scholarly journals Sustained maternal inflammation during the early third-trimester yields intrauterine growth restriction, impaired skeletal muscle glucose metabolism, and diminished β-cell function in fetal sheep1,2

2019 ◽  
Vol 97 (12) ◽  
pp. 4822-4833 ◽  
Author(s):  
Caitlin N Cadaret ◽  
Elena M Merrick ◽  
Taylor L Barnes ◽  
Kristin A Beede ◽  
Robert J Posont ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Intrauterine Growth Restriction ◽  
Cell Function ◽  
Ex Vivo ◽  
White Blood Cells ◽  
Β Cell ◽  
Intrauterine Growth ◽  
Maternal Inflammation ◽  
Β Cell Function

Abstract Maternal inflammation causes fetal intrauterine growth restriction (IUGR), but its impact on fetal metabolism is not known. Thus, our objective was to determine the impact of sustained maternal inflammation in late gestation on fetal inflammation, skeletal muscle glucose metabolism, and insulin secretion. Pregnant ewes were injected every third day from the 100th to 112th day of gestation (term = 150 d) with saline (controls) or lipopolysaccharide (LPS) to induce maternal inflammation and IUGR (MI-IUGR). Fetal femoral blood vessels were catheterized on day 118 to assess β-cell function on day 123, hindlimb glucose metabolic rates on day 124, and daily blood parameters from days 120 to 125. Fetal muscle was isolated on day 125 to assess ex vivo glucose metabolism. Injection of LPS increased (P < 0.05) rectal temperatures, circulating white blood cells, and plasma tumor necrosis factor α (TNFα) concentrations in MI-IUGR ewes. Maternal leukocytes remained elevated (P < 0.05) and TNFα tended to remain elevated (P < 0.10) compared with controls almost 2 wk after the final LPS injection. Total white blood cells, monocytes, granulocytes, and TNFα were also greater (P < 0.05) in MI-IUGR fetuses than controls over this period. MI-IUGR fetuses had reduced (P < 0.05) blood O2 partial pressures and greater (P < 0.05) maternofetal O2 gradients, but blood glucose and maternofetal glucose gradients did not differ from controls. Basal and glucose-stimulated insulin secretion were reduced (P < 0.05) by 32% and 42%, respectively, in MI-IUGR fetuses. In vivo hindlimb glucose oxidation did not differ between groups under resting conditions but was 47% less (P < 0.05) in MI-IUGR fetuses than controls during hyperinsulinemia. Hindlimb glucose utilization did not differ between fetal groups. At day 125, MI-IUGR fetuses were 22% lighter (P < 0.05) than controls and tended to have greater (P < 0.10) brain/BW ratios. Ex vivo skeletal muscle glucose oxidation did not differ between groups in basal media but was less (P < 0.05) for MI-IUGR fetuses in insulin-spiked media. Glucose uptake rates and phosphorylated-to-total Akt ratios were less (P < 0.05) in muscle from MI-IUGR fetuses than controls regardless of media. We conclude that maternal inflammation leads to fetal inflammation, reduced β-cell function, and impaired skeletal muscle glucose metabolism that persists after maternal inflammation ceases. Moreover, fetal inflammation may represent a target for improving metabolic dysfunction in IUGR fetuses.

scholarly journals Impaired β-Cell Function and Inadequate Compensatory Increases in β-Cell Mass after Intrauterine Growth Restriction in Sheep

Endocrinology ◽  
2008 ◽  
Vol 149 (10) ◽  
pp. 5118-5127 ◽  
Author(s):  
Kathryn L. Gatford ◽  
Saidatul N. B. Mohammad ◽  
M. Lyn Harland ◽  
Miles J. De Blasio ◽  
Abigail L. Fowden ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Intrauterine Growth Restriction ◽  
Cell Function ◽  
Cell Mass ◽  
Growth Restriction ◽  
Adult Males ◽  
Β Cell ◽  
Voltage Gated ◽  
Intrauterine Growth ◽  
Β Cell Function

