Diabetologia

Wollheim, C.; Blondel, B.; Renold, A.; Sharp, G.

doi: 10.1007/BF00420970pmid: 786765

125 12 12 4 4 C. B. Wollheim B. Blondel A. E. Renold G. W. G. Sharp Institut de Biochimie Clinique and Institut d'Histologie et d'Embryologie Université de Genève Genève Switzerland Summary The possible role of Ca 2+ in glucagon release has been investigated by the use of ionophore A23187. This ionophore permits Ca 2+ entry down a suitable concentration gradient by complexing and releasing Ca 2+ , thereby acting as a carrier in plasma membranes. Cultured cells obtained by enzymatic digestion of pancreases from newborn rats were studied on the third day of culture. As expected the effects of the ionophore were dependent upon the presence of Ca 2+ in the medium. However, either stimulation or inhibition of glucagon release resulted when different concentrations of ionophore and Ca 2+ were used. With 1.0 mM Ca 2+ in the medium, glucagon release was stimulated in the presence of 0.01 and 0.1 μg/ml ionophore, but inhibited in the presence of 3.0 and 10.0 μg/ml. With 0.1 μg/ml ionophore, glucagon release was stimulated by 0.3 and 1.0 mM Ca 2+ but not by 2.5 mM Ca 2+ . With 10 μg/ml ionophore glucagon release was stimulated by 0.03, 0.1 and 0.3 mM Ca 2+ , whereas at 1.0 mM, glucagon release was depressed. These findings suggest that by increasing Ca 2+ , glucagon is released from the A-cells, whereas too large an increase in Ca 2+ is inhibitory. The effect to stimulate release was not completely specific for Ca 2+ in that while the ionophore did not stimulate release in the presence of either Mg 2+ or Sr 2+ in the absence of Ca 2+ , it did stimulate release when Ba 2+ was tested. Furthermore Ba 2+ at 0.3 mM was stimulatory even in the absence of ionophore. Glucagon release in the absence of ionophore was also enhanced by addition of 30 mM Ca 2+ or by omission of Ca 2+ from the medium. It is concluded that Ca 2+ , which plays an essential role in the stimulus-secretion coupling in several different cell types, may be involved in the stimulation of glucagon release from the A-cells of the pancreas.

Kühl, C.

doi: 10.1007/BF00420971pmid: 964507

125 12 12 4 4 C. Kühl Dept. of Internal Medicine (T), Bispebjerg Hospital and Diabetes Centre Univ. of Copenhagen Copenhagen Denmark Dept. of Obstetrics and Gynaecology (Y), Rigshospitalet Univ. of Copenhagen Copenhagen Denmark Summary The concentration of proinsulin-like components (PLC) in serum has been determined by gel filtration on samples obtained from eight normal pregnant women and eight nonobese gestational diabetics. The normal women were investigated early in pregnancy and all subjects were investigated in mid pregnancy, late pregnancy, and postpartum. At each occasion, samples were obtained after an overnight fast and after glucose ingestion. In both groups, the concentration of PLC in serum after overnight fast rose with gestation as well as after glucose ingestion, but there were no significant differences between mean levels of PLC of the normals and the gestational diabetics. With gestation, serum insulin rose in parallel with PLC in either group. The proportion of total insulin immunoreactivity composed by PLC thus remained constant and, furthermore, the proportions of PLC in gestation were equal to those observed postpartum. Four to six weeks after delivery, the basal concentration of PLC in serum was higher in the gestational diabetics than in the normals, whereas the concentrations of insulin were equal. Since the biological potency of proinsulin is much less than that of insulin, the results exclude the possibility that the decrease of glucose tolerance in normal pregnant women and gestational diabetics is due to an increased concentration of proinsulin in serum.

Oliver, J.; Williams, V.; Wright, P.

doi: 10.1007/BF00420972pmid: 183996

125 12 12 4 4 J. R. Oliver V. L. Williams P. H. Wright Dept. of Pharmacology Indiana University School of Medicine Indianapolis Indiana USA Summary Glucagon secretion and its control have been studied in perifused isolated islets of Langerhans of the rat. It was shown that a low concentration of glucose per se does not cause increased glucagon secretion, but that at low glucose concentrations the amino acid arginine stimulates a biphasic secretory response. Such amino acid stimulated glucagon secretion can be suppressed by increasing the glucose content of the perifused media from 1.67 to 5.5 or 16.7 mM; insulin secretion is also then increased. Since high concentrations of added porcine insulin (10 mU/ml) did not affect amino acid stimulated glucagon secretion at low glucose concentration, it was concluded that high concentrations of glucose and not insulin secreted in response to that glucose are probably responsible for suppression of glucagon secretion. At low concentrations of glucose, epinephrine (2.5 × 10 −7 M) also stimulated glucagon secretion. It is concluded that isolated rat islets of Langerhans can be used for the study of glucagon secretion in vitro, and that substances appearing in the blood in vivo at low glucose concentrations are probably responsible for increased glucagon secretion under conditions associated with hypoglycemia.

