Effects of pulsatile delivery of insulin and glucagon in humans.

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 ▲]

Perspectives concernant les voies d'administration inhabituelles de l'insuline. Les voies orale, rectale et nasale.

in Annales d'Endocrinologie (1988), 49(4-5), 386-90

The present review concerns the current possibilities of insulin administration through the oral, rectal or nasal routes. The use of vehicle such as liposomes or various polymers protecting the hormone ... [more ▼]

The present review concerns the current possibilities of insulin administration through the oral, rectal or nasal routes. The use of vehicle such as liposomes or various polymers protecting the hormone against the digestive enzymes allowed to improve the absorption of insulin after its oral administration. Moreover, the use of various surfactants favours the resorption of insulin through the intestinal, rectal and nasal mucosae. However until now, none of these routes has sufficient reliability and reproducibility to be considered for routine treatment of diabetes mellitus. [less ▲]

Pulsatile insulin delivery is more efficient than continuous infusion in modulating islet cell function in normal subjects and patients with type 1 diabetes.

in Journal of Clinical Endocrinology and Metabolism (1988), 66(6), 1220-6

The respective modulating effects of continuous and intermittent insulin delivery on pancreatic islet cell function were studied in seven normal men and nine insulin-dependent (type 1) diabetic patients ... [more ▼]

The respective modulating effects of continuous and intermittent insulin delivery on pancreatic islet cell function were studied in seven normal men and nine insulin-dependent (type 1) diabetic patients. In the normal men, saline or continuous (0.8 mU kg-1 min-1) or pulsatile (5.2 mU kg-1 min-1, with a switching on/off length of 2/11 min) human insulin were delivered on different days and in random order. Despite hyperinsulinemia, blood glucose was kept close to its basal value by the glucose clamp technique. The diabetic patients also were infused in random order and on different days with either saline or a smaller amount of insulin delivered continuously (0.15 mU kg-1 min-1) or in a pulsatile manner (0.97 mU kg-1 min-1 for 2 min, followed by 11 min during which no insulin was infused). In all experiments, 5 g arginine were given iv as a bolus dose 30 min before the end of the study, and plasma C-peptide and glucagon levels were determined to assess islet cell function. In the normal men, insulin administration resulted in a significant decline of basal plasma glucagon and C-peptide levels and in a clear-cut decrease in the arginine-induced glucagon response. These effects of insulin were significantly more marked when insulin was delivered in a pulsatile rather than a continuous manner. In the insulin-dependent diabetic patients, the lower dose of insulin infused continuously did not alter the basal or arginine-stimulated glucagon response. In contrast, when the same amount of insulin was delivered intermittently, arginine-induced glucagon release was greatly reduced. Thus, these data support the concept that insulin per se is a potent physiological modulator of islet A- and B-cell function. Furthermore, they suggest that these effects of insulin are reinforced when the hormone is administered in an intermittent manner in an attempt to reproduce the pulsatile physiological release of insulin. [less ▲]

Insulin sensitivity in anorexia nervosa: a mirror image of obesity?

in Diabetes/Metabolism Reviews (1988), 4(7), 681-90

Although, in many respects and from a metabolic point of view, obesity and AN are clearly two opposite pathological conditions, the available data concerning insulin sensitivity in these two syndromes are ... [more ▼]

