Diabetes, Diet and Biochemistry
IN introducing the lecturer the Society's President, Lord Halsbury, said:
"We are gathered here this evening to hear the 29th Stephen Paget Memorial Lecture entitled Diabetes. Diet and Biochemistry, which will be delivered by Professor F. G. Young and it is my privilege first to introduce him: He is Master of Darwin College Cambridge; Sir William Dunn Professor of Biochemistry at theUniversityofCambridge: Croonian lecturer of the Royal Society in 1962. He has had a long and distinguished career in his own field and in addition has done a tremendous amount of public work. He was on the Medical Research Council from 1950-1954: on the Commission of Higher Education for Central Africa: the Commission of the newChineseUniversity.Hong Kong: the Medical Sub-committee of the University Grants Committee, the Royal Commission on Medical Education. He has been President of the European Association for the Study of Diabetes and has logged up a still further honour by becoming President of the International Diabetes Association in September of this year. So we are going to have the privilege of listening to a very distinguished man. It is with great pleasure that I now ask Professor Young to deliver his lecture."
Diabetes, Diet and Biochemistry
BY F. G. YOUNG
I was naturally very honoured to be invited to give this 39th Stephen Paget Memorial Lecture, especially so since a biochemist who began life as a chemist, as 1 did. is often not so dependent upon the use of living animals for investigations as is the physiologist and others in the field of medical research. But my researches have at times vitally depended upon the availability for investigation of the right sort of animal, and I had no hesitation in accepting the invitation to speak this evening about some of the research which has interested me over the past 40 years.
The pituitary gland and diabetes mellitus
(a) The anterior pituitary lobe and sensitivity to insulin
In the early 1920s, the great Argentinian investigator, Bernardo A. Houssay, with his colleagues, began a series of investigations designed to reveal how the sensitivity to the action of insulin was controlled in the body. Insulin had only recently been made available for the treatment of human diabetes mellitus, as the result of the investigations in Canada of Banting, Best, MacLeod and Collip. InArgentinaat that time, the only way that one could obtain sufficient insulin for investigation of the sort that Houssay intended to carry out was to prepare the insulin oneself. This Houssay and his colleagues did, and proceeded to discover whether the effectiveness if insulin in causing a fall in the amount of glucose in the blood, was altered by the removal of various organs from an animal body. These investigations were carried out in a whole series of species of animal, and demonstrated conclusively that when the pituitary gland, situated at the base of the brain, and in the human being behind the nose, was removed the effectiveness of a given amount of administered insulin in lowering the amount of sugar in the blood, was greatly increased.
The pituitary gland, which in the human being only weighs around one gram, is a complex organ and can be divided for convenience into three separate glands, the anterior lobe, the posterior lobe, and the intermediate lobe. In the 1920s the functions of the anterior lobe of the pituitary gland were obscure, and there was much more interest in the posterior lobe, particularly since it contained, and was presumed to secrete, substances which could cause a rise of blood pressure, an inhibition of urine secretion, and a contraction of uterine muscle. So at first the effect of ablation of the pituitary gland in increasing the sensitivity of the body to the blood-glucose lowering action of insulin, was tentatively ascribed to the posterior pituitary gland, and indeed one investigator in the United States claimed that removal of the posterior pituitary gland alone would increase sensitivity to the action of insulin. Bernardo Houssay, on the other hand, was at first extremely cautious in ascribing the effect he had observed to one of the three parts of the pituitary gland, and since the removal of one part of that complex organ without disturbance of the rest was a surgically difficult operation in mammals he studied it in lower species. In this way, he discovered that in the frog and in the toad, the two main parts of the pituitary gland, the anterior lobe and the posterior lobe, could be removed separately fairly easily. Some complication is introduced by the fact that in the toad and frog the part of the gland which corresponds to the anterior lobe in the mammal, is in fact posterior. But there is no doubt about the identity in the frog of what corresponds to the anterior lobe of the pituitary gland in the mammal.
The experiments with the frog and with the toad clearly indicated that removal of the part of the gland that corresponds to the anterior lobe of the mammal greatly increased the sensitivity of the animal to the effects of administered insulin, while removal of the part of the gland corresponding to the posterior lobe in the mammal had no such effect.
