sweet-thoughts-on-diabetes-mellitus

ON DIABETES MELLITUSINTRODUCTIONThis fascinating illness afflicts over 170 million people, a number that is expected to double by the year 2030. It consumes over 5% of the NHS healthcare budget and its various afflictions lead to a vastly increased use of hospital beds. It affects over 12% of Middle Eastern and Asian peoples and is therefore worthy of our greatest attention.I have heard it being said that having diabetes is worse than having cancer or HIV, and although this may be said in just pure frustration, there may be an element of truth in that. It is a disease of glucose utilisation, and since all body cells require glucose, all of them are afflicted by it. This contrasts with cancer, usually a disease of a single organ, or HIV, a disease of the CD4 cells of the immune system. Aretaeus, a Cappadocian physician of the second century vividly characterized it as “being a melting-down of the flesh and limbs into urine” and coined the term diabetes, meaning ‘to run through’.Diabetes occurs when we have a lack of (type 1), or deficient action (type 2) of the hormone insulin, which is involved in many different biochemical processes, including protein synthesis, lipid and carbohydrate metabolism. Some types of diabetes are secondary to increased antagonism of insulin, such as thyrotoxicosis, Cushing’s syndrome and phaeochromocytoma, but most are primary, due to insulin-related problems.EPIDEMIOLOGY OF DIABETESOne of the saddest things about diabetes is that it is more prevalent in the poor, and affects them in the worst manner with the most complications. A BBC report recently stated:“Britain's poorest communities are 2.5 times more likely to develop Type 2 diabetes than the general population, research suggests. They are also 3.5 times more likely to develop serious complications of diabetes, including heart disease.”Overall it is a common disorder, and is increasing in incidence. The table above shows the current prevalence of diabetes in many parts of the world, with over 10% of Hong Kong, Pakistanis and Czechs, and a ridiculously high prevalence among Egyptians and Cubans too. The following table illustrates how things will worsen within the next few decades:But by far, the highest prevalence of diabetes is in the Pima Indians, native American Indians who live in Arizona and Mexico – with a prevalence of 21%. The study of this population has taught us much about diabetes, most importantly, one of the biggest risk factors for type II diabetes – the sudden shift in diet from traditional agricultural goods towards processed foods. The more Westernised Arizona Pimans are those primarily affected, and the genetically similar Pimas in Mexico have virtually no type 2 diabetes. The rising incidence of diabetes around the world can be attributed to the rise of obesity, and the increasing inactivity (due to the comfortable lives we lead) and reliance on processed foods. The Arab world is increasingly afflicted by diabetes and its ills, which can be explained by the thrifty genotype hypothesis. As explained by Raz et al (2008):“This phenomenon of shifting disease patterns, termed epidemiological transition, initially occurred in developed countries and subsequently spread to developing nations. Arthur Koestler coined the term 'Coca- colonization' to describe the impact of the lifestyle of Western societies on developing countries. The devastating results of intrusion by Western society into the lives of traditional living indigenous communities can now be seen across the globe”.Having introduced syphilis and tuberculosis to the developing word in the 19th century, the West has introduced diabetes everywhere else. Does the answer for modern civilization still lie in the Western civilization, with so much mental and physical illness around? There is so much good in it no doubt, but anyone looking deeply into it, will find that all the basic ideas of any quality in the Western world are embodies, to an even greater extent.In addition, the great poverty that afflicts some leads to lack of education, and a further misunderstanding and poor treatment of the condition. Because it is a chronic condition, with poverty, appropriate drugs are not bought as they are too expensive, and traditional herbal remedies are used. For instance, in the Gaza Strip, where the annual income (for those lucky enough to work) is just under £350 a year, people are resorting to pomegranate seeds and chamomile for treatment, and the management of the condition is careless, with no monitoring facilities, a crucial aspect of its care. This sad truth illustrates the importance of justice, social equality and even distribution of wealth in medical care, things which can only be found in