Specific appetite, energetic and metabolomics responses to fat overfeeding in resistant-to-bodyweight-gain constitutional thinness.

BACKGROUND: Contrasting with obesity, constitutional thinness (CT) is a rare condition of natural low bodyweight. CT exhibits preserved menstruation in females, no biological marker of undernutrition, no eating disorders but a bodyweight gain desire. Anorexigenic hormonal profile with high peptide tyrosine tyrosine (PYY) was shown in circadian profile. CT could be considered as the opposite of obesity, where some patients appear to resist diet-induced bodyweight loss. OBJECTIVE: The objective of this study was to evaluate appetite regulatory hormones in CTs in an inverse paradigm of diet-induced weight loss. METHODS: A 4-week fat overfeeding (2640 kJ excess) was performed to compare eight CT women (body mass index (BMI)<17.5 kg m(-)(2)) to eight female controls (BMI 18.5-25 kg m(-)(2)). Appetite regulatory hormones profile after test meal, food intake, bodyweight, body composition, energy expenditure and urine metabolomics profiles were monitored before and after overfeeding. RESULTS: After overfeeding, fasting total and acylated ghrelin were significantly lower in CTs than in controls (P=0.01 and 0.03, respectively). After overfeeding, peptide tyrosine tyrosine (PYY) and glucagon-like-peptide 1 both presented earlier (T15 min vs T30 min) and higher post-meal responses (incremental area under the curve) in CTs compared with controls. CTs failed to increase bodyweight (+0.22±0.18 kg, P=0.26 vs baseline), contrasting with controls (+0.72±0.26 kg, P=0.03 vs baseline, P=0.01 vs CTs). Resting energy expenditure increased in CTs only (P=0.031 vs baseline). After overfeeding, a significant negative difference between total energy expenditure and food intake was noticed in CTs only (-2754±720 kJ, P=0.01). CONCLUSION: CTs showed specific adaptation to fat overfeeding: overall increase in anorexigenic hormonal profile, enhanced post prandial GLP-1 and PYY and inverse to controls changes in urine metabolomics. Overfeeding revealed a paradoxical positive energy balance contemporary to a lack of bodyweight gain, suggesting yet unknown specific energy expenditure pathways in CTs.

[Metabolic rhabdomyolysis during statin therapy]. / Rhabdomyolyse métabolique au cours d'un traitement par statine.

The occurrence of rhabdomyolysis during statin treatment for dyslipidemia is a well-known side effect. However, the differential diagnosis of rhabdomyolysis is large. We report on a patient treated with statin who presented a rhabdomyolysis. The persistence of laboratory abnormalities allowed to discover a metabolic rhabdomyolysis, namely a carnitine palmitoyltransférase II deficiency. The diagnosis of the genetic abnormality allows to modify the therapeutic care.

Expression of insulin target genes in skeletal muscle and adipose tissue in adult patients with growth hormone deficiency: effect of one year recombinant human growth hormone therapy.

Our aim was to investigate the effects of one year recombinant human growth hormone (rhGH) therapy on the regulation by insulin of gene expression in muscle and adipose tissue in adults with secondary GH deficiency (GHD). Six GHD subjects without upper-body obesity were submitted to a 3-h euglycemic hyperinsulinemic clamp before and after one year of rhGH therapy. Muscle and abdominal subcutaneous adipose tissue biopsies were taken before and at the end of each clamp. The mRNA levels of insulin receptor, p85 alpha-phosphatidylinositol-3 kinase (p85 alpha PI-3K), insulin dependent glucose transporter (Glut4), hexokinase II, glycogen synthase, lipoprotein lipase (LPL) in muscle and in adipose tissue, hormone sensitive lipase and peroxisome proliferator-activated receptor gamma (PPAR gamma) in adipose tissue were quantified by RT-competitive PCR. One year treatment with rhGH (1.25 IU/day) increased plasma IGF-I concentrations (54+/-7 vs 154+/-11 ng/ml, P<0.01) but did not affect insulin-stimulated glucose disposal rate measured during the hyperinsulinemic clamp (74+/-9 vs 85+/-5 micromol/kg free fat mass/min). Insulin significantly increased p85 alpha PI-3K, hexokinase II and Glut4 mRNA levels in muscle both before and after rhGH treatment. One year of GH therapy increased LPL mRNA levels in muscle (38+/-2 vs 70+/-7 amol/microg total RNA, P<0.05) and in adipose tissue (2490+/-260 vs 4860+/-880 amol/microg total RNA, P<0.05), but did not change the expression of the other mRNAs. We conclude from this study that GH therapy did not alter whole body insulin sensitivity and the response of gene expression to insulin in skeletal muscle of adult GHD patients, but it did increase LPL expression in muscle and adipose tissue. This result could be related to the documented beneficial effect of GH therapy on lipid metabolism.

