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SUMMARY
Plasma growth hormone (GH) levels were measured in 55 patients with advanced breast cancer, before and 3 months after pituitary ablation either by yttrium-90 implantation or by transethmoidal hypophysectomy. It was found that four of the 46 patients tested before ablation had an 'absent' GH response to insulin-induced hypoglycaemia. A comparison of the GH response to insulin-induced hypoglycaemia after yttrium implantation and transethmoidal hypophysectomy revealed no difference between the two procedures in the degree of pituitary ablation achieved. A partial GH deficiency occurred in 30% of patients after yttrium implantation but in only 4% after transethmoidal hypophysectomy.
Department of Internal Medicine, United Arab Emirates University, Al Ain, United Arab Emirates
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Department of Internal Medicine, United Arab Emirates University, Al Ain, United Arab Emirates
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Department of Internal Medicine, United Arab Emirates University, Al Ain, United Arab Emirates
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Department of Internal Medicine, United Arab Emirates University, Al Ain, United Arab Emirates
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The sympathetic nervous system and adrenomedullin (AM) both participate in the regulation of cardiac and circulatory function but their interaction remains uncertain. We have examined the effects of AM on cardiac sympathetic nerve activity (CSNA) and hemodynamics and contrasted these effects with pressure-matched nitro-prusside (NP) administration in normal conscious sheep. Compared with vehicle control, arterial pressure fell similarly with AM (P=0.04) and NP (P<0.001). Heart rate rose in response to both AM (P<0.001) and NP (P=0.002) but the rise with AM was significantly greater than that induced by NP (P<0.001). Cardiac output increased in response to AM compared with both control and NP (both P<0.001). CSNA burst frequency (bursts/min) were increased in response to both AM (P<0.001) and NP (P=0.005) with the rise in burst frequency being greater with AM compared with NP (P<0.001). CSNA burst area/min was also raised by both AM (P=0.03) and NP (P=0.002) with a trend for burst area being greater with AM than NP (P=0.07). CSNA burst incidence (bursts/100 beats) showed no significant differences between any treatment day. In conclusion, we have demonstrated that AM is associated with a greater increase in CSNA and heart rate for a given change in arterial pressure than seen with the classic balanced vasodilator NP.
Henry Wellcome Signalling Laboratories and Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK
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Henry Wellcome Signalling Laboratories and Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK
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Henry Wellcome Signalling Laboratories and Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK
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Henry Wellcome Signalling Laboratories and Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK
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Henry Wellcome Signalling Laboratories and Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK
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Treatment of type 1 diabetes by islet transplantation is currently limited by loss of functional β-cell mass after transplantation. We investigated here whether adenovirus-mediated changes in AMP-activated protein kinase (AMPK) activity, previously shown to affect insulin secretion in vitro, might affect islet graft function in vivo. In isolated mouse and rat islets, insulin secretion stimulated by 17 (vs 3) mmol/l glucose was inhibited by 36.5% (P<0.01) and 43% (P<0.02) respectively after over-expression of constitutively-active AMPK- (AMPK CA) versus null (eGFP-expressing) viruses, and glucose oxidation was decreased by 38% (P<0.05) and 26.6% (P<0.05) respectively. Increases in apoptotic index (terminal deoxynucleotide transferase-mediated deoxyuridine trisphosphate biotin nick end-labelling) (TUNEL)) were also observed in AMPK CA- (22.8 ± 3.6% TUNEL-positive cells, P<0.001), but not AMPK DN- (2.72 ± 3.9%, positive cells, P=0.05) infected islets, versus null adenovirus-treated islets (0.68 ± 0.36% positive cells). Correspondingly, transplantation of islets expressing AMPK CA into streptozotocin-diabetic C57 BL/6 mice improved glycaemic control less effectively than transplantation with either null (P<0.02) or AMPK-DN-infected (P<0.01) islets. We conclude that activation of AMPK inhibits β-cell function in vivo and may represent a target for therapeutic intervention during islet transplantation.
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School of Medicine, University of Tasmania, Hobart, Tasmania, Australia
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School of Medicine, University of Tasmania, Hobart, Tasmania, Australia
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Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
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Insulin stimulates glucose disposal in skeletal muscle in part by increasing microvascular blood flow, and this effect is blunted during insulin resistance. We aimed to determine whether metformin treatment improves insulin-mediated glucose disposal and vascular insulin responsiveness in skeletal muscle of insulin-resistant rats. Sprague–Dawley rats were fed a normal (ND) or high-fat (HFD) diet for 4 weeks. A separate HFD group was given metformin in drinking water (HFD + MF, 150 mg/kg/day) during the final 2 weeks. After the intervention, overnight-fasted (food and metformin removed) anaesthetised rats underwent a 2-h euglycaemic–hyperinsulinaemic clamp (10 mU/min/kg) or saline infusion. Femoral artery blood flow, hindleg muscle microvascular blood flow, muscle glucose disposal and muscle signalling (Ser473-AKT and Thr172-AMPK phosphorylation) were measured. HFD rats had elevated body weight, epididymal fat pad weight, fasting plasma insulin and free fatty acid levels when compared to ND. HFD-fed animals displayed whole-body and skeletal muscle insulin resistance and blunting of insulin-stimulated femoral artery blood flow, muscle microvascular blood flow and skeletal muscle insulin-stimulated Ser473-AKT phosphorylation. Metformin treatment of HFD rats reduced fasting insulin and free fatty acid concentrations and lowered body weight and adiposity. During euglycaemic-hyperinsulinaemic clamp, metformin-treated animals showed improved vascular responsiveness to insulin, improved insulin-stimulated muscle Ser473-AKT phosphorylation but only partially restored (60%) muscle glucose uptake. This occurred without any detectable levels of metformin in plasma or change in muscle Thr172-AMPK phosphorylation. We conclude that 2-week metformin treatment is effective at improving vascular and metabolic insulin responsiveness in muscle of HFD-induced insulin-resistant rats.