a fair society governed by wisdom and truth.There are many famous diabetics out there, what I would like to focus here on some of its more interesting victims, whose stories may teach us something about the condition.FAMOUS DIABETICSWith regards to aetiology, knowledge that former Egyptian president Jamal Abdel Nasser had diabetes, and possibly slipped into a diabetic coma before he died would help us recall two points – the high prevalence of the disease among Egyptians, and the existence of secondary cause of diabetes; his biographers insist that he had haemochromatosis, although his physician, Alsaway Habib recently published his memoirs and, “He denies that Nasser (1918-1970) had slipped into a diabetic coma before his death. Nor did Nasser suffer from bronzed diabetes as once published in the local press. "Nasser suffered from the ordinary type of adult diabetes," says Dr Habib.”One of the more recent victims is Halle Berry, the American award winning actress. Her story highlights one of the problems that celebrities can cause to the health awareness of people, and how misinformed they can be.Halle Berry is a type 1 diabetic – in other words dependent on insulin. She has made many fascinating comments on the condition, like "Diabetes turns out to be a gift. It gave me strength and toughness because I had to face reality, no matter how uncomfortable or painful it was", and interesting stories, like her diagnosis, when she “lay dangerously ill in a diabetic coma for a week before waking to a life that would never be the same again”. As a result of this, she became a spokesperson for Novo Nordisk, the pharmaceutical company specialising in diabetic products.But it is terrifying when such celebrities make comments on therapeutic aspects of a disease. On 6th of November 2007, the ABC News Channel reported Berry to have said, "I've managed to wean myself off insulin, so now I'd like to put myself in the Type 2 category". As everyone knows, this is nonsense, and what Berry is saying is suicidal. I very much doubt that Berry actually said that, because she remains with us to this day. But what her story highlights is that one should always take celebrities comments on the treatment of disease with a pinch of salt. Symptoms yes, management no. The damage that actors and actresses can cause by making statements such as these in our celebrity culture could be devastating. Another celebrity whose story I am tempted to discuss here is the Honorary Vice President of ‘Diabetes UK’, the great British oarsman and Olympic champion Sir Steve Redgrave, the only person ever to have won gold medals at five consecutive games. But I have opted to discuss his case in the section on ulcerative colitis, since that is a rarer disease, with fewer famous victims that I can think of. Talking of Diabetes UK, the creation of this excellent charity society which provides a lot of patient support and guidance as well as funding for scientific research and publications over the disease, was due to the efforts of two great men, both diabetic and both very influential.The story of Robert Daniel Lawrence, the ENT surgeon is so fascinating that his version is quoted in full in that excellent pharmacology book, ‘Clinical Pharmacology’, by Bennett and Brown (2005). I will do the same:“Many doctors, after they have developed a disease, take up the speciality in it... But that was not so with me. I was studying for surgery when diabetes took me up. The great book of Joslin said that by starving you might live four years with luck. [He went to Italy and, whilst his health was declining there, he received a letter from a biochemist friend which said] there was something called 'insulin' appearing with a good name in Canada, what about going there and getting it. I said 'No thank you; I've tried too many quackeries for diabetes; I'll wait and see'. Then I got peripheral neuritis ...So when [the friend] cabled me and said, 'I've got insulin — it works — come back quick', I responded, arrived at King's College Hospital,London, and went to the laboratory as soon as it opened ... It was all experimental for [neither of us] knew a thing about it... So we decided to have 20 units a nice round figure. I had a nice breakfast. I had bacon and eggs and toast made on the Bunsen. I hadn't eaten bread for months and months ... by 3 o'clock in the afternoon my urine was quite sugar free. That hadn't happened for many months. So we gave a cheer for Banting and Best.But at 4 pm I had a terrible shaky feeling and a terrible sweat and hunger pain. That was my first experience of hypoglycaemia. We remembered that Banting and Best had described an overdose of insulin in dogs. So I had some sugar and a biscuit and soon got quite well, thank