Influence of dietary fat on postprandial glucose metabolism (exogenous and endogenous) using intrinsically (13)C-enriched durum wheat.

The present study evaluates the influence of different amounts of fat added to starch on postprandial glucose metabolism (exogenous and endogenous). Nine women (24 (se 2) years old, BMI 20.4 (se 0.7) kg/m(2)) ingested 1 week apart 75 g glucose equivalent of (13)C-labelled starch in the form of pasta without (low fat; LF) or with 15 (medium fat; MF) or 40 (high fat; HF) g sunflower oil. During the 7 h following meal consumption, plasma glucose, non-esterified fatty acids, triacylglycerols (TG) and insulin concentrations, and endogenous (using [6,6-(2)H(2)]glucose) and exogenous glucose turnover were determined. With MF and HF meals, a lower postprandial glucose peak was observed, but with a secondary recovery. A decrease in exogenous glucose appearance explained lower glycaemia in HF. At 4 h after the HF meal the insulin, insulin:glucose and postprandial blood TG were higher than those measured after the LF and MF meals. Despite higher insulinaemia, total glucose disappearance was similar and endogenous glucose production was suppressed less than after the LF and MF meals, suggesting insulin resistance. Thus, the addition of a large amount of fat appears to be unfavourable to glucose metabolism because it leads to a feature of insulin resistance. On the contrary, the MF meal did not have these adverse effects, but it was able to decrease the initial glycaemic peak.

Regulation of uncoupling protein-2 and uncoupling protein-3 mRNA expression during lipid infusion in human skeletal muscle and subcutaneous adipose tissue.

To study the effect of nonesterified fatty acids (NEFAs) on uncoupling protein-2 (UCP-2) and uncoupling protein-3 (UCP-3) gene expression, a triglyceride emulsion was infused for 5 h in 14 healthy volunteers. A euglycemic-hyperinsulinemic clamp was administered concomitantly in 7 of the 14 subjects. The mRNA levels of UCP-2 and of the short (UCP-3S) and long (UCP-3L) isoforms of UCP-3 were quantified by reverse transcription-competitive polymerase chain reaction in tissue biopsies taken before and at the end of the infusion periods. Plasma NEFA concentrations increased from 362+/-52 to 989+/-157 micromol/l (P = 0.018) during triglyceride infusion. UCP-3L (8+/-1 vs. 19+/-2 amol/microg total RNA, P = 0.018) and UCP-3S (11+/-2 vs. 17+/-3 amol/microg total RNA, P = 0.027) mRNA levels increased in skeletal muscle during triglyceride infusion. UCP-3L mRNA levels were positively correlated with plasma NEFA concentrations (r = 0.53, P = 0.005) and with lipid oxidation rates (r = 0.56, P = 0.004) determined by indirect calorimetry. In contrast, the expression of UCP-2 was not affected by lipid infusion in skeletal muscle or in subcutaneous adipose tissue. During the hyperinsulinemic clamp (plasma insulin concentrations 202+/-12 pmol/l), NEFA levels (405+/-49 vs. 648+/-77 micromol/l, P = 0.063) and lipid oxidation rates (0.67+/-0.09 vs. 0.84+/-0.10 mg x kg(-1) x min(-1), P = 0.091) were not significantly increased during triglyceride infusion. Under such conditions, the induction of UCP-3L and UCP-3S mRNA expression was totally prevented (8+/-2 vs. 8+/-1 and 8 +/-2 vs. 9+/-2 amol/microg total RNA, respectively). We conclude that increased plasma NEFA levels by lipid infusion for 5 h induces the expression of UCP-3 but not UCP-2 in humans. During triglyceride infusion, physiological hyperinsulinemia appears to prevent the induction of UCP-3 mRNA levels.