Although, in many respects and from a metabolic point of view, obesity and AN are clearly two opposite pathological conditions, the available data concerning insulin sensitivity in these two syndromes are not so obviously opposite. Indeed, whereas everybody is convinced that obesity is characterized by an increased insulin resistance, the papers reporting insulin sensitivity parameters in AN contain some apparently contradictory results. The observations of simultaneously low fasting blood glucose and plasma-insulin levels in anorectic patients could suggest increased insulin sensitivity in AN. However, if this is the case, it would be present despite other metabolic and hormonal changes (increased plasma concentrations of free fatty acids, cortisol, and growth hormone) which are known factors of insulin resistance. During an oral glucose-tolerance test, an impaired glucose-tolerance occurring despite sustained insulin response to glucose is usually found in anorectic patients before treatment; these abnormalities are, at least partially, reversed after successful refeeding. From these results, such conclusive, if indirect, evidence exists for relative insulin insensitivity in untreated AN. Similar results were initially reported with the intravenous glucose-tolerance test. Typically, the coefficient of glucose assimilation K was reduced in anorectic patients before treatment and increased after realimentation. This seemed to occur despite a relative increase in insulin response to glucose, which again may be related to insulin resistance in these undernourished subjects. However, more recent data demonstrated that the early insulin response is significantly lower in anorectic patients than in controls and that more than half of these patients have normal glucose-tolerance despite decreased peripheral plasma insulin levels. These latter observations, on the contrary, suggest an increased insulin sensitivity, at least in some patients with AN. Only the recently developed minimal model method allows us to discriminate between changes in insulin secretion and action after intravenous glucose injection and thus to infer accurately the sensitivity of the tissues to insulin. Unfortunately, this technique has not been applied to anorectic patients, until now, to solve the controversy. The simplest way to assess the action in vivo of insulin is to perform an intravenous insulin-tolerance test. However, the initial findings with this test, which showed exaggerated fall in plasma-glucose values and delayed return to basal levels after intravenous injection of insulin in AN, do not necessarily mean increased insulin sensitivity in these self-starved patients.(ABSTRACT TRUNCATED AT 400 WORDS) [less ▲]

Prostaglandines, secretion d'insuline et diabete sucre.

in Diabète & Métabolisme (1988), 14(6), 721-7

The islets of Langerhans have the enzymatic equipment permitting the synthesis of the metabolites of arachidonic acid: cyclo-oxygenase and lipo-oxygenase. Numerous studies have shown that cyclo-oxygenase ... [more ▼]

The islets of Langerhans have the enzymatic equipment permitting the synthesis of the metabolites of arachidonic acid: cyclo-oxygenase and lipo-oxygenase. Numerous studies have shown that cyclo-oxygenase derivatives, mainly PGE2, reduce the insulin response to glucose whereas lipo-oxygenase derivatives, mainly 15-HPETE, stimulate insulin secretion. So, for instance, drugs that increase prostaglandins synthesis as colchicine or furosemide inhibit insulin secretion while non steroid anti-inflammator drugs, mainly salicylates, which inhibit cyclo-oxygenase, enhance the insulin response to various stimuli. In type-2 (non insulin-dependent) diabetes, an increased sensitivity to endogenous prostaglandins has been proposed as a possible cause for the insulin secretion defect which characterizes this disease. Play in favor of this hypothesis the fact that the administration of PGE inhibits the insulin response to arginine in type-2 diabetics but not in normal subject and the fact that the administration of salicylates could improve the insulin response to glucose in some of these patients. [less ▲]

Effets métaboliques et hormonaux d'un spray nasal d'insuline chez le sujet normal

in Acta Clinica Belgica (1987, April), 42(5),

Prevention of metabolic alterations by insulin supplements administered either before or after 2-h nocturnal interruption of CSII.

in Diabetes Care (1987), 10(5), 567-72

To evaluate the efficacy of a bolus insulin injection to prevent the metabolic alterations induced by a 2-h nocturnal interruption of a continuous subcutaneous insulin infusion (CSII), nine type I ... [more ▼]

To evaluate the efficacy of a bolus insulin injection to prevent the metabolic alterations induced by a 2-h nocturnal interruption of a continuous subcutaneous insulin infusion (CSII), nine type I (insulin-dependent) C-peptide-negative diabetic patients were studied from 2200 to 0800 h during two randomized tests. An insulin bolus (2.1 +/- 0.2 U) was administered via the pump either at 2300 h, just before CSII interruption, or at 0100 h, after reactivating the pump at its usual basal rate (1.05 +/- 0.11 U/h). The insulin bolus at 2300 h induced a significant rise in plasma free-insulin levels at 2400 h (+6.9 +/- 1.8 mU/L, P less than .01), resulting in an early and marked fall in blood glucose concentrations between 2300 and 0100 h (-2.7 +/- 0.5 mM, P less than .001), with hypoglycemic values in five patients. The insulin bolus at 0100 h counteracted the fall in plasma free-insulin levels observed between 2300 and 0100 h and significantly increased plasma insulin at 0200 h (+3.2 +/- 0.8 mU/L, P less than .01). Blood glucose concentrations that remained stable during the 2-h arrest of the pump fell significantly between 0100 and 0400 h (-2.1 +/- 0.5 mM, P less than .005). This fall rate was significantly lower than that measured within the 3 h after the insulin bolus given before CSII interruption but significantly higher than that observed in a reference control group of patients whose pump was functioning normally throughout the night.(ABSTRACT TRUNCATED AT 250 WORDS) [less ▲]