you"The disease changed Lawrence’s life entirely, and he devoted all his time to research on the condition and the care of its patients. He set up a clinic which quickly became overcrowded, and this is where Herbert George Wells comes in. The great creator of science of fiction was also a diabetic and a patient of Lawrence. The details were summarised by Curnow (2002):“The number of people with diabetes attending the clinic doubled within four years, conditions were crowded and the equipment was inadequate. The hospital authorities supported Lawrence’s request to make a personal appeal to his more wealthy private patients to fund improvements to the facilities available to outpatients, and possibly build a small unit for in-patients. HG Wells, who had been referred to Lawrence in 1931, was one of the patients Lawrence approached. Wells donated half a crown, saying he was not a wealthy man and believed that the appeal should be of interest to all people with diabetes, and offered to write to The Times to involve a wider audience. The letter to ‘The Select Company of Diabetics – for the Benefit of Their Cult’ was published on 19th April 1933. He ended it saying, "I am a little surprised we have not already formed a Diabetic Association to watch over and extend this most benign branch of medicine to which we owe our lives" (Br J Diabetes Vasc Dis 2002;2:469–72).In 1934, the ‘Diabetic Association’ was founded, with RD Lawrence as the Chairman and HG Wells the President of the Association, with the nominated Vice Presidents including Professor FG Banting and Dr CH Best and two diabetic well-known novelists, GDH Cole and Hugh Walpole.I cannot help but digress and talk a little about H G Wells, who was one of the best writers of both fiction and non fiction of the 20th century. There are an abundant number of biographies of the great man, to which I would like to refer the kind reader, for he is a most interesting person. For the medical man, Wells is interesting for several reasons. Firstly, because of his diabetes, and his massive contribution to the creation of the ‘Diabetic Association’ (now Diabetes UK) together with Lawrence, as explained above. Indeed, the first time it was revealed to me that Wells was diabetic was while reading a very moving letter of his to the great Bertrand Russell, who incorporated it in his ‘Autobiography’, one of the most beautiful books I have ever read. An extract from the letter, written the year before his death in 1946, says a lot about the impact diabetes can have on one’s life:“I have been ill & I keep ill. I am President of the Diabetic Society and diabetes keeps one in and out, in and out of bed every two hours or so. This exhausts, and this vast return to chaos which is called the peace, the infinite meanness of great masses of my fellow creatures, the wickedness of organised religion give me a longing for a sleep that will have no awakening. There is a long history of heart failure on my paternal side but modern palliatives are very effective holding back that moment of release. Sodium bicarbonate keeps me in a grunting state of protesting endurance. But while I live I have to live and I owe a lot to the decaying civilisation which has anyhow kept alive enough of the spirit of scientific devotion to stimulate my curiosity and make me its debtor.” Secondly, because of his very interesting ideas regarding future health care. Wells was a great historian, and he illustrated this with his tour-de-force, ‘An Outline of History’, a 1324 page work that was the most popular book sold in America after its publication (after the Bible). Backed with this huge historical expertise, he gave some marvellous visions of how the future may turn out to be, and in one work, ‘An Englishman Looks At The World’, he envisages a system that seems to predate the GMC and NHS by many years:“In that extravagant world of which I dream, in which people will live in delightful cottages and ground rents will serve instead of rates, and everyone will have a chance of being happy--in that impossible world all doctors will be members of one great organisation for the public health, with all or most of their income guaranteed to them: I doubt if there will be any private doctors at all.Heaven forbid I should seem to write a word against doctors as they are. Daily I marvel at the wonders the general practitioner achieves, having regard to the difficulties of his position.But I cannot hide from myself, and I do not intend to hide from anyone else, my firm persuasion that the services the general practitioner is able to render us are not one-tenth so effectual as they might be if, instead of his being a private adventurer, he were a member of a sanely organised public machine. Consider what