As the result of these investigations Houssay turned his attention again to the formidable surgical task of removing the separate parts of the anterior pituitary' gland from mammals, and ultimately succeeded, demonstrating that removal of the anterior pituitary' gland greatly increases the sensitivity of the body to the blood glucose lowering action of administered insulin, while the removal of the posterior lobe did not. A corollary of these observations was that the administration to an animal of material from the anterior pituitary gland should diminish the sensitivity of the animal to the effects of administered insulin, and this Houssay and his colleagues were also able to show. The idea then began to take root that insulin, the anti-diabetic substance secreted by the islets of Langerhans of the pancreas, and something secreted by the anterior pituitary gland, acted antagonistically in the body. Investigations were therefore pursued to find out whether the experimental removal of the pituitary gland, or of its anterior lobe only, would diminish the intensity of experimentally-induced diabetes in animals.
During the late 1920s and the early 1930s Houssay and his colleagues found that excision of the pituitary gland from animals which had been made diabetic by the removal of the pancreas, greatly diminished the intensity of the diabetes of such animals so that they were able to survive for a long time, although if the pancreas alone were removed they died from the severe diabetes induced by removal of the pancreas in a relatively short time. These findings suggested the possibility that the administration to experimental animals of an extract of anterior pituitary tissue might induce a diabetic condition, and in 1932, Houssay and Biasotti found that in partially depancreatised but non-diabetic animals, this was indeed so.
(b) Bernardo A. Houssay
Let me digress a moment and let me say a few words about Houssay himself. At the age of 83, he recently was President of Honour of the Congress of" the International Diabetes Federation in Buenos Aires, Argentina, taking a full part in the proceedings. In 1946, at the time when his discoveries were being internationally acclaimed, Houssay had been forced to retire from his Professorship in Buenos Aires by the then Government in Argentina, and although he received invitations to Professorships in other countries, he preferred, as he said, to wait until the Government in Argentina changed, when he would go back to his University Post. In 1947, Houssay was awarded jointly the Nobel Prize for Physiology and Medicine and indeed did go back to his post inBuenos Airesafter the change in Government in 1955. His example as a pioneer in research and as a man of courage and integrity, standing out against oppression, has had an immense effect throughoutSouth America. He is indeed a remarkable man.
(c) The diabetes-inducing agent in anterior pituitary tissue
In 1935 I began a study of the diabetes-inducing action of anterior pituitary tissue with the idea of isolating the substance or substances responsible for this effect, and of determining the mechanism of action involved. At that time some of the work of Houssay was being called in question because the administration of various types of extract of anterior pituitary tissue to different sorts of animal did not consistently, or even at all, induce the appearance of diabetes mellitus. In my own investigations 1 quickly realised that an important species difference existed in this respect, and that the common and useful laboratory animal the rat did not develop diabetes when treated with an extract of anterior pituitary gland which would induce diabetes when administered to an adult dog. Subsequently, 1 found that carnivorous animals in particular were sensitive to the diabetes-inducing action of anterior pituitary tissue: in particular, the dog, the cat and the ferret.
At this stage experiments with dogs produced an unexpected result. The daily administration of a simple extract of anterior pituitary tissue for from one to three weeks would induce not only a temporarily diabetic condition, but in some instances a diabetes which persisted indefinitely after treatment with the pituitary extract ceased. After cessation of the daily injections such animals exhibited no signs of the pituitary treatment apart from the persistant diabetes. I can still recall the excitement with which histological sections of the pancreases of these animals which had been prepared by Mr. K. C. Richardson were examined, and gross lesions. In the islets of Langerhans—the insulin secreting cell of the pancreas—were revealed. A persisting diabetic condition had thus been induced by a short lived treatment of a type which could be regarded as initially physiological, although ultimately the excessive emphasis of physiological processes had led to pathological changes in the insulin-secreting mechanism. The possibility could then be considered that human diabetes mellitus might sometimes arise from a short lived period of hyperactivity of the anterior pituitary lobe, such as might not induce detectable signs of pituitary over-action other than persisting diabetes. If this were so, search in the diabetic patient for the primary cause of the diabetic condition might prove to be fruitless because that cause might have disappeared by the time the condition had been diagnosed and the patient examined, the persistence of the diabetes being due to secondarily induced lesions in the pancreatic islets. I shall return to this possibility later.
The discovery of this persisting diabetes delayed investigations on the nature of the substance responsible for the effects because the persistently diabetic condition, or metahypophyseal diabetes, as it came to be called, was such an interesting condition in itself.
