Tuesday, 16 September 2008

SWEET THOUGHTS - ON DIABETES MELLITUS

ON DIABETES MELLITUS

INTRODUCTION

This 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 DIABETES

One 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 DIABETICS

With 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 PATHOPHYSIOLOGY

One 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 & PATHOGENESIS

But 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 diabetics
Detection 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.



GENE
% OF MODY
CASES
CLASSIFICATION
Glucokinase
20
MODY 2 – mild; complications are rare
HNF-1a
60
MODY 3 – diagnosed later (around 35 years of age)
HNF-4a
1
MODY 1
HNF-1b
1
MODY 5
IPF-1
1
MODY 4
Unknown
15
MODY X
SUR1
<1
Hyperinsulinism in infancy and beta cell failure in childhood

The main risk factor for type 2 diabetes is obesity, with the accumulation of visceral abdominal fat rather than subcutaneous fat being deleterious. About 80% of type 2 diabetics are obese. Fat is a highly active tissue, and not as inert as people think. It produces a variety of hormones and chemicals which modulate insulin action, including TNF-alpha. Why should the distribution of the fat be of any significance? The mechanism is still unclear.

Now we shall discuss obesity and its complications in due course, but it is worthwhile mentioning the verse, “Eat and drink but not to excess” (7:32). Umar, the second Caliph, is reported to have said: “Avoid getting a pot-belly, for it spoils the body, causes diseases, and makes doing the prayer tiring. And avoid all excess, for God hates a learned man who is fat.” Ali ibn al-Husayn ibn al-Wafid said. ‘God put all medicine into half of one verse [of the Qur’an] when He said: Eat and drink but not to excess.’ The Prophet (PBUH) also drew attention to obesity and over-eating. For example, as recorded by Al-Haythami, on seeing a fat man, he said: “If you did not have a paunch, it would be better for you”. He also is reported to have said, “Overeating does not go with good health”.

It is also felt that physical inactivity is a risk factor for type 2 DM independent of weight gain. Exercise possibly reduces the risk but increasing whole body insulin sensitivity. Hence, there is great wisdom in the Islamic advice regarding physical activity.



CONSEQUENCES OF DIABETES



KNIVES

· Kidneys - leading eventually to diabetic nephropathy and chronic renal failure
· Neuromuscular – causing peripheral neuropathy, autonomic neuropathy, mononeuritis, radiculopathy, and amyotrophy
· Infective – increased risk of urinary tract infections, skin and soft tissue infections, tuberculosis and moniliasis
· Vascular – affecting both large vessels (leading to ischaemic heart disease and peripheral vascular disease) and small vessels (microangiopathy producing renal failure, gangrene of skin and feet, with wedge-shaped infarcts.
· Eyes – an increased risk of cataracts, retinopathy, glaucoma, blurred vision, and retinal detachment.
· Skin – particularly affecting the feet (deformities, ulcers and gangrene, necrobiosis lipoidica, granuloma annulare, cellulitis, acanthosis nigricans)


Almost all organs and body processes are afflicted by diabetes. The main chronic ones are summarized by KNIVES. However, it is important to realize that diabetes affects virtually all body organs in one way or another, to the extent that I have heard consultants advise their students that, if asked about the causes of any illness (or risk factors) then saying diabetes and drugs is likely to be a successful choice! The reason for this is simple – all organs need metabolism to survive, and glucose is its chief currency. If glucose cannot be utilized, metabolism will eventually fail in one way or another. In addition, if it accumulates it can cause microvascular and macrovascular damage. The former is how the eyes and kidneys are damaged, and the latter is how the nerves and arteries are damaged.

How does this occur? Several mechanisms have been suggested. The most established one is that of nonenzymatic glycosylation of proteins in capillary basement membranes and other tissues, leading to damage through loss of function, turning on and off of signal pathways within cells, or alteration in gene expression. Very cleverly, this observation is used in the assessment of long term control of diabetic patients. One of the proteins which is glycated is haemoglobin. Because red blood cells survive in the blood for 90-120 days, the HbA1c provides a means to assess glycaemic control over this period. I have seen many patients who, in order to please their doctor, decide to optimize their glucose control in the days immediate to their next appointment with him, failing to realize that by HbA1C, we have the truest reflection of their control over the past three months. BMs can be easily manipulated, through an excess intake of medication, but glycated haemoglobins are not. The following table illustrates the average BMs of patients with relation to their glycated haemoglobin:

HbA1c(%)
Avg. Blood Sugar
(mmol/L)
(mg/dL)
4
3.3
60
5
5.0
90
6
6.7
135
7
8.3
170
8
10.0
205
9
11.7
240
10
13.3
275
11
15.0
310
12
16.7
345
13
18.3
380
14
20.0
415

Note therefore, that in patients with a shortened RBC lifespan, such as those with haemolytic anaemia or sickle cell disease, there is no point using HbA1C. In these patients, fructosamine is used; this is formed when the carbonyl group of glucose reacts with an amino group of a protein. This is usually albumin, and because the half life of albumin is about 3 weeks, fructosamine assays are only true measures of diabetic control for that time. Unfortunately, patients with thalassemia have an increased affinity to glucose anyway, as well as patients with uraemia – this may lead to falsely high HbA1C, and this possibility should be raised in such cases.

