Aberrant insulin-induced GLUT4 translocation predicts glucose intolerance in the offspring of a diabetic mother

Thamotharan, Manikkavasagar; McKnight, Robert A.; Thamotharan, Shanthie; Kao, Doris J.; Devaskar, Sherin U.

doi:10.1152/ajpendo.00516.2002

Cited by 32 publications

(58 citation statements)

References 40 publications

(51 reference statements)

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“…GLUT 4 protein concentrations were assessed by quantification of the protein bands by densitometry. The presence of linearity between the time of autoradiographic exposure and the optical density of the GLUT 4 bands was initially ensured (47).…”

Section: Methodsmentioning

confidence: 99%

Postnatal glucocorticoid exposure alters the adult phenotype

He¹,

Varma²,

Weissfeld³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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He, Jing, Amit Varma, Lisa A. Weissfeld, and Sherin U. Devaskar. Postnatal glucocorticoid exposure alters the adult phenotype. Am J Physiol Regul Integr Comp Physiol 287: R198 -R208, 2004. First published March 4, 2004 10.1152/ajpregu.00349.2003We examined the effect of six doses of dexamethasone (Dex) administered daily (2-7 days of age) to postnatal rats on body weight gain, food and water intake, peripheral hormonal/metabolic milieu, and hypothalamic neuropeptides that regulate food intake. We observed a Dex-induced acute (3 days of age) suppression of endogenous corticosterone and an increase in circulating leptin concentrations that were associated with a decrease in body weight in males and females. Followup during the suckling, postsuckling, and adult stages (7-120 days of age) revealed hypoleptinemia in males and females, and hypoinsulinemia, a relative increase in the glucose-to-insulin ratio, and a larger increase in skeletal muscle glucose transporter (GLUT 4) concentrations predominantly in the males, reflective of a catabolic state associated with a persistent decrease in body weight gain. The increase in the glucose-to-insulin ratio and hyperglycemia was associated with an increase in water intake. In addition, the changes in the hormonal/metabolic milieu were associated with an increase in hypothalamic neuropeptide Y content in males and females during the suckling phase, which persisted only in the 120-day-old female with a transient postnatal decline in ␣-melanocyte-stimulating hormone and corticotropin-releasing factor. This increase in neuropeptide Y (NPY) during the suckling phase in males and females was associated with a subsequent increase in adult food intake that outweighed the demands of body weight gain. In contrast to the adult hypothalamic findings, cerebral ventricular dilatation was more prominent in adult males. We conclude that postnatal Dex treatment causes permanent sex-specific changes in the adult phenotype, setting the stage for future development of diabetes (increased glucose:insulin ratio), obesity (increased NPY and food intake), and neurological impairment (loss of cerebral volume). development; food intake; neuropeptide Y; glucose transporters POSTNATAL GLUCOCORTICOID THERAPY constituted a standard intervention to combat chronic lung disease in the newborn premature infant (18,40). Recent reports of adverse outcomes such as cerebral palsy have cautioned the clinicians into judicious use of this drug (2, 17, 50). However, there still continue to be certain infants with chronic lung changes who are resilient to conventional modes of therapy warranting the use of postnatal glucocorticoids as a life-saving intervention (19,42). Furthermore, despite the absence of well-controlled trials, glucocorticoids are still used in term infants for differing indications other than prevention of chronic lung disease. While the adverse effects of antenatal glucocorticoid therapy have been examined and long-term changes reported in animals (13,20,33,37,38), limited studies exist in resp...

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Section: Methodsmentioning

confidence: 99%

Postnatal glucocorticoid exposure alters the adult phenotype

He¹,

Varma²,

Weissfeld³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

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“…The day 2 neonatal pups (under gentle restraint), day 60 and days 180 -240 adult female animals (in plastic rat restrainers), were subjected to a glucose tolerance test (GTT) as described previously (53). The neonatal pups from several litters were pooled to perform a single GTT.…”

Section: Glucose Tolerance Testmentioning

confidence: 99%

GLUT4 expression and subcellular localization in the intrauterine growth-restricted adult rat female offspring

Thamotharan¹,

Shin²,

Suddirikku³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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144

