bluuebunny/crossref_metadata_2025 huggingface dataset:
Fetal growth and the physiological control of glucose tolerance in adults: a minimal model analysis
Authors: Flanagan Daniel E. , Moore Vivienne M. , Godsland Ian F. , Cockington Richard A. , Robinson Jeffrey S. , Phillips David I. W.
Published: December 2017

Although there is now substantial evidence linking low birthweight with impaired glucose tolerance and type 2 diabetes in adult life, the extent to which reduced fetal growth is associated with impaired insulin sensitivity, defective insulin secretion, or a combination of both factors is not clear. We have therefore examined the relationships between birth size and both insulin sensitivity and insulin secretion as assessed by an intravenous glucose tolerance test with minimal model analysis in 163 men and women, aged 20 yr, born at term in Adelaide, South Australia. Birth size did not correlate with body mass index or fat distribution in men or women. Men who were lighter or shorter as babies were less insulin sensitive ( P = 0.03 and P = 0.01, respectively), independently of their body mass index or body fat distribution. They also had higher insulin secretion ( P = 0.007 and P = 0.006) and increased glucose effectiveness ( P = 0.003 and P = 0.003). Overall glucose tolerance, however, did not correlate with birth size, suggesting that the reduced insulin sensitivity was being compensated for by an increase in insulin secretion and insulin-independent glucose disposal. There were no relationships between birth size and insulin sensitivity or insulin secretion in women. These results show that small size at birth is associated with increased insulin resistance and hyperinsulinemia in young adult life but that these relationships are restricted to the male gender in this age group.
Interstitial glucose concentration and glycemia: implications for continuous subcutaneous glucose monitoring
Authors: Aussedat B. , Dupire-Angel M. , Gifford R. , Klein J. C. , Wilson G. S. , Reach G.
Published: December 2017

The changes in plasma glucose concentration and in interstitial glucose concentration, determined with a miniaturized subcutaneous glucose sensor, were investigated in anesthetized nondiabetic rats. Interstitial glucose was estimated through two different calibration procedures. First, after a glucose load, the magnitude of the increase in interstitial glucose, estimated through a one-point calibration procedure, was 70% of that in plasma glucose. We propose that this is due to the effect of endogenous insulin on peripheral glucose uptake. Second, during the spontaneous secondary decrease in plasma glucose after the glucose load, interstitial glucose decreased faster than plasma glucose, which may also be due to the effect of insulin on peripheral glucose uptake. Third, during insulin-induced hypoglycemia, the decrease in interstitial glucose was less marked than that of plasma glucose, suggesting that hypoglycemia suppressed transfer of glucose into the interstitial tissue; subsequently, interstitial glucose remained lower than plasma glucose during its return to basal value, suggesting that the stimulatory effect of insulin on peripheral glucose uptake was protracted. If these observations obtained in rats are relevant to human physiology, such discrepancies between plasma and interstitial glucose concentration may have major implications for the use of a subcutaneous glucose sensor in continuous blood glucose monitoring in diabetic patients.
Decreased cardiac output at the onset of diabetes: renal mechanisms and peripheral vasoconstriction
Authors: Brands Michael W. , Fitzgerald Sharyn M. , Hewitt William H. , Hailman Allison E.
Published: December 2017

Recently we reported that hindquarter blood flow, measured 24 h/day, decreased progressively over the first 6 days of type 1 diabetes in rats. That response, coupled with the tendency of mean arterial pressure to increase, suggested a vasoconstrictor response. The purpose of this study was to measure the changes in cardiac output together with the renal hemodynamic and excretory responses to allow integrative determination of whether vasoconstriction likely accompanies the onset of type 1 diabetes. Rats were instrumented with a Transonic flow probe on the ascending aorta and with artery and vein catheters, and cardiac output and mean arterial pressure were measured continuously, 24 h/day, throughout the study. The induction of diabetes, by withdrawing intravenous insulin-replacement therapy in streptozotocin-treated rats, caused a progressive decrease in cardiac output that was 85 ± 5% of control levels by day 7. This was associated with significant increases in glomerular filtration rate, renal blood flow, and microalbuminuria as well as urinary fluid and sodium losses, with a negative cumulative sodium balance averaging 15.7 ± 1.6 meq by day 7. Restoring insulin-replacement therapy reversed the renal excretory responses but did not correct the negative sodium balance, yet cardiac output returned rapidly to control values. Increasing sodium intake during the diabetic and recovery periods also did not significantly affect the cardiac output response during any period. These results indicate that cardiac output decreases significantly at the onset of type 1 diabetes without glycemic control, and although volume loss may contribute to this response, there also is a component that is not volume or sodium dependent. We suggest this may be due to vasoconstriction, but to what extent local blood flow autoregulation or active vasoconstriction may have mediated that response is not known.
The oviduct produces erythropoietin in an estrogen- and oxygen-dependent manner
Authors: Masuda Seiji , Kobayashi Toshihiro , Chikuma Mariko , Nagao Masaya , Sasaki Ryuzo
Published: December 2017

Previously, we showed that erythropoietin (Epo) is produced in the mouse uterus, where Epo is indispensable for estrogen (E2)-dependent angiogenesis. Expression of uterine Epo mRNA is stimulated by E2and hypoxia. The hypoxic induction requires the presence of E2. In the present study, we examined other female reproductive organs in the mouse with respect to Epo mRNA expression and its stimuli (E2and hypoxia)-induced changes. Although Epo mRNA expression was seen in the ovary and oviduct, the E2-induced stimulation of Epo mRNA was found only in the oviduct. The E2-induced stimulation in the oviduct was transient and rapidly downregulated. Epo mRNA expression in the oviduct was hypoxia inducible, in both the presence and the absence of E2. E2-dependent production of Epo and its mRNA expression were also found by use of cultured oviducts. The E2action is probably mediated through the E2receptor, and de novo protein synthesis is not required for E2induction of Epo mRNA. In the oviduct, the ampulla and isthmus regions produce Epo.
Training does not protect against exhaustive exercise-induced lactate transport capacity alterations
Authors: Eydoux Nicolas , Py Guillaume , Lambert Karen , Dubouchaud Hervé , Préfaut Christian , Mercier Jacques
Published: December 2017

