Insulin has important effects on the metabolism, whereby its properties and functions are outlined as the "storage hormone". Notwithstanding, it is antagonized by other hormones,  particularly by hydrocortisone, adrenaline, glucagon and the growth hormone. A description of how these hormones affect insulin`s function is provided. Additionally, insulin`s association with Cushing`s syndrome is evaluated.peer-reviewe

Ganado, Walter

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OAR@UM

INSULIN ANTAGONISTS W. GANADO B.Sc., M.D. (MALTA) B.sc. (LO::-;D.) F.R.C.P. (LOND.) Professor of Medicine, Royal University of Malta. Senior Physician, St. Luke's Hospital It is known that insulin is antagon-ised by other hormones. This is an attempt to describe the functions of all these hor-mones but one (thyroxin). Insulin: the storage hormone Man eats intermittently and stores some food for periods of fasting. The digestive system limits the quanity of food that can be taken in at a time; but even before digestion of a meal is complete, renewed pangs of hunger may stimulate man to ingest more food. At times food is taken in excess, but all the food that is digested is absorbed and none of the food that is absorbed is lost. Prevention of food loss is due to secretion of insulin in response to glucose absorption. Insulin specifically enhances glucose uptake by muscle and adipose tis-sue within minutes of its secretion. This specific action on cell membranes is not followed by specific action on glucose phosphorylation. Insulin does not act directly on glycogen turnover, but indir-ectly it favours glycogen synthesis by accelerating glucose uptake. Excess glucose is incorporated in adipose tissue. The triglycerides of this tissue are in continuous breakdown and resynthesis (Fig. I). After breakdown, glycerol is released into the bloodstream; so that resynthesis has to make use of glycerol phosphate, and this is formed from glucose. Insulin enhances esterifica-tion of glycerides and inhibits release into the bloodstream of fatty acids that have been set free by breakdown of these gly-cerides. Hence, insulin favours glyceride synthesis as part of its overall function to preserve muscle and adipose tissue stores and to increment them. Hydrocortisone: the stress hormone Hydrocortisone inhibits glucose up-take by cell membranes, thereby reducing phosphorylation and formation of glycerol phosphate. Reduced supply of glycerol phosphate delays resynthesis of fatty acids in adipose tissue, so that fatty acids accu-mulate and are released into the blood stream. There follows a high concentra-tion of non-esterified fatty acids or "NEF A" in plasma. It woul appear that high plasma NEF A concentrations inhibit glucose uptake by cell membranes, so that this action of hydrocortisone is reinforced by its own effect and plasma glucose con-centration tends to rise. This rise of plasma glucose concentration is particu-larly useful during fasting, which is a form of stress. It would appear that the main func-tion of hydrocortisone is to maintain suffi-cient supplies of glucose to the brain dur-ing periods of stress without emergency, as during fasting. The central nervous system has a high metabolic rate whether one is awake or asleep, and glucose is its principal nutrient. The adult brain takes up about 65% of glucose that is available to the body, and of the glucose that is taken up, only 35% is used directly for oxidation. The rest is converted into aminoacids, lipids and proteins in a con-tinuous process of breakdown and resyn-thesis of the brain constituents. Hence continuous supply of glucose to the brain is vitally important. Since there is no glu-cose or glycogen store in the brain, the blood stream supply must be uninterrupted and high, and this is taken care of by hydrocortisone. The main action of hydrocortisone is on the liver, where it stimulates gluconeo-genesis. In other terms hydrocortisone ensures a good depot of hepatic glycogen for secretion into the blood. Liver glyco-gen is not a store of carbodydrate in the same sense as muscle glycogen. Whereas muscle builds up its glycogen from t.he general plasma supply of glucose and will not give glucose back to plasma under any circumst.ances, the liver builds up its gly-cogen from several sources and supplies it 3 td the blood. Hence muscle glycogen is a local depot; but hepatic glycogen is a store for general use. . Sources of hepatic glycogen are seve-ral. Some of these are economical as glycerol or fatty acids derived from lipo-lysis, and as pyruvic or lactic acid over-flowing into the blood stream from con-tracting muscle. But at times the source of hepatic glycogen is highly unecono-mical, as amino-acids derived from tissue proteins, generally from proteins of peri-pheral supporting tissues. Gluconeogenesis is therefore potentially wasteful of valu-able material, and may be harmful. It seems likely that hydrocortisone raises plasma NEF A concentration and plasma glucose concentration to reduce gluconeo-genesis from amino-acids as much as pos-sible. During intestinal absorption of glu-cose, gluconeogenesis becomes superfluous. It is therefore inhibited by insulin, which is secreted in response to glucose absorp-tion. Insulin rebuilds the stores of carbo-hydrate and triglyceride that hydrocorti-sone had reduced; and it seems likely that it promotes amino-acid incorporation into protein to repair faults to body tissues which fasting may have caused. Adrenaline: the emergency hormone Adrenaline is generally released under emergency conditions, and one of its func-tions is to supply additional glucose to the blood