The other mechanism by which microvascular damage is caused is by hyperglycaemia increasing the activity of the enzyme aldose reductase, which converts glucose to sorbitol. This causes damage by the mechanisms outlined below, and indeed one of the exciting developments in the management of diabetic complications is the manufacture of specific aldose reductase inhibitors, which have been successful in many animal trials, but owing to their high toxicity profile, remain far from human application.

Macrovascular complications are due to atherosclerosis, which we explain in the section on ischaemic heart disease. One of the interesting suspected reasons for increased atherosclerosis in type 2 diabetics is hyperinsulinaemia; this occurs due to increased insulin resistance. This explains why drugs that increase peripheral insulin sensitivity such as biguanides (e.g. metformin) are preferred to insulin secretagogues such as the sulphonylureas.

A reflection point here is that, if hyperinsulinaemia were to cause disease, it is an absolute prerequisite that a system to counteract it, namely the hyperglycaemic hormones – glucagon, adrenaline and cortisol – should be present at the same time to ensure survival. This is another pointer in the direction of intelligent design.



KIDNEYS

Significant renal disease occurs in 40% of type 1 diabetics and 20% of type 2 diabetics. The reason for the higher incidence in type ones may be the earlier onset of the disease in their case.

So why is the kidney affected by diabetes? Partly, it is because of the fact that the kidney is an extremely vascular organ, and a huge proportion of the body’s cardiac output is delivered to it.

It is interesting to note that there appears to be a genetic link in diabetic nephropathy; a history of nephropathy in other members of the family with diabetes greatly increases the risk of nephropathy. Studies have shown the possibility of problems with the ACE gene; there may be increased secretion of ACE, leading to increased microvascular damage. This may explain why ACE-inhibitors are of prognostic value in diabetic patients, and, as put by the OHCM, every type II diabetic should be on one. There is another reason how ACE-I may help, which we shall explain later.

The kidneys of diabetics show an increase in the mesangial matrix, increased width of the glomerular basement membrane and arteriosclerosis of the afferent and efferent arterioles. The kidneys become malnourished and disfigured, so to speak, with what are called ‘Kimmelsteil-Wilson’ nodules, characteristic of diabetic nephropathy. This leads to an increase in transglomerular pressure, and eventually to a decrease on capillary filtering area. The GFR declines. The increased transglomerular pressure is followed by loss of the negative charge on the basement membrane and thus reduced repulsion between it and the polyanionic albumin molecule. This leads to microlalbuminuria initially, then macroalbuminuria when the pore size enlarges. Later on, the tubules start to fail to reabsorb filtered protein.

Microalbuminuria is the first manifestation of diabetic nephropathy. This can be assessed by timed urine collections (20-200 micrograms/minute, or 30-300 mg/day). To make life easier, and rather than get a patient to give a 24-hour sample, the urinary albumin:creatinine ratio in a random sample of urine can be used. An ACR of >2.5 defines microalbuminuria. Later on, grams of albumin may be lost in a day, at which point the patient may have what is called the nephrotic syndrome, defined as proteinuria of >3.5 g/day, hypoalbuminaemia and oedema.

Now, let us for a few moments discuss this concept of nephrotic syndrome, which has previously puzzled me. Why is this disease, defined by a clinical finding (oedema) and two biochemical tests (proteinuria and hypoalbuminaemia) discussed in textbooks as if it were a separate disease entity? Are they not all part of the same thing – in other words, isn’t proteinuria obviously going to cause hypoalbuminaemia and oedema? Why do we call it a syndrome?

The usefulness of the concept of the nephrotic syndrome is that, once its triad occurs, the patient is at a highly increased risk of hyperlipidaemia, infection, thromboembolism and iatrogenic acute renal failure (due to the diuretics used for the oedema), and the patient must be put on appropriate anticoagulants, antibiotics, and statins. The diagnosis simply guides more cautious treatment of the patient, and not new pathology. That is why some believe that syndromes should not be in the ICD, the list of human diseases as published by the World Health Organisation (WHO), because they are not diseases, but the disease and its sequelae.