The effects of endurance training on lactate transport capacity remain controversial. This study examined whether endurance training 1) alters lactate transport capacity, 2) can protect against exhaustive exercise-induced lactate transport alteration, and 3) can modify heart and oxidative muscle monocarboxylate transporter 1 (MCT1) content. Forty male Wistar rats were divided into control (C), trained (T), exhaustively exercised (E), and trained and exercised (TE) groups. Rats in the T and TE groups ran on a treadmill (1 h/day, 5 days/wk at 25 m/min, 10% incline) for 5 wk; C and E were familiarized with the exercise task for 5 min/day. Before being killed, E and TE rats underwent exhaustive exercise (25 m/min, 10% grade), which lasted 80 and 204 min, respectively ( P < 0.05). Although lactate transport measurements (zero- trans) did not differ between groups C and T, both E and TE groups presented an apparent loss of protein saturation properties. In the trained groups, MCT1 content increased in soleus (+28% for T and +26% for TE; P < 0.05) and heart muscle (+36% for T and +33% for TE; P < 0.05). Moreover, despite the metabolic adaptations typically observed after endurance training, we also noted increased lipid peroxidation byproducts after exhaustive exercise. We concluded that 1) endurance training does not alter lactate transport capacity, 2) exhaustive exercise-induced lactate transport alteration is not prevented by training despite increased MCT1 content, and 3) exercise-induced oxidative stress may enhance the passive diffusion responsible for the apparent loss of saturation properties, possibly masking lactate transport regulation.
Whole body and abdominal lipolytic sensitivity to epinephrine is suppressed in upper body obese women
Authors: Horowitz Jeffrey F. , Klein Samuel
Published: December 2017

We measured whole body and regional lipolytic and adipose tissue blood flow (ATBF) sensitivity to epinephrine in 8 lean [body mass index (BMI): 21 ± 1 kg/m2] and 10 upper body obese (UBO) women (BMI: 38 ± 1 kg/m2; waist circumference >100 cm). All subjects underwent a four-stage epinephrine infusion (0.00125, 0.005, 0.0125, and 0.025 μg ⋅ kg fat-free mass−1⋅ min−1) plus pancreatic hormonal clamp. Whole body free fatty acid (FFA) and glycerol rates of appearance (Ra) in plasma were determined by stable isotope tracer methodology. Abdominal and femoral subcutaneous adipose tissue lipolytic activity was determined by microdialysis and133Xe clearance methods. Basal whole body FFA Raand glycerol Rawere both greater ( P < 0.05) in obese (449 ± 31 and 220 ± 12 μmol/min, respectively) compared with lean subjects (323 ± 44 and 167 ± 21 μmol/min, respectively). Epinephrine infusion significantly increased FFA Raand glycerol Rain lean (71 ± 21 and 122 ± 52%, respectively; P < 0.05) but not obese subjects (7 ± 6 and 39 ± 10%, respectively; P = not significant). In addition, lipolytic and ATBF sensitivity to epinephrine was blunted in abdominal but not femoral subcutaneous adipose tissue of obese compared with lean subjects. We conclude that whole body lipolytic sensitivity to epinephrine is blunted in women with UBO because of decreased sensitivity in upper body but not lower body subcutaneous adipose tissue.
Differences in skeletal and muscle mass with aging in black and white women
Authors: Aloia John F. , Vaswani Ashok , Feuerman Martin , Mikhail Mageda , Ma Ruimei
Published: December 2017

Previous cross-sectional studies using delayed gamma neutron activation analysis and whole body counting suggested that the relationship of total body calcium (TBCa) to total body potassium (TBK) (muscle mass, body cell mass) remained constant with age. This led to the hypothesis that the muscle mass and skeletal mass compartments are integrated in their response to aging. It had also been hypothesized that loss of skeletal and muscle mass was similar between races. In the current study, delayed gamma neutron activation analysis and whole body counting were performed on 90 black and 143 white women 20–69 yr of age. Black women had higher TBCa and TBK values than white women, even when the data were adjusted for age, height, and weight. TBCa was correlated with height and TBK with weight. The estimated decline of skeletal mass (TBCa) from 20 to 70 yr was 18% in black women and 19% in white women. However, the lifetime decline of TBK was only 8% for black women, compared with 22% for white women. Black women may lose TBK more slowly than TBCa with aging, compared with white women. In particular, correlation of TBCa and age was similar for blacks and whites ( r = −0.44 and r = −0.54, respectively). However, for TBK these correlations were r = −0.14 and r = −0.42. These data confirm a higher musculoskeletal mass in black women and suggest that the loss of muscle mass with age may be lower in black than in white women. These ethnic differences do not support the hypothesis of an integrated musculoskeletal system, so that these two components should be considered separately. A prospective study is needed to confirm these findings.
Renal resistance to vasopressin in poorly controlled type 1 diabetes mellitus
Authors: McKenna K. , Morris A. D. , Ryan M. , Newton R. W. , Frier B. M. , Baylis P. H. , Saito T. , Ishikawa S. , Thompson C. J.
Published: December 2017