his training and equipment are, consider the peculiar difficulties of his work, and then consider for a moment what better conditions might be invented, and perhaps you will not think my estimate of one-tenth an excessive understatement in this matter.” How nice is it to see praise of the general practitioner, at a time when he or she is regarded, somewhat unfairly, as a second class physician!Moving on from Wells, who has taught us so much, we can move smoothly to another British genius, who shared much with Wells – his creativity and invention, disbelief in God, faith in eugenics (which is almost inextricably intertwined) and last but not least, his diabetes. It’s the great inventor of the telephone, Alexander Graham Bell.I will not deal here with the full biographical details of this great man, his numerous struggles and tragedies, his many success stories, and his great romanticism and his love and marriage to his deaf student Mabel Hubbard. But I will focus on what I regard as interesting from the medical point of view.Robert V. Bruce writes in his biography, ‘Bell: Alexander Graham Bell and the Conquest of Solitude’:“By 1915 Bell himself was in the grip of that incurable and (in pre-insulin days) perilous condition, diabetes. He had occasion for somber thought now in his sessions of nocturnal solitude. He could not have been deaf to the meaning of what was upon him. Diabetes had been the death of his uncle David 14 years before, but Bell's motto was 'keep on fighting'”.He was later diagnosed with pernicious anaemia, which is a recognized association with diabetes, although not with type 2 diabetes, which is what Bell likely had (no one with type 1 diabetes survives without insulin to the age of 75). And although it is stated in many places that Bell died of pernicious anaemia, including in the Wikipaedia article on him, I feel that is unlikely to be the case. Although it sounds paradoxical, diabetes, particularly when uncared for is a more pernicious than the pernicious disease! It is clear that Bell’s diabetes was uncared for, for obvious reasons. Firstly, he lived in the pre-insulin age – he was unlucky to have died in the same year Banting and Best discovered insulin, although it would be difficult to foresee if their treatment would have made any difference to him had he survived. For example, he developed neuropathy, as Charlotte Gray discloses in her biography of Bell, ‘Reluctant Genius’ (pages 418-419) – he was able to keep on wiggling “his toes, even though he had lost sensation in them. None of his family realized that the loss of sensation was an indication that he had pernicious anemia". (Although giving a clever possibility, it will never be known which one it is that led to his peripheral neuropathy). Neuropathy happens after years of damage, as we will soon see.There was an absence of the routine care we now have for diabetes (which has been formulated after many years of intensive research into its most appropriate management). Knowing the above, Bell would have surely benefited from seeing a chiropodist, something all diabetics of today are routinely familiar with. He would have also possibly benefited from a dietitian, but by sounds of things, he would have probably been, as are most diabetics, pretty non-compliant with their recipes. As Bruce illustrates in the aforementioned biography:“Always a hearty eater, Bell broke loose now and then from the coils of medical caution and, to the distress of his family, defied restrictions on starch and sugar. “Melville," he would say to his grandson as they walked by a redolent bakeshop on Wisconsin Avenue, "would you like some apple pie?" Bell himself would then join in the snack. "Don't you say a word to your grandmother," he would caution the boy. But when he toyed with his dinner, Mabel would notice. "Alec, you stopped in that bakeshop, I know." Ignoring the smoke screen of an exciting story, she would keep after him until he confessed like a small boy caught out. Charles Thompson kept an eye on the state of the refrigerator, but one night Bell made a raid, washed the china, and brushed up every crumb. Called to treat his acute indigestion, the doctor extracted the confession, "To go downstairs at three in the morning, load up on Smithfield ham, cold potatoes, macaroni cheese, and then go right to bed is the most ridiculous thing imaginable, " said the doctor severely; "that meal might have put an end to you, sir" "Well, as it is," said Bell, "the game was worth the candle. It was the best meal I've enjoyed in an age"!”In knowing that Alexander Graham Bell had type 2 diabetes we will immediately dispel the idea that type 2 diabetes is a twentieth century phenomenon. It is not, although it certainly has increased in