Defective regulation of phosphatidylinositol-3-kinase gene expression in skeletal muscle and adipose tissue of non-insulin-dependent diabetes mellitus patients.

We investigated the regulation of the mRNA expression of the insulin receptor, insulin receptor substrate-1 (IRS-1) and p85alpha-phosphatidylinositol-3-kinase (PI-3K), three major actors of insulin action, in skeletal muscle from 10 healthy lean volunteers, 13 obese patients with Type II (non-insulin-dependent) diabetes mellitus and 7 non-diabetic obese subjects. The in vivo regulation by insulin was studied using a 3-h euglycaemic, hyperinsulinaemic clamp. There were no differences in the basal concentrations of the three mRNAs in skeletal muscle between groups. Insulin infusion produced a twofold reduction in insulin receptor substrate-1 mRNA expression in the three groups (p<0.02). In contrast, insulin increased p85alpha-phosphatidylinositol-3-kinase mRNA expression in muscle from non-diabetic subjects (+98+/-22% in lean and +127+/-16% in obese, p<0.02) but this effect was totally impaired in Type II diabetic patients (+5+/-12%, NS). A similar defect in insulin action on p85alpha-phosphatidylinositol-3-kinase mRNA expression was observed in abdominal subcutaneous adipose tissue (+138+/-25%, p<0.01 in lean and +46+/-14%, p<0.02 in obese and +29+/-11%, NS in Type II diabetic patients). The lack of action of insulin on p85alpha-phosphatidylinositol-3-kinase mRNA in diabetic subjects was probably not due to a deleterious effect of hyperglycaemia since improvement of the glycaemic control for 10 days did not restore the response in muscle or in adipose tissue. This study provides evidence for a defect in the regulation by insulin of PI-3K gene expression in Type II diabetic patients, thus reinforcing the concept that alterations at the gene expression might be involved in the pathogeny of Type II diabetes.

Effect of modafinil on plasma melatonin, cortisol and growth hormone rhythms, rectal temperature and performance in healthy subjects during a 36 h sleep deprivation.

Modafinil is an alerting substance which has been used successfully to treat narcolepsy. Nothing is known about its effect on hormone secretions. For this purpose, eight healthy young men were enrolled in a double blind trial to test the effects of modafinil on daily plasma melatonin, cortisol and growth hormone (GH) rhythms. Blood was sampled for hormone assays, every hour during the daytime and every 30 min during the nighttime. In addition, rectal temperature and mental performances were determined during the study which comprised 3 sessions, two weeks apart: a 24 h control session including a night with sleep (S1) and two 48 h sessions S2 and S3 with a sleep-deprived night (N1) followed by a recovery night (N2). Modafinil (300 mg x 2) or placebo were randomly attributed during N1 at 22 h and 8 h. As expected, performance was improved after modafinil administration and body temperature was maintained or increased. Plasma melatonin and cortisol profiles were similar after modafinil and placebo administration. The levels observed during the recovery and the control nights (N2) displayed no difference. For GH, during both sleep deprived nights, secretion was dramatically reduced compared with the control one, although the number of secretory episodes was unchanged. These data show that the alerting property of modafinil is not related to an alteration of hormone profiles and suggest that the acute modafinil administration is devoid of short-term side-effects.

Acute regulation by insulin of phosphatidylinositol-3-kinase, Rad, Glut 4, and lipoprotein lipase mRNA levels in human muscle.

We have investigated the acute regulation by insulin of the mRNA levels of nine genes involved in insulin action, in muscle biopsies obtained before and at the end of a 3-h euglycemic hyperinsulinemic clamp. Using reverse transcription-competitive PCR, we have measured the mRNAs encoding the two insulin receptor variants, the insulin receptor substrate-1, the p85alpha subunit of phosphatidylinositol-3-kinase, Ras associated to diabetes (Rad), the glucose transporter Glut 4, glycogen synthase, 6-phosphofructo-l-kinase, lipoprotein lipase, and the hormone-sensitive lipase. Insulin infusion induced a significant increase in the mRNA level of Glut 4 (+56 +/- 13%), Rad (+96 +/- 25%), the p85alpha subunit of phosphatidylinositol-3-kinase (+92 +/- 18%) and a decrease in the lipoprotein lipase mRNA level (-49 +/- 5%), while the abundance of the other mRNAs was unaffected. The relative expression of the two insulin receptor variants was not modified. These results demonstrate an acute coordinated regulation by insulin of the expression of genes coding key proteins involved in its action in human skeletal muscle and suggest that Rad and the p85alpha regulatory subunit of phosphatidylinositol-3-kinase can be added to the list of the genes controlled by insulin.

