A drop in the circulating concentrations of soluble receptor for advanced glycation end products is associated with seroconversion to autoantibody positivity but not with subsequent progression to clinical disease in children en route to type 1 diabetes.

BACKGROUND: Advanced glycation end products (AGEs) and their interaction with the receptor for AGEs (RAGE) have been studied for their role in the pathogenesis and complications of type 1 diabetes. Decreased concentrations of soluble RAGE (sRAGE) have been reported in acute autoimmune inflammation. We set out to analyze the changes in sRAGE concentration during preclinical diabetes in children seroconverting to islet autoantibody positivity. METHODS: We measured serum concentrations of sRAGE in 168 children who progressed to clinical disease and 43 children who turned positive for at least 2 diabetes-associated autoantibodies but remained nondiabetic. We analyzed the sRAGE before seroconversion in the first autoantibody-positive sample and annually thereafter until the diagnosis of type 1 diabetes or end of follow-up. RESULTS: Both groups had similar sRAGE before seroconversion, but subsequently, sRAGE concentrations were lower (P < .001) in the progressors. The progressors had significantly higher sRAGE concentrations before than after seroconversion (P < .001). The nonprogressors did not experience a similar decrease. The sRAGE concentrations remained stable after seroconversion in both groups. CONCLUSIONS: These data indicate that sRAGE may be involved in the initiation of beta-cell autoimmunity but not in the progression from beta-cell autoimmunity to clinical disease.

Coenzyme Q10 attenuates diastolic dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis in the db/db mouse model of type 2 diabetes.

AIMS/HYPOTHESIS: An increase in the production of reactive oxygen species is commonly thought to contribute to the development of diabetic cardiomyopathy. This study aimed to assess whether administration of the antioxidant coenzyme Q(10) would protect the diabetic heart against dysfunction and remodelling, using the db/db mouse model of type 2 diabetes. Furthermore, we aimed to compare the efficacy of coenzyme Q(10) to that of the ACE inhibitor ramipril. METHODS: Six-week-old non-diabetic db/+ mice and diabetic db/db mice received either normal drinking water or water supplemented with coenzyme Q(10) for 10 weeks. Endpoint cardiac function was assessed by echocardiography and catheterisation. Ventricular tissue was collected for histology, gene expression and protein analysis. RESULTS: Untreated db/db diabetic mice exhibited hyperglycaemia, accompanied by diastolic dysfunction and adverse structural remodelling, including cardiomyocyte hypertrophy, myocardial fibrosis and increased apoptosis. Systemic lipid peroxidation and myocardial superoxide generation were also elevated in db/db mice. Coenzyme Q(10) and ramipril treatment reduced superoxide generation, ameliorated diastolic dysfunction and reduced cardiomyocyte hypertrophy and fibrosis in db/db mice. Phosphorylation of Akt, although depressed in untreated db/db mice, was restored with coenzyme Q(10) administration. We postulate that preservation of cardioprotective Akt signalling may be a mechanism by which coenzyme Q(10)-treated db/db mice are protected from pathological cardiac hypertrophy. CONCLUSIONS/INTERPRETATION: These data demonstrate that coenzyme Q(10) attenuates oxidative stress and left ventricular diastolic dysfunction and remodelling in the diabetic heart. Addition of coenzyme Q(10) to the current therapy used in diabetic patients with diastolic dysfunction warrants further investigation.

Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes.

AIMS/HYPOTHESIS: This group of studies examines human genetic susceptibility conferred by the receptor for advanced glycation end-products (RAGE) in type 1 diabetes and investigates how this may interact with a western environment. METHODS: We analysed the AGER gene, using 13 tag SNPs, in 3,624 Finnish individuals from the FinnDiane study, followed by AGER associations with a high risk HLA genotype (DR3)-DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 (n = 546; HLA-DR3/DR4), matched in healthy newborn infants from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study (n = 373) using allelic analysis. We also studied islets and circulating RAGE in NODLt mice. RESULTS: The rs2070600 and rs17493811 polymorphisms predicted increased risk of type 1 diabetes, whereas the rs9469089 SNP was related to decreased risk, on a high risk HLA background. Children from the DIPP study also showed a decline in circulating soluble RAGE levels, at seroconversion to positivity for type 1 diabetes-associated autoantibodies. Islet RAGE and circulating soluble RAGE levels in prediabetic NODLt mice decreased over time and were prevented by the AGE lowering therapy alagebrium chloride. Alagebrium chloride also decreased the incidence of autoimmune diabetes and restored islet RAGE levels. CONCLUSIONS/INTERPRETATION: These studies suggest that inherited AGER gene polymorphisms may confer susceptibility to environmental insults. Declining circulating levels of soluble RAGE, before the development of overt diabetes, may also be predictive of clinical disease in children with high to medium risk HLA II backgrounds and this possibility warrants further investigation in a larger cohort.