By 1949, I and my collaborators had identified the substance which could induce diabetes in dogs and cats as the anterior pituitary growth hormone, while others, notablyConnin the United Slates, had shown that experimental administration of pituitary corticotropin can also induce diabetes under some conditions.
The diabetes-inducing action of growth hormone probably accounts for the fact that diabetes mellitus often complicates acromegaly, while the similar action of corticotropin and of certain adrenal steroids could account for the diabetes frequently seen in Cushing's syndrome.
(d) Growth and diabetes
In 1932, Herbert M. Evans and his colleagues published the results of investigations in which puppies had been treated daily for many months with a crude growth promoting extract of the anterior pituitary gland with the aim of producing giant animals. After six to eight months of treatment some of the animals were found to be diabetic. The fact that diabetes mellitus is often a complication of acromegaly has already been mentioned. In experiments with puppies and kittens, I found that the early administration for many months of an extract containing growth hormone to puppies and kittens did not cause a diabetic condition in the young growing animals, but stimulated excessive growth (Young 1953). This was so despite the fact that the amount of material administered daily was similar to or more than that required for the induction of diabetes in the adult animal. When treating some of the puppies for a long time we found that a proportion of them did develop diabetes, although the long-treated kittens did not. In the long-treated puppies which became diabetic the growth response to the pituitary treatment diminished with the development of a diabetic condition, and ultimately the animal stopped growing or even began to lose weight. In these animals growth could then be induced by the administration of insulin simultaneously with the pituitary extract, although the amount of insulin needed was very large indeed.
In these experiments the diabetes-inducing action of growth hormone could apparently be converted into a growth-promoting one in the dog if enough insulin were administered with the growth hormone. This fact suggested the possibility that the administration of growth hormone normally induces an enhanced rate of secretion of insulin by the pancreas and that the growth-promoting action of growth hormone depends on the availability of insulin from the pancreas. There is no doubt at all that when growth hormone is administered to an animal or to a human being the amount of insulin in the circulating blood increases, but there is no evidence that growth hormone exerts a direct action on the pancreatic islets in stimulating the liberation of pre-formed insulin, though there is some evidence that growth hormone may promote the biosynthesis of insulin by the pancreatic islets. This particular point is still not completely resolved.
The conclusion that we drew from a fairly extensive range of experiments was that it is only when a relatively large amount of growth hormone is given to an adult animal of a limited number of species—mostly carnivorous ones, that the diabetes-inducing action of this hormone is readily seen. Unfortunately in our hands that very useful laboratory animal the rat does not develop diabetes when treated with very large amounts of growth hormone alone. Even elderly senile rats respond well to the growth promoting stimulus of growth hormone, with no signs of the development of diabetes.
The experiments to which I have referred have all been carried out on animals but subsequently parallel observations have been made on human beings, a factor of some importance in the consideration of the application to man of results from experiments with animals.
The possibility has been considered that the complications of human diabetes mellitus, and particularly the malignant ones such as retinopathy which may lead to blindness, and renal hypertension, may be attributable to hyperactivity of the anterior pituitary gland. On the basis of such a possibility, hypophysectomy has been carried out on patients with such serious complications of diabetes with some success. This is an example of treatment of human disease which is directly based on observations made on animals. Whether growth hormone is the pituitary factor concerned in this possible effect of the pituitary gland is not at present certain.
(e) Growth hormone and general metabolic regulation
In investigations on animals the observation was made that pregnant or lactating dogs or cats do not develop diabetes when treated with growth hormone in an amount which is highly effective in inducing diabetes in normal cats or dogs. There is a possibility, though there is no firm evidence as yet, that an enhanced secretion of growth hormone by the anterior pituitary gland is a factor of significance in the excessive foetal growth sometimes observed in diabetic or pre-diabetic mothers.
The administration of growth hormone to cows in declining lactation can stimulate the milk yield under conditions in which neither prolactin nor corticotropin has such an action. Many years ago I wrote "Growth, including foetal growth and milk production are processes requiring a special type of metabolic control in that they both necessitate the preservation from oxidation of foodstuffs that would otherwise, in an animal in equilibrium, be oxidised." The possibility that growth hormone is a factor of which an excessive action can lead to a pathological outcome of diabetes mellitus is an interesting possibility that still remains to be proved.