Effects of a continuous lipid infusion on glucose metabolism in critically ill patients.

The effects of lipid administration on carbohydrate oxidation rate remain controversial, particularly in critically ill patients. The aim of this study was to determine the effects of these patients of a continuous lipid infusion on glucose metabolism using indirect calorimetry and stable isotopes. We studied seven patients, mechanically ventilated, during two consecutive 24-h periods. Throughout the first period they received a continuous infusion of glucose (2 mg.kg-1.min-1) and amino acids. During the second period, in addition to the glucose, they received a continuous infusion of 1 mg.kg-1.min-1 of long-chain triglycerides emulsion. Substrate oxidation rates were calculated from pulmonary gas exchange and nitrogen excretion measurements. Glucose kinetic parameters were measured using primed constant infusions of [6,6-2H2]glucose and [1-13C]glucose. The lipid infusion did not modify the glucose metabolism parameters; 45% of the lipid supply was stored.

Magnetic resonance imaging evidence of decreased putamenal iron content in idiopathic Parkinson's disease.

OBJECTIVE: To determine the changes in basal ganglia iron content associated with various stages of idiopathic Parkinson's disease. DESIGN: Prospective magnetic resonance imaging study using a 2-T magnet. SETTING: Ambulatory care referral center. PATIENTS AND PARTICIPANTS: Forty-five patients suffering from levodopa-responsive Parkinson's disease and 45 age-matched controls. MAIN OUTCOME MEASURES: The T2 relaxation time calculated in various regions of the basal ganglia, the duration of Parkinson's disease, and the age of subjects. RESULTS: Patients with Parkinson's disease exhibited significantly decreased T2 relaxation time in the pars compacta of the substantia nigra compared with controls (P < .01), regardless of disease duration. Patients with a duration of illness above 10 years (n = 12) exhibited significantly increased T2 relaxation time in the anterior and posterior putamen (P < .005 and P < .01, respectively) and in the pallidum (P < .05) compared with age-matched controls. Putamental T2 relaxation time positively correlated with disease duration (P < .05). CONCLUSION: These results suggest that more complex brain iron changes than those previously reported are associated with idiopathic Parkinson's disease, including increased nigral iron content and decreased putamenal and pallidal iron concentration in patients with a duration of illness above 10 years.

Determination of (13C) urea enrichment by gas chromatography/mass spectrometry and gas chromatography/isotope ratio mass spectrometry.

We present gas chromatographic/mass spectrometric and gas chromatographic/isotope ratio mass spectrometric assays of the 13C enrichment of plasma urea converted to its dimethylaminomethylene derivative. The limits of sensitivity of the two techniques are 0.2% and 0.02%, respectively. The techniques were tested in rats and humans infused with (13C)urea or (3-13C)lactate. (13C)Urea enrichment during the infusion of (3-13 C)lactate in humans was not detectable by gas chromatography/mass spectrometry but was easily measured by gas chromatography/isotope ratio mass spectrometry. These assays should be useful for clinical investigations, in which the incorporation of a (13C)gluconeogenic substrate into glucose must be corrected for the incorporation of 13CO2 derived from the oxidation of the substrate. This correction involves measuring the low-level 13C enrichment of urea.

Ophthalmic results in patients with macroprolactinomas treated with a new prolactin inhibitor CV 205-502.

