Pulsatile insulin delivery has greater metabolic effects than continuous hormone administration in man: importance of pulse frequency.
; Scheen, André ; et al
in Journal of Clinical Endocrinology and Metabolism (1991), 72(3), 607-15
The aim of this study was to see if the greater effect of insulin on hepatic glucose output when insulin is given using 13-min pulses in man remains when the same amount of insulin is delivered using 26 ... [more ▼]
The aim of this study was to see if the greater effect of insulin on hepatic glucose output when insulin is given using 13-min pulses in man remains when the same amount of insulin is delivered using 26-min pulses. The study was performed on nine male healthy volunteers submitted to a 325 min glucose-controlled glucose iv infusion using the Biostator. The endogenous secretion of pancreatic hormones was inhibited by somatostatin. Three experiments were performed in each subject on different days and in random order. In all cases glucagon was replaced (58 ng min-1). The amounts of insulin infused were identical in all instances and were 0.2 mU kg-1 min-1 (continuous), 1.3 mU kg-1 min-1, 2 min on and 11 min off (13-min pulses) or 2.6 mU kg-1 min-1, 2 min on and 24 min off (26-min pulses). Blood glucose levels and glucose infusion rate were monitored continuously by the Biostator, and classic methodology using D-[3-3H] glucose infusion allowed to study glucose turnover. When compared with continuous insulin, 13-min insulin pulses induced a significantly greater inhibition of endogenous glucose production. This effect disappeared when insulin was delivered in 26-min pulses. We conclude that, in man, an adequate pulse frequency is required to allow the appearance of the greater inhibition of pulsatile insulin on endogenous glucose production. [less ▲]Detailed reference viewed: 12 (0 ULg)
Improvement of insulin-induced glucose disposal in obese patients with NIDDM after 1-wk treatment with d-fenfluramine.
Scheen, André ; ; et al
in Diabetes Care (1991), 14(4), 325-32
OBJECTIVE: To study the short-term effects of the serotoninergic anorectic drug d-fenfluramine on insulin-induced glucose disposal. RESEARCH DESIGN AND METHODS: A randomized double-blind placebo ... [more ▼]
OBJECTIVE: To study the short-term effects of the serotoninergic anorectic drug d-fenfluramine on insulin-induced glucose disposal. RESEARCH DESIGN AND METHODS: A randomized double-blind placebo-controlled crossover trial with 1-wk treatment periods (2 x 15 mg/day d-fenfluramine) was conducted. Twenty obese subjects, 10 with normal oral glucose tolerance and 10 with non-insulin-dependent diabetes mellitus (NIDDM), were all treated with a weight-maintaining diet. Euglycemic-hyperinsulinemic glucose clamps with measurement of glucose kinetics with D-[3-3H]glucose were performed at either two (patients without NIDDM, 0.05 and 0.10 U.kg-1.h-1) or three (patients with NIDDM, 0.05, 0.10, and 0.50 U.kg-1.h-1) insulin delivery rates. RESULTS: In the nondiabetic subjects, no significant changes in any metabolic or hormonal parameter were measured in the basal state or during the clamp despite a slight reduction in body weight (-1.2 +/- 0.5 kg, P less than 0.05). In the diabetic patients, no significant changes in body weight or basal plasma insulin levels were observed, but fasting blood glucose levels (8.0 +/- 0.8 vs. 9.4 +/- 1.1 mM, P less than 0.005) and plasma free fatty acid concentrations (1150 +/- 227 vs. 1640 +/- 184 microM, P less than 0.05) were significantly reduced after d-fenfluramine compared with placebo. During the clamp, insulin metabolic clearance rate (MCR) was similar after both placebo and d-fenfluramine; endogenous (hepatic) glucose production was similarly and almost completely suppressed, whereas glucose disposal was remarkably enhanced after d-fenfluramine (average increase of glucose MCR 35 +/- 12%, P less than 0.02). CONCLUSIONS: Whatever the mechanism(s) involved, a 1-wk treatment with d-fenfluramine induces better blood glucose control and improves insulin sensitivity in obese patients with NIDDM independent of significant weight reduction; this last effect is not present in obese subjects with normal oral glucose tolerance. [less ▲]Detailed reference viewed: 7 (1 ULg)
Prévention de l'athérosclérose chez le sujet diabétique
PAQUOT, Nicolas ; SCHEEN, André
in Medical trends (1990), 1Detailed reference viewed: 4 (0 ULg)
Pourquoi, quand et comment traiter une hyperlipoprotéinémie chez le patient diabétique ?