Growth hormone is not a good name for the pituitary hormone concerned, even though it does play a decisive role in stimulating somatic growth and indeed was discovered because of this action. But this hormone plays a much wider part in metabolic control in general, and the secretion of growth hormone is of significance in adults who have ceased to grow in a vertical direction. Thinking along these lines in 1952, I wrote "There is as yet no evidence of which I am aware to show that growth hormone is secreted during starvation by the pituitary gland of an adult animal, but it seems to me probable that this is so. So far the methods available for the estimation of growth hormone are not adequate for this task" (Young, 1953). There is now expanding evidence that variations in the rate of secretion of growth hormone, as well as in the rate of liberation of insulin, are involved in those metabolic alterations in the body which relate to changes from a state of fasting to that of feeding, and conversely. For example when the amount of glucose in the blood falls towards a fasting amount the secretion of growth hormone may be stimulated, and conversely. And one effect of growth hormone is to diminish the effectiveness of insulin in promoting the utilisation of glucose in the tissues—that is growth hormone antagonises the action of insulin in this respect.
The rate of secretion of growth hormone by the anterior pituitary gland is controlled by a glucose-sensitive centre in the hypothalamus, the activity of which helps to keep the blood-glucose from falling, during starvation, to such a low level that the activity of the brain might be impaired.
In the remote past, before our remote ancestors had brought about conditions in which there was a reasonably constant daily supply of food, they were almost certainly liable to periods of starvation, periods that might be measured in days or weeks. Those individuals in whom, during such a period of starvation, the amount of glucose in the blood could not be maintained at a sufficiently high level for effective functioning of the brain, were vulnerable and liable not to survive. One can see biological sense in the evolutionary association of the anterior pituitary gland with the brain, and a control of its secretory activity by a hypothalamic centre, if the regulation of the secretion of growth hormones is of special importance in insuring that an adequate supply of glucose can get to the brain.
At a stage in human evolution when starvation could be a danger to survival those individuals in whom a factor of safety existed in the form of the maintenance of a more than adequate amount of glucose in blood during starvation, would be those with a better chance of survival. Such a state might well be brought about by the existence of a slightly higher than normal rate of secretion of growth hormone with respect to the blood glucose content. In other words, in the remote past a diathesis towards growth-hormone diabetes might have had survival value. But when we, descendents of these individuals, live under modern conditions with a continual, and perhaps more than ample, supply of food, the trait that assisted survival under primitive conditions is likely to lead to a strain on the islets of Langerhans of the pancreas, and perhaps to the development of diabetes mellitus, through the action of continually repeated slightly excessive secretion of growth hormone in relation to the movement of blood glucose to or from thefasting value. In time perhaps hypertrophy of and then damage to the insulin secreting cells of the pancreatic islets might occur, and ultimately diabetes mellitus might develop which was directly attributable to damage to the islets of Langerhans of the pancreas but could be primarily related to an abnormality of control of the liberation of growth-hormone.
Such a view can provide a rational basis for the fact that in developed countries diabetes mellitus seems to become steadily commoner. There is evidence that a recessive genetic factor may be involved, and this being so, one can reasonably ask the question: Why have our ancestors who carried such a trait found survival value in it? 1 hope that I have made my answer clear to this question—what has survival value at one stage of evolution may have none at all, or the reverse, at a later stage.
Recent surveys such as those carried out by Professor W. J. H. Butterfield and his colleagues at Guy's Hospital Medical School, London, seem to indicate that as the human being gets older the metabolism of carbohydrate changes in such a way that the post-absorptive blood-glucose increases. This is particularly so with women. I should emphasise that the diabetes mellitus which occurs in the elderly is usually mild and not harmful. Perhaps as we get older our brains need more glucose to keep them functioning properly, and this tendency to the development of diabetes mellitus is in fact a benign one. But on the other hand, all that may be needed to prevent this development is a restraint of gluttony. Here there may be a conflict between the higher and lower centres in the brain, with an opportunity for therapeutic treatment by means of artificial substances. I look forward with interest to the development of an antagonist to the substances formed in the hypothalamus which are carried to the pituitary gland and there stimulate the release of growth hormone, and the application to the treatment of diabetes mellitus of such antagonists. Treatment centrally may well be more desirable than peripheral control of such a condition.