NEUROPATHY

This is the most common chronic complication of diabetes. The pathogenesis of these neuropathies is mainly microvascular, although lack of neurotrophic factor support (important in maintenance of normal neural function) and laminin expression (involved in neurite extension and normal function) are also likely to be important. There are many different forms which it can take, summarized as follows:


There is a lot to learn from neuropathy, in particular the importance of pain. Anyone who denies the existence of God based on the fact that pain exists should attend a diabetic clinic, and observe the feet of a patient with poorly controlled diabetes. The most distal parts of the longest nerves are the first things to be affected, with feet first then hands. Perhaps it is because the longest nerves are the ones that need the most support. There is loss of pain sensation firstly, then numbness and tingling, and eventually unrecognized trauma, severe pain, ulcers and neuropathic joints. The ulcers may become infected, leading to osteomyelitis and possible amputation.

Here we have a clear illustration of the importance of pain. As one philosopher put it, “Despite its unpleasantness, pain is an important part of the existence of humans and other animals; in fact, it is vital to survival. Pain encourages an organism to disengage from the noxious stimulus associated with the pain. Preliminary pain can serve to indicate that an injury is imminent, such as the ache from a soon-to-be-broken bone. Pain may also promote the healing process, since most organisms will protect an injured region in order to avoid further pain. People born with congenital insensitivity to pain usually have short life spans, and suffer numerous ailments such as broken bones, bed sores, and chronic infection.” To argue that the presence of pain is inconsistent with the presence of a merciful deity is invalid. Pain is – if anything – a pointer towards the contrary.

Virtually any nerve can be affected by diabetes. The brain is affected chiefly through the increased risk of stroke, which is actually a macrovascular, not a microvascular complication.

The cranial nerves are also affected. Most commonly, the third, fourth and sixth cranial nerves are affected, causing diplopia. Why these nerves are most affected is unclear.

The autonomic nervous system has its origins in the brainstem. Neuropathy may manifest itself in cardiac arrhythmias, postural hypotension, vomiting (gastroparesis), diarrhoea, urinary retention (neuropathic bladder) and impotence.




INFECTION

The risk of infection is increased in diabetes because of impaired leukocyte, particularly neutrophil, function. Urinary tract and skin infections (e.g. cellulitis, boils, abscesses), as well as candida and tuberculosis, are increased. The destructive effects of the infection in diabetics are multiplied, because the infection leads to activation of the fight-and-flight (sympathetic) response, in an attempt to counteract the insult. This results in release of the hyperglycaemic hormones, cortisol and adrenaline, which further worsen the hyperglycaemia, and may lead to such severe consequences as DKA. Knowledge of this can only lead to gratefulness about the perfect metabolic state of the immune system in the 97% of human beings, who are not diabetic.

EYES


Several aspects of the eye are affected by diabetes. This includes the nervous control (discussed above due to neuropathy), the lens (cataracts), aqueous humour (glaucoma) and retina.

The mechanism for diabetic retinopathy is analogous to that of nephropathy. In both cases, there is thickening of the basement membrane as an early pathological feature. There is loss of vascular tone regulation (similar to that which occurs in the afferent and efferent renal arterioles), which is partly due to loss of pericytes (contractile cells which control vessel caliber and flow). There is loss of endothelial cells like in the kidneys. The capillaries become more fragile and leaky, and the first sign usually seen with an opthalmoscope is microaneurysm formation, which are blind outpouchings of the capillaries which appear as red dots. These aneurysms, like any aneurysm, can bleed, and these are the ‘blots’, and once they become more frequent and more severe, cotton-wool spots form. These are not areas of infarction as is commonly believed, but elevations of the nerve fibre layer due to intracellular accumulation of axoplasmic material at the areas of microvascular infarction. Whereas in the kidneys there is mainly leakage of albumin and other protein, in the eyes there is leakage of both protein and lipid, and these form hard exudates. All these changes form the non-proliferative phase.

Once the above becomes excessive, the preproliferative phase occurs. This is characterized by multiple haemorrhages in all four quadrants, five or more cotton wool spots, venous dilatation and beading, and intraretinal microvascular abnormalities (IRMAs) – abnormally branched vessels in the retina, representing attempts to revascularise the ischaemic retina.

Contrary to intuition, when one would expect ischaemia to mean reduction and loss of activity, the ischaemic areas of the retina actually secrete several growth factors, especially VEGF. This is the body’s attempt to compensate, and if they were normal vessels, then all would be well. However, these vessels are both histologically and anatomically defective. They are very fragile, and bleed easily, and grow forward towards the vitreous fluid and can overlie the optic disc. These are the most dangerous ones. Their bleeding can lead to vitreous haemorrhage and retinal detachment. Growth of new vessels can also occur over the iris, leading to ‘rubeosis iridis’. Obstruction of the drainage angle by new vessels may then cause a painful secondary glaucoma. All these things constitute proliferative retinopathy. Maculopathy occurs if any of the above takes place around the macula site. The following table summarises the pathophysiology of diabetic retinopathy.







SKIN


The skin is affected in diabetes through multiple mechanisms. In fact, one can use the surgical sieve to organize skin disease in diabetes.