Increased risk of cardiovascular disease in Type 1 diabetes: arterial exposure to remnant lipoproteins leads to enhanced deposition of cholesterol and binding to glycated extracellular matrix proteoglycans.

AIMS: To determine fasting and postprandial metabolism of apolipoprotein B48 (apoB48) remnant lipoproteins in subjects with Type 1 diabetes and the relationship to progressive cardiovascular disease, and to investigate the impact of remnant lipoprotein cholesterol accumulation associated with arterial wall biglycan using a rodent model of Type 1 diabetes. METHODS: Normolipidaemic subjects (n = 9) with long-standing Type 1 diabetes (and advanced cardiovascular disease) and seven healthy control subjects were studied. Fasting and postprandial apoB48 concentration was determined following a sequential meal challenge. A rodent model of streptozotocin-induced diabetes was used to investigate the ex vivo retention of fluorescent-conjugated remnants. Binding of remnant lipoproteins to human recombinant biglycan was assessed in vitro. RESULTS: A significantly higher concentration of fasting plasma apoB48 remnants was observed in patients with Type 1 diabetes compared with control subjects. Patients with Type 1 diabetes exhibited a greater total plasma apoB48 area under the curve (AUC) and an increased incremental AUC following a second sequential meal compared with control subjects. The arterial retention of remnants ex vivo and associated cholesterol was increased sevenfold in Type 1 diabetes rats relative to controls. Remnants were shown to bind with significant affinity to human biglycan in vitro and a further 2.3-fold increased binding capacity was observed with glycated biglycan. Remnants were shown to colocalize with both arterial biglycan and glycated matrix proteins in the Type 1 diabetes rodent model. CONCLUSION: Impaired metabolism of remnant lipoproteins associated with enhanced binding to proteoglycans appears to contribute to the arterial cholesterol deposition in Type 1 diabetes. Our findings support the hypothesis that impaired remnant metabolism may contribute to accelerated progression of atherosclerosis in the hyperglycaemic and insulin-deficient state.

Receptor for AGEs (RAGE) blockade may exert its renoprotective effects in patients with diabetic nephropathy via induction of the angiotensin II type 2 (AT2) receptor.

AIMS/HYPOTHESIS: The receptor for AGEs (RAGE) contributes to the development and progression of diabetic nephropathy. In this study, we examined whether the protective effects of RAGE blockade are exerted via modulation of the renal angiotensin II type 2 (AT2) receptor. METHODS: Control and streptozotocin diabetic mice, wild-type or deficient in the AT2 receptor (At2 knockout [KO]) or RAGE (Rage KO), were studied for 24 weeks. Adenoviral overexpression of full-length Rage in primary rat mesangial cells was also used to determine the effects on AT2 production. RESULTS: With diabetes, Rage-deficient mice had less albuminuria, and an attenuation of hyperfiltration and glomerulosclerosis as compared with diabetic wild-type and At2 KO mice. Renal gene and protein expression of RAGE was elevated with diabetes. Diabetic Rage KO mice had a greater increase in renal AT2 receptor protein than was seen in diabetic wild-type mice. Diabetes-induced increases in renal cytosolic and mitochondrial superoxide generation were prevented in diabetic Rage KO mice, but enhanced in all At2 KO mice. Adenoviral overexpression of RAGE or AGE treatment decreased cell surface AT2 expression, in association with increasing superoxide generation; both were reversed using antioxidants N-acetylcysteine and apocynin, and soluble RAGE in primary mesangial cells. CONCLUSIONS/INTERPRETATION: RAGE appears to be a common and key modulator of AT2 receptor expression, a finding that would implicate a newly defined RAGE-AT2 axis in the development and progression of diabetic nephropathy.

The Ionospheric Connection Explorer Mission: Mission Goals and Design.