To investigate the hypothesis that diabetes induces nephrogenic diabetes insipidus, we studied the urine-concentrating ability in response to vasopressin (AVP) in 12 patients with insulin-dependent diabetes mellitus (IDDM) and 12 nondiabetic controls. Subjects were euglycemic-clamped, and after oral water loading, AVP was infused intravenously for 150 min. AVP induced a greater ( P < 0.001) rise in urine osmolality in controls (67.6 ± 10.7 to 720 ± 31.1 mosmol/kg, P < 0.001) than in IDDM patients (64.3 ± 21.6 to 516.7 ± 89.3 mosmol/kg, P < 0.001). Urinary aquaporin-2 concentrations after AVP infusion were higher in controls (611.8 ± 105.6 fmol/mg creatinine) than in IDDM (462.0 ± 94.9 fmol/mg creatinine, P = 0.003). Maximum urine osmolality in IDDM was inversely related to chronic blood glucose control, as indicated by Hb AIc ( r = −0.87, P = 0.002). To test the hypothesis that improved glycemic control could reverse resistance to AVP, 10 IDDM subjects with poor glycemic control (Hb AIc >9%) were studied before ( B) and after ( A) intensified glycemic control. Maximum urine osmolality in response to AVP increased with improved glycemic control ( B, 443.8 ± 49.0; A, 640.0 ± 137.2 mosmol/kg, P < 0.001), and urinary aquaporin-2 concentrations after AVP increased from 112.7 ± 69 to 375 ± 280 fmol/mg creatinine ( P = 0.006), with improved glycemic control. Poorly controlled IDDM is associated with reversible renal resistance to AVP.
Endothelin-1 in hypertension in the baroreflex-intact SHR: a role independent from vasopressin release
Authors: Rossi Noreen F. , O'Leary Donal S. , Woodbury Dixon , Chen Haiping
Published: December 2017

This study sought to identify whether central endothelin (ET) receptor activation contributes to the elevated pressure in spontaneously hypertensive rats (SHR) and whether an ET-stimulated vasopressin (AVP) release mediates the increased pressure. In Wistar Kyoto (WKY) rats, intracerebroventricular ET-1 induced a dose-dependent pressor response that was shifted rightward in SHR. ETA antagonism decreased mean arterial pressure in baroreflex-intact SHR ( P < 0.01), consistent with inhibition of endogenous ET-1, and blocked the pressor response to exogenous ET-1 in both strains. ET-1 increased AVP only after sinoaortic denervation ( P < 0.05). Contrary to WKY, sinoaortic denervation was required to elicit a significant pressor response with 5 pmol ET-1 in SHR. Sinoaortic denervation permitted ET-1 to increase AVP in both strains, and peripheral V1 blockade decreased pressure in denervated but not intact rats. After nitroprusside normalized pressure in SHR, the pressor and AVP secretory responses paralleled those in WKY. Thus endogenous ETA receptor mechanisms contribute to hypertension, independent of AVP, in baroreflex-intact SHR. Although blunted in the hypertensive state, the arterial baroreflex buffers the ET-1-induced pressor and AVP secretory responses in both strains.
Fatty acid cycling in the fasting rat
Authors: Kalderon Bella , Mayorek Nina , Berry Elliot , Zevit Noam , Bar-Tana Jacob
Published: December 2017

Adipose tissue lipolysis and fatty acid reesterification by liver and adipose tissue were investigated in rats fasted for 15 h under basal and calorigenic conditions. The fatty acid flux initiated by adipose fat lipolysis in the fasted rat is mostly futile and is characterized by reesterification of 57% of lipolyzed free fatty acid (FFA) back into adipose triglycerides (TG). About two-thirds of FFA reesterification are carried out before FFA release into plasma, whereas the rest consists of plasma FFA extracted by adipose tissue. Thirty-six percent of the fasting lipolytic flux is accounted for by oxidation of plasma FFA, whereas only a minor fraction is channeled into hepatic very low density lipoprotein-triglycerides (VLDL-TG). Total body calorigenesis induced by thyroid hormone treatment and liver-specific calorigenesis induced by treatment with β,β′-tetramethylhexadecanedioic acid (Medica 16) are characterized by a 1.7- and 1.3-fold increase in FFA oxidation, respectively, maintained by a 1.5-fold increase in adipose fat lipolysis. Hepatic reesterification of plasma FFA into VLDL-TG is negligible under both calorigenic conditions. Hence, total body fatty acid metabolism is regulated by adipose tissue as both source and sink. The futile nature of fatty acid cycling allows for its fine tuning in response to metabolic demands.
Thyroid status and response to endothelin-1 in rat arterial vessels
Authors: McAllister Richard M. , Luther Kelli L. , Pfeifer P. Charles
Published: December 2017

We have previously reported that changes in thyroid status are associated with significant alterations in skeletal muscle blood flow during exercise and that changes in endothelium-dependent vasodilation may contribute to these blood flow abnormalities. The purpose of this study was to test the hypothesis that altered endothelium-dependent vasoconstriction is also associated with changes in thyroid status. To test this hypothesis, rats were rendered hypothyroid with propylthiouracil (Hypo, n = 14) or hyperthyroid with triiodothyronine (Hyper, n = 14) over ∼3 mo. Treatment efficacy was confirmed by altered ( P < 0.05) citrate synthase activity in several hindlimb skeletal muscles from Hypo and Hyper, compared with that in muscles from euthyroid rats (Eut, n = 12). Vascular rings were prepared from abdominal aortae, and responses to several vasoactive agents were determined in vitro. As found previously, maximal acetylcholine-induced vasorelaxation was modulated by thyroid status (Eut, 47 ± 9; Hypo, 28 ± 6; Hyper, 68 ± 5%; P < 0.05). Contractile responses of vascular rings with intact endothelium to the endothelium-derived constrictor endothelin-1 (ET-1), however, were similar among groups across a range of ET-1 concentrations. In addition, maximal responses [Eut, 3.75 ± 0.47; Hypo, 2.72 ± 0.25; Hyper, 3.22 ± 0.42 g; not significant (NS)] and sensitivities (Eut, 8.12 ± 0.09; Hypo, 8.10 ± 0.06; Hyper, 8.28 ± 0.09 −log M; NS) to ET-1 were similar among groups. If these findings from the conduit-type abdominal aorta extend into resistance vasculature, it appears that changes in endothelium-dependent vasoconstriction do not contribute to skeletal muscle blood flow abnormalities associated with thyroid disease states.
Malonyl-CoA content and fatty acid oxidation in rat muscle and liver in vivo
Authors: Chien David , Dean David , Saha Asish K. , Flatt J. P. , Ruderman Neil B.
Published: December 2017