Vascular disease can lead to arterial ulcers. Infections lead to cellulitis, boils, abscesses, candidiasis, and tinea (dermatophyte infections). Trauma, due to neuropathy, can also lead to ulcers and all sorts of skin damage. Autoimmune conditions such as vitiligo are associated with type 1 diabetes. The condition necrobiosis lipoidica diabeticorum is felt by some to be a metabolic condition, where there is hyaline degeneration of collagen (necrobiosis) surrounded by fibrosis. Lysyl oxidase levels have been found in some diabetic persons to be elevated and are responsible for increased collagen cross-linking. Increased collagen cross-linking could explain basement membrane thickening in this condition. (Why it occurs only in the legs is an interesting question).

Iatrogenic skin conditions in diabetes include lipoatrophy and lipohypertrophy. Neoplastic conditions (although not malignant) include Dupytren’s contracture and acanthosis nigricans, a hyperpigmented velvety outgrowth of the epidermis, usually in the flexural areas of the axilla, groin and neck. It also occurs in several malignancies. It is most likely caused by factors that stimulate keratinocyte, melanocyte and dermal fibroblast proliferation. The factor is probably insulin or an insulinlike growth factor. In malignant AN, the stimulating factor is believed to be a substance secreted either by the tumor or in response to the tumor.

OTHER ORGANS

The liver and most other organs are affected by diabetes. LFTs can be deranged.

HISTORY

Patient presents with symptoms of fatigue, thirst, polyuria, weight loss or weight gain, features of complications, or are completely asymptomatic and detected on assessment for other illnesses. The patient may present for the first time with diabetic ketoacidosis, i.e., smelling of ketones, hyperventilating, dehydrated, and even drowsy, confused, or comatose






PMH

Other HLA-DR3 associated disorders; rare causes of DM – chronic pancreatitis, cystic fibrosis, Cushing’s syndrome, acromegaly, phaechromocytoma, pregnancy, MJ THREADS.



DH

Steroids
Thiazides
Beta-blockers

FH/SH

Smoking
Determine if patient drives or not in ADL (need to notify DVLA if private vehicle license, and is banned permanently if HGV)
Alcohol (needs to stop)
May be a strong FH of DM

ROS

As appropriate; all systems are affected by DM.

PHYSICAL EXAMINATION

GENERAL

Unwell, obese or wasted patient – check BMI in all endocrine patients
Raised BP very common
Urine output increased
Other vital signs variable
JACCOL may or may not be relevant, e.g. jaundice in fatty liver, anaemia in pernicious disease. May be dehydrated

CVS

Blood pressure must be measured sitting & standing (to detect any postural drop)
Peripheral pulses may be absent
Signs of ischaemic heart disease or PVD

RS

Apart from the increased risk of tuberculosis, no marked consequences here

ABDOMEN

Hepatomegaly possible
Ensure urine is dipsticked, looking for PBL KNG


NEUROLOGICAL

Diabetic neuropathy may be somatic (including polyneuropathy which may be symmetrical, sensory and distal or asymmetrical motor and proximal); to remember which is which – remember pROximal is motOR (includes amyotrophy), therefore distal is sensory
Cranial nerves commonly affected include optic nerve, oculomotor and abducens nerves.
Examine eyes fully, including the red reflex (cataracts), acuity, colour vision, and fundoscopy.

Fundoscopy may reveal any of the four grades of diabetic retinopathy; spots (cotton wool spots which are ischaemic nerve fibres), dots (microaneurysms) and blots (haemorrhages due to rupture of microaneurysms)

1) Background à dots and blots and hard exudates
2) Preproliferative à add soft exudates
3) Proliferative à add new vessels
4) Maculopathy à if visual acuity is down and no cataract
- Hypertensive changes commonly co-exist; also note that venous dilatation is the earliest change, including central vein occlusion

Other commonly affected nerves include the femoral and sciatic nerves. Lateral polpliteal nerve palsy and carpal tunnel syndrome also may occur.

SKIN

The dermatological complications of diabetes are:

CENTURY

· Cellulitis / Candidiasis
· Eruptive xanthomas
· Necrobiosis lipoidica (the most specific; occur on shins mainlyl yellow plaques with red edges & may ulcerate)
· Tense bullae over lower legs
· Ulcers (neuropathic, arteriopathic)
· Rubeosis (chronic flushed appearance of face caused by decreased vascular tone and pooling of blood)
· Yellow skin (increased beta carotene levels)







INVESTIGATIONS

DIAGNOSTIC

Random blood glucose > 11 in a symptomatic patient (only one value needed); in asymptomatic patient blood glucose > 11 on two separate occasions