Macroprolactinomas are pituitary tumours which have been effectively treated medically since the introduction of bromocriptine. The visual function of 13 patients treated with a new prolactin (PRL) inhibitor CV 205-502 (Sandoz Basle), a potent and selective dopamine D2 receptor agonist, was evaluated. This is the first detailed ophthalmic report of the use of this drug in macroprolactinomas. Patients were enrolled from June 1988 to July 1990 (mean follow up 30 months). Visual function including visual acuity, ocular pressure, and visual fields was regularly controlled. Visual fields (VF) were tested with Goldmann and automatic static perimetry (Vision Monitor). Treatment was globally effective. No modifications of the visual function were observed in nine patients (six normal, three previous VF losses after surgery). In four other patients, visual function dramatically improved (regression of a III paresis, one case; disappearance of a chiasmatic syndrome, three cases). A pituitary necrosis was observed in one case and successfully cured. CV 205-502 seems to be an effective and well tolerated treatment of macroprolactinomas.

Relief of akinesia by apomorphine and cerebral metabolic changes in Parkinson's disease.

The cerebral metabolic rate of glucose was measured in 14 Parkinson's disease patients with severe on-off fluctuations. Two positron emission tomography (PET) scans with [18F]fluorodeoxyglucose were performed, one after a challenge of subcutaneous apomorphine at a dose able to relieve akinesia within 15 min and the other with the vehicle. Apomorphine reduced glucose utilization by 4-6% in the lenticular nuclei and the occipital cortex and by 6-9% in the thalamic nuclei, but this effect was not statistically significant. Thus, central stimulation of dopamine receptors by apomorphine in advanced Parkinson's disease is not associated with cerebral metabolic changes as assessed by PET. Despite a dramatic improvement of the motor state, the global neuronal activity in the striatum and its downstream projections remains stable, suggesting an equilibrium between excitatory and inhibitory dopaminergic activities.

13C appearance in plasma glucose and breath CO2 during feeding with naturally 13C-enriched starchy food in normal humans.

We have used a recently developed technique (isotope-ratio mass spectrometer) to measure 13C appearance in plasma glucose and breath CO2 in eight normal subjects during feeding with naturally 13C-enriched starch. 13C in CO2 and plasma glucose, metabolites and insulin concentrations, carbohydrates, and lipid oxidation were measured after ingestion of 76 g glucose equivalent of crackers, pasta, or polenta. 13C in plasma glucose displays a very different pattern from plasma glucose concentration. It increases steadily for 90 min before reaching a plateau for approximately 2 h and slowly declines during the last 2 h of the study. No significant difference was observed with the three different starchy foods tested although plasma glucose tended to be higher during feeding with polenta. In summary measurement of 13C in plasma glucose during feeding with naturally 13C-labeled carbohydrates yields new insight in the study of carbohydrate bioavailability in humans.

Pituitary adenomas: automatic static perimetry and Goldmann perimetry. A comparative study of 345 visual field charts.

In a series of 81 cases of pituitary adenoma 345 charts of visual field performed with static automatic perimetry (AP) on the Vision Monitor and Goldmann perimetry (GP) were compared. Generally both methods were equivalent in the detection of chiasmal compression. The charts were divided into two groups: (A) 208 charts and (B) 137 charts according to the number of isoptres investigated: two (V4, 112) or three (V4, 112, 12). In group A the AP was more often altered than the GP, and the difference was statistically significant (p less than 0.001). In group B the GP seemed more effective, but the number of questionable cases was greater and the difference was not statistically significant. When the most internal isoptre of GP was outside the central 30 degrees, AP was more often abnormal (29%) than GP (2.2%), and the difference was statistically significant (chi 2, p less than 0.001). Within the central 30 degrees the GP seemed more often to be altered (23% of cases) than the AP (19.4%), but one-third of the cases were questionable. Within the central 30 degrees both techniques gave identical results and there was no statistically significant difference. The discrepancies between both static and kinetic techniques are an argument for their complementary use.

Dose-effect study of intranasal administration of growth hormone-releasing hormone-44-NH2 in healthy subjects.