The Ionospheric Connection Explorer, or ICON, is a new NASA Explorer mission that will explore the boundary between Earth and space to understand the physical connection between our world and our space environment. This connection is made in the ionosphere, which has long been known to exhibit variability associated with the sun and solar wind. However, it has been recognized in the 21st century that equally significant changes in ionospheric conditions are apparently associated with energy and momentum propagating upward from our own atmosphere. ICON's goal is to weigh the competing impacts of these two drivers as they influence our space environment. Here we describe the specific science objectives that address this goal, as well as the means by which they will be achieved. The instruments selected, the overall performance requirements of the science payload and the operational requirements are also described. ICON's development began in 2013 and the mission is on track for launch in 2017. ICON is developed and managed by the Space Sciences Laboratory at the University of California, Berkeley, with key contributions from several partner institutions.

Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE).

Tubulointerstitial disease, a prominent phenomenon in diabetic nephropathy, correlates with decline in renal function. The underlying pathogenic link between chronic hyperglycemia and the development of tubulointerstitial injury has not been fully elucidated, but myofibroblast formation represents a key step in the development of tubulointerstitial fibrosis. RAGE, the receptor for advanced glycation end products (AGEs), induces the expression of TGF-beta and other cytokines that are proposed to mediate the transdifferentiation of epithelial cells to form myofibroblasts. Here we report specific binding of (125)I-AGE-BSA to cell membranes prepared from a rat proximal tubule cell line and show that the binding site was RAGE. AGE exposure induced dose-dependent epithelial-myofibroblast transdifferentiation determined by morphological changes, de novo alpha smooth-muscle actin expression, and loss of epithelial E-cadherin staining. These effects could be blocked with neutralizing Ab's to RAGE or to TGF-beta. Transdifferentiation was also apparent in the proximal tubules of diabetic rats and in a renal biopsy from a patient with type 1 diabetes. The AGE cross-link breaker, phenyl-4,5-dimethylthiazolium bromide (ALT 711) reduced transdifferentiation in diabetic rats in association with reduced tubular AGE and TGF-beta expression. This study provides a novel mechanism to explain the development of tubulointerstitial disease in diabetic nephropathy and provides a new treatment target.

Role of the AGE crosslink breaker, alagebrium, as a renoprotective agent in diabetes.

The biochemical process of advanced glycation appears to play a central role in the development and progression of diabetic vascular complications. A number of strategies to influence this pathway have been designed, one of which involves the putative advanced glycation end-product (AGE) crosslink breaker, alagebrium which has been shown in in vitro studies to cleave preformed AGE crosslinks. This agent has been studied in various models of diabetic complications and has been shown to attenuate diabetic renal disease, cardiac dysfunction, and atherosclerosis. In addition to the ability of alagebrium to reduce tissue levels of AGEs, this drug appears to inhibit activation of certain protein kinase C isoforms. Planned clinical studies in diabetic subjects at risk of complications should assist in determining the role of alagebrium in the prevention, retardation, and reversal of diabetic micro- and macrovascular disease.

Diabetic nephropathy: where hemodynamics meets metabolism.

Diabetic nephropathy (DN), the most common cause of end stage renal disease in developed nations, is thought to result from interactions between metabolic and haemodynamic factors. Specific metabolically driven, glucose dependent pathways are activated within diabetic renal tissues. These pathways induce oxidative stress, polyol pathway flux, hexosamine flux and accumulation of advanced glycated end-products (AGEs). Haemodynamic factors are also implicated in the pathogenesis of DN and include elevations of systemic and intraglomerular pressure and activation of various vasoactive hormone pathways including the renin-angiotensin aldosterone system (RAAS), endothelin and urotensin. These altered hemodynamics act independently and in concert with metabolic pathways, to activate intracellular second messengers such as protein kinase C (PKC) and MAP kinase (MAPK), nuclear transcription factors such as nuclear factor-kappaB (NF-kappaB) and various growth factors such as the prosclerotic cytokines, transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF) and the angiogenic, permeability enhancing growth factor, vascular endothelial growth factor, VEGF. Ultimately these molecular mechanisms lead to increased renal albumin permeability, and extracellular matrix accumulation, which results in increasing proteinuria, glomerulosclerosis and tubulointerstitial fibrosis. In the past, the treatment of diabetic nephropathy has focused on control of hyperglycemia and the interruption of the RAAS with certain anti-hypertensive agents. Newer novel targets, some of which are linked to glucose dependent pathways, appear to be a major focus of new therapies directed against the development and progression of renal damage as a result of diabetes. It is likely that resolution of diabetic nephropathy will require synergistic therapies to target multiple mediators of this disease.