Malonyl-CoA acutely regulates fatty acid oxidation in liver in vivo by inhibiting carnitine palmitoyltransferase. Thus rapid increases in the concentration of malonyl-CoA, accompanied by decreases in long-chain fatty acyl carnitine (LCFA-carnitine) and fatty acid oxidation have been observed in liver of fasted-refed rats. It is less clear that it plays a similar role in skeletal muscle. To examine this question, whole body respiratory quotients (RQ) and the concentrations of malonyl-CoA and LCFA-carnitine in muscle were determined in 48-h-starved rats before and at various times after refeeding. RQ values were 0.82 at baseline and increased to 0.93, 1.0, 1.05, and 1.09 after 1, 3, 12, and 18 h of refeeding, respectively, suggesting inhibition of fat oxidation in all tissues. The increases in RQ at each time point correlated closely ( r = 0.98) with increases (50–250%) in the concentration of malonyl-CoA in soleus and gastrocnemius muscles and decreases in plasma FFA and muscle LCFA-carnitine levels. Similar changes in malonyl-CoA and LCFA-carnitine were observed in liver. The increases in malonyl-CoA in muscle during refeeding were not associated with increases in the assayable activity of acetyl-CoA carboxylase (ACC) or decreases in the activity of malonyl-CoA decarboxylase (MCD). The results suggest that, during refeeding after a fast, decreases in fatty acid oxidation occur rapidly in muscle and are attributable both to decreases in plasma FFA and increases in the concentration of malonyl-CoA. They also suggest that the increase in malonyl-CoA in this situation is not due to changes in the assayable activity of either ACC or MCD or an increase in the cytosolic concentration of citrate.
Plasma leptin in moderately obese men: independent effects of weight loss and aerobic exercise
Authors: Thong Farah S. L. , Hudson Robert , Ross Robert , Janssen Ian , Graham Terry E.
Published: December 2017

The independent effects of weight loss and exercise on plasma leptin and total (AT), subcutaneous (SAT), and visceral (VAT) adipose tissue were investigated in 52 obese men. Subjects were randomly assigned to four 12-wk protocols: 1) control (C, n = 8), 2) diet-induced weight loss (DWL, n = 14), 3) exercise-induced weight loss (EWL, n = 14), and 4) exercise with weight maintenance (EWS, n = 16). Plasma leptin was unchanged in C (from 7.8 ± 1.3 to 7.7 ± 1.0 ng/ml). Equivalent weight loss (7.5 kg) decreased leptin significantly but similarly (DWL, from 8.5 ± 1.0 to 4.8 ± 0.6 ng/ml; EWL, from 10.1 ± 1.0 to 5.0 ± 0.6 ng/ml). Exercise in the absence of weight loss did not alter leptin levels (from 10.1 ± 1.3 to 9.2 ± 1.2 ng/ml). Changes in leptin correlated with changes in AT and SAT (both P < 0.05) but not in VAT. We conclude that reduction in adipose tissue after weight loss results in a collateral decrease in circulating leptin, and exercise, independent of its effects on weight loss, has no profound influence on leptin secretion.
Differential regulation of leptin expression and function in A/J vs. C57BL/6J mice during diet-induced obesity
Authors: Watson Patricia M. , Commins Scott P. , Beiler Rudolph J. , Hatcher Heather C. , Gettys Thomas W.
Published: December 2017

Obesity-resistant (A/J) and obesity-prone (C57BL/6J) mice were weaned onto low-fat (LF) or high-fat (HF) diets and studied after 2, 10, and 16 wk. Despite consuming the same amount of food, A/J mice on the HF diet deposited less carcass lipid and gained less weight than C57BL/6J mice over the course of the study. Leptin mRNA was increased in white adipose tissue (WAT) in both strains on the HF diet but to significantly higher levels in A/J compared with C57BL/6J mice. Uncoupling protein 1 (UCP1) and UCP2 mRNA were induced by the HF diet in brown adipose tissue (BAT) and WAT of A/J mice, respectively, but not in C57BL/6J mice. UCP1 mRNA was also significantly higher in retroperitoneal WAT of A/J compared with C57BL/6J mice. The ability of A/J mice to resist diet-induced obesity is associated with a strain-specific increase in leptin, UCP1, and UCP2 expression in adipose tissue. The findings indicate that the HF diet does not compromise leptin-dependent regulation of adipocyte gene expression in A/J mice and suggest that maintenance of leptin responsiveness confers resistance to diet-induced obesity.
Impact of endotoxin on UCP homolog mRNA abundance, thermoregulation, and mitochondrial proton leak kinetics
Authors: Yu Xing Xian , Barger Jamie L. , Boyer Bert B. , Brand Martin D. , Pan Guohua , Adams Sean H.
Published: December 2017