Pulsatile hyperglucagonemia fails to increase hepatic glucose production in normal man.

in American Journal of Physiology (1987), 252(1 Pt 1), 1-7

To study the metabolic effects of pulsatile glucagon administration, six male volunteers were submitted to a 260-min glucose-controlled glucose intravenous infusion using the Biostator. The endogenous ... [more ▼]

To study the metabolic effects of pulsatile glucagon administration, six male volunteers were submitted to a 260-min glucose-controlled glucose intravenous infusion using the Biostator. The endogenous secretion of the pancreatic hormones was inhibited by somatostatin (100 micrograms X h-1), basal insulin secretion was replaced by a continuous insulin infusion (0.2 mU X kg-1 X min-1), and glucagon was infused intravenously in two conditions at random: either continuously (125 ng X min-1) or intermittently (812.5 ng X min-1, with a switching on/off length of 2/11 min). Blood glucose levels and glucose infusion rate were monitored continuously by the Biostator, and classical methodology using a D-[3-3H]glucose infusion allowed us to study glucose turnover. While basal plasma glucagon levels were similar in both conditions (122 +/- 31 vs. 115 +/- 18 pg X ml-1), they plateaued at 189 +/- 38 pg X ml-1 during continuous infusion and varied between 95 and 501 pg X ml-1 during pulsatile infusion. When compared with continuous administration, pulsatile glucagon infusion initially induced a similar increase in endogenous (hepatic) glucose production and blood glucose, did not prevent the so-called "evanescent" effect of glucagon on blood glucose, and after 3 h tended to reduce rather than increase hepatic glucose production. In conclusion, in vivo pulsatile hyperglucagonemia in normal man fails to increase hepatic glucose production. [less ▲]

Primary role of glucagon release in the effect of beta-endorphin on glucose homeostasis in normal man.

in Acta Endocrinologica (1987), 115(2), 161-9

The present study aimed at evaluating the effect of human beta-endorphin on pancreatic hormone levels and on glucose metabolism in normal subjects. Infusion of 143 nmol/h beta-endorphin in 7 subjects ... [more ▼]

The present study aimed at evaluating the effect of human beta-endorphin on pancreatic hormone levels and on glucose metabolism in normal subjects. Infusion of 143 nmol/h beta-endorphin in 7 subjects caused a significant rise in plasma glucose concentrations (+ 1.7 +/- 0.3 mmol/l) which was preceded by a significant increase in peripheral plasma glucagon levels (+ 44 +/- 13 ng/l). No changes occurred in the plasma concentrations of insulin and catecholamines (adrenaline and noradrenaline). The influence of beta-endorphin per se on glucose homeostasis was studied in 7 other subjects using the euglycaemic clamp technique in which the endocrine pancreatic function was fixed at its basal level with somatostatin together with replacement of basal insulin and glucagon by the exogenous infusion of these hormones. In this new metabolic conditions, beta-endorphin failed to have significant influences on the various parameters of tracer-estimated glucose metabolism (production, utilization, and clearance) and on the plasma levels of the gluconeogenic precursors (glycerol and alanine). Moreover, the levels of pancreatic and counterregulatory hormones (cortisol and catecholamines) were not different between beta-endorphin and control studies. We conclude that the naturally occurring opioid peptide beta-endorphin produced an hyperglycaemic effect in man which appears to be mediated by glucagon. The opioid seems to have no direct effect on glucose metabolism. These results suggest that the metabolic effects of beta-endorphin in normal man are secondary to its impact on pancreatic hormone secretion and not a consequence of a direct modulation of glucose metabolism. [less ▲]

Utilisation d'une charge orale de glucose donnée avant, pendant ou après un exercice musculaire prolongé

in Cahiers de Nutrition et de Diététique (1986), XXI