support cell growth and development ( Nath & Villadsen 2015 ). However, in certain pathophysiological states, cells utilize glycolysis for the production of ATP, known as the Warburg effect ( Sancho et al . 2016 ). As early as the 1920s, German biologist
Yan Su, Sujuan Guo, Chunyan Liu, Na Li, Shuang Zhang, Yubin Ding, Xuemei Chen, Junlin He, Xueqing Liu, Yingxiong Wang and Rufei Gao
Olivier Dumortier, Gaia Fabris, Didier F Pisani, Virginie Casamento, Nadine Gautier, Charlotte Hinault, Patricia Lebrun, Christophe Duranton, Michel Tauc, Stéphane Dalle, Julie Kerr-Conte, François Pattou, Marc Prentki and Emmanuel Van Obberghen
trait is that glycolysis is initiated by glucokinase having a high K m for glucose associated to an elevated V max , and being devoid of feedback control ( Prentki et al . 2013 ). As beta cells express low levels of plasma membrane
W.-T. HUM, A. BARTA-BARTOVA and M. K. BIRMINGHAM
The effects of nucleotides and nucleosides on steroidogenesis and aerobic lactic-acid production were examined in unsectioned mouse adrenal glands preincubated for 1 h and then incubated for 2 h in Krebs–Ringer bicarbonate and 0·01 m-glucose medium equilibrated with 95% O2:5% CO2. Of all the compounds tested, at a concentration of 10 mmol/l (cyclic AMP, cyclic GMP, AMP, ADP, ATP, GMP, IMP, adenosine, guanosine and inosine), only cyclic AMP was capable of stimulating steroidogenesis and induced a nine- to 12-fold increase in corticosterone production. Cyclic GMP inhibited corticosterone production by 40–55%. The nucleotides and nucleosides, except for ATP, all increased lactic-acid production. Cyclic AMP caused a three- to fivefold stimulation, cyclic GMP an increase of only 20–30%, and GMP, AMP and ADP increases of 80–100%. Cyclic GMP, protected from hydrolysis, may thus inhibit lactic-acid as well as steroid production in the mouse adrenal gland. By contrast, cyclic GMP was nearly as effective as cyclic AMP in stimulating glycolysis and steroidogenesis of rat adrenal glands. The proportion of corticosterone to 18-hydroxydeoxycorticosterone (18-OH-DOC) obtained with cyclic GMP was, however, always lower than that obtained with cyclic AMP. Cyclic AMP, as opposed to cyclic GMP, increased the formation of corticosterone and lactic acid in the presence of exogenous deoxycorticosterone (DOC) beyond that expected from an additive response. Lactic-acid production was inhibited by 18-OH-DOC, a major secretory product of the rat but not the mouse adrenal. This steroid, furthermore, greatly reduced the stimulation of glycolysis evoked by added DOC, 11β-hydroxyprogesterone and corticosterone, facts that could account for the greater glycolytic activity of mouse compared with rat adrenals. The yield of corticosterone in the presence of added 11β-hydroxyprogesterone, but not of DOC, was also reduced by 18-OH-DOC, denoting a selective inhibition of 21-hydroxylation. A structural analogue of 18-OH-DOC, 18,20-cyclo-20,21-dihydroxypregn-4-en-3-one, added by itself stimulated lactic-acid production. Added in combination with other steroids, it specifically counteracted the inhibitory effect of 18-OH-DOC, a steroid of potentially adverse biological properties. Our results are compatible with the concept that adrenal aerobic glycolysis is to a significant extent, but not exclusively, steroid-mediated. The glycolytically active but steroidogenically inert nucleotides and nucleosides offer examples of a dissociation between the two events.
E. L. KNODEL and K. A. DOEG
Biochemistry and Biophysics Section, University of Connecticut, Storrs, Connecticut 06268, U.S.A.
(Received 2 September 1976)
Polycystic ovaries can be induced by a series of 20 daily injections of human chorionic gonadotrophin (HCG; 10 i.u./day, s.c.) in rats previously made hypothyroid with 0·5% 2-thiouracil in their feed (Leathem, 1958). Slices of polycystic ovaries convert glucose stoichiometrically to lactate under aerobic conditions, while slices of normal or luteinized (HCG) ovaries or those from hypothyroid rats convert less than 50% of the glucose consumed to lactate, under similar conditions (Surwilo & Doeg, 1973). High rates of aerobic glycolysis, as seen in polycystic ovarian slices, are also characteristic of a variety of tumours (Aisenberg, 1961). Some of these tumours have low activities of one of the 'shuttle' enzymes involved in the transfer of reducing equivalents from the cytosol to the mitochondria (Boxer & Devlin, 1961; Criss, 1973), and, thus, pyruvate reduction to lactate provides
PATRICIA W. MAJOR and D. T. ARMSTRONG
Small doses of luteinizing hormone (LH) have been shown to exert a stimulating effect on the in vitro carbohydrate metabolism of the prepubertal rat ovary. In order to determine the specificity of the response, studies were undertaken comparing the effects caused by LH with those of other anterior pituitary hormones. Preparations of thyroid stimulating hormone (TSH) caused responses similar to those caused by LH, when added to the media in which prepubertal rat ovaries were incubated. A detailed study of the effects of TSH preparations (prepared by different procedures with known low levels of LH contamination) on lactic acid production, has been undertaken. All TSH preparations tested caused considerably greater stimulation of glycolysis than could be accounted for on the basis of their contamination with LH when the latter was appraised by the ovarian ascorbic acid depletion assay.