In my discussion I have fastened attention particularly to the influence of growth hormone on the metabolism of glucose, but I should say that there is growing evidence that the rate of liberation of growth hormone from the pituitary gland may be influenced by variations in the amount of certain amino-acids in the circulating blood plasma, and undoubtedly growth hormone plays an important role in the mobilisation of fat from adipose tissue and its utilisation in muscle tissue.
(f) Mechanism of action of growth hormone
There is still remarkably little one can say about the mechanism involved in the multiferous actions of growth hormone. It certainly acts ultimately in antagoning insulin in some respects by diminishing the sensitivity of tissues to the action of insulin in promoting glucose up-take, and in enhancing the mobilisation of fat, an action which insulin again antagonises. But with respect to protein biosynthesis insulin and growth hormone have many effects in common, and my colleagues Professor A. Korner and Dr. K. L. Manchester, have studied the effects of growth hormone and of insulin respectively on the biosynthesis of protein. Professor J. Born-stein ofMonashUniversitybelieves that the molecule of growth hormone can be cleaved into two parts, one which has an insulin-like action and the other the reverse. So far these interesting possibilities have not been independently investigated, and 1 personally prefer to retain the view, until the contrary is proved, that growth hormone is a single molecule with a multiplicity of actions.
Diet, and diabetes mellitus
In the course of investigations of the diabetes-inducing action of growth hormone in intact dogs, I observed, many years ago. that the dog is more sensitive to the diabetes-inducing action of growth hormone when it receives a diet rich in protein and relatively poor in carbohydrate, than when it receives an isocaloric diet with an increase in carbohydrate at the expense of protein. This seemed to some extent to be the converse of what one might expect on general grounds, but the observations were well established although as far as I am aware they have never been independently confirmed.
In investigations of the dog with metahypo-physeal diabetes, that is an animal in which a persistent diabetes has been induced by a short period of treatment with pituitary growth hormone, ketosis was found to depend on the protein (meat) content of the food, being much greater on a meat-rich diet than on one containing much carbohydrate. Subsequently. I observed that the ketosis could be reduced by the administration of a high-fat diet, and observed, as had been found by those treating diabetes before the availability of insulin, that a high-fat diet could reduce the ketosis of diabetes. I am still not clear about the explanation of these effects in terms of intermediary metabolic processes, and attempts to isolate from meat a factor which stimulates ketosis in rats fed on a high-fat diet have not been successful. There are clearly unanswered questions to consider in this connection.
I have already referred to the increasing prevalence of diabetes in developed countries. Even more striking is the increase in cardiovascular and cerebrovascular disease, and there is evidence that the composition of the food is of importance in this respect. Two years ago those in Scandinavian countries were advised to reduce the fat content of their food in order to diminish the risk of cardiovascular and cerebrovascular disease, while in the United States there has been much concern about the possibility that animal fats in the food, in contrast to vegetable fats, may predispose to cardiovascular and cerebrovascular disease, and that a protective action against such disease is provided by the polyunsaturated fatty acids in food, and in particular in vegetable fats and oils. Cerebrovascular and cardiovascular accidents are also more common in people with diabetes mellitus than in non-diabetic people and there appears to be some underlying common factor in relation to fat metabolism in these conditions.
A growing body of evidence suggests that mortality from cardiovascular disease is higher in areas where the water supply is soft than in those where the water is hard. The interpretation of this relationship is uncertain at the present time, but the validity of the evidence is hard to question. Clearly there is much of importance to be learned in this connection.
Biochemistry and the structure of hormones
The isolation of hormones such as insulin and pituitary growth hormone has provided a challenge to the chemist and biochemist in the elucidation of the primary chemical structure of these substances. The primary structure of insulin was elucidated by Frederick Sanger in the 1950s in an investigation in which the full chemical structure of a protein was determined for the first time. This pioneering investigation earned Dr. F. Sanger a Nobel Prize for Chemistry in 1966. Quite recently the X-Ray Crystal-lographic Studies of Professor Dorothy Crow-foot-Hodkin elucidated the tertiary structure of the insulin molecule, and there are interesting juxtapositions one of which I shall mention shortly.
Sanger's investigations revealed clearly that hormones from different species of animal can differ in primary chemical structure, and similar observations have been made with respect to many other hormones and non-hormonal proteins. The species* variations of insulin are remarkable, and the chemical differences between insulin from certain fish and that from the human pancreas are extensive, even though the same general molecular pattern is retained. Dr. L. F. Smith, in Dr. Sanger's laboratory', ascertained differences in primary chemical structure between insulins from many different species of animal and has observed variations among 30 of the 50 amino-acid residues that exist in mammalian insulins. Rat pancreas contains two different insulins, which differ by a single amino-acid, and Dr. Smith has evidence that every rat is homozygous for two genes, each of which is responsible for production of one of the insulins.
