Effects of adrenaline on lactate, glucose, lipid and protein metabolism in the placebo controlled bilaterally perfused human leg.

AIM: Adrenaline has widespread metabolic actions, including stimulation of lipolysis and induction of insulin resistance and hyperlactatemia. Systemic adrenaline administration, however, generates a very complex hormonal and metabolic scenario. No studies employing regional, placebo controlled and adrenaline infusion exist. Our study was designed to test the hypothesis that local placebo controlled leg perfusion with adrenaline directly increases local lactate release, stimulates lipolysis, induces insulin resistance and leaves protein metabolism unaffected. METHODS: We studied seven healthy volunteers with bilateral femoral vein and artery catheters during 3-h basal and 3-h hyperinsulinemic (0.6 mU kg(-1) min(-1) ) euglycemic clamp conditions. One femoral artery was perfused with saline and the other with adrenaline (0.4 µg min m(-2) ). Lipid metabolism was quantified with [9,10-(3) H] palmitate and amino acid metabolism with (15) N-phenylalanine and lactate and glucose by raw arterio-venous differences. RESULTS: Femoral vein plasma adrenaline increased ≈eightfold in the perfused leg with unaltered blood flows. Adrenaline perfusion significantly increased local leg lactate release from 0.01 to 0.25 mmol min(-1) per leg, palmitate release in the basal state 11.5-16.9 µmol min(-1) per leg and during the clamp 2.62-8.44 µmol min(-1) per leg. Glucose uptake decreased during the clamp from ≈180 to 30 µmol min(-1) per leg. Phenylalanine kinetics was not affected by adrenaline. CONCLUSION: Adrenaline directly increases lactate release and lipolysis and inhibits insulin-stimulated glucose uptake in the perfused human leg. Adrenaline has no direct effects on peripheral amino acid metabolism. Adrenaline-induced lactate release from striated muscle may be an important mechanism underlying hyperlactatemia in the critically ill.

Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis.

BACKGROUND: TZP-101 is a synthetic, selective ghrelin agonist in development for gastroparesis. AIM: To assess safety and effects of TZP-101 in diabetes patients with symptomatic gastroparesis. METHODS: Adults with type 1 or type 2 diabetes mellitus received placebo and TZP-101 (80, 160, 320 or 600 microg/kg) infusions in a cross-over manner following a radiolabelled meal. Blood glucose levels were stabilized using a hyperinsulinemic-euglycemic clamp. Primary endpoints were gastric half emptying and latency times. Secondary measures included assessment of gastroparesis symptoms and endocrine responses. RESULTS: Ten patients with type 1 (n = 7) or 2 (n = 3) diabetes, moderate-to-severe gastroparesis symptoms and > or =29% retention 4 h after a radiolabelled solid meal were enrolled. TZP-101 produced significant reductions in solid meal half-emptying (20%, P = 0.043) and latency (34%, P = 0.037) times vs. placebo. Reductions in overall postmeal symptom intensity (24%) and postprandial fullness (37%) following TZP-101 infusion were not statistically significant. Most adverse events were mild and self-limiting and there were no identifiable differences in numbers or types of adverse events between TZP-101 and placebo. CONCLUSIONS: This proof-of-concept study demonstrates that the ghrelin agonist TZP-101 is well-tolerated in diabetes patients with moderate-to-severe chronic gastroparesis and shows statistically significant improvements in gastric emptying.

Visceral fat mass is a strong predictor of circulating ghrelin levels in premenopausal women.

OBJECTIVE: A well known inverse relationship exists between obesity and circulating ghrelin concentrations. However, obesity is a heterogeneous disease entity and upper-body obesity (UBO) is associated with more profound metabolic disturbances than lower-body obesity (LBO). We therefore aimed to investigate the impact of body composition on circulating ghrelin levels in women spanning a wide range of body composition phenotypes. SUBJECTS AND METHODS: Ten (UBO; waist-to-hip ratio (WHR) >0.85, body mass index (BMI) >28 kg/m(2)), ten LBO (WHR <0.80, BMI >28 kg/m(2)) and ten lean women (BMI<25 kg/m(2)) were studied. Total ghrelin levels were measured under basal and hyperinsulinemic (0.6 mU/kg per min) conditions. Body fat distribution was determined by dual X-ray absorptiometry in combination with computed tomography at the L2-L3 level. RESULTS: As expected, an inverse correlation existed between basal ghrelin concentration and BMI (r=-0.40, P=0.03) and total fat mass (r=-0.39, P=0.04). Visceral fat mass was a strong predictor (r=-0.56, P=0.003) of circulating ghrelin levels, even when adjusted for BMI (P=0.02) or body composition group (P=0.04). The suppressive effect of insulin on ghrelin concentration was significantly diminished in the UBO compared with the lean controls (P=0.012) and a highly significant inverse correlation existed with visceral fat mass (r=-0.52, P=0.004). CONCLUSIONS: Visceral fat mass is a strong predictor of basal ghrelin concentrations and also attenuates the suppressive effect of insulin on ghrelin concentrations. These data provide further evidence that the UBO phenotype is associated with more profound metabolic abnormalities than obesity per se.

Insulin and glucose profiles during continuous subcutaneous insulin infusion compared with injection of a long-acting insulin in Type 2 diabetes.