Linking tissue uncoupling protein (UCP) homolog abundance with functional metabolic outcomes and with expression of putative genetic regulators promises to better clarify UCP homolog physiological function. A murine endotoxemia model characterized by marked alterations in thermoregulation was employed to examine the association between heat production, UCP homolog expression, and mitochondrial proton leak (“uncoupling”). After intraperitoneal lipopolysaccharide (LPS, ∼6 mg/kg) injection, colonic temperature (Tc) in adult female C57BL6/J mice dropped to a nadir of ∼30°C by 8 h, preceded by a four- to fivefold drop in liver UCP2 and UCP5/brain mitochondrial carrier protein 1 mRNA levels, with no change in their hindlimb skeletal muscle (SKM) expression. SKM UCP3 mRNA rose fivefold during development of hypothermia and was correlated with an LPS-induced increase in plasma free fatty acid concentration. UCP2 and UCP5 transcripts recovered about three- to sixfold in both tissues starting at 6–8 h, preceding a recovery of Tcbetween 16 and 24 h. SKM UCP3 followed an opposite pattern. Such results are not consistent with an important influence of UCP3 in driving heat production but do not preclude a role for UCP2 or UCP5 in this process. The transcription coactivator PGC-1 displayed a transient LPS-evoked rise (threefold) or drop (two- to fivefold) in SKM and liver expression, respectively. No differences between control and LPS-treated mouse liver or SKM in vitro mitochondrial proton leak were evident at time points corresponding to large differences in UCP homolog expression.
Meal fatty acid uptake in adipose tissue: gender effects in nonobese humans
Authors: Romanski Susan A. , Nelson Rita M. , Jensen Michael D.
Published: December 2017

We tested for gender differences in dietary fatty acid metabolism in 12 nonobese men and 12 nonobese women using the meal fatty acid tracer/adipose tissue biopsy study design. In addition to determining body composition, measurements of regional adipose tissue lipoprotein lipase activity, blood flow, and fat cell size were performed to place the meal fatty acid kinetic studies in perspective. Twenty-four hours after ingesting the test meal, the concentration of meal fatty acids was greater ( P < 0.05) in abdominal subcutaneous than in thigh adipose tissue in both men (0.61 ± 0.12 vs. 0.45 ± 0.09 mg/g) and women (0.59 ± 0.10 vs. 0.43 ± 0.05) but was not different between men and women. A greater percentage of dietary fat was stored in subcutaneous adipose tissue in women than in men (38 ± 3 vs. 24 ± 3%, respectively, P < 0.05), and a greater portion of meal fatty acid disposal was unaccounted for in men. Significant gender differences in regional adipose tissue blood flow after meal ingestion were noted; the differences were in the direction that could support greater nutrient storage in lower body fat in women.
Central neuropeptide Y stimulates ingestive behavior and increases urine output in the ovine fetus
Authors: Roberts Todd J. , Caston-Balderrama Anne , Nijland Mark J. , Ross Michael G.
Published: December 2017

We hypothesized that central neuropeptide Y (NPY) increases swallowing activity and alters renal function in the near-term ovine fetus. Six ewes with singleton fetuses (130 ± 2 days of gestation; 148 days = term) were chronically prepared with arterial and venous catheters, a fetal lateral cerebroventricular cannula, and fetal bladder and amniotic fluid catheters. For determination of fetal swallowing, electromyogram wires were placed in the fetal thyrohyoid muscle and the upper and lower nuchal esophagus. Electrodes were implanted on the parietal dura for determination of fetal electrocorticogram (ECoG). After 5 days of recovery, fetal swallowing, ECoG, blood pressure, and heart rate were monitored during a 3-h basal period. At t = 3 h, ovine NPY (0.05 mg/kg) was administered into the lateral ventricle, and fetuses were monitored for an additional 8 h. A control study of central administration of artificial cerebral spinal fluid was performed on an alternate day. Central NPY significantly increased swallowing activity during low-voltage ECoG from basal activity (1.26 ± 0.15 swallows/min) at 4 h (1.93 ± 0.37 swallows/min), 6 h (1.69 ± 0.27 swallows/min), and 8 h (2.38 ± 0.31 swallows/min). NPY significantly increased fetal urine flow (basal: 0.13 ± 0.02; 4 h: 0.21 ± 0.04; 6 h: 0.19 ± 0.03 ml·kg−1·min−1). These results demonstrate that central NPY stimulates fetal swallowing activity and increases urine output, which may contribute to the in utero development of ingestive behavior.
Systemic administration of a novel octapeptide, amylin-(1—8), increases bone volume in male mice
Authors: Cornish Jillian , Callon Karen E. , Gasser Juerg A. , Bava Usha , Gardiner Edith M. , Coy David H. , Cooper Garth J. S. , Reid Ian R.
Published: December 2017

Amylin increases bone mass when administered systemically to mice. However, because of its size, the full peptide is not an ideal candidate for the therapy of osteoporosis. The fragment, amylin-(1—8), stimulates osteoblast proliferation in vitro, although it is without effect on carbohydrate metabolism. The present study assessed the effects of daily administration of this peptide on sexually mature male mice for 4 wk. Amylin-(1—8) almost doubled histomorphometric indices of osteoblast activity but did not change measures of bone resorption. Trabecular bone volume increased by 36% as a result of increases in both trabecular number and trabecular thickness, and tibial cortical width increased by 8%. On three-point bending tests of bone strength, displacement to fracture was increased by amylin-(1—8), from 0.302 ± 0.013 to 0.351 ± 0.017 mm ( P = 0.02). In a separate experiment using dynamic histomorphometry with bone-seeking fluorochrome labels, amylin-(1—8) was administered by local injection over the calvariae of female mice. Amylin-(1—8) (40 nM) increased the double-labeled surface threefold. The effect was dose dependent from 0.4 to 40 nM and was greater than that of an equimolar dose of human parathyroid hormone-(1—34) [hPTH-(1—34)]. Mineral apposition rate was increased by 40 nM amylin-(1—8) but not by hPTH-(1—34). Amylin-(1—8) thus has significant anabolic effects in vivo, suggesting that this peptide or analogs of it should be further evaluated as potential therapies for osteoporosis.
Nitric oxide may be required to prevent hypertension at the onset of diabetes
Authors: Fitzgerald Sharyn M. , Brands Michael W.
Published: December 2017