Novel therapeutics for diabetic micro- and macrovascular complications.

Diabetic patients have a two- to four-fold increased risk for the development of microvascular (renal, neuronal and retinal) and macrovascular complications. Unfortunately, these complications may develop in both Type 1 and Type 2 diabetic patients even with careful glycaemic, blood pressure and lipid control. With the worldwide increase in the incidence diabetes, new strategies to prevent the complications are urgently needed. Mediators of vascular damage of diabetes include poor glycemic control, lipoprotein abnormalities, hypertension, oxidative stress, inflammation and advanced glycation end-products (AGEs), which are modified proteins formed by non-enzymatic glycation. AGEs are resistant to enzymatic degradation and therefore very stable, thus their accumulation continues throughout aging. AGE accumulation causes arterial stiffening in the vessel wall, glomerulosclerosis in the kidney, and vascular hyperpermeability in the retina. Through their interaction with their putative receptor the so-called receptor for AGEs (RAGE), AGEs activate endothelial cells and macrophages, generate reactive oxygen species (ROS), induce overexpression of vascular endothelial growth factor (VEGF) and vascular cell adhesion molecule-1 (VCAM-1), and quench nitric oxide (NO). The pharmacological treatment currently available for either Type 1 or Type 2 diabetic patients does not directly address the excess accumulation of AGEs. Novel compounds that inhibit AGE formation, cleave AGE cross-links or reverse their interaction with RAGE are now accessible and could prove useful in meeting this challenge. Other strategies such as inhibition of the hexosamine pathway, vitamin therapy to reduce oxidation and AGE accumulation, reduction of the ROS, or blocking the actions of growth factors or intracellular messengers of cell differentiation are also currently under research. This review will recount recent advances in the development of therapeutic approaches for inhibiting and treating the development of diabetic end-organ damage.

DNA stability in plant tissues: implications for the possible transfer of genes from genetically modified food.

The potential for transfer of antibiotic resistance genes from genetically modified (GM) plant material to microbes through genetic recombination in the human or animal gut is a consideration that has engendered caution in the use of GM foods. This study was aimed at defining the optimal physical and chemical conditions necessary to ensure sufficient fragmentation of DNA in plant tissues to a size where it would be unlikely to be stably transferred to bacterial gut microflora. The ribulose 1,5-bisphosphate carboxylase/oxygenase small subunit (Rubisco SS) genes are of similar size (approximately 1.4 kb) to transgenes present in GM plants. DNA analysis and PCR amplification of Rubisco SS genes showed that fresh maize and maize silage contained high molecular weight DNA and intact Rubisco SS genes. Relatively high temperatures and pressurised steam were necessary to degrade fully genomic DNA and Rubisco SS genes in maize and wheat grains, the source of most animal feedstuffs. Furthermore, chemical expulsion and extrusion of oilseeds resulted in residues with completely degraded genomic DNA. These results imply that stringent conditions are needed in the processing of GM plant tissues for feedstuffs to eliminate the possibility of transmission of transgenes.

Diurnal variations of plasma prolactin in growing sheep under two lighting régimes and the effect of pinealectomy.

The role of the pineal gland in mediating the stimulatory effect of long daylength on blood levels of prolactin was investigated in 24 growing castrated sheep. Eight were pinealectomized, eight were sham-pinealectomized and eight remained as unoperated control animals. After a preliminary period with 12 h light : 12 h darkness (12L : 12D) pairs of similar sheep were allocated to photoperiods of 16L : 8D or 8L : 16D for 15 weeks. Each animal was individually fed at the same level as its partner exposed to the other daylength. Blood samples were taken weekly by jugular venepuncture. On two occasions, once in the preliminary period (12L : 12D) and again 41 days after the start of the subsequent photoperiods, samples were taken through indwelling jugular catheters at frequent intervals for 24 h. The plasma samples were assayed for prolactin by radioimmunoassay and concentrations were higher in samples taken by jugular puncture. There was a consistent positive effect of daylength on plasma prolactin in sheep with pineal glands that did not occur in pinealectomized sheep. In contrast, pinealectomy did not block the marked rise in prolactin that occurred at dusk. It appears that the effect of the photoperiod on levels of plasma prolactin throughout the day and night is not mediated by the same mechanism as that which controls the surge of prolactin at dusk in the sheep.

Effect of pinealectomy on the plasma concentrations of prolactin, cortisol and testosterone in sheep in short and skeleton long photoperiods.