Fasting glucose > 7.0 (at least 8 hour fast) is diagnostic; if borderline .i.e. 6-7.0 then do an OGTT (75 g glucose, a lucozade bottle); if it shows 7.8-11.0 then it is diagnostic of impaired glucose tolerance; 20-50% of people with impaired glucose tolerance will progress to type 2 diabetes within 10 years of diagnosis. In addition, people with impaired glucose tolerance are known to be at significantly increased risk of cardiovascular disease, which may present before the onset of diabetes. Rates of cardiovascular risk factors are intermediate between those with normal glucose tolerance and those with diabetes. Impaired fasting glycaemia has not been shown to be a risk factor for cardiovascular disease. Baseline plasma glucose is the most consistent predictor of progression to diabetes. Impaired glucose tolerance has not been clearly associated with microvascular complications, e.g. nephropathy, retinopathy or neuropathy

CAUSE

BMI (obesity)
TFTs (thyroid disease so commonly associated)
US or CT (pancreatic disease)
Iron & TIBC (haemochromatosis)

CONSEQUENCES

HbA1C or fructosamine (long-term diabetic control)
U&Es & creatinine & urinalysis (kidneys)
ECG (IHD)
ABPI (PVD)
Blood cultures (infections)
Retinal photography (retinopathy)
LFTs (fatty liver, GGT)
Lipids
Ketones, blood glucose, ABG – diabetic ketoacidosis







DIABETIC KETOACIDOSIS

Its clinical features are DKA:

· Dehydrated / Drowsiness that can lead to coma
· Ketoacidosis/Kussmauls breathing / K+ imbalance
· Acidosis / Acetone breath / Abdominal pain

The treatment involves the following ABC, MOVE & FUCKING:

Fluids (crystalloids) (1 L over first 30 minutes, then over 1 hour, then 2 hours, then 4, then 6 – use normal saline, switching over to dextrose when glucose < 11 mmol)
Urea & Creatinine (check it)
CXR / Cultures (blood, urine) / Clexane
K+ (potassium)
Insulin sliding scale
Nasogastic tube (if patient comatose)
Glucose (once serum levels < 12)

*Soluble insulin mixed with normal saline should be given intravenously by syringe pump. The rate is usually 4-12 units per hour according to the blood glucose level. When the blood glucose level has normalized and the patient is rehydrated and eating, the patient may be returned to subcutaneous insulin.

*Under MOVE, monitor all vital signs, including GCS and urine output (often neglected)

*Example of sliding scale is as follows:

- The aim is to maintain the blood glucose between 4.0 and 7.0mmol/l.- Prescribe 50U soluble insulin (e.g. actrapid) in 50mls N Saline to run IV according to sliding scale below (a stat dose of insulin is not necessary).- Measure glucose hourly for the first 4 hours, then 2-4 hourly thereafter, and alter insulin infusion accordingly.
Capillary glucose (mmol/l)
Soluble insulin (units/hour) e.g. actrapid
0 - 4.0
If appropriate treat for hypoglycaemia
4.1 – 7.0
1
7.1 - 11.0
2
11.1 – 14.0
3
14.1 – 17.0
4
17.1 – 20.0
5
>20
6
This is one of the most common and important emergencies. Although it is commonly believed that it only occurs in type one diabetics, this is not true. Any patient with severe starvation of any sort can becoming ketotic, and severe type 2 diabetes (usually they would be on insulin too) can be regarded as a form of starvation – body cells are starved of glucose, so to speak, which they cannot use. They resort to ketones instead. Indeed, ketoacidosis is less common in type 2 diabetics, because they have some insulin which suppresses ketogenesis by the liver.

One of the clever aspects of starvation physiology is that the brain, normally glucose-exclusive in its fuel usage, can then switch over to ketone use. The ketones are acids, which lead to the acidosis.

The most important aspect of DKA is fluid replacement. Patients die first of hypovolaemia, not hyperglycaemia. Fluid losses of over 5 litres are not uncommon; this is a huge proportion of the cardiac output, with severe possible complications (see below). The fluid replacement not only rehydrates the dry patient but also lowers serum glucose levels even without the insulin, which we shall come to next. This is does by increasing urine flow (and hence glycosuria) and by decreasing the levels of catecholamines and cortisol, which were increased by the stimulus of hypovolaemia.

It is always said that fluids should be replaced in a specific order (see figure below). Why should fluids be replaced in that way? Well, it is important to realize that no randomized trials of fluid replacement have been conducted, and over the years, a variety of regimens have been proposed. This is simply the most common one used in England, and it appears pretty safe.

The next question is – should all DKA patients have a central line put in to monitor their fluid balance? This is a difficult question to answer. CVP lines are not without complications, and two of them in particular – infection and thrombosis – may even worsen the scenario.

Because insulin is important in shifting potassium into the intracellular compartment, DKA patients often have hyperkalaemia initially, which increases their cardiovascular morbidity. The insulin that is administered to control the hyperglycaemia will treat this, and infact may lower potassium to hypokalaemia levels, at which point replacement may be necessary.

The insulin is the second most important aspect of the treatment, and must be administered intravenously. This is because volume depletion and vascular collapse impair the absorption of IM or SC insulin.