From his results, Dr. Smith has drawn up a possible scheme for the evolution of some mammalian species. He has observed that insulin from the pig, the dog and the sperm whale, have the same primary structure and infers that this structure is likely to be the primary mammalian one from which the others have been derived by mutation in the course of evolution. More recently studies on the biosynthesis of insulin in human islet cell adenomata with the aid of isotopic labels, with subsequent investigations on normal pancreatic islet tissue from a wide range of species, have revealed the presence in pancreatic islet cells of a precursor of insulin, which has been named proinsulin. Insulin appears to be formed from proinsulin before the hormone is liberated from the fi cells of the pancreatic islet. The primary chemical structure of proinsulin from pig pancreas has been elucidated, the molecule containing a peptide of 31 amino-acids which joins the N terminal glycine of the A chain of the pig insulin molecule to the C terminal alanine of the B chain. Interestingly enough the X-Ray Crystallographic studies of Professor Crowfoot-Hodgkin have demonstrated that these two positions are quite close together in the molecule. Proinsulin is probably converted to insulin by the action of a proteolytic enzyme in the β cells of the pancreatic islets, but there is some evidence that a small amount of proinsulin may be present in the circulation. The biological activity of proinsulin is much less than that of insulin, and perhaps only 1 or 2% of it. One possibility which is still not clear is that growth hormones stimulate a production of proinsulin, which may or may not then be converted into active insulin.
The molecule of insulin has been completely cynthesized by Zahn and his colleagues, among others, and artificial variations upon the molecule are now available. The possibility that diabetes mellitus might arise as the result of naturally occurring variations in the insulin molecule, has so far no clear support, but the availability of artificially constructed variations of the molecule which might inhibit the action of insulin, is an interesting one for the future.
Although the primary structure of human growth hormone has been elucidated by C. H. Li and his colleagues, the molecule has not yet been artificially synthesized in the laboratory. InCambridge, Dr. Anne Stockell Hartree is preparing human growth hormone in large amounts for clinical use and has carried out investigations on the structure of growth hormones and of other hormones of the human pituitary gland.
The more that is learned about the biosynthesis of hormones such as insulin and growth hormone, the more is the possibility of learning how to put right these processes when they have gone wrong. The biochemist and the molecular biologist are already tinkering with heredity in the interior of the cell nucleus, and the possibility that the hormonal imbalance which leads to diabetes mellitus may ultimately be treated and permanently cured by some such biochemical operation is an attractive one for the future, and may not be so far off as one may think.
These days every school boy knows about RNA and DNA. Genes can be produced artificially and biology now holds its own in no uncertain fashion. But however far we get from the intact living animal, the fact that an important part of our present knowledge has been attained through the agency of investigations which involve laboratory animals cannot be ignored.
The President called upon Professor Henry Barcroft to pass a vote of thanks.
"My Lord Chairman. Ladies and Gentlemen: It is a very great privilege to me to have been asked to move this vote of thanks. In my case, and I expect in yours too, this lecture has been a very memorable one. It has been a great pleasure to us to have our President back again in the chair. It has been a privilege for us to have had the use of this lecture hall and we must thank the Director of the Institute. It has been a privilege to have been here with so many of you together: it has been a privilege to hear a lecture in which there have been so many original ideas: a lecture which has been given to us by somebody who has partaken so much in the research which is the foundation of our present day diabetic knowledge. This morning Professor Macdonald gave me a volume of the R.D.S. Stephen Paget lectures for the year 1938 when the lecture was given by Professor C. H. Best and after describing the work there in Toronto his next reference was to the work of Professor Young on the diabetogenic action of the pituitary—an aspect of the subject which has been of the greatest importance from those early days 22 years ago. We would, I am sure like to congratulate Professor Young on the important discoveries he has made in connection with diabetes. Our President has already said that he is to be the Chairman of the International Diabetes Association. We would like to congratulate him on the excellence of his address this evening, and we look forward very much to reading it in our journal. May I, on your behalf, convey to him our very warmest thanks for coming to us and delivering this address this evening.