prevalence since. Indeed, the two different types of diabetes were distinguished as early as 1875, by Apollinaire Bouchardat in his book on glycosuria (Kiple, 2003).In addition, the story of his doctor suspecting that “Bell’s diabetes had affected his liver” reveals a very clever insight into diabetes, which has only recently been recognized. Liver disease is now thought to be a not uncommon cause of problems in diabetics. Indeed, it is now felt that NASH, non-alcoholic steatohepatitis, the commonest liver pathology seen in diabetics is now a not uncommon cause of progressive chronic liver injury overall (Evans et al, 2002).Quite smoothly, history moves us on to discuss one of Bell’s close associates, Thomas Edison, the great American inventor. If Bell invented the telephone, it was Edison who made improved on it greatly and made it the technological masterpiece that it is today. He devised a mouthpiece for it that contained carbon powder, which when compressed, carried more current than when not compressed. As the sound waves compressed and decompressed it, the electric current fluctuated accordingly.Edison died of complications of diabetes aged 84, namely renal failure. In ‘Edison - Inventing the Century’, Neil Baldwin describes the experience of his physician:“Dr. Howe had a challenging patient in Thomas Edison - a totally deaf, eighty-four-year-old-man who did not bathe more than once a week, but did not believe in exercise, still (by his own account) "chewed tobacco continuously" and smoked several cigars a fay, and whose only foods were milk and the occasional glass of orange juice... In later years, Edison also suffered from diabetes and Bright's disease”. Bright’s disease is the old name for renal failure. He died uraemic on October 18th 1931. One can see how Edison would have benefited, like Bell, from attending a dietitian, and having smoking cessation advice. And unlike his Scottish counterpart, he would have been more likely to heed their advice. After all, wasn’t Edison the one who famously said:“The doctor of the future will give no medicine, but will interest her or his patients in the care of the human frame, in a proper diet, and in the cause and prevention of disease”?Now let us move on to diabetes itself. DIABETES – THOUGHTS ON PATHOPHYSIOLOGYOne of the biggest lessons of diabetes, is that it induces a feeling of appreciation of normal metabolism. The primitive human being, by virtue of instinct, knows that through lack of food and water, oxygen and warmth, he will die. We know this death is caused by cardiac arrest, and treating these three, if present, is part of the established cardiac arrest management algorithm (namely hypothermia, hypoxia, hypovolaemia). We always pierce the patient’s finger to check his blood glucose (in any comatose patient, including that due to a cardiac arrest). Both hypoglycaemia and hyperglycaemia are sinister and are treated aggressively, and what is important to realise is that they are both forms of ‘body starvation’ – not just hypoglycaemia. Whereas in hypoglycaemia, the body is starved of fuel, in diabetic hyperglycaemia, the body is starved of glucose utilisation, and in a desperate attempt, tries to consume other fuels, fats and proteins, which is only possible for a short while without severe consequences, which we shall discuss later. What is important to realise too is that hyperglycaemia not only leads to metabolic consequences, but also to hypovolaemia. This is because of the increased urine output and intracellular fluid loss due to osmotic shift. Indeed, in a patient with severe uncontrolled hyperglycaemia, such as diabetic ketoacidosis or HONK (hyperosmolar non-ketotic diabetic coma), it is dehydration that kills them, not the hyperglycaemia per se.Normal glucose regulation is maintained by several complex mechanisms. After any carbohydrate meal, the pancreas responds by releasing insulin from its beta cells (islets of Langerhans). This serves to stop gluconeogenesis and glycogenolysis, and stimulate glycogen synthesis (stimulating the enzyme glycogen synthase) by the liver (as well as glycerol for triglyceride synthesis), and shifts glucose intracellularly (via GLUT-4 receptors) into skeletal muscles and adipose tissue. Note that the liver does not need insulin to get glucose into its cells. It enters simply via a concentration gradient.Why should this be the case? Perhaps the body is being economical with its insulin, knowing that the insulin is required for the insulin-induced stimulation of glycogen synthase and triglyceride synthesis. I do not know, but am sure there is a clever reason behind it.One of the fascinating facts is that the brain, which consumes about 80% of the glucose utilised at rest in the fasting