Now, the logical explanation to a severe hyperglycaemia, as occurs in DKA, is to lower it as much as possible as quickly as possible. However, this should never be done. This is because of the risk of cerebral oedema. Brain cells take longer than other cells to adjust, and if plasma glucose is reduced too fast, water enters the brain cells by osmosis. The aim therefore is to reduce glucose by 3 mmol/litre/hour. Indeed, cerebral oedema is the main cause of death in children with DKA.

It is important to realize another point with regards to the sliding scale. It should not be stopped even if the BMs of the patient have normalized. This is because patients may still be acidotic and need insulin to metabolize their ketones.

Because of the severe hypovolaemia, the patient’s urea, electrolytes and creatinine are vastly deranged. Sodium may be high (due to dehydration) or low (pseudohyponatraemia or vomiting). The patient is an increased risk of DVT due to haemoconcentration of the clotting factors and the ‘stickiness’ if you like of the blood – it is hyperviscous. It is important to monitor U&Es regularly (initially two hourly) and put the patient on clexane.

Finally it is important to look for and treat the cause of DKA. This is frequently forgotten but crucial. Perhaps it is because the majority of cases have unknown triggers. The table below illustrates this. Causes can be recalled thus:

8 I

Initial presentation
Infection (UTI, pneumonia)
Insulin reduction or omission
Injury
Intercurrent illness (e.g. MI)
Ignorance (poor control)
Intoxication (alcohol)
Idiopathic






HONK is very similar in management; it occurs in type 2 diabetics. The onset of this is gradual over days. The patient is often elderly and may not be a known diabetic. Polyuria leads to dehydration. The blood glucose is very high and plasma osmolality is increased – this is calculated follows:

- Plasma osmolality = 2 (Na+K) + urea + glucose; normal = 285 – 295 mOsm/L

There is no acidosis or ketonuria as there is no change to ketone metabolism. Patients require small doses of intravenous insulin and hypotonic saline, although long-term insulin may not be required. Central venous pressure monitoring may be required. Patients are at a high risk of DVT and are given prophylactic subcutaneous heparin. The mortality rate is up to 50%.

What about hyperosmolar non-ketotic coma (HONK)? This is treated in the same way as DKA, with more aggressive attention to the fluid balance and osmolality; whereas in DKA the main aim is to reduce plasma glucose by 3 mmol/l/hr but in HONK plasma osmolality is the more important guide; aim to reduce plasma osmolality by 3 mOsmol/l/hr.

TREATMENT OF CHRONIC DIABETES

The management of diabetes is multidisciplinary and involves attention to SAFE WEIGHT & INFORM:

Salt reduced/Smoking stop
Alcohol stop
Fats reduce
Exercise increase
Weight loss
Information – diabetic nurses, leaflets, websites, exaplining DM, control, complications, consequences of disease & implications on life, pregnancy, breast feeding. Need to inform DVLA unless controlled by diet alone
Nutrition – optimising meal plan, diet comprising complex carbohydrates, SAFE WEIGHT, dietitian referral
Foot care – regular inspection and chiropody inpit
Organisations – local and national support groups, e.g. diabetes UK
Recognition of hypoglycaemia
Monitoring of glycaemic control

The oral types of drugs used in type II diabetes include SMART:

Sulphonylureas
Metformin
Acarbose
Repaglinide
Thiazolidinediones (e.g. rosiglitazone, proglitazone)

Very interestingly, intensive BP control is believed to be at least as important as intensive treatment of glucose levels in reduction of complications in diabetic patients.
REVIEW ASSESSMENT

All patients with type 2 diabetes should have glycaemic control reviewed at 2-6 monthly intervals. Other aspects of diabetes should be reviewed every 6-12 months and should include:

Glycaemic control and any perceived problems
Reinforce need for lifestyle measures
BMI
HbA1c (check every 2-6 months, aim for level of 6.5%-7.5%)
Full lipid profile
Level of urinary albumin/protein
+/- U+Es
BP measurement (Maintain below 130/80)
Examination of eyes for signs of retinopathy and cataracts
Examination of feet for ulceration /sensation/peripheral pulses
Examination of injection sites if appropriate
If male, ask about impotence

SPECIAL CIRCUMSTANCES

Surgery - diabetic patients should be first on the operating list, and fasted on the morning of surgery. Oral agents should be stopped 24 hours before surgery, and restarted postoperatively unless the patient is ill or the blood glucose is very high, necessitating a period on insulin.

For patients already on insulin, the usual insulin should be given the night before the operation. An intravenous infusion of 500 mL of 5% glucose with 10 mmol KCl should be started early on the day of the operation and run at a constant rate to the patient's fluid requirements. A 1 unit/mL solution of soluble insulin in 0.9% saline should also be infused intravenously using a syringe pump. The rate varies according to the patient's blood glucose concentration, which should be measured every 2 hours until stable and every 6 hours thereafter. When the patient starts to eat and drink, he or she may be restarted on the normal insulin regimen.

