Effect of pharmacological doses of oxytocin on insulin response to glucose in normal man

In this study we have examined the effect of the administration of oxytocin on basal blood concentrations of insulin, glucagon, cortisol, growth hormone, and on the dynamic secretory response of these hormones to intravenous glucose administration (0.33 g/kg) in basal condition and after the injection of 3 IU (1 plus 2 IU/1 h) or 6 IU (2 plus 4 IU/1 h) of oxytocin (6 subjects for each group). The highest dose of oxytocin (6 IU) used significantly increased insulin secretion in response to intravenously administered glucose. No significant change of insulin secretion was observed with 3 IU of oxytocin. Glucagon, cortisol, and growth hormone response to intravenous injection of glucose was not affected by oxytocin (3 or 6 IU) administration. These results suggest that high doses of oxytocin affect beta-cell function in normal man.     

Electric footshocks differentially affect plasma and spinal cord vasopressin and oxytocin levels

Rats exposed for three minutes to repeated electric footshocks showed an approximate 10-fold increase of basal plasma vasopressin (AVP) and oxytocin (OXT) levels. In contrast, spinal AVP and OXT contents measured in the same rats remained unchanged when compared to undisturbed controls. This observation suggests that spinal AVP and OXT do not play a major role in the short-term adaptation of the organism to stress.     

Influence of amphetamines on plasma corticosteroid and growth hormone levels in man

Plasma fluorogenic corticosteroid and immunoreactive growth hormone levels rose significantly after the intravenous administration of methylamphetamine to healthy young men at various times of the day. The rise in corticosteroids was most pronounced in the evening and was accompanied by an increase in circulating levels of immunoreactive corticotrophin. Oral dexamphetamine also resulted in significant rises in plasma corticosteroids but not in growth hormone. These hormonal changes were accompanied by evidence of mild central stimulation. Though they may be part of an associated and non-specific response, it is more likely that they represent specific effects of amphetamines on centres in the hypothalamus or midbrain controlling secretion of corticotrophin and growth hormone releasing factors.     

Effect of exogenous insulin on plasma free carnitine levels during exercise in normal man

Preliminary data from our laboratory have shown that the decrease in plasma free carnitine levels normally found during prolonged exercise is blunted in type 1 diabetic man. This study was designed to test the hypothesis that this might be due to the sustained peripheral hyperinsulinemia seen during exercise in diabetics treated by subcutaneous insulin. Ten male subjects underwent 90 min of cycle ergometry at 60% of their maximal oxygen uptake capacity on two occasions, one with and the other without a constant 0.13 mU.kg-1.min-1 i.v. insulin infusion. Blood samples were taken at rest, during exercise, and after exercise for measurement of plasma glucose, insulin, C-peptide, free fatty acids, and carnitine. Plasma glucose dropped significantly (p less than 0.01) from basal during both infusions, but values at 30, 45, and 60 min of exercise were lower (p less than 0.05) during insulin infusion compared with the saline infusion. Exercise produced a significant (p less than 0.01) fall in plasma insulin in both infusions. However, from 30 to 90 min of exercise, the plateau insulin level was higher during the insulin infusion compared with the saline infusion (91.4 +/- 3.0 vs. 32.9 +/- 3.0 pmol/L; p less than 0.001). Plasma C-peptide decreased significantly (p less than 0.01) during exercise and recovery in both infusions, but values between infusions were not significantly different. Plasma free fatty acids increased significantly (p less than 0.01) at 90 min of exercise during the saline infusion, while during the insulin infusion this was noted during recovery only.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mice deficient in the insulin-regulated membrane aminopeptidase show substantial decreases in glucose transporter GLUT4 levels but maintain normal glucose homeostasis