Intranasal (in) administration of GH-releasing hormone-40- (GHRH-40) has been demonstrated to be efficient in stimulating GH secretion at doses equal to or higher than 30 micrograms/kg in man. We performed a dose-response study with GHRH-44-NH2 (GHRH) given by nasal spray and closely monitored local tolerance. Twelve normal young men were given 5 GNRH doses (125, 250, 500, 750, and 1000 micrograms) and placebo in random order according to a latin square design. Mild symptoms of local intolerance, subjective, objective, or both, were noted in the first 20 min after spray in 30 of 72 tests, and a significant difference (P = 0.003) was obtained in their frequency between the group placebo plus the lowest dose and the group of the other doses. The areas under the GH curves were significantly different between the subjects and the doses (by analysis of variance, P = 0.001 and P = 0.025, respectively). Multiple comparison tests showed a significant difference between the 3 highest doses and the placebo (P = 0.005, P = 0.05, and P = 0.02, respectively) and a significant difference between the highest dose and the 2 lowest doses (P = 0.005). By weighted linear regression between GH areas under the curve and GHRH doses the dose-response relationship was established as: y = 1.226x + 457. The magnitude of the GH peaks induced by in GHRH was significantly lower than that induced by iv GHRH. We conclude that in the normal young men tested, who were high responders to GHRH (as demonstrated by iv test), a 500-micrograms dose is sufficient to elicit GH secretion. Local tolerance, although imperfect, appears satisfactory to permit a clinical trial in children.

Effects of a new prolactin inhibitor, CV 205-502, in the treatment of human macroprolactinomas.

The effects of a new PRL inhibitor, CV 205-502 (CV), on human macroprolactinomas were studied in nine patients according to a prospective protocol. Five patients had undergone surgery leaving tumor remnants and persistent hyperprolactinemia. The four others were de novo patients, two of whom had received short term treatment with Parlodel. Plasma PRL levels ranged from 235-6050 micrograms/L before treatment. The doses of CV used in this trial ranged from 0.075-0.600 mg. Plasma PRL normalized in eight of the nine patients during treatment with CV. The time to normalize varied from 2 weeks to 9 months, and the doses from 0.075-0.450 mg. A tumor volume reduction of more than 50% was obtained in all four patients who had not been operated on before CV treatment. Only one of the five patients with postoperative tumor remnants had no reduction in tumor size. The drug was generally well tolerated, and no patient interrupted the treatment. Slight and short-lasting gastrointestinal symptoms were noted in several patients, and a single episode of fainting occurred in one patient when the drug was not taken at bedtime as instructed. A noticeable and persistent weight loss with anorexia was noted in two patients. Since CV 205-502, administered in a single daily dose, has tolerable side-effects and is effective in reducing PRL secretion and tumor size, it can be considered to be a useful treatment for macroprolactinomas.

Effects of the somatostatin analog BIM 23014 on the secretion of growth hormone, thyrotropin, and digestive peptides in normal men.

BIM 23014 (BIM) is a long-acting octapeptide somatostatin analog. We studied the effects of this analog on the secretion of GH, TSH, and gastroenteropancreatic hormones [secretin, motilin, and pancreatic polypeptide (PP)] in normal men. In the first protocol three BIM doses (125, 250, and 500 micrograms) and vehicle were administered sc in random order at 2000 h to eight normal young men. Plasma GH concentrations decreased during the first part of the night only after the highest dose (P less than 0.05). Plasma secretin levels did not change, while plasma motilin decreased after the 250- and 500-micrograms doses (P = 0.05 and P = 0.02, respectively), and plasma PP decreased after all three doses (P less than 0.05, P less than 0.01, and P less than 0.01, respectively) during the first part of the night. In the second protocol, eight men received BIM, administered by constant sc infusion during the night in a dose of 2 mg/12 h, or vehicle, either alone or in association with a 10 ng/kg.min iv GHRH or vehicle infusion. Nocturnal GH secretion was suppressed by the BIM infusion (P less than 0.001). GH secretion, stimulated by GHRH infusion (P less than 0.001), was reduced by concomitant BIM infusion (P less than 0.001) and was pulsatile during the combined infusions. BIM infusion suppressed the physiological nighttime rise in plasma TSH levels. Plasma motilin and PP levels were reduced by BIM, when administered either alone or in combination with GHRH. We conclude that: 1) BIM is capable of reducing GH secretion when administered sc in a dose of 500 micrograms and of abolishing nocturnal GH secretion when constantly infused at a dose of 2 mg/12 h; 2) BIM, constantly infused, reduces the nocturnal rise in TSH secretion; and 3) motilin and PP secretion are more sensitive than that of GH to BIM, as they are reduced by a lower dose.

