin secretion) following increased amino acid supply may be due to increased generation of secondary messengers in the β-cell. This may be enhanced by the paracrine action of glucagon on the β-cell.

Exercise as an intervention to improve metabolic outcomes after intrauterine growth restriction

2014 ◽  
Vol 306 (9) ◽  
pp. E999-E1012 ◽  
Author(s):  
Kathryn L. Gatford ◽  
Gunveen Kaur ◽  
Filippe Falcão-Tebas ◽  
Glenn D. Wadley ◽  
Mary E. Wlodek ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Intrauterine Growth Restriction ◽  
Cell Mass ◽  
Growth Restriction ◽  
Metabolic Effects ◽  
Β Cell ◽  
Early Exercise ◽  
Intrauterine Growth ◽  
Increased Risk

Individuals born after intrauterine growth restriction (IUGR) are at an increased risk of developing diabetes in their adult life. IUGR impairs β-cell function and reduces β-cell mass, thereby diminishing insulin secretion. IUGR also induces insulin resistance, with impaired insulin signaling in muscle in adult humans who were small for gestational age (SGA) and in rodent models of IUGR. There is epidemiological evidence in humans that exercise in adults can reduce the risk of metabolic disease following IUGR. However, it is not clear whether adult IUGR individuals benefit to the same extent from exercise as do normal-birth-weight individuals, as our rat studies suggest less of a benefit in those born IUGR. Importantly, however, there is some evidence from studies in rats that exercise in early life might be able to reverse or reprogram the long-term metabolic effects of IUGR. Studies are needed to address gaps in current knowledge, including determining the mechanisms involved in the reprogramming effects of early exercise in rats, whether exercise early in life or in adulthood has similar beneficial metabolic effects in larger animal models in which insulin resistance develops after IUGR. Human studies are also needed to determine whether exercise training improves insulin secretion and insulin sensitivity to the same extent in IUGR adults as in control populations. Such investigations will have implications for customizing the recommended level and timing of exercise to improve metabolic health after IUGR.

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