stream for use by essential tissues, including brain. This additional supply is obtained from the liver, where adrenaline provokes glycogenolysis by maintaining a larger proportion of phosphorylase than usual in its active form, thus increasing the effective concentration of the enzyme mainly responsible for glycogen break-down. Adrenaline also enhances release of fatty acids by adipose tissue. In this way it provides economical material for gluco-neogenesis, and by reducing material for resynthesis of triglycerides it spares the glycerol phosphate, which is derived from glucose. Adrenaline causes also rapid muscu-lar contraction for which rapid supply of energy is required. Yet adrenaline may 4 decrease the uptake of glucose by; muscle, thereby impairing glucose phosphoryla-tion. This means that muscle has to rely on its local glycogen store for contraction . Because the supply of energy has to be rapid and abundant, muscle uses anaerobic glycolysis, with accumulation of pyruvic and lactic acid. These products overflow into the blood stream and provide more material for gluconeogenesis, so that the additional supply of glucose which adre-naline brings about into the plasma from the liver, is not obtained from unecono-mical sources. Adrenaline therefore pro-vides for rapid muscular contraction with-out curtailment of glucose available for use in other tissues and without inducing gluconeogenesis at the expense of support-ing tissues. Glucagon The function of this hormone is diffi-cult to understand. Like adrenaline, glu-cagon increases glycogenolysis and like adrenaline it exerts this effect by increas-ing the effective concentration of phos-phorylase in the liver. Both hormones me-diate their effect on glycogen metabolism by the initial formation of adenine -ribose, 3, 5 - phosphate, but glucagon af-fects only hepatic glycogen. The growth hormone Like hydrocortisone, this hormone acts on cell membranes by reducing muscle uptake of glucose, as has been con-firmed in man with acromegaly. There results a high plasma NEF A concentration and some rise of plasma glucose concen-tration. Growth hormone presumably ob-tains these effects to provide economical material for neoglucogenesis and spare amino-acids which are essential for growth. Cushing"s syndrome It is clear that each and everyone of the above hormones has a definite specific function to perform. They all affect carbo-hydrate and glyceride metabolism, and excess of hormone may provoke a meta-bolic state with reduced glucose tolerance, which insulin administration cannot cor-rect well. The most typical of these states is Cushing's syndrome. This is due to over-production of hydrocortisone by gross overacting of the adrenal cortex or gross overstimulation by ACTH. Hydrocortisone in physiological doses does not lead to fat deposition in the subcutaneous tissues or elsewhere; indeed it mobilises fatty acids from glyceride depots and its physiolo-gical effect is characterised by increased plasma NEF A concentration arid by inhibition of glucose storage. But hydro-cortisone stimulates also neoglucogenesis and the hyperglycaemia which follows the oversecretion of hepatic glucose into the blood stream provokes a response by the pancreatic islets with overproduction of insulin. Hence Cushing's syndrome may give rise to severe glycosuria; but more frequently, in the presence of an adequate reserve of insulin, it produces excessive deposition of glycerides in adipose tissue. The hyperglycaemia of Cushing's syn-drome is produced by liver secretion at the expense of sources of glycogen which include amino-acids derived from body tissue proteins. Hence there is mobilisa-tion of peripheral supporting tissue with muscle weakness and fatigueability, osteo-porosis, cutaneous striae and weakening of vascular tissue with easy bruising at sites of mild trauma. In addition there are hypertension, emotional changes and androgenic changes which apparently are independent of the effects of hydrocorti-sone on food metabolism. It is evident from this picture that the antagonism of insulin to hydrocortisone does not correct the pathological effects. FIGURE I Glucose - Fatty Acid Cycle Glucose -----) triose phosphate glycerol phosphate I ,-----~ I fatty acyl CoA i triglyc!ide NEFA --------------. glycerol fatty acids .. ------1 ,.-------THE THALASSAEMIA TRAIT IN MALTA AND GOZO F. VELLA B.sc., M.D. (MALTA), M.A. (OXON), PH.D. (SINGAPORE), F.R.T.C., M.C.PATH. Assoc.;wte Professor, University of Saskatchewan, Canada Introduction An increased osmotic resistance of the erythrocytes can be tested for, and detected, by mixing a measured amount of fresh blood with a hypotonic solution of inorganic salts of an osmolarity such that the majority of erythrocytes with nor-mal resistance will rupture in it and pro-duce a clear solution; if the erythrocytes are more resistant than normal under the same conditions, the mixture remains an opaque suspension. A solution of sodium chloride in water which contains 0.35 grams per 100 ml has this critical osmolar-ity (120 milliosmoles per litre). By making a suspension of er ythrocytes from fresh blood in this solution, in a haemocyto-meter pipette (blood 1 part, hypotonic solution 199 parts) and allowing time for lysis to occur (2 to 5 minutes), individuals with a raised osmotic resistance can clear-ly be distinguished from those in whom the resistance is normal. In 1943, Silvestroni and Bianco des-cribed this simple test, making use of a 5 

Insulin antagonists

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Insulin antagonists

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