PAQUOT, Nicolas ; Scheen, André ;
in Médecine et Hygiène (1990), 48Detailed reference viewed: 6 (0 ULg)
Etude de la sécrétion et de la clairance métabolique de l'insuline avant et après cure de jeûne protidique chez le sujet obèse
Paquot, Nicolas ; Scheen, André ; et al
in Diabètes & Métabolism (1990), 16(suppl), 81Detailed reference viewed: 6 (0 ULg)
Insulin secretion, metabolism and sensitivity before and after a protein-sparing modified fast in obese subjects.
Paquot, Nicolas ; Scheen, André ; et al
in Diabetologia (1990), 33(suppl), 216Detailed reference viewed: 4 (0 ULg)
Pulsatile glucagon has greater hyperglycaemic, lipolytic and ketogenic effects than continuous hormone delivery in man: effect of age.
; ; et al
in Diabetologia (1990), 33(5), 272-7
The present study aimed at investigating the hyperglycaemic, lipolytic and ketogenic effects of small doses of glucagon delivered continuously or in a pulsatile manner. The study was performed in eight ... [more ▼]
The present study aimed at investigating the hyperglycaemic, lipolytic and ketogenic effects of small doses of glucagon delivered continuously or in a pulsatile manner. The study was performed in eight healthy young volunteers (24.2 +/- 1.2 years) and in eight healthy aged subjects (69.4 +/- 2.0 years). In all the subjects, endogenous pancreatic hormone secretion was inhibited by somatostatin and only glucagon was replaced. Consequently, the effects of pulsatile and continuous glucagon delivery were studied in conditions of progressive somatostatin-induced insulin deficiency. In both the young and the aged subjects, pulsatile glucagon delivery resulted in increases in plasma glucose, non-esterified fatty acid, glycerol and beta-hydroxybutyrate levels greater than those observed when the same amount of glucagon was delivered in a continuous manner. The net increases in plasma glucose, glycerol and non-esterified fatty acid levels were similar between the young and the aged subjects when glucagon was infused continuously; in contrast, the rise in plasma beta-hydroxybutyrate in the aged was only about half that observed in the young subjects. Surprisingly, when glucagon was infused in a pulsatile manner, the rises in plasma glycerol, non-esterified fatty acid and beta-hydroxybutyrate levels were all significantly smaller in the aged subjects, while no significant differences were observed in the blood glucose responses. We conclude that, in the presence of somatostatin-induced insulin deficiency, pulsatile glucagon exerts greater effects on blood glucose, plasma non-esterified fatty acid, glycerol and beta-hydroxybutyrate levels than its continuous delivery. In the elderly, the lipolytic and ketogenic, but not the hyperglycaemic, responses to pulsatile glucagon are significantly reduced. [less ▲]Detailed reference viewed: 13 (0 ULg)
Effects of ethinyl estradiol combined with desogestrel and cyproterone acetate on glucose tolerance and insulin response to an oral glucose load: a one-year randomized, prospective, comparative trial.
Jandrain, Bernard ; Humblet, Dominique ; et al
in American Journal of Obstetrics and Gynecology (1990), 163(1 Pt 2), 378-81
To investigate the effects of two slightly estrogen-dominant, monophasic, low-dose oral contraceptives on carbohydrate metabolism, 40 healthy young women were randomly allocated to receive either 30 ... [more ▼]
To investigate the effects of two slightly estrogen-dominant, monophasic, low-dose oral contraceptives on carbohydrate metabolism, 40 healthy young women were randomly allocated to receive either 30 micrograms of ethinyl estradiol + 150 micrograms of desogestrel, a 19-nortestosterone-derived progestin (Marvelon; n = 21) or 35 micrograms of ethinyl estradiol + 2 mg of cyproterone acetate, a 17-acetoxyprogesterone derivative (Diane-35; n = (19) for a prospective observation period of 1 year. At baseline, 6, and 12 months, blood glucose, plasma insulin, and plasma C-peptide levels were measured during an oral glucose tolerance test. Although the changes were absent (Marvelon) or minimal (Diane-35) at 6 months, both groups had a slight increase in blood glucose levels at 12 months; overall glucose tolerance remaining, however, within the normal range. Plasma insulin levels remained unchanged in the Diane-35-group, which suggested increased insulin resistance, but were significantly decreased in the Marvelon group despite significant rises in plasma C-peptide levels. Comparison of plasma C-peptide and insulin changes suggests enhanced pancreatic insulin secretion and increased hepatic insulin metabolism with both Marvelon and Diane-35. [less ▲]Detailed reference viewed: 66 (2 ULg)
Magnesium and glucose homeostasis.