NOTES ON MEDICATION

Metformin is the first line oral antihyperglycaemic. This is because the vast majority of type 2 diabetics are obese, and metformin is an appetite suppressant. How it does this is by unclear; perhaps it is because it is derived from a bitter herb – Galega Officinalis, or French lilac. It is biguanide; and this name helps us remember ‘bi’ (two) actions of the drug – suppressing gluconeogenesis and increasing peripheral metabolism of glucose. Because it does not act on insulin, it cannot cause hypoglycaemia. Its most interesting side effect is lactic acidosis – caused by reducing pyruvate dehydrogenase activity and mitochondrial transport of reducing agents, thus enhancing anaerobic metabolism. Because of this risk, it is contraindicated in those with creatinine of >150 (where the excretion of lactate would be reduced), and other conditions where lactic acidosis is a risk, such as sepsis, severe heart failure, liver disease or any potentially nephrotoxic procedure.

The thiazolidinediones are a product of genetic studies. One of the current pocketbooks popular among medical students, Baby Kumar, describes them as follows: “Glitazones e.g. rosiglitazone bind to and activate a transcription factor called nuclear peroxisome proliferators-activated receptor gamma (PPAR-gamma), which is a nuclear receptor expressed predominantly in adipose tissue.” As you can see, this is a very poor and confused explanation, and should be revised. What the authors should have done is reverse the order – the glitazones bind to and activate PPAR-gamma, which is an intracellular receptor (as it says on the tin), which in turn shifts into the nucleus, acts as a transcription factor, and stimulates the transcription and synthesis of lipoprotein lipase, fatty acid transporter protein, insulin-sensitive glucose transporter (GLUT-4) and other proteins. In addition, they are believed to reduce the production of TNF-alpha, which is implicated in the pathogenesis of type 2 diabetes.

These two types are antihyperglycaemic, and need insulin to act, unlike the sulphonylureas, whose mechanism of action was explained earlier.

Many type 2 diabetic patients will eventually require insulin, and all type 1 diabetics need it. There are many peripheral issues which we can discuss with regards to this amazing hormone.

Its remarkable history is outlined in the endocrine drugs section in the Cannon. The genius of Banting, McLeod and Best (then a medical student), and the grace of God, is the reason why so many diabetics survive their difficult illness. It is truly fascinating that the patent for this life saving medication was sold for just one dollar.

Insulin was originally extracted from dogs, then cows and oxen, and eventually pigs and finally, we have the human version.

There are two questions that are raised here. Are Muslims allowed to use porcine insulin?

Unfortunately, there is a huge misunderstanding with regards to this issue. The Muslim position is believed by some to go along the following lines, "Muslims are strictly forbidden to drink alcohol. Eating pork is totally prohibited, so porcine insulin is unacceptable to Muslims" (Gwen Hall, 2007). Other authoritative textbook states, “Animal-derived insulins are unacceptable to devout followers of Islam and Judaism and to strict vegans” (Krentz & Bailey, 2005).

The truth of the matter is that – porcine insulin is not forbidden in Islam, and in essence, the refusal of Muslims to use it, is due to psychological, rather than religious issues. This is because the Islamic stance over pig products is clear. The verses are:

"Forbidden to you for (food) are: dead meat, blood and the flesh of the swine and that which hath been invoked the name other than Allah." (5:4)

"Allah has forbidden you only what dies of itself and blood and the flesh of swine and that over which any other name than that of Allah has been invoked; but whoever is driven to (it), not desiring nor exceeding the limit, then surely Allah is Forgiving, Merciful." (16:115).

So it is the ‘flesh’ of swine, not its products that are forbidden. Insulin is not flesh – it is a hormone. Even if it were flesh, the Qur’an does not forbid it if it were a medical necessity, as the second verse concludes.

This brings us to the broad topic of the use of ‘prohibited substances’ in the case of illness. The Islamic stance is discussed very comprehensively by Yusuf Al-Qaradawi, as follows:

“In case of a necessity a different rule applies, as was discussed earlier. Allah Ta'ala says: ...He has explained to you what He has made haram for you, except that to which you are compelled... (6:119)

And after mentioning the prohibitions concerning the flesh of dead animals, blood, and so, He says: ...but if one is compelled by necessity, neither craving (it) nor transgressing, there is no sin on him; indeed, Allah is Forgiving, Merciful. (2:172-173)

The consensus of the jurists is that necessity in this case signifies the need for food to alleviate hunger when no food other than the prohibited food is available, some jurists holding the opinion that at least one day and one night should pass without food. In such a situation a person may eat as much will satisfy his hunger and thus save himself from death. Said Imam Malik, "The amount of it is what will alleviate his hunger, and he should not eat more than what will keep him alive." This, perhaps, is the meaning of Allah's words, "neither craving (it) nor transgressing,"—that is, neither desiring it nor eating more than necessary. That hunger can be a compelling need is expressly mentioned in the Qur'anic ayah: ...but if one is compelled by hunger, without any inclination to sin, then indeed Allah is Forgiving, Merciful. (5:4 (3))

Concerning the question of whether some of the prohibited food substances can be used as medicine, there is a difference of opinion among jurists. Some do not consider medicine to belong in the category of a compelling necessity like food, and in support of their position they cite the hadith: "Assuredly Allah did not provide a cure for you in what He has prohibited to you." (Reported by al-Bukhari on the authority of Ibn Mas'ood.)