Poor growth before birth increases the risk of non-insulin-dependent diabetes mellitus (NIDDM) and impairs insulin secretion relative to sensitivity. We investigated the effects of intrauterine growth restriction in sheep on insulin secretion, β-cell mass, and function from before birth to young adulthood and its molecular basis. Pancreas was collected from control and placentally restricted sheep as fetuses (d 143 gestation), lambs (aged 42 d), and young adults (aged 556 d), following independent measures of in vivo insulin secretion and sensitivity. β-Cells and islets were counted after immunohistochemical staining for insulin. In lambs, gene expression was measured by RT-PCR and expressed relative to 18S. β-Cell mass correlated positively with fetal weight but negatively with birth weight in adult males. Glucose-stimulated insulin disposition and β-cell function correlated negatively with fetal weight but positively with birth weight in adult males. Placental restriction increased pancreatic expression of IGF-II and IGF-I but decreased that of voltage-gated calcium channel, α1D subunit (CACNA1D) in lambs. In male lambs, pancreatic IGF-II and insulin receptor expression correlated strongly and positively with β-cell mass and CACNA1D expression with glucose-stimulated insulin disposition. Restricted growth before birth in the sheep does not impair insulin secretion, relative to sensitivity, before birth or in young offspring. IGF-II and insulin receptor are implicated as key molecular regulators of β-cell mass compensation, whereas impaired expression of the voltage-gated calcium channel may underlie impaired β-cell function after intrauterine growth restriction. With aging, the insulin secretory capacity of the β-cell is impaired in males, and their increases in β-cell mass are inadequate to maintain adequate insulin secretion relative to sensitivity.

scholarly journals Maternal inflammation at midgestation impairs subsequent fetal myoblast function and skeletal muscle growth in rats, resulting in intrauterine growth restriction at term1

2019 ◽  
Vol 3 (2) ◽  
pp. 867-876 ◽  
Author(s):  
Caitlin N Cadaret ◽  
Robert J Posont ◽  
Kristin A Beede ◽  
Hannah E Riley ◽  
John Dustin Loy ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Glucose ◽  
Intrauterine Growth Restriction ◽  
Muscle Growth ◽  
Maternal Blood ◽  
Protein Catabolism ◽  
Fetal Blood ◽  
Intrauterine Growth ◽  
Skeletal Muscle Growth ◽  
Maternal Inflammation

Abstract Maternal inflammation induces intrauterine growth restriction (MI-IUGR) of the fetus, which compromises metabolic health in human offspring and reduces value in livestock. The objective of this study was to determine the effect of maternal inflammation at midgestation on fetal skeletal muscle growth and myoblast profiles at term. Pregnant Sprague-Dawley rats were injected daily with bacterial endotoxin (MI-IUGR) or saline (controls) from the 9th to the 11th day of gestational age (dGA; term = 21 dGA). At necropsy on dGA 20, average fetal mass and upper hindlimb cross-sectional areas were reduced (P < 0.05) in MI-IUGR fetuses compared with controls. MyoD+ and myf5+ myoblasts were less abundant (P < 0.05), and myogenin+ myoblasts were more abundant (P < 0.05) in MI-IUGR hindlimb skeletal muscle compared with controls, indicating precocious myoblast differentiation. Type I and Type II hindlimb muscle fibers were smaller (P < 0.05) in MI-IUGR fetuses than in controls, but fiber type proportions did not differ between experimental groups. Fetal blood plasma TNFα concentrations were below detectable amounts in both experimental groups, but skeletal muscle gene expression for the cytokine receptors TNFR1, IL6R, and FN14 was greater (P < 0.05) in MI-IUGR fetuses than controls, perhaps indicating enhanced sensitivity to these cytokines. Maternal blood glucose concentrations at term did not differ between experimental groups, but MI-IUGR fetal blood contained less (P < 0.05) glucose, cholesterol, and triglycerides. Fetal-to-maternal blood glucose ratios were also reduced (P < 0.05), which is indicative of placental insufficiency. Indicators of protein catabolism, including blood plasma urea nitrogen and creatine kinase, were greater (P < 0.05) in MI-IUGR fetuses than in controls. From these findings, we conclude that maternal inflammation at midgestation causes muscle-centric fetal programming that impairs myoblast function, increases protein catabolism, and reduces skeletal muscle growth near term. Fetal muscle sensitivity to inflammatory cytokines appeared to be enhanced after maternal inflammation, which may represent a mechanistic target for improving these outcomes in MI-IUGR fetuses.