; Scheen, André ; et al
in Diabetologia (1990), 33(9), 511-4
Magnesium is an important ion in all living cells being a cofactor of many enzymes, especially those utilising high energy phosphate bounds. The relationship between insulin and magnesium has been ... [more ▼]
Magnesium is an important ion in all living cells being a cofactor of many enzymes, especially those utilising high energy phosphate bounds. The relationship between insulin and magnesium has been recently studied. In particular it has been shown that magnesium plays the role of a second messenger for insulin action; on the other hand, insulin itself has been demonstrated to be an important regulatory factor of intracellular magnesium accumulation. Conditions associated with insulin resistance, such as hypertension or aging, are also associated with low intracellular magnesium contents. In diabetes mellitus, it is suggested that low intracellular magnesium levels result from both increased urinary losses and insulin resistance. The extent to which such a low intracellular magnesium content contributes to the development of macro- and microangiopathy remains to be established. A reduced intracellular magnesium content might contribute to the impaired insulin response and action which occurs in Type 2 (non-insulin-dependent) diabetes mellitus. Chronic magnesium supplementation can contribute to an improvement in both islet Beta-cell response and insulin action in non-insulin-dependent diabetic subjects. [less ▲]Detailed reference viewed: 36 (0 ULg)
Alimentation avant, pendant et après l'exercice physique chez le sujet normal et diabétique
Jandrain, Bernard ; Lefèbvre, Pierre ; Pirnay, Freddy et al
in Journées Annuelles de Diabetologie de l'Hôtel-Dieu (1990)Detailed reference viewed: 70 (3 ULg)
Insulin secretion rate and hepatic insulin extraction during an intravenous glucose tolerance test in obese subjects: effect of a protein-supplemented fast.
PAQUOT, Nicolas ; SCHEEN, André ; et al
Poster (1989, July)Detailed reference viewed: 6 (0 ULg)
Metabolic modifications induced by a combined insulin-glucose intravenous infusion before and after a protein-supplemented fast in obese subjects.
; SCHEEN, André ; et al
Poster (1989, May)Detailed reference viewed: 5 (0 ULg)
Sandostatin, a new analogue of somatostatin, reduces the metabolic changes induced by the nocturnal interruption of continuous subcutaneous insulin infusion in type 1 (insulin-dependent) diabetic patients.
Scheen, André ; ; et al
in Diabetologia (1989), 32(11), 801-9
With the aim of assessing a new somatostatin analogue to prevent the metabolic changes induced by a 6-h nocturnal arrest of an insulin pump, nine C-peptide negative Type 1 (insulin-dependent) diabetic ... [more ▼]
With the aim of assessing a new somatostatin analogue to prevent the metabolic changes induced by a 6-h nocturnal arrest of an insulin pump, nine C-peptide negative Type 1 (insulin-dependent) diabetic patients were submitted blindly to two interruptions (from 23.00 to 05.00 hours) of their continuous s.c. insulin infusion, once after a single s.c. injection at 23.00 hours of 50 micrograms SMS 201-995 (Sandostatin, Sandoz) and once after 0.9% NaCl. Plasma SMS 201-995 levels peaked at 24.00 hours and then declined with an elimination half-life averaging 144 +/- 15 min. Plasma glucagon and growth hormone levels were significantly reduced after SMS 201-995 whereas the progressive fall in plasma-free insulin levels from 23.00 to 05.00 hours was unaffected. In the control test, blood glucose levels tended to decrease slightly from 23.00 to 02.00 hours and then increased markedly from 02.00 to 05.00 hours (+5.3 +/- 1.5 mmol/l) while after SMS 201-995 they decreased significantly from 23.00 to 02.00 hours (-2.6 +/- 0.5 mmol/l), resulting in values below 3 mmol/l in seven subjects, but showed a secondary increase until 05.00 hours (+3.5 +/- 1.5 mmol vs 23.00 h; p less than 0.05 vs 0.9% NaCl). While the rises in plasma non-esterified fatty acid and glycerol levels were not reduced by SMS 201-995, the increase in plasma 3-hydroxbutyrate levels, although similar from 23.00 to 02.00 hours, was significantly reduced from 02.00 to 05.00 hours (+77 +/- 20 vs +124 +/- 31 mumols.l-1.h-1; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) [less ▲]Detailed reference viewed: 32 (13 ULg)
Insulin versus insulin plus sulfonylureas in type 2 diabetic patients with secondary failure to sulfonylureas.