Two experiments were carried out to investigate the effects of pinealectomy on the responses of prolactin, cortisol and testosterone to skeleton long photoperiods (7 h light: 10 h darkness: 1 h light: 6 h darkness; 7L: 10D: 1L: 6D) compared with short photoperiods (8L: 16D) in lambs. The first experiment included 23 female Suffolk cross sheep aged 10 months, of which six were pinealectomized. The skeleton long photoperiod significantly increased plasma levels of prolactin but this was blocked by pinealectomy; there was a peak around dusk and a trough around dawn and at the time of the 1-h period of light. There was no effect of either photoperiod or pinealectomy on plasma levels of cortisol. Testosterone was not measured in this experiment. In the second experiment there were 12 intact males and 11 castrated males aged 3 months; six of the lambs in each group were pinealectomized. Prolactin was again greatly stimulated by skeleton long photoperiods and the effect was blocked by pinealectomy; there was a trough in plasma prolactin at dawn in all groups. In addition, castration increased prolactin levels on two of the four sampling days. Plasma cortisol concentrations were significantly lower under skeleton long photoperiods and this was also blocked by pinealectomy; there was no effect of castration. Testosterone was much higher in intact males. After 10 weeks of exposure, skeleton long photoperiods produced significantly lower concentrations than short photoperiods in the intact ram with pineal glands but not in those which were pinealectomized.

Somatomedin-like activity in cattle: the effect of breed, lactation and time of day.

Somatomedin-like activity (SLA) was measured in plasma samples from cattle using the porcine costal cartilage disk bioassay. In 40-day-old pre-ruminant bull calves, SLA was highest in the plasma of eight Friesians (mean potency 0.97 +/- 0.06 (S.E.M.) units/ml), lowest in five Aberdeen Angus x Friesians (0.78 +/- P < 0.05) and intermediate in six Hereford x Friesians (9.89 +/- 0.09). Plasma levels of SLA were significantly (P < 0.01) lower in eight lactating Friesian (high-yielding) cows (0.53 +/- 0.04) than in five dry cows (0.76 +/- 0.06). Levels of SLA in the plasma of a further eight lactating Hereford x Friesian (low-yielding) cows (0.76 +/- 0.07) were similar to the levels in the plasma of the five dry dairy cows. Large diurnal changes in plasma SLA occurred in lactating Hereford x Friesian and Friesian heifers. In three Hereford x Friesian heifers plasma levels of SLA were lowest at 19.00 h (0.39 +/- 0.07) and highest at 03.00 h (0.77 +/- 0.08). A similar pattern was present in plasma samples from three Friesian heifers; the lowest levels of SLA being at 21.00 h (0.37 +/- 0.07) and the highest at 05.00 h (0.61 +/- 0.13). Throughout the period of 24 h the overall mean levels of SLA were significantly (P < 0.01) higher in the plasma samples from the three Hereford x Friesian heifers (0.6 +/- 0.01) than in the samples from the three Friesian heifers (0.49 +/- 0.02 units/ml).

Somatomedin-like activity in plasma after foetal hypophysectomy or nephrectomy and in experimental intra-uterine growth retardation in sheep.

Plasma samples from pregnant ewes and their foetuses during the last quarter of gestation were assayed for somatomedin-like activity (SLA) using the procine costal cartilage assay. In maternal plasma, the mean potency (compared with pooled serum from six sheep) was 0.84 +/- 0.05 (S.E.M.) units/ml (n = 15). Somatomedin-like activity in the plasma of five control foetuses (0.91 +/- 0.1 units/ml) was similar to the maternal levels and did not change with gestational age. After foetal hypophysectomy the SLA in foetal plasma (0.37 +/- 0.05 units/ml, n = 4) was significantly less than in control animals. In two nephrectomized foetuses, the mean SLA in plasma (0.08 and 0.51 units/ml respectively) was less than in control animals. Retardation of intra-uterine foetal growth was induced by removal of endometrial caruncles before pregnancy in four sheep. The SLA in plasma from these foetuses was 0.38 +/- 0.05 units/ml (P less than 0.01 v. control animals). The results suggest that SLA in the foetus may be important in the regulation of foetal growth, but they also indicate that factors other than growth hormone may be important in the control of SLA in foetal plasma.

The effect of daylength and level of feeding on serum prolactin in growing lambs.