Effect of epinephrine on the relationship between nonesterified fatty acid availability and ketone body production in postabsorptive man: evidence for a hepatic antiketogenic effect of epinephrine.

The effect of epinephrine (EPI) on the transformation of nonesterified fatty acids (NEFA) into ketone bodies (KB) in normal subjects was determined by measuring simultaneously NEFA ([1-13C]palmitic acid) and KB ([3-13C]- or [3,4-13C2]acetoacetate) kinetics at different NEFA levels in the presence of basal (control test) or increased (EPI infusion test) EPI concentrations. During the control test the initial (postabsorptive state) concentrations and turnover rates of NEFA and KB were 476 +/- 47 (+/- SEM) and 4.30 +/- 0.17 mumol kg-1 min-1 (NEFA) and 126 +/- 17 and 2.49 +/- 0.07 mumol kg-1 min-1 (KB). The fraction of NEFA converted into KB was between 11.5-14.6%. Raising NEFA levels to about 650 mumol L-1 (iv infusion of a triglyceride emulsion) resulted in an increase in this fraction to between 26-30.3% (P less than 0.01). When NEFA concentrations were next abruptly raised to high levels (near 3 mmol L-1) by heparin injection this fraction returned to near the initial values (15-19.2%). During the EPI infusion test the initial (postabsorptive) concentrations and turnover rates of NEFA and KB as well as the fraction of NEFA converted into KB (10.5-11.5%) were comparable to the initial values of the control test. Intravenous infusion of EPI (10 ng kg-1 min-1) raised NEFA between 600 and 750 mumol L-1, comparable to values during the triglyceride test, but the fraction of NEFA converted into KB remained between 8.2-12% (P less than 0.05 vs. control test); when NEFA then were raised to even higher values (near 2.5 mmol L-1) by the infusion of a triglyceride emulsion and the injection of heparin, this fraction decreased to between 4-8% (P less than 0.05 vs. initial values of the EPI test and P less than 0.05 vs. the control test). In conclusion, 1) the fraction of NEFA converted into KB appears to depend in part on the NEFA concentration; and 2) the net effect of EPI infusion was to decrease the fraction of NEFA converted into KB.

Insulin-mediated glucose disposal in type 1 (insulin-dependent) diabetic subjects treated by continuous subcutaneous or intraperitoneal insulin fusion.

In order to determine if intraperitoneal insulin infusion could improve the insulin resistance of type 1 diabetic patients we have used the englycaemic insulin clamp technique in order to study the effects of insulin on glucose disposal in four C peptide negative type 1 diabetic patients treated by continuous subcutaneous or intraperitoneal insulin infusion and in five control subjects. Compared to control subjects, the diabetic patients treated by subcutaneous insulin infusion had a decreased maximal capacity of glucose utilization (diabetics: 12.6 +/- 0.3 mg.kg-1.min-1; controls: 15.7 +/- 0.7 mg/kg-1.min-1, p less than 0.01) and a trend towards higher half-maximally effective insulin concentrations (diabetics: 70 +/- 11 mU/l-1, controls: 48 +/- 4 mU/l-1). Treatment of the diabetic patients by intraperitoneal insulin infusion for 2 months decreased their mean peripheral free insulin levels (during subcutaneous infusion: 23.5 +/- 2.2 mU/l-1; during intraperitoneal infusion: 18.4 +/- 1.4 mU/l-1, p less than 0.05). However, mean daily insulin requirements were not decreased (during subcutaneous infusion: 0.59 +/- 0.05 U/kg-1.day-1; during intraperitoneal infusion: 0.57 +/- 0.03 U/kg-1.min-1). Moreover, the diabetic patients had a consistently lower maximal capacity of glucose utilization (12.6 +/- 0.7 mg kg-1.min-1) than control subjects (p less than 0.01) without modification of the half-maximally effective insulin concentration (62 +/- 10 mU.l-1). In conclusion, the only benefit of intraperitoneal insulin infusion was a reduction of peripheral free insulin levels; this decrease of peripheral insulinaemia was not associated with an improvement in the insulin resistance of diabetic patients.