Scheen, André ; Lefebvre, Pierre
in Diabetes Research & Clinical Practice (1989), 6(4), 33-4242-3
According to the modern pathophysiological understanding of type 2 diabetes and the mechanisms of sulfonylurea action, combined insulin-sulfonylurea therapy appears to be an interesting alternative for ... [more ▼]
According to the modern pathophysiological understanding of type 2 diabetes and the mechanisms of sulfonylurea action, combined insulin-sulfonylurea therapy appears to be an interesting alternative for treating diabetic patients with secondary failure to sulfonylureas. From its revival in the early 1980s, combination therapy has been shown to have a positive effect on blood glucose control although initially published clinical studies, generally open and uncontrolled, have been widely criticized. Several recent well-designed studies confirmed these favorable results, with better glucose profiles and/or decreased insulin needs, which were shown to persist after 1 year or more. Most of the studies investigating the mechanism of action indicate that the effect is mainly due to stimulation of the residual insulin secretion with minimal or no effect on insulin sensitivity. The risk of hypoglycemic episodes is rather small when insulin doses are adapted at the beginning of the combined therapy. Effects on lipid metabolism are minimal and controversial. Thus, insulin-sulfonylurea treatment may be a safe and effective solution in type 2 diabetic patients with secondary failure to sulfonylureas, particularly in those with significant residual endogenous insulin secretion. The additional cost of such combined therapy should be weighed against the potential advantages of better metabolic control. [less ▲]Detailed reference viewed: 16 (0 ULg)
Effect of osmolality on availability of glucose ingested during prolonged exercise in humans.
Jandrain, Bernard ; Pirnay, Freddy ; et al
in Journal of Applied Physiology (Bethesda, Md. : 1985) (1989), 67(1), 76-82
The aim of this study was to investigate whether the osmolality of a glucose solution, ingested at the beginning of a prolonged exercise bout, affects exogenous glucose disposal. We investigated the ... [more ▼]
The aim of this study was to investigate whether the osmolality of a glucose solution, ingested at the beginning of a prolonged exercise bout, affects exogenous glucose disposal. We investigated the hormonal and metabolic response to a 50-g glucose load dissolved in either 200 (protocol A), 400 (protocol B), or 600 (protocol C) ml of water and given orally 15 min after adaptation to exercise in five healthy male volunteers. Naturally labeled [13C]glucose was used to follow the conversion of the ingested glucose to expired-air CO2. Total carbohydrate oxidation (indirect calorimetry) was similar in the three protocols (A, 237 +/- 20; B, 258 +/- 17; C, 276 +/- 20 g/4 h), as was lipid oxidation (A, 128 +/- 4; B, 132 +/- 15; C, 124 +/- 12 g/4 h). Exogenous glucose oxidation rates were similar under the three experimental conditions, and the total amount of exogenous glucose utilized was slightly, but not significantly, increased with the more diluted solution (A, 42.6 +/- 4.4; B, 43.4 +/- 4.1; C, 48.7 +/- 7.2 g/4 h). The blood glucose response was similar in the three protocols. Thus, within the range investigated, the osmolality of the glucose solution ingested had no significant influence either on its oxidation (which was 86-98% of the load ingested) or on the utilization of endogenous carbohydrate, lipid, or protein stores. [less ▲]Detailed reference viewed: 16 (0 ULg)
Effects of pulsatile delivery of insulin and glucagon in humans.