Others consider the need for medicine equal to that of food, as both are necessary for preserving life. In support of their position that prohibited food substances may be used as medicine, they argue that the Prophet (peace be on him) allowed 'Abd al-Rahman bin 'Awf and al-Zubair bin al-'Awwam to wear silk because they were suffering from scabies. (The text of this hadith is quoted in the subsection of this book entitled "Clothing and Ornaments.")

Perhaps this latter view is closer to the spirit of Islam which, in all its legislations and teachings, is concerned with the preservation of human life. However, taking medicine containing some of the haram substances is permissible only under the following conditions:

The patient's life is endangered if he does not take this medicine.
No alternative or substitute medication made from entirely halal sources is available.
The medication is prescribed by a Muslim physician who is knowledgeable as well as God-fearing.

We may, however, add that on the basis of our own observations and the opinions of expert physicians, we have arrived at the conclusion that there hardly exists any medical necessity which requires ingesting what is haram, as for example, taking medicine. Nevertheless, we have stated this principle in case a Muslim happens to be in a place where he cannot find medications other than those which contain haram substances.”

To this I may add that God created the entirety of the universe for the service of man. This is clear from the following verse, "Do you not see that Allah made available for you all what is in the skies and what is in the earth, flooded you with many blessings known and unknown." (31:20).

Now, the other interesting issue that arises with insulin is the topic of genetic engineering. The vast majority of insulin these days is genetically engineered, which is regarded by some as ‘playing God’ or changing the creation.

There is no changing the creation here – all that is done is an organism is modified to serve a function that it does not normally have, and since the entire universe was made for the service of humans, there can be no real objection to the use of the products of genetic engineering. Once again, it is valuable to quote Qaradawi on this issue, in an article published on his IslamOnline website:

“One of the blessings of Islam is that it never abstracts scientific programs or narrows the scope of the mind in the field of science and technology. Unlike other religions, there is no conflict between science and religion in Islam. Christian clergy opposed scientists, thinkers and pioneers of technology that we take for granted today. Many were punished, tortured and sentenced to death.

The Qur’an shows that Allah, Almighty, bestows many gifts on mankind enabling them to discover the mysterious nature around them and to recognize the laws that control the universe. Allah Almighty also submits the whole universe with its heavens, earth, sun and moon to mankind.

Allah Almighty says: (See ye not how Allah hath made serviceable unto you whatsoever is in the skies and whatsoever is in the earth and hath loaded you with His favors both without and within? Yet of mankind is he who disputeth concerning Allah, without knowledge or guidance or a Scripture giving light.) (Luqman 31: 20)

He Almighty also says, (And in the earth are portents for those whose faith is sure. And (also) in yourselves. Can ye then not see??w (Adh-dhariat 51: 20-21)

When man’s knowledge advances, it becomes compulsory for him to deepen his faith and moral virtues. One must not go alone, doing whatever one wants, ignoring religious morals or the welfare of people in general. The problem in Western civilization is that science is separated from religion and in some cases it fights religion. Allah Almighty says, (And when he turneth away (from thee) his effort in the land is to make mischief therein and to destroy the crops and the cattle; and Allah loveth not mischief.) (Al-Baqarah 2: 205)

We welcome the idea of genetic engineering. It is one of the greatest discoveries of our time and is shared by many countries. Whether it is considered more important than the discovery of penicillin or man landing on the moon, we hope it is used for the benefit of humanity and that its guidelines will be according to the views of qualified jurists.

There are many benefits we can derive from this, say, for instance, in treating genetic diseases by using the effective genes to prevent harm or disease. This is something commendable in Islam according to the legal rule "Prevention is better than cure"; the rule is taken from the hadith; “There should be neither harm nor reciprocating injury.” By this, through the assistance of such a scientific device, man will be able to prevent many diseases.”

The ultimate dream of the diabetic is to retrieve normal pancreatic function and/or peripheral sensitivity to insulin. They would like to stop taking these tablets, stop injecting themselves, and retrieve a normal metabolism. That is a gift many of us do not appreciate. By reflecting on their adversity, we must learn to be appreciative of normal glucose metabolism and the gift of not being a diabetic.

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