The insulin-regulated aminopeptidase (IRAP) is a zinc-dependent membrane aminopeptidase. It is the homologue of the human placental leucine aminopeptidase. In fat and muscle cells, IRAP colocalizes with the insulin-responsive glucose transporter GLUT4 in intracellular vesicles and redistributes to the cell surface in response to insulin, as GLUT4 does. To address the question of the physiological function of IRAP, we generated mice with a targeted disruption of the IRAP gene (IRAP-/-). Herein, we describe the characterization of these mice with regard to glucose homeostasis and regulation of GLUT4. Fed and fasted blood glucose and insulin levels in the IRAP-/- mice were normal. Whereas IRAP-/- mice responded to glucose administration like control mice, they exhibited an impaired response to insulin. Basal and insulin-stimulated glucose uptake in extensor digitorum longus muscle, and adipocytes isolated from IRAP-/- mice were decreased by 30-60% but were normal for soleus muscle from male IRAP-/- mice. Total GLUT4 levels were diminished by 40-85% in the IRAP-/- mice in the different muscles and in adipocytes. The relative distribution of GLUT4 in subcellular fractions of basal and insulin-stimulated IRAP-/- adipocytes was the same as in control cells. We conclude that IRAP-/- mice maintain normal glucose homeostasis despite decreased glucose uptake into muscle and fat cells. The absence of IRAP does not affect the subcellular distribution of GLUT4 in adipocytes. However, it leads to substantial decreases in GLUT4 expression.     

Role of glucose in modulating Mg2+ homeostasis in liver cells from starved rats

Alpha1- and beta-adrenoceptor stimulation elicits Mg2+ extrusion from liver cells in conjunction with hepatic glucose output (T. Fagan and A. Romani. Am J Physiol Gastrointest Liver Physiol 279: G943-G950, 2000.). To characterize the role of intrahepatic glucose on Mg2+ transport, male Sprague-Dawley rats were starved overnight before being anesthetized and used as organ donors. Perfused livers or collagenase-dispersed hepatocytes were stimulated by alpha1 (phenylephrine)- or beta (isoproterenol)-adrenergic agonists. Mg2+ extrusion was assessed by atomic absorbance spectrophotometry. In both experimental models, the administration of pharmacological doses of adrenergic agonists did not elicit Mg2+ extrusion. The determination of cellular Mg2+ indicated an approximately 9% decrease in total hepatic Mg2+ content in liver cells after overnight fasting, whereas the ATP level was unchanged. Hepatocytes from starved rats accumulated approximately four times more Mg2+ than liver cells from fed animals. This enlarged Mg2+ accumulation depended in part on extracellular glucose, since it was markedly reduced in the absence of extracellular glucose or in the presence of the glucose transport inhibitor phloretin. The residual Mg2+ accumulation observed in the absence of extracellular glucose was completely abolished by imipramine or removal of extracellular Na+. Taken together, these data indicate 1) that hepatic glucose mobilization is essential for Mg2+ extrusion by adrenergic agonist and 2) that starved hepatocytes accumulate Mg2+ via two distinct pathways, one of which is associated with glucose transport, whereas the second can be tentatively identified as an imipramine-inhibited Na+-dependent pathway.     

Relationship between increasing duodenal lipid doses, gastric perception, and plasma hormone levels in humans

Duodenal lipid causes gastric relaxation, CCK secretion, and nausea. Vasopressin has been implicated in motion sickness-related nausea. We hypothesized that increasing doses of lipid enhance gastric relaxation and CCK-vasopressin secretion, resulting in a dose-related exacerbation of nausea. Nine healthy subjects received isotonic saline or lipid (1, 2, or 3 kcal/min, L1, L2, L3) duodenally. Changes in gastric volume, sensations, and plasma hormone levels were assessed during infusions and isobaric gastric distensions. Lipid infusions increased gastric volume, plasma CCK (but not vasopressin) levels, and gastric compliance during distensions, compared with saline. Plasma CCK levels were related to the dose of lipid administered [CCK levels at 30 min (pmol/l), saline: 1.1 +/- 0.2, L1: 1.8 +/- 0.2, L2: 3.0 +/- 0.2, L3: 4.3 +/- 0.6]. During distensions, nausea increased in intensity with increasing doses of lipid [score (where 0 is no sensation and 100 is strongest sensation), saline: 7 +/- 4, L1: 19 +/- 7, L2: 44 +/- 7, L3: 66 +/- 8]; however, no further rise in plasma CCK occurred. Because neither lipid nor distension alone induced significant nausea, we conclude that the interaction between these stimuli together with a modulation by CCK is responsible for the effects observed. Vasopressin is not involved in lipid- and distension-induced nausea.     