state, it too, like the liver, does not depend on insulin to get to it. The brain has exclusive GLUT-3 receptors. Now, imagine if the brain depended on insulin. This would be a disaster for all type 1 diabetics, who would quickly go into a coma and die once their pancreas is overwhelmed by the disease.Now we mentioned above a fact that everyone knows – after a high carbohydrate meal, the pancreas releases insulin. What we fail to realise and appreciate is that, these four words – ‘the pancreas releases insulin’ is one of the most majestic events of the cosmos. This is not an exaggeration, as I will explain below. Perhaps because we are see so many diabetic patients in hospital and in general practice that we regard it all as monotonous, and so we do not reflect on or appreciate this majesty. But let me break away and begin reflecting on this process like an intelligent child, and prove my point.To begin with – the pancreas needs to detect the glucose cells. Harun Yahya summarises this amazing process as follows, “First, the pancreas cells would find and distinguish the sugar molecules from among all the millions of other molecules in your blood. Moreover, they would count the sugar molecules to decide if the number were too high or too low. Amazingly, cells too small for the eye to see, without eyes, hands, or a brain know the correct proportion of sugar molecules in a fluid.” The glucose enters the beta cells by facilitated diffusion through the glucose transporter, GLUT-2. Although the majority of human cells require insulin to shift insulin into them, the pancreas, like the liver, doesn’t. It is a basic rule of the human body that an organ synthesising a chemical or hormone is never itself dependent on it. It is a form of altruism.Within the beta cells, glucose is metabolised to produce ATP. This ATP closes ATP-dependent potassium channels present in the beta cell membrane, which then depolarises the cell, causing calcium entry, which stimulates exocytosis of insulin. Sulphonylurea drugs, like gliclazide act like ATP here, inhibiting the ATP-dependent potassium channels.The insulin is synthesised as a large molecule – called pre-proinsulin. The reason for this is that it includes a signal peptide, called C-peptide, which is important for directing its proper folding and movement through the Golgi apparatus where it is synthesised (Kaufmann, p.240). Just before storage this is converted to insulin and C-peptide.Unfortunately, for reasons of space, we will not be able to talk about many of these magnificent processes which we are passing by here without much reflection. ATP manufature, depolarisation, insulin (protein) synthesis, exocytosis and cleavage. But the details may be found in any decent biochemistry textbook. I preferred Stryer back in the day.Once insulin is secreted into the bloodstream it exerts its action by binding to receptors primarily in the liver, muscle and adipose tissue; these are tyrosine kinase linked receptors which when bound to insulin result in a conformational change and autophosphorylation, and phosphorylation of IRS (insulin receptor substrate) proteins which activates intracellular signal cascades and enzymes.The actions of insulin are summarised in the table below:Following discussion of insulin’s roles, Harun Yahya concluded wondering, “How can it be that cells without a brain, nervous system, eyes or ears can manage to make such a complex calculation and carry out their function perfectly? How can these unconscious cells formed by the coming together of proteins and fat molecules do things too complicated for humans to achieve? What is the source of this remarkable awareness demonstrated by these unconscious molecules? Surely all of these delicate operations taking place in our bodies show us the existence and power of God Who rules over the universe and all living things.” I wish I were the first to say that!So insulin’s main role is in glucose homeostasis, and indeed, it is the only hormone in the human body that lowers blood glucose, whereas several other hormones can raise it. Why is this the case? As one researcher postulates, “Our body has no back-up system if insulin stops working. Why would that be, do you think? Does it not strike you as odd that in the fabulous system that is our body there is no back-up system for insulin, when our body tends to have all kinds of fall-back plans if something should fail? Perhaps it is worth looking at the question through the eyes of primitive humankind. Not having lived at that time I can't be certain, but I would imagine that there would have been times of limited food, and being able to increase blood sugar levels would have been critically important in order to fuel the body when there was very little