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Intrauterine growth restriction (IUGR) leads to obesity, glucose intolerance, and type 2 diabetes mellitus in the adult. To determine the mechanism(s) behind this “metabolic imprinting” phenomenon, we examined the effect of total calorie restriction during mid- to late gestation modified by postnatal ad libitum access to nutrients (CM/SP) or nutrient restriction (SM/SP) vs. postnatal nutrient restriction alone (SM/CP) on skeletal muscle and white adipose tissue (WAT) insulin-responsive glucose transporter isoform (GLUT4) expression and insulin-responsive translocation. A decline in skeletal muscle GLUT4 expression and protein concentrations was noted only in the SM/SP and SM/CP groups. In contrast, WAT demonstrated no change in GLUT4 expression and protein concentrations in all experimental groups. The altered in utero hormonal/metabolic milieu was associated with a compensatory adaptation that persisted in the adult and consisted of an increase in the skeletal muscle basal plasma membrane-associated GLUT4 concentrations. This perturbation led to no further exogenous insulin-induced GLUT4 translocation, thereby disabling the insulin responsiveness of the skeletal muscle but retaining it in WAT. These changes, which present at birth, collectively maximize basal glucose transport to the compromised skeletal muscle with a relative resistance to exogenous/postprandial insulin. Preservation of insulin responsiveness in WAT may serve as a sink that absorbs postprandial nutrients that can no longer efficiently access skeletal muscle. We speculate that, in utero, GLUT4 aberrations may predict type 2 diabetes mellitus, whereas postnatal nutrient intake may predict obesity, thereby explaining the heterogeneous phenotype of the IUGR adult offspring.

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“…The remaining homogenate was centrifuged at 3,000 g for 10 min at 44°C. The supernatant was saved for preparing the low-density microsome (LDM) enriched fraction, and the pellet was used to prepare the plasma membrane (PM) as previously described (22,36). PM and LDM fraction samples were frozen at 70°C pending Western blot analysis.…”

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confidence: 99%

“…They were exposed to a chemiluminescence reagent (Amersham Life Sciences, Little Chalfont, Buckinghamshire, UK), and the chemiluminescence was captured on X-ray film over exposure times of 1-5 min to determine the optimal exposure time. GLUT4 protein concentrations were measured by densitometry (1,22,36).…”

mentioning

confidence: 99%

Effects of acute hyperinsulinemia on insulin signal transduction and glucose transporters in ovine fetal skeletal muscle

Anderson

Thamotharan²,

Kao³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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. Effects of acute hyperinsulinemia on insulin signal transduction and glucose transporters in ovine fetal skeletal muscle. Am J Physiol Regul Integr Comp Physiol 288: R473-R481, 2005. First published November 11, 2004; doi:10.1152/ajpregu.00405.2004.-To test the effects of acute fetal hyperinsulinemia on the pattern and time course of insulin signaling in ovine fetal skeletal muscle, we measured selected signal transduction proteins in the mitogenic, protein synthetic, and metabolic pathways in the skeletal muscle of normally growing fetal sheep in utero. In experiment 1, 4-h hyperinsulinemiceuglycemic clamps were conducted in anesthetized twin fetuses to produce selective fetal hyperinsulinemia-euglycemia in one twin and euinsulinemia-euglycemia in the other. Serial skeletal muscle biopsies were taken from each fetus during the clamp and assayed by Western blot for selected insulin signal transduction proteins. Tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1, and the p85 subunit of phosphatidylinositol 3-kinase doubled at 30 min and gradually returned to control values by 240 min. Phosphorylation of extracellular signal-regulated kinase 1,2 was increased fivefold through 120 min of insulin infusion and decreased to control concentration by 240 min. Protein kinase B phosphorylation doubled at 30 min and remained elevated throughout the study. Phosphorylation of p70 S6K increased fourfold at 30, 60, and 120 min. In the second experiment, a separate group of nonanesthetized singleton fetuses was clamped to intermediate and high hyperinsulinemic-euglycemic conditions for 1 h. GLUT4 increased fourfold in the plasma membrane at 1 h, and hindlimb glucose uptake increased significantly at the higher insulin concentration. These data demonstrate that an acute increase in fetal plasma insulin concentration stimulates a unique pattern of insulin signal transduction proteins in intact skeletal muscle, thereby increasing pathways for mRNA translation, glucose transport, and cell growth. insulin signaling; fetal growth; glucose transporter 4 IN ADULT ANIMALS and humans, insulin has primarily a metabolic role to regulate skeletal muscle glucose uptake with less effect on skeletal muscle protein synthesis than in rapidly growing tissues. Although increased serum insulin concentration in the fetal sheep has been shown to increase fetal skeletal muscle glucose uptake, especially at pharmacological doses (17,18,20,21), insulin in the rapidly growing fetus seems to act largely as an anabolic hormone, promoting skeletal muscle protein synthesis and growth. In human fetuses, abnormal insulin concentrations contribute to variations in fetal growth; excessive insulin promotes fetal overgrowth, whereas insufficient insulin leads to fetal growth restriction. Animal studies have produced experimental deficiencies in insulin secretion in fetal lambs, resulting in fetal growth restriction and limited carcass protein accretion (27). Also, it has been shown in the neonatal pig that insulin action to promote s...

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Aberrant insulin-induced GLUT4 translocation predicts glucose intolerance in the offspring of a diabetic mother

Cited by 32 publications

References 40 publications

Postnatal glucocorticoid exposure alters the adult phenotype

Postnatal glucocorticoid exposure alters the adult phenotype

GLUT4 expression and subcellular localization in the intrauterine growth-restricted adult rat female offspring

Effects of acute hyperinsulinemia on insulin signal transduction and glucose transporters in ovine fetal skeletal muscle

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