Ketosis-Prone Type 2 Diabetes: Effect of Hyperglycemia on β-Cell Function and Skeletal Muscle Insulin Signaling

2007 ◽  
Vol 13 (3) ◽  
pp. 283-290 ◽  
Author(s):  
Guillermo Umpierrez ◽  
Dawn Smiley ◽  
Aidar Gosmanov ◽  
Donald Thomason
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Insulin Signaling ◽  
Cell Function ◽  
Β Cell ◽  
Β Cell Function

scholarly journals Maternal high-fat diet impairs glucose metabolism, β-cell function and proliferation in the second generation of offspring rats

2017 ◽  
Vol 14 (1) ◽  
Author(s):  
Yan-Hong Huang ◽  
Ting-Ting Ye ◽  
Chong-Xiao Liu ◽  
Lei Wang ◽  
Yuan-Wen Chen ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
High Fat Diet ◽  
Second Generation ◽  
Cell Function ◽  
High Fat ◽  
Β Cell ◽  
Β Cell Function

scholarly journals The Cardiolipin Transacylase Tafazzin Regulates Basal Insulin Secretion and Mitochondrial Function in Pancreatic Islets from Mice

2021 ◽  
Author(s):  
Laura K. Cole ◽  
Prasoon Agarwal ◽  
Christine Doucette ◽  
Mario Fonseca ◽  
Bo Xiang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Mitochondrial Function ◽  
Cell Function ◽  
Ex Vivo ◽  
Rna Seq ◽  
Β Cell ◽  
Mitochondrial Oxygen Consumption ◽  
Β Cell Function ◽  
Low Glucose

ABSTRACTObjectiveTafazzin (TAZ) is a cardiolipin (CL) biosynthetic enzyme important for maintaining mitochondrial function. TAZ impacts both the species and content of CL in the inner mitochondrial membrane which are essential for normal cellular respiration. In pancreatic β-cells, mitochondrial function is closely associated with insulin secretion. However, the role of TAZ and CL in the secretion of insulin from pancreatic islets remains unknown.MethodsMale 4-month-old doxycycline-inducible TAZ knock-down (TAZ KD) mice and wild-type littermate controls were utilized. Immunohistochemistry was used to assess β-cell morphology in whole pancreas sections, while ex vivo insulin secretion, CL content, RNA-Seq analysis and mitochondrial oxygen consumption were measured from isolated islet preparations.ResultsEx vivo insulin secretion under non-stimulatory low-glucose concentrations was reduced ∼52% from islets isolated from TAZ KD mice. Mitochondrial oxygen consumption under low-glucose conditions was also reduced ∼58% in islets from TAZ KD animals. TAZ-deficiency in pancreatic islets was associated with significant alteration in CL molecular species and reduced oxidized CL content. In addition, RNA-Seq of isolated islets showed that TAZ KD increased expression of extracellular matrix genes which are linked to pancreatic fibrosis, activated stellate cells and impaired β-cell function.ConclusionThese data indicate a novel role for TAZ in regulating normal β-cell function, particularly under low-glucose conditions.

scholarly journals Cigarette Smoke Exposure Impairs β-Cell Function Through Activation of Oxidative Stress and Ceramide Accumulation

2019 ◽  
Author(s):  
Xin Tong ◽  
Zunaira Chaudry ◽  
Chih-Chun Lee ◽  
Robert N. Bone ◽  
Sukrati Kanojia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smoking Cessation ◽  
Weight Gain ◽  
Cell Function ◽  
Ex Vivo ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Β Cell Function ◽  
Ceramide Accumulation