Nitric oxide (NO) plays an important role in the regulation of vascular tone, and evidence suggests that endothelial-dependent relaxation, possibly mediated via NO, is impaired in diabetes. However, the role of the endothelium in arterial pressure control early in diabetes, before dysfunction develops, is not known. This was evaluated in the present study by comparing the responses to induction of diabetes in vehicle-treated rats (D, n = 7) vs. rats chronically treated with NG-nitro-l-arginine methyl ester (l-NAME; D+L, n = 8). A nondiabetic group also was treated with l-NAME (L, n = 7) to control for l-NAME effects over time, independent of diabetes. After baseline measurements, rats were given either vehicle or l-NAME (10 μg · kg−1· min−1iv) infusion throughout the experiment. Six days later, streptozotocin (60 mg/kg iv) was administered, followed by a 3-wk diabetic study period. Induction of diabetes in the D+L rats caused a marked and progressive increase in mean arterial pressure throughout the diabetic period, averaging ∼70 mmHg greater than in the D rats and ∼20 mmHg greater than in the L rats. Glomerular filtration rate and renal plasma flow tended to increase during diabetes, but this trend was reversed in the D+L rats. In addition, plasma renin activity increased in the D and D+L rats during week 1 of diabetes but then returned to control in the D rats, while continuing to increase in the D+L rats. These results suggest that, in the early stages of diabetes, NO synthesis is important to prevent hypertension from developing, possibly through actions to maintain glomerular filtration and suppress renin secretion.
DOPA, dopamine, and DOPAC concentrations in the rat gastrointestinal tract decrease during fasting
Authors: Eldrup Ebbe , Richter Erik A.
Published: December 2017

The aim of the present study was to test the hypothesis that 3,4-dihydroxyphenylalanine (DOPA) and dopamine (DA) in the gastrointestinal tract are to a large extent of exogenous origin and derived from food. Tissue concentrations of norepinephrine (NE), epinephrine (Epi), DA, DOPA, and 3,4-dihydroxyphenylacetic acid (DOPAC), as measured by reverse-phase HPLC with electrochemical detection, were studied in fed and 4-day-fasted Wistar rats as well as in sympathectomized and adrenodemedullated rats. Sympathectomy and adrenal demedullectomy decreased tissue concentrations of NE and Epi, respectively, but had no effect on the level of tissue DOPA. Large amounts of DOPA and DA were present in the gastrointestinal tract. Fasting decreased DOPA and DA in the stomach and DOPA concentrations in the quadriceps muscle but no concentrations in other organs. DOPAC in the heart decreased both in response to sympathectomy and to fasting, whereas DOPAC decreased in plasma after fasting and in skeletal muscle after sympathectomy. We conclude that the food content of DOPA and DA is of major importance for the metabolism of DA and, thus, for the dopamine-sulfate content in the gastrointestinal tract and in plasma. The decrease in muscle DOPA after fasting may be explained by less insulin being available during fasting for stimulation of DOPA uptake in the muscle depot. DOPAC in the organism seems to be of a dual origin, derived partly from DA in the food and partly from DA synthesized in sympathetic nerves.
Identification and characterization of leptin-containing intracellular compartment in rat adipose cells
Authors: Roh Cecilia , Thoidis Galini , Farmer Stephen R. , Kandror Konstantin V.
Published: December 2017

The major leptin-containing membrane compartment was identified and characterized in rat adipose cells by means of equilibrium density and velocity sucrose gradient centrifugation. This compartment appears to be different from peptide-containing secretory granules present in neuronal, endocrine, and exocrine cells, as well as from insulin-sensitive GLUT-4-containing vesicles abundant in adipocytes. Exocytosis of both leptin- and GLUT-4-containing vesicles can be induced by insulin; however, only leptin secretion is responsive to serum stimulation. This latter effect is resistant to cycloheximide, suggesting that serum triggers the release of a stored pool of presynthesized leptin molecules. We conclude that regulated secretion of leptin and insulin-dependent translocation of GLUT-4 represent different pathways of membrane trafficking in rat adipose cells. NIH 3T3 cells ectopically expressing CAAT box enhancer binding protein-α and Swiss 3T3 cells expressing peroxisome proliferator-activated receptor-γ undergo differentiation in vitro and acquire adipocyte morphology and insulin-responsive glucose uptake. Only the former cell line, however, is capable of leptin secretion. Thus different transcriptional mechanisms control the developmental onset of these two major and independent physiological functions in adipose cells.
Responses of adipose tissue lipoprotein lipase to weight loss affect lipid levels and weight regain in women
Authors: Nicklas Barbara J. , Rogus Ellen M. , Berman Dora M. , Dennis Karen E. , Goldberg Andrew P.
Published: December 2017