or no food being consumed. Just like many other animals, in the spring and summer when fruit, plants and grains were available, it was advantageous to have insulin store some fat to aid chances of survival through the lean winter months. Fruit would be dried, and other foods fermented, but especially in the colder climates, people would rely on wild animals or fish for most of their food in the winter. Meat and fat do not induce a big insulin response. So, perhaps in the body's wisdom, it did not think it needed more than one method to lower blood sugar, as high carbohydrate (plant food) diets simply did not happen day in day out all year round except possibly in tropical climates.”So what happens if there is not enough insulin? Quite simply, there is unopposed action of glucagon and other anti-insulin hormones (catecholamines, cortisol), and the following results:DIABETES AETIOLOGY & PATHOGENESISBut how is diabetes caused? The general consensus is that type 1 is an autoimmune condition triggered by environmental and genetic factors.The autoimmune aspect is postulated because three reasons:The association of type 1 diabetes with other autoimmune diseases such as vitiligo, pernicious anaemia, Grave’s disease, and Addison’s disease.The presence of T-cell infiltrates within the islets of type 1 diabeticsDetection of antibodies to islet cell antibodies (ICA) and glutamic acid decarboxylase (GAD) in their serum.Autoimmune diseases are a minefield, and we will discuss them in more detail in the immunology section, but just to overview, they chiefly result from what is known as loss of tolerance. The normal human body has mechanisms that ensure B-cells are unresponsive to self-components, and that T-cells are not mobilized by self-peptides expressed on the MHC of healthy cells. This tolerance may be central, achieved by clonal inactivation or deletion of autoreactive T-cells in the thymus and B-cells in the bone marrow, as well as peripheral.Autoimmune diseases, although dreadful, highlight to the majority of mankind the presence of these mechanisms. Were they not present, would we have appreciated ‘tolerance’ and its very clever mechanisms? The answer is probably not. This is another argument for intelligent design – a normal human body cannot exist without a perfect immune system, which recognizes itself and only attacks others. Even with a normal heart, lung, joints, GI tract etc; if the immune system does not institute tolerance, disaster will follow, as all type 1 diabetics, and patients of other autoimmune disease know. Other examples of autoimmune disease are tabled below. The autoimmune event may be triggered or propagated by environmental factors. This is suggested by epidemiological studies, which show that clinical onset of type 1 diabetes peaks in the spring and autumn months, coinciding with higher incidence of viral infections at these times.Genetic factors are suggested by studies on its prevalence in twins – 50% in monozygotic twins, and 6% in dizygotic twins, and an increased risk of 6% of developing type 1 DM in first-degree relatives of patients with it. It is interesting to note that people at such increased risk may be monitored in the future by measuring the aforementioned ICA antibodies, which precede development of hyperglycaemia by many months, possibly years.An interesting observation is that the body has a huge reserve of islet cells, and that hyperglycaemia only develops once 75% of beta cells are lost. Such is the kindness of the Creator. He has given us more than we need.As for type 2 diabetes, there is no autoimmune component, but genetic, environmental and possibly also fetomaternal factors are important. Let us reflect on these aspects for a minute.Genetic factors are suggested by a higher concordance in monozygotic than dizygotic twins, as for type 1 diabetes, and also a higher prevalence in certain full-blooded populations compared to mixed races (e.g. Naurans in the South Pacific). Indeed, certain genetic defects have been illustrated in some cases (MODY – maturity onset diabetes of the young). These are listed in the tables below, with a table of the classification of MODY disorders. It is important to have an intact enzymatic pathway for insulin action and beta cell function. In addition, there are a number of ‘insulinopathies’, very rare genetic conditions inherited also in an AD fashion where abnormal insulin is secreted. The amino acid changes are so subtle, yet end in disaster, highlighting the magnificent accuracy of the human body in the majority of us with normal insulin. Had we not known about these insulinopathies, would we have appreciated this aspect, one wonders? Very unlikely, and the synthesis of insulin would have been taken for granted.