; Scheen, André ; Albert, Adelin et al
in American Journal of Physiology (1989), 257(5 Pt 1), 686-96
The purpose of the present study was to investigate the respective effects of continuous intravenous delivery of both insulin and glucagon compared with those of pulsatile insulin (and continuous glucagon ... [more ▼]
The purpose of the present study was to investigate the respective effects of continuous intravenous delivery of both insulin and glucagon compared with those of pulsatile insulin (and continuous glucagon), pulsatile glucagon (and continuous insulin) and both hormones administered in a pulsatile manner (but out of phase) on various parameters of glucose turnover. The study was performed on six healthy male volunteers submitted to a 325-min glucose-controlled glucose intravenous infusion using the Biostator. The endogenous secretion of pancreatic hormones was inhibited by somatostatin (2 micrograms/min). Four combinations of continuous and pulsatile infusions of insulin and glucagon were performed on different days and in random order. The amounts of hormone infused were identical in all instances and were 0.2 mU.kg-1.min-1 (continuous insulin), 67 ng/min (continuous glucagon), 1.3 mU.kg-1.min-1 and 435 ng/min with a switching on-off length of 2-11 min (for intermittent insulin and glucagon delivery, respectively). In the case of pulsatile administration of both hormones, the pulses of insulin and glucagon were given out of phase with a 6-min interval. Blood glucose levels and glucose infusion rate were monitored continuously by the Biostator, and classic methodology using a D-[3-3H]glucose infusion allowed to study glucose turnover. When compared with pulsatile insulin and continuous glucagon, pulsatile glucagon and continuous insulin were characterized by a significantly higher endogenous (hepatic) glucose production. When both insulin and glucagon were delivered in a pulsatile manner, the effect of pulsatile glucagon was predominant, maintaining a high endogenous glucose production. Under no circumstance was an effect on glucose utilization or clearance detected. This study demonstrates that pulsatile delivery of insulin or glucagon in humans has greater effects in modulating endogenous glucose production than continuous infusion. Furthermore, when both insulin and glucagon are delivered intermittently and out of phase, the stimulatory effect of glucagon on endogenous glucose production prevails over the inhibitory effect of insulin. [less ▲]Detailed reference viewed: 20 (0 ULg)
Papel de la insulina y hormonas de contra-regulacion en las alteraciones metabolicas por deprivacion de insulina en pacientes diabeticos.
; Scheen, André ; et al
in Revista Espanola de Fisiologia (1989), 45(1), 53-9
In eight insulin dependent diabetic patients treated by continuous subcutaneous insulin infusion (1.1 +/- 0.2 U/h), the levels (measured hourly from 23 h to 05 h) of blood glucose, non esterified fatty ... [more ▼]
In eight insulin dependent diabetic patients treated by continuous subcutaneous insulin infusion (1.1 +/- 0.2 U/h), the levels (measured hourly from 23 h to 05 h) of blood glucose, non esterified fatty acids (NEFA), glycerol and 3-OH-butyrate (3-OH-B) have been correlated to the circulating levels of free insulin (FIRI), glucagon, growth hormone or cortisol, in two experimental conditions: A. Insulin being infused as usual (physiological FIRI levels) and B. Progressively declining FIRI levels (insulin infusion arrested at 23 h). In condition A, blood glucose levels correlated significantly to both insulin and glucagon; NEFA, glycerol and 3OH-B correlated only to insulin. In condition B, blood glucose was significantly correlated to insulin but not to glucagon while NEFA, glycerol and 3-OH-B were significantly correlated to both hormones but not to growth hormone or cortisol. Therefore, on the metabolic deterioration that follows insulin withdrawal, growth hormone and cortisol seem to play a minor role, the main role being played by the decrease in circulating insulin levels and to a lesser extent by the increase in glucagon levels. [less ▲]Detailed reference viewed: 101 (0 ULg)
Pharmacocinetique de l'insuline administree par voie sous-cutanee. Application au traitement par pompe portable (1).
in Diabète & Métabolisme (1989), 15(3), 128-38
Continuous subcutaneous insulin infusion is characterized by a basal insulin delivery rate to which insulin boluses are added. The basal delivery rate maintains a small insulin reserve in the local ... [more ▼]
Continuous subcutaneous insulin infusion is characterized by a basal insulin delivery rate to which insulin boluses are added. The basal delivery rate maintains a small insulin reserve in the local subcutaneous depot. This reserve averages 2 to 5 times the hourly basal rate at the steady-state which is reached after about 7 hours but depends on numerous factors: subcutaneous blood flow, skinfold thickness, insulin concentration, etc. It explains the pharmacokinetics time-lag of the system, more particularly the similar effects of a basal rate delivered in either a pulsatile/intermittent or a continuous manner, the lack of deleterious effect of a 1-h pump arrest, the 2-h delay before significant metabolic deterioration during a more prolonged interruption of the infusion, the delayed plasma insulin changes when the basal insulin delivery rate is doubled or reduced by half, etc. Insulin boluses pharmacokinetics is not fundamentally different from that of soluble insulin injection in conventional therapy. As an example, insulin boluses should ideally be given 30 min before the meals in order to better prevent post-prandial hyperglycaemia. However, the absence of intermediate zinc-insulin in the system may result in an earlier increase of plasma free insulin levels, which for instance allows a rapid correction of the metabolic alterations induced by a prolonged interruption of the basal infusion rate. This kinetics does not seem to be significantly altered by insulin concentration nor by the profile of the bolus but is affected by the insulin content of the subcutaneous depot at the time the bolus is delivered.(ABSTRACT TRUNCATED AT 250 WORDS) [less ▲]Detailed reference viewed: 118 (0 ULg)