This study determines whether changes in abdominal (ABD) and gluteal (GLT) adipose tissue lipoprotein lipase (LPL) activity in response to a 6-mo weight loss intervention, comprised of a hypocaloric diet and low-intensity walking, affect changes in body composition, fat distribution, lipid metabolism, and the magnitude of weight regain in 36 obese postmenopausal women. Average adipose tissue LPL activity did not change with an average 5.6-kg weight loss, but changes in LPL activity were inversely related to baseline LPL activity (ABD: r= −0.60, GLT: r = −0.48; P < 0.01). The loss of abdominal body fat and decreases in total and low-density lipoprotein cholesterol were greater in women whose adipose tissue LPL activity decreased with weight loss despite a similar loss of total body weight and fat mass. Moreover, weight regain after a 6-mo follow-up was less in women whose adipose tissue LPL activity decreased than in women whose LPL increased (ABD: 0.9 ± 0.5 vs. 2.8 ± 0.6 kg, P < 0.05; GLT: 0.2 ± 0.5 vs. 2.8 ± 0.5 kg, P < 0.01). These results suggest that a reduction in adipose tissue LPL activity with weight loss is associated with improvements in lipid metabolic risk factors with weight loss and with diminished weight regain in postmenopausal women.
Feeding stimulates protein synthesis in muscle and liver of neonatal pigs through an mTOR-dependent process
Authors: Kimball Scot R. , Jefferson Leonard S. , Nguyen Hahn V. , Suryawan Agus , Bush Jill A. , Davis Teresa A.
Published: December 2017

Protein synthesis is repressed in both skeletal muscle and liver after a short-term fast and is rapidly stimulated in response to feeding. Previous studies in rats and pigs have shown that the feeding-induced stimulation of protein synthesis is associated with activation of the 70-kDa ribosomal protein S6 kinase (S6K1) as well as enhanced binding of eukaryotic initiation factor eIF4E to eIF4G to form the active eIF4F complex. In cells in culture, hormones and nutrients regulate both of these events through a protein kinase termed the mammalian target of rapamycin (mTOR). In the present study, the involvement of mTOR in the feeding-induced stimulation of protein synthesis in skeletal muscle and liver was examined. Pigs at 7 days of age were fasted for 18 h, and then one-half of the animals were fed. In addition, one-half of the animals in each group were administered rapamycin (0.75 mg/kg) 2 h before feeding. The results reveal that treating 18-h fasted pigs with rapamycin, a specific inhibitor of mTOR, before feeding prevented the activation of S6K1 and the changes in eIF4F complex formation observed in skeletal muscle and liver after feeding. Rapamycin also ablated the feeding-induced stimulation of protein synthesis in liver. In contrast, in skeletal muscle, rapamycin attenuated, but did not prevent, the stimulation of protein synthesis in response to feeding. The results suggest that feeding stimulates hepatic protein synthesis through an mTOR-dependent process involving enhanced eIF4F complex formation and activation of S6K1. However, in skeletal muscle, these two processes may account for only part of the stimulation of protein synthesis, and thus additional steps may be involved in the response.
Isoform-specific regulation of the lactate transporters MCT1 and MCT4 by contractile activity
Authors: Bonen Arend , Tonouchi Mio , Miskovic Dragana , Heddle Catherine , Heikkila John J. , Halestrap Andrew P.
Published: December 2017

We examined the isoform-specific regulation of monocarboxylate transporter (MCT)1 and MCT4 expression by contractile activity in red and white tibialis anterior muscles. After 1 and 3 wk of chronic muscle stimulation (24 h/day), MCT1 protein expression was increased in the red muscles (+78%, P< 0.05). In the white muscles, MCT1 was increased after 1 wk (+191%) and then was decreased after 3 wk. In the red muscle, MCT1 mRNA accumulation was increased only after 3 wk (+21%; P < 0.05). In the white muscle, MCT1 mRNA was increased after 1 wk (+30%; P < 0.05) and 3 wk (+15%; P < 0.05). MCT4 protein was not altered in either the red or white muscles after 1 or 3 wk. MCT4 mRNA was transiently lowered (∼15%) in both muscles in the 1st wk, but MCT4 mRNA levels were back to control levels after 3 wk. In conclusion, chronic contractile activity induces the expression of MCT1 but not MCT4. This increase in MCT1 alone was sufficient to increase lactate uptake from the circulation.
Glucocorticoids oppose translational control by leucine in skeletal muscle
Authors: Shah O. Jameel , Anthony Joshua C. , Kimball Scot R. , Jefferson Leonard S.
Published: December 2017

Glucocorticoids comprise an important class of hormonal mediators of fuel and protein homeostasis in normal and pathological scenarios. In skeletal muscle, exposure to glucocorticoids is characterized by a reduction in protein synthetic rate coincident with hampered translation initiation. However, it is unclear whether this involves attenuation of anabolic stimuli or is simply due to inhibition of the basally activated translational apparatus. Therefore, this inquiry was designed to determine whether leucine, administered orally, could rescue the translational inhibition induced by glucocorticoids. Dexamethasone, injected intraperitoneally, acutely diminished protein synthetic rates to 80% of control values in skeletal muscle from rat hindlimb. The eukaryotic initiation factor (eIF)4 regulatory element was simultaneously and negatively impacted via sequestration of eIF4E by the hypophosphorylated form of the translational suppressor, eIF4E binding protein 1 (4E-BP1). The 70-kDa ribosomal protein S6 kinase (S6K1) was also dephosphorylated, notably at T389, in response to glucocorticoids. Leucine, administered orally, effectively restored each aforementioned translational parameter to control levels. Inasmuch as leucine's potency in modulation of the translational machinery, and indeed of protein turnover in general, is widely appreciated, this amino acid may prove useful in normalizing the impairment of mRNA translation associated with various muscle-wasting pathologies, such as glucocorticoid excess.
Determinants of glucose toxicity and its reversibility in the pancreatic islet β-cell line, HIT-T15
Authors: Gleason Catherine E. , Gonzalez Michael , Harmon Jamie S. , Robertson R. Paul
Published: December 2017