Marco, J.; Calle, C.; Hedo, J.; Villanueva, M.

doi: 10.1007/BF00420973pmid: 786766

125 12 12 4 4 J. Marco C. Calle J. A. Hedo M. L. Villanueva Clínica Puerta de Hierro Universidad Autónoma de Madrid Madrid Spain Summary This work was undertaken to study the effect of prednisolone on glucagon release in mouse pancreatic islets isolated by the collagenase technique. Pretreatment of the donors with prednisolone (0.2–0.3 mg daily) induced an increase in glucagon release both in the absence (1005±75, SEM, vs. 796±46 pg/10 islets/60 min, p = 0.019) and in the presence of 7.5 mM arginine (1500±119 vs. 1236±61 pg/10 islets/60 min, p = 0.05). The glucagon content of the islets was not modified by the treatment (28.6±1.1 vs. 28.0±1.1 ng/50 islets). The addition of prednisolone (5 · 10 −5 M) into the medium, failed to affect significantly glucagon secretion. In agreement with previous human studies, our data indicate that chronic glucocorticoid administration augments the secretory activity of the A-cell. This does not seem to be a result of increased glucagon synthesis nor a direct effect of glucocorticoids on the glucagon-releasing mechanism. Rather, environmental changes induced by these hormones could be responsible for A-cell hyperfunction.

Florey, C.; Lowy, C.; Uppal, S.

doi: 10.1007/BF00420974pmid: 964508

125 12 12 4 4 C. du V. Florey C. Lowy S. Uppal Department of Community Medicine and Department of Chemical Pathology St. Thomas' Hospital Medical School London England Department of Cardiology University of Leiden Leiden The Netherlands Summary In a study of risk factors for cardiovascular disease in 2388 school children aged 9–12 years carried out in Westland, Holland, serum insulin levels at one hour after an oral challenge of 50 g glucose were measured in a systematically selected subsample of 715 children. The distribution and associations of serum insulin in these children are described. The mean insulin values were 24.6 μU/ml for boys and 32.0 μU/ml for girls. The difference between these means was statistically significant and remained so even after taking measures of adiposity into account. Insulin values were positively related to levels of plasma sugar and systolic blood pressure in both sexes.

Recant, L.; Perrino, P.; Bhathena, S.; Danforth, D.; Lavine, R.

doi: 10.1007/BF00420975pmid: 183997

125 12 12 4 4 L. Recant P. V. Perrino S. J. Bhathena D. N. Danforth Jr. R. L. Lavine Veterans Administration Hospital and Georgetown University School of Medicine Washington, D.C. Surgery Branch, National Cancer Institute National Institutes of Health Bethesda Maryland USA Summary Immunoreactive glucagon (IRG) fractions from plasma of 8 normal subjects and 4 patients with glucagon secreting tumors were studied by gel filtration techniques on Bio Gel P-30 and Sephadex G-50 columns. The pancreatic glucagon specific anti serum (30K) of Unger was utilized to measure IRG. Columns were calibrated with labelled albumin, proinsulin, insulin and glucagon. Four peaks were defined in normal and tumor bearing patients: peak I (>20000 mol. wt.), peak II (primarily 9000 mol. wt.), peak III pancreatic glucagon (3500 mol. wt.) and peak IV small glucagon (<3500 mol. wt.). Glucagonoma patients differed from our normal and reported normal subjects in that peak II contained most of the circulating IRG. The percent of IRG associated with peak II was 9.5–31.5% in normals and 39.1–61.2% in glucagonomas. Glucagon-like biological activity in an isolated hepatocyte system was demonstrated for all peaks. However, relative to immunoreactivity, peak II showed reduced activity (25–33%). Immunoassay of dilutions of all peaks revealed the probability of immuno determinants identical with porcine pancreatic glucagon. The presence of heterogeneous IRG peaks with biological glucagon-like activity suggest that the larger molecules may be prohormones. Further, it is possible that specific elevation of peak II may be a diagnostic feature of glucagonomas.