ABSTRACTObjectivesEpidemiological studies indicate that first- and second-hand cigarette smoke (CS) exposure are important risk factors for the development of type 2 diabetes (T2D). Additionally, elevated diabetes risk has been reported to occur within a short period of time after smoking cessation, and health risks associated with smoking are increased when combined with obesity. At present, the mechanisms underlying these associations remain incompletely understood. The objective of this study was to test the impact of CS exposure on pancreatic β-cell function using rodent and in vitro models.MethodsBeginning at 8 weeks of age, C57BL/6J mice were concurrently fed high fat-diet (HFD) and exposed to CS for 11 weeks, followed by an additional 11 weeks of smoking cessation with continued HFD exposure. Glucose tolerance testing was performed during CS exposure and during the cessation period. Cultured β-cells (INS-1) and primary islets were exposed ex vivo to CS extract (CSE), and β-cell function and viability were tested. Since CS increases ceramide in lungs cells and these bioactive sphingolipids have been implicated in pancreatic β-cell dysfunction in diabetes, islet and β-cell sphingolipid levels were measured in islets from CS-exposed mice and in CSE-treated islets and INS-1 cells using liquid chromatography-tandem mass spectrometry.ResultsCompared to HFD-fed ambient air-exposed mice, HFD-fed and CS- exposed mice had reduced weight gain and better glucose tolerance during the active smoking period. Following smoking cessation, CS-mice exhibited rapid weight gain and a significantly greater increase in glucose intolerance compared to non-smoking control mice. CS-exposed mice had higher serum proinsulin/insulin ratios, indicative of β-cell dysfunction, significantly lower β-cell mass (p=0.02), and reduced β-cell proliferation (p=0.006), and increased islet ceramide accumulation. Ex vivo exposure of isolated islets to CSE was sufficient to increase islet ceramide accumulation, reduce insulin gene expression and glucose-stimulated insulin secretion, and increase β-cell oxidative and ER stress. Treatment with the antioxidant N-acetylcysteine, markedly attenuated the effects of CSE on ceramide levels, restored β-cell function and survival, and increased cyclin D2 expression, while also reducing activation of β-cell ER and oxidative stress.ConclusionsOur results indicate that CS exposure inhibits insulin production, processing, and secretion and reduced β-cell viability and proliferation. These effects were linked to increased β-cell oxidative and ER stress and ceramide accumulation. Mice fed HFD continued to experience detrimental effects of CS exposure even during smoking cessation. Elucidation of mechanisms by which CS exposure impairs β-cell function in synergy with obesity will help design therapeutic and preventive interventions for both active and former smokers.

scholarly journals Lipocalin-2 counteracts metabolic dysregulation in obesity and diabetes

2020 ◽  
Vol 217 (10) ◽  
Author(s):  
Ioanna Mosialou ◽  
Steven Shikhel ◽  
Na Luo ◽  
Peristera Ioanna Petropoulou ◽  
Konstantinos Panitsas ◽  
...  
Keyword(s):  
Food Intake ◽  
Glucose Metabolism ◽  
Cell Function ◽  
Endocrine Function ◽  
Protective Mechanism ◽  
Lipocalin 2 ◽  
Obese Mice ◽  
Β Cell ◽  
Obesity And Diabetes ◽  
Β Cell Function

Regulation of food intake is a recently identified endocrine function of bone that is mediated by Lipocalin-2 (LCN2). Osteoblast-secreted LCN2 suppresses appetite and decreases fat mass while improving glucose metabolism. We now show that serum LCN2 levels correlate with insulin levels and β-cell function, indices of healthy glucose metabolism, in obese mice and obese, prediabetic women. However, LCN2 serum levels also correlate with body mass index and insulin resistance in the same individuals and are increased in obese mice. To dissect this apparent discrepancy, we modulated LCN2 levels in mice. Silencing Lcn2 expression worsens metabolic dysfunction in genetic and diet-induced obese mice. Conversely, increasing circulating LCN2 levels improves metabolic parameters and promotes β-cell function in mouse models of β-cell failure acting as a growth factor necessary for β-cell adaptation to higher metabolic load. These results indicate that LCN2 up-regulation is a protective mechanism to counteract obesity-induced glucose intolerance by decreasing food intake and promoting adaptive β-cell proliferation.

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