HIT-T15 cells, a clonal β-cell line, were cultured and passaged weekly for 6 mo in RPMI 1640 media containing various concentrations of glucose. Insulin content decreased in the intermediate- and late-passage cells as a continuous rather than a threshold glucose concentration effect. In a second series of experiments, cells were grown in media containing either 0.8 or 16.0 mM glucose from passages 76 through 105. Subcultures of passages 86, 92,and 99 that had been grown in media containing 16.0 mM glucose were switched to media containing 0.8 mM glucose and also carried forward to passage 105. Dramatic increases in insulin content and secretion and insulin gene expression were observed when the switches were made at passages 86 and 92but not when the switch was made at passage 99. These findings suggest that glucose toxicity of insulin-secreting cells is a continuous rather than a threshold function of glucose concentration and that the shorter the period of antecedent glucose toxicity, the more likely that full recovery of cell function will occur.
Nonhepatic response to portal glucose delivery in conscious dogs
Authors: Moore Mary Courtney , Hsieh Po-Shiuan , Neal Doss W. , Cherrington Alan D.
Published: December 2017

The glycemic and hormonal responses and net hepatic and nonhepatic glucose uptakes were quantified in conscious 42-h-fasted dogs during a 180-min infusion of glucose at 10 mg · kg−1 · min−1 via a peripheral (Pe10, n = 5) or the portal (Po10, n = 6) vein. Arterial plasma insulin concentrations were not different during the glucose infusion in Pe10 and Po10 (37 ± 6 and 43 ± 12 μU/ml, respectively), and glucagon concentrations declined similarly throughout the two studies. Arterial blood glucose concentrations during glucose infusion were not different between groups (125 ± 13 and 120 ± 6 mg/dl in Pe10 and Po10, respectively). Portal glucose delivery made the hepatic glucose load significantly greater (36 ± 3 vs. 46 ± 5 mg · kg−1 · min−1 in Pe10 vs. Po10, respectively, P < 0.05). Net hepatic glucose uptake (NHGU; 1.1 ± 0.4 vs. 3.1 ± 0.4 mg · kg−1 · min−1) and fractional extraction (0.03 ± 0.01 vs. 0.07 ± 0.01) were smaller ( P < 0.05) in Pe10 than in Po10. Nonhepatic (primarily muscle) glucose uptake was correspondingly increased in Pe10 compared with Po10 (8.9 ± 0.4 vs. 6.9 ± 0.4 mg · kg−1 · min−1, P < 0.05). Approximately one-half of the difference in NHGU between groups could be accounted for by the difference in hepatic glucose load, with the remainder attributable to the effect of the portal signal itself. Even in the absence of somatostatin and fixed hormone concentrations, the portal signal acts to alter partitioning of a glucose load among the tissues, stimulating NHGU and reducing peripheral glucose uptake.
Increased density of glucagon receptors in liver from endurance-trained rats
Authors: Légaré A. , Drouin R. , Milot M. , Massicotte D. , Péronnet F. , Massicotte G. , Lavoie C.
Published: December 2017

The binding properties of glucagon receptors were determined in plasma membranes isolated from liver of untrained ( n = 6) and swimming endurance-trained Sprague-Dawley male rats ( n = 7; 3 h/day, 5 days/wk, for 8 wk). Plasma membranes were purified from liver by aqueous two-phase affinity partitioning, and saturation kinetics were obtained by incubation of plasma membranes (10 μg of proteins/150 μl) with125I-labeled glucagon at concentrations ranging from 0.15 to 3.0 nM for 30 min at 30°C. Saturating curve analysis indicated no difference in the affinity of glucagon receptors (0.57 ± 0.06 and 0.77 ± 0.09 nM in untrained and trained groups, respectively) but a significant higher glucagon receptor density in liver from untrained vs. trained rats (3.09 ± 0.12 vs. 4.28 ± 0.19 pmol/mg proteins). These results suggest that the reported increase in liver glucagon sensitivity in endurance-trained subjects (Drouin R, Lavoie C, Bourque J, Ducros F, Poisson D, and Chiasson J-L. Am J Physiol Endocrinol Metab 274: E23–E28, 1998) could be partly due to an increased glucagon receptor density in response to training.
Quantitative indexes of β-cell function during graded up&down glucose infusion from C-peptide minimal models
Authors: Toffolo Gianna , Breda Elena , Cavaghan Melissa K. , Ehrmann David A. , Polonsky Kenneth S. , Cobelli Claudio
Published: December 2017

Availability of quantitative indexes of insulin secretion is important for definition of the alterations in β-cell responsivity to glucose associated with different physiopathological states. This is presently possible by using the intravenous glucose tolerance test (IVGTT) in conjunction with the C-peptide minimal model. However, the secretory response to a more physiological slowly increasing/decreasing glucose stimulus may uncover novel features of β-cell function. Therefore, plasma C-peptide and glucose data from a graded glucose infusion protocol (seven 40-min periods of 0, 4, 8, 16, 8, 4, and 0 mg · kg−1 · min−1) in eight normal subjects were analyzed by use of a new model of insulin secretion and kinetics. The model assumes a two-compartment description of C-peptide kinetics and describes the stimulatory effect on insulin secretion of both glucose concentration and the rate at which glucose increases. It provides in each individual the insulin secretion profile and three indexes of pancreatic sensitivity to glucose: Φs, Φd, and Φb, related, respectively, to the control of insulin secretion by the glucose level (static control), the rate at which glucose increases (dynamic control), and basal glucose. Indexes (means ± SE) were Φs = 18.8 ± 1.8 (109min−1), Φd = 222 ± 30 (109), and Φb = 5.2 ± 0.4 (109 min−1). The model also allows one to quantify the β-cell times of response to increasing and decreasing glucose stimulus, equal to 5.7 ± 2.2 (min) and 17.8 ± 2.0 (min), respectively. In conclusion, the graded glucose infusion protocol, interpreted with a minimal model of C-peptide secretion and kinetics, provides a quantitative assessment of pancreatic function in an individual. Its application to various physiopathological states should provide novel insights into the role of insulin secretion in the development of glucose intolerance.