AIMS: To compare insulin and glucose profiles during basal continuous subcutaneous infusion of a rapid-acting insulin analogue and once daily subcutaneous injection of a long-acting insulin analogue in Type 2 diabetes. METHODS: Twenty-one patients with Type 2 diabetes treated with oral glucose-lowering agents were randomized in this two-period crossover study to an equivalent 24-h dose of continuous subcutaneous infusion of insulin aspart and subsequently once-daily bedtime subcutaneous injection of insulin glargine, or vice versa, for eight consecutive days. Plasma profiles of insulin and glucose were recorded. RESULTS: On the last day of each treatment period, the area under the curve (AUC) for glucose was 10% lower on the continuous subcutaneous infusion regimen compared with the insulin injection regimen (P = 0.002). This was accomplished by a flat exogenous insulin infusion profile compared with a peaking profile with injected insulin (AUC was 74% higher after injection compared with pre-injection levels (P = 0.001)). During the last 6 days in each treatment period, the intra-subject variability of exogenous fasting insulin levels in the mornings was 41% lower during insulin infusion compared with insulin injection (P = 0.012). The corresponding intra-subject variability for fasting glucose only showed a tendency to be lower during infusion as compared to the injection regimen (28%; P = 0.104). Thirteen symptomatic-only or minor hypoglycaemic episodes were recorded during the entire infusion period compared with three episodes during the injection period. CONCLUSIONS: Basal continuous subcutaneous infusion of a rapid-acting insulin analogue improved plasma insulin (more flat insulin profile with a lower variability) and glucose (lower AUC) profiles compared with once-daily subcutaneous injection of a long-acting insulin analogue in Type 2 diabetes.

The ghrelin response to exercise before and after growth hormone administration.

CONTEXT: We have previously shown that exercise-induced GH release is not mediated by ghrelin, but it remains to be studied whether the increase in GH may suppress postexercise ghrelin levels. OBJECTIVE: The objective of this study was to characterize systemic ghrelin levels after exercise with and without concomitant GH administration. DESIGN, PARTICIPANTS, AND INTERVENTION: Group A: Twenty-nine elite athletes (age, 18-37 yr) were studied after a maximal exercise test. Group B: In a double blind, placebo-controlled, parallel study, 32 healthy subjects (age, 18-33 yr) were randomized to placebo, GH 0.1 IU/kg per day, or GH 0.2 IU/kg per day for 4 wk. These subjects performed a multistage fitness test to assess maximum oxygen uptake at baseline and after 4 wk. We measured total circulating ghrelin levels before and immediately after exercise and at 15, 30, 60, 90, and 120 min after exercise. RESULTS: Group A: Serum ghrelin levels after exercise decreased significantly (P < 0.01). Group B: Exercise at baseline was associated with a significant lowering of ghrelin levels after exercise (P < 0.0001). In addition, 4 wk of high-dose GH were followed by a further approximately 20% reduction in basal and after exercise serum ghrelin (micrograms per liter): 0.78 (range 0.52-1.17) vs. 0.63 (range 0.50-0.91), P < 0.05. CONCLUSIONS: 1) Ghrelin levels decrease significantly after exercise in elite athletes and healthy subjects. 2) High-dose GH suppresses ghrelin levels. 3) These data support the hypothesis that GH feedback inhibits ghrelin secretion.

Effects of GH replacement therapy in adults on serum levels of leptin and ghrelin: the role of lipolysis.

OBJECTIVE: The regulation and function of systemic ghrelin levels appear to be associated with food intake and energy balance rather than GH. Since GH, in turn, acutely induces lipolysis and insulin resistance in skeletal muscle, we aimed to study the isolated and combined effects of GH, free fatty acids (FFAs) and insulin sensitivity on circulating ghrelin levels in human subjects. DESIGN: Seven GH-deficient patients (aged 37 +/- 4 years (mean +/- s.e.)) were studied on four occasions in a 2 x 2 factorial design with and without GH substitution and with and without administration of acipimox, which lowers FFA levels by inhibition of the hormone-sensitive lipase, in the basal state and during a hyperinsulinemic euglycemic clamp. RESULTS: Serum FFA levels decreased with acipimox administration irrespective of GH status. The GH-induced reduction in insulin sensitivity was countered by acipimox. Fasting ghrelin levels decreased insignificantly during GH administration alone, but were reduced by 33% during co-administration of GH and acipimox (Aci) (in ng/l): 860 +/- 120 (-GH - Aci), 711 +/- 130 (-GH + Aci), 806 +/- 130 (+GH - Aci), 574 +/- 129 (+GH + Aci), P < 0.01. The clamp was associated with a further, moderate lowering of ghrelin. GH and acipimox induced a reciprocal 25% increase in serum leptin levels (microg/l): 11.2 +/- 4.4 (-GH - Aci), 11.7 +/- 4.4 (-GH + Aci), 11.5 +/- 4.4 (+GH - Aci), 13.9 +/- 4.2 (+GH + Aci), P = 0.005. CONCLUSION: Our data suggest that antilipolysis via suppression of the hormone-sensitive lipase in combination with GH administration is associated with significant and reciprocal changes in ghrelin and leptin.