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Studies from genetic modification and spontaneous mutations show that C-type natriuretic peptide (CNP) signalling plays an essential part in postnatal endochondral growth, but measurement of CNP proteins and changes in their abundance in tissues and plasma during normal growth has not been reported. Using rodent pups with GH deficiency, we now describe the pharmacodynamic response of CNP and rat amino-terminal proCNP (NTproCNP) in plasma and tissues, and relate these to changes in linear growth (nose–tail length, tibial length and tibial growth plate width) during the course of 1 week of GH or saline (control) administration. Compared with saline, significant increases in plasma and tissue CNP forms were observed after 24 h in GH-treated pups and before any detectable change in linear growth. Whereas CNP abundance was increased in most tissues (muscle, heart and liver) by GH, enrichment was the greatest in extracts from growth plates and kidney. Plasma and tissue concentrations in GH-treated pups were sustained or further increased at 1 week when strong positive associations were found between plasma NTproCNP and linear growth or tissue concentrations. High content of NTproCNP in kidney tissue strongly correlated with plasma concentrations, which is consistent with previous data showing renal extraction of the peptide. In showing a prompt and significant increase in CNP in tissues driving normal endochondral growth, these findings provide further rationale for CNP agonists in the treatment of growth disorders resistant to current therapies and support the use of CNP concentrations as biomarkers of linear growth.
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Although previous studies have described the hypothalamo–pituitary–adrenal (HPA) response to the stress of acute myocardial infarction, it is not possible to study the hormone changes immediately after infarction in humans. Accordingly, we have examined the HPA response to microembolization of coronary arteries in 13 sheep compared with 5 sham control sheep. Plasma vasopressin (AVP; P<0·001), ACTH (P=0·005) and cortisol (P=0·005) were all increased 2 h (first sample time) after embolization. Plasma ACTH and cortisol levels returned to baseline levels by 6 h but plasma AVP levels did not return to baseline levels until more than 12 h after embolization. Plasma corticotrophin-releasing hormone (CRH) showed no significant change in response to embolization. In a subset of six animals which were sampled more frequently, the peak responses for plasma AVP, ACTH and cortisol occurred at 40 min after embolization. The maximum responses in any individual sheep observed at this time point were 744 pmol/l for AVP, 144 pmol/l for ACTH and 492 nmol/l for cortisol. CRH levels tended to increase across the first hour but these changes were not statistically significant. In conclusion, the stress hormone responses to microembolization of the coronary arteries have been defined in an ovine model of myocardial infarction. This model is suitable for studying the effects of novel treatments to reduce the stress of myocardial infarction.
Journal of Endocrinology (1997) 152, 489–493
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Sedentary behavior is associated with an attenuated thermogenic response to β-adrenergic receptor (β-AR) stimulation, an important regulator of energy expenditure (EE) in humans. Chronic stimulation of β-ARs, via heightened activity of the sympathoadrenal system, leads to diminished β-AR function. We have investigated the hypothesis that the thermogenic response of sedentary adults to β-AR stimulation will be increased during short-term sympathoadrenal inhibition. Using a randomly ordered, repeated measures study design, resting EE (REE; indirect calorimetry, ventilated hood technique) and the % increase in EE above REE (%ΔEE) during acute i.v. isoproterenol administration (nonselective β-AR agonist; 6, 12, and 24 ng/kg fat-free mass per min) were determined in 16 sedentary adults (nine females and seven males, 25±1 years, body mass index: 26.1±0.9 kg/m2, maximal oxygen uptake: 40±2 ml/kg per min (mean±s.e.m.)) in the basal state and on the 6th day of transdermal clonidine administration (centrally acting α2-AR agonist; 0.2 mg/day). Relative to baseline, clonidine inhibited sympathoadrenal activity, as evidenced by decreased plasma norepinephrine concentration (1.04±0.13 vs 0.34±0.03 nmol/l; P<0.001), skeletal muscle sympathetic nerve activity (22.5±3.8 vs 8.5±1.9 bursts/min; P=0.003), and resting heart rate (63±2 vs 49±1 beats/min; P<0.001). Sympathoadrenal inhibition decreased REE (6510±243 vs 5857±218 kJ/day; P<0.001), increased respiratory exchange ratio (0.84±0.01 vs 0.86±0.01; P=0.03), and augmented the thermogenic response to β-AR stimulation (%ΔEE: 11±2, 16±2, and 24±2 vs 14±1, 20±2, and 31±2; P=0.04). These data demonstrate that in sedentary humans, short-term inhibition of sympathoadrenal activity increases the thermogenic response to β-AR stimulation, an important determinant of EE and hence energy balance.