Role of insulin-like growth factor iin maintaining normal glucose homeostasis

Insulin-like growth factor I (IGF-I) has significant structural homology with insulin. IGF-I has been shown to bind to insulin receptors to stimulate glucose transport in fat and muscle, to inhibit hepatic glucose output and to lower blood glucose while simultaneously suppressing insulin secretion. However, the precise role of IGF-I in maintaining normal glucose homeostasis and insulin sensitivity is not well defined. Studies in patients with diabetes have shown that in insulin-deficient states, serum IGF-I concentrations are low and increase with insulin therapy. Similarly, administration of insulin via the portal vein results in optimization of plasma IGF-I concentrations. A patient with an IGF1 gene deletion was shown to have severe insulin resistance that improved with IGF-I therapy. Studies conducted in experimental animals have shown that if IGF-I synthesis by the liver is deleted, the animals become insulin-resistant, and this is improved when IGF-I is administered. Likewise, deletion of the IGF-I receptor in muscle in mice induces severe insulin resistance. Administration of IGF-I to patients with type 2 diabetes mellitus has been shown to result in an improvement in insulin sensitivity and a reduction in the requirement for exogenously administered insulin to maintain glucose homeostasis. A polymorphism in the IGF1 gene that has been shown to reduce serum IGF-I results in an increased prevalence of type 2 diabetes. Taken together, these findings support the conclusion that IGF-I is necessary for normal insulin sensitivity, and impairment of IGF-I synthesis results in a worsening state of insulin resistance.     

Changes in plasma inhibin levels following pulsatile gonadotrophin-releasing hormone therapy in a man with idiopathic hypogonadotrophic hypogonadism

Changes in circulating inhibin levels were related to changes in testosterone (T) and the gonadotrophins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in a hypogonadotrophic hypogonadal man before and during pulsatile gonadotrophin-releasing hormone therapy which resulted in normal spermatogenesis. Before treatment, the plasma inhibin levels in the patient (210 +/- 50 U/l; mean +/- SD of four samples) were lower than in normal controls (552 +/- 150 U/l; p less than 0.01), as were T (1.1 nmol/l) and gonadotrophin (less than 1.0 IU/l) levels. Within 1 week of gonadotrophin-releasing hormone treatment, plasma LH (14.1 +/- 0.7 IU/l) and FSH (14.4 +/- 0.6 IU/l) reached supraphysiological levels. In response, T and inhibin concentrations increased progressively to reach high normal levels (27.7 +/- 1.6 nmol/l and 609 +/- 140 U/l) at 4 weeks, by which time the gonadotrophin levels stared to decline and gradually returned to the normal range between 12 and 24 weeks of treatment. There was a concomitant decrease in T and inhibin levels which remained within the normal range. The decline in the FSH level following the rise in testicular hormones was earlier and steeper than that of LH (37.5% decrease at 4 weeks vs. 30.4% at 12 weeks), suggesting that T and inhibin may act together to inhibit pituitary FSH secretion as opposed to LH secretion which is primarily controlled by T. It is concluded that, in man, during maturation of the pituitary-testicular axis, changes in circulating inhibin parallel those of T, and quantitatively normal inhibin secretion is dependent on gonadotrophin stimulation. FSH secretion may be regulated through negative feedback control, by both T and inhibin.