Twenty-four castrated male lambs initially maintained on a photoperiod of 12 h light:12 h dark were allocated to a factorial experiment with two daylengths (8 h L: 16 h D or 16 h L: 8 h D) and two levels of feeding (restricted or ad libitum). Blood samples were taken every 4 h for 24 h during the introductory period and after 24, 51 and 79 days of treatment. There were highly significant positive effects of daylength and level of feeding on serum prolactin: mean concentrations increased from a mean of 38 plus or minus 1 ng/ml during the introductory period until at day 79 they were: 8L: 16D (restricted diet), 81 ng/ml; (food ad libitum), 167 ng/ml; 16L:8D (restricted diet), 262 ng/ml; (food ad libitum), 262 ng/ml (S.E. of treatment mean plus or minus 4). Long daylength and feeding ad libitum also significantly increased growth rate.

Survival of free DNA encoding antibiotic resistance from transgenic maize and the transformation activity of DNA in ovine saliva, ovine rumen fluid and silage effluent.

To assess the likelihood that the bla gene present in a transgenic maize line may transfer from plant material to the microflora associated with animal feeds, we have examined the survival of free DNA in maize silage effluent, ovine rumen fluid and ovine saliva. Plasmid DNA that had previously been exposed to freshly sampled ovine saliva was capable of transforming competent Escherichia coli cells to ampicillin resistance even after 24 h, implying that DNA released from the diet could provide a source of transforming DNA in the oral cavity of sheep. Although target DNA sequences could be amplified by polymerase chain reaction from plasmid DNA after a 30-min incubation in silage effluent and rumen contents, only short term biological activity, lasting less than 1 min, was observed in these environments, as shown by transformation to antibiotic resistance. These experiments were performed under in vitro conditions; therefore further studies are needed to elucidate the biological significance of free DNA in the rumen and oral cavities of sheep and in silage effluent.

Exogenous cholecystokinin octapeptide in broiler chickens: satiety, conditioned colour aversion, and vagal mediation.

Intraperitoneal injections of 3.5, 7.0, 14.0, and 28.0 micrograms/kg of CCK-8 into free-feeding broiler chickens significantly reduced food intake and delayed feeding (p < 0.05). To determine whether CCK can condition preference or aversion and to investigate the latency and the reversal of the effect, a low (2 micrograms/kg) and a high (14 micrograms/kg) dose of CCK-8 were administered using the coloured food paradigm. One colour, the conditioning stimulus (CS+), was paired with injections of CCK-8; the other colour was paired with injections of saline (CS-). The 2 micrograms/kg dose of CCK-8 neither reduced food intake nor conditioned a colour aversion. The 14 micrograms/kg dose significantly reduced food intake and conditioned a colour aversion (p < 0.05). When vagotomy was performed, the 14 micrograms/kg dose of CCK suppressed feeding in sham-operated birds (p < 0.05) but not in vagotomized birds (p > 0.05). A significant aversion for the food paired with CCK was obtained in sham-operated birds (p < 0.001) but not in vagotomized birds (p > 0.05). It was concluded that IP injections of CCK-8 reduce food intake in broiler chickens and that chicks can learn to associate the colour of the food with injections of CCK, developing an aversion. It was also shown that the vagus nerve mediates the CCK satiety effects and that aversion conditioning to CCK is dependent upon intact vagal innervation of the viscera.

A role for the liver in the effects of glucagon on food intake in domestic fowl.

Adolescent cockerels of an egg-laying strain were prepared with catheters into the hepatic portal vein (HPV) and offered a standard poultry ration ad lib. Injection of 10, 100 and 1000 micrograms of bovine glucagon into the HPV caused a depression in intake which was significantly different from the control from 60 to 90 minutes after injection and was related to the logarithm of the dose. In birds prepared with HPV and jugular vein catheters, 1000 micrograms of glucagon had a similar depressing effect on intake irrespective of route of administration. In cockerels vagotomised at the level of the proventriculus, doses of glucagon up to 1000 micrograms injected into the HPV had no significant effect on intake. When vagotomised and sham-operated birds, in direct comparison, were injected with 0, 5 and 50 micrograms glucagon, there was s significant depression with both doses in the sham-operated cockerels but no effect in those which were vagotomised. However, the vagotomised birds had low control food intakes and the data obtained from them must be interpreted with caution. The conclusion is drawn that glucagon affects liver metabolism to influence the information transmitted via the vagus nerves to the central nervous system circuits involved in the control of feeding.