M. REISS and JEAN M. HALKERSTON
The role of adreno-corticotrophic hormone in the carbohydrate metabolism of adrenal cortical tissue has been indicated by its effect on respiration and glycolysis of the surviving tissue [Carpenter, Macleod & Reiss, 1946] and also by its effect on the 32P concentration in the acid-soluble phosphate extract [Gemzell, 1948]. The latter method offers the easier approach to problems of carbohydrate metabolism, and has been used by us in this connexion to investigate the effects on the adrenals of a variety of abnormal conditions, such as hypophysectomy and various kinds of stress, and the manner in which such effects may be altered by corticotrophic hormone.
Wistar rats were used for the investigation. Mature animals were mainly used, but experiments were also carried out on infantile and 3 to 8-day-old rats. Hypophysectomy was performed by the paratracheal route. In most cases, the groups of animals used were kept under identical
D. ATKINS, JOAN M. ZANELLI, M. PEACOCK and B. E. C. NORDIN
An organ culture system was used to examine the effects of oestrogens on the response of 5-day-old mouse calvaria to parathyroid hormone (PTH). Parathyroid hormone released calcium and phosphate from the bone and this was associated with an increase in glucose consumption, an accumulation of citric acid and an inhibition of citrate oxidation. Oestradiol, oestriol, oestrone and ethinyl oestradiol all inhibited the PTH-induced release of calcium. The accumulation of citrate was prevented without the PTH-induced block on citrate oxidation being removed, and this was explained in terms of a reduction in glycolysis. Oestradiol, oestriol and oestrone appeared to be of equal potency. However, ethinyl oestradiol was active at much lower doses but appeared to be toxic at higher levels.
M. C. Sugden and M. J. Holness
Theories for the mechanisms underlying the development of insulin resistance have included defects in insulin binding, inhibition of insulin receptor tyrosine kinase, and impaired translocation of glucose across the plasma membrane. However, little attention has been paid to the possibility that altered reciprocal regulatory interactions between lipid and carbohydrate fuels may underly the development of insulin resistance. We would like to review recent developments in metabolic regulation which indicate that this neglected aspect of intermediary metabolism may have more widespread physiological significance than hitherto suspected.
The major pathways of glucose utilization are storage (glycogen), non-oxidative degradation (glycolysis) and oxidative degradation. It has been demonstrated in post-absorptive man by indirect calorimetry that the ability of insulin to stimulate non-oxidative disposal of glucose is decreased by the prior oxidation of lipid (Thiebaud, DeFronzo, Jacot et al. 1982). In these studies, a neutral lipid emulsion was infused before insulin concentrations were raised by
D. LISTER, J. N. LUCKE and B. N. PERRY
Certain mesomorphic breeds and strains of pig characteristically show a marked acceleration of post-mortem glycolysis in muscle of up to 20 times that normally found. This is thought to be brought about in the living animal by the triggering of a hypersensitive myofibrillar ATPase activity which persists even when muscle relaxants are administered. The same pigs may also develop a fatal hyperpyrexia after exposure to halothane or succinyl choline. Several authors have suggested an alteration in the hormonal balance of susceptible animals and have laid particular emphasis on adrenal hypofunction (Lister, 1970). Differences in the patterns of post-mortem change in muscle can be demonstrated by treatments designed to modify tissue electrolyte balance (Passbach, Mullins, Wipf & Pane, 1970), but the evidence to support a notion of adrenal hypofunction as a causal agency in the syndrome is, in the main, of a circumstantial and indirect nature.
We therefore used standard clinical
D. ATKINS and M. PEACOCK
A bone culture system was used to compare the effects of several hormones on the response of 5-day-old mouse calvaria to parathyroid hormone (PTH). The results showed that salmon calcitonin was almost 105 times more active than any other hormone in preventing the PTH-induced release of calcium and caused a dose-related inhibition of calcium release over a range of 0·2–200 milli MRC units/culture. A high dose of calcitonin (200 milli MRC units) caused a net accretion of calcium in the absence of PTH. Progesterone and testosterone were more active than the naturally occurring oestrogens although a synthetic oestrogen (stilboestrol diphosphate) had approximately the same potency. High concentrations of these hormones caused a net accretion of calcium whether or not PTH was present. Cortisol was only effective at high doses, as was the steroid precursor cholesterol. In the present culture system the thyroid hormones (triiodothyronine and thyroxine) inhibited the action of PTH.
It was concluded that these agents acted in a similar fashion to the oestrogens. That is, they prevented the accumulation of citric acid induced by PTH by reducing the rate of glycolysis. None of the hormones affected the inhibition of citrate oxidation caused by PTH.
The results also showed that, whilst these hormones inhibited PTH-mediated bone resorption, they had an action on bone independent of PTH. Experiments with clomiphene citrate failed to demonstrate an oestrogen receptor in bone.