Girard, J.; Guillet, I.; Marty, J.; Assan, R.; Marliss, E.

doi: 10.1007/BF00420976pmid: 964509

125 12 12 4 4 J. R. Girard I. Guillet J. Marty R. Assan E. B. Marliss Laboratoire de Physiologie du Développement and Hôtel Dieu Université Pierre et Marie Curie Paris France Department of Medicine University of Toronto Toronto Ontario Canada Summary The present study examines the role of insulin, glucagon and cortisol in the regulation of gluconeogenesis from lactate and amino acids in fetal and newborn rats. Injection of glucagon in the fullterm fetal rat caused a rise in glucose (and insulin) and a fall in blood levels of most individual amino acids, stimulated hepatic accumulation of 14 C-amino isobutyric acid and 14 C-cycloleucine and increased the conversion of 14 C lactate, alanine and serine to glucose in vivo and in vitro (liver slices). Such changes were equivalent to the changes seen in 4 h old newborn rats. When glucagon was administered at birth, little difference was observed between control and treated animals in plasma amino acids and a smaller increment in conversion of 14 C substrate to glucose occurred. By contrast, insulin injection at birth caused hypoglycemia, suppression of levels of certain amino acids and inhibition of conversion of 14 C substrates into glucose. Glucose injection at birth caused elevated glycemia and plasma insulin and suppression of most amino acid levels and of conversion of 14 C substrate into glucose. Cortisol injection at birth caused a marked, generalized hyperaminoacidemia, a stimulation of glucagon secretion and of conversion of 14 C substrates into glucose. These observations support the thesis that glucagon plays a major role in the induction of hepatic gluconeogenesis and that insulin acts as an antagonist hormone.

Gotfredsen, C.

doi: 10.1007/BF00420977pmid: 134920

125 12 12 4 4 C. F. Gotfredsen Department of Pharmacology NOVO Industri A/S Bagsvaerd Denmark Summary In the isolated perfused rat pancreas various sulfonylurea drugs were tested with a basal glucose level of 1 mg/ml in the perfusion buffer and were found to cause a biphasic insulin response. NOVO CS 476, a new and potent sulfonylurea, and glibenclamide qualitatively differed from tolbutamide, glibornuride, glipizide, and glisoxepide, which were all alike in terms of the relationship between first and second phases of insulin release.

Lewis, S.; Wallin, J.; Kuzuya, H.; Murray, W.; Coustan, D.; Daane, T.; Rubenstein, A.

doi: 10.1007/BF00420978pmid: 964510

125 12 12 4 4 S. B. Lewis J. D. Wallin H. Kuzuya W. K. Murray D. R. Coustan T. A. Daane A. H. Rubenstein Clinical Investigation Center Naval Regional Medical Center Oakland California The Department of Medicine Fisher Endocrinology Laboratories The University of Chicago Chicago Illinois USA Summary To examine differences among pregnant diabetic and nondiabetic subjects, serum glucose, and immunoreactivity of C-peptide, free and total insulin were measured at hourly intervals during a 24-h third trimester metabolic ward evaluation. Six normals, three mild, and four juvenile-onset type diabetics were studied. Diets were identical for all subjects. Mild diabetics differed from juvenile diabetics by having significant residual pancreatic B-cell function, as measured by C-peptide immunoreactivity. Short and intermediate acting insulins given once or twice daily to diabetics maintained serum glucose levels within the normal range throughout the 24 h. Despite wide variation in serum total insulin levels, peripheral free insulin concentrations in well-controlled diabetics fell within a relatively narrow range that was higher than in controls. Infants of the diabetic subjects were comparable to the offspring of the control women.

Reckless, J.; Galton, D.

doi: 10.1007/BF00420979pmid: 183998

125 12 12 4 4 J. P. D. Reckless D. J. Galton Diabetes and Lipid Research Laboratory St. Bartholomew's Hospital London England Summary The sensitivity of alpha- and beta-adrenergic receptors, and the antilipolytic actions of prostaglandin E 1 or insulin on adipose tissue of obese diabetic and non-diabetic subjects have been studied. Accumulation of cyclic AMP in adipose tissue and release of glycerol in response to several catecholamines (adrenaline, noradrenaline and isoprenaline) in the presence or absence of an alpha-adrenergic blocker (phentolamine) have been used to assess catecholamine receptor sensitivity. No differences in beta-receptor activity were observed between diabetics and non-diabetics, either on glycerol release or accumulation of cyclic AMP; alpha-receptor activity was also similar, except for significantly less accumulation of cyclic AMP in diabetic tissue incubated with noradrenaline and phentolamine (p<0.01). The antilipolytic action of prostaglandin E 1 (at concentrations of 30 fM to 30 pM) on lipolysis (stimulated submaximally with isoprenaline, 10 −7 M) was similar in diabetic and control groups. The antilipolytic action of insulin (from 10 −10 to 10 −6 M) on lipolysis was also similar between the groups. It is concluded that neither disorders of the catecholamine receptor nor of the antilipolytic actions of prostaglandin E 1 or insulin are responsible for the abnormalities of fatty acid metabolism in adult diabetes.