Diabetes

Diabetes mellitus: a metabolic disorder characterised by high blood sugar.

Three main types of diabetes:

Type 1 – reduction in insulin production from pancreas- autoimmune disease

Type 2 – insensitivity to insulin by the tissues- adult onset diabetes and its due to insulin resistance

Gestational – similar to type II caused by pregnancy hormones

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It is estimated that 180 million people worldwide have diabetes. This is likely to double by 2030.

In the UK alone:

Over 4% of men and 3% of women in England have diagnosed diabetes.

3% of men and 0.7% of women aged 35 and over have undiagnosed diabetes (about 589,000 adults.) This is number of people that have not even been identified with diabetes

the current situation that we are living in and obesity as a problem, this is probably an underestimation. So it's thought that at least there are 2.5 million adults who have diabetes today. And my feeling is that there's this current lead. This is an underestimation.

This means there are around 2.5 million adults with diabetes today.

The World Health Organisation has recognised that there is a "global epidemic of obesity" with the prevalence of type 2 diabetes rising in parallel. The number of Americans with diagnosed diabetes is projected to increase from 4.0% in 2000 to a prevalence of 7.2% in 2050.

Now we can measure blood glucose level. And historically, we also measure the glycosylated haemoglobin level in our blood, which is referred to as the HbA1c levels or the HBA1C test score. If an individual has been given a drink of glucose to take, in a healthy person, their glucose level will increase and then it will come back to normal because the body knows how to deal with excess blood glucose. In a diabetic patient, if the same drink is taken, their blood glucose level will continue to rise for a very long time. Blood glucose level is very important to maintain this because our brain can only use glucose as a substrate. It cannot use fats and proteins so to have good concentration, we must have a steady level of blood glucose. Our muscles and other organs, of course, can use all different food substrates.

So blood glucose level follows a diurnal rhythm, so it changes during the day during the morning it may be slightly lower than during the night because we need that blood glucose to take care of us during the night when our brain is very highly metabolically active. And of course, during meal times, we get a peak in insulin here and also glucose. Every time we have a meal there are peaks in insulin and glucose level. So this illustration is to demonstrate that insulin glucose goes hand-in-hand and also follows a diurnal rhythm. And also changes during mealtimes.

And this is a really good place, some integration. So be warned that historically, we've had long questions where there's integration on this subject.

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So the pancreas is very important when we look at insulin, of course. And as you know, the pancreas is situated slightly below the stomach and it consists of exocrine and endocrine glands. The islets of Langerhans consist of the endocrine portion. Now we're going to just focus on the endocrine portion, which consists of three different types of cells: the alpha cells, beta cells and delta cells. Alpha cells are really important to secrete the hormone glucagon, which increases our blood sugar level or glucose level. And that consists of 20 percent of the population. Now it's the beta cells that consists of the majority of the population, and that's around about 70 percent and it secretes the hormone insulin. Of course, insulin determines blood sugar level, and it basically keeps in the homeostatic range. Then there's the delta cells, which is about 10 percent of the Isletpopulation, which secrete somatostatin, which acts as a paracrine to inhibit the secretion of insulin and glucagon. So it kind of monitors hovers around the blood. It monitors the level of glucagon and insulin and it could inhibit either of this.

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Now this is quite important because the peptide molecule can be sometimes used as a diagnostic test to see if insulin is being produced adequately and functioning properly. So insulin when it is stored is associated with zinc and sp that's really important for the storage. And when it's released, it needs calcium. It's released via calcium dependent exocytosis.

Insulin release

So glucose binds to GLUT2 , which is a transporter of glucose. When it binds, ATP is released, which binds to this channel here. This used to allow potassium out, but when ATP binds to it, it closes the channel. Now what happens when there is more potassium inside the cell because it is positively charged? We're going to get depolarisation. So depolarisation because there's more potassium inside the beta cell allows calcium to enter, so the depolarisation opens calcium channels. Calcium enters. Some calcium binds to these vesicles that contain insulin, just like neurotransmitters. And as a result, when calcium and ions bind to the vesicle the vesicle will merge with the plasma membrane, allowing the release of insulin.

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So when we get an increase in that plasma glucose. Let's think about plasma glucose increase first. We get a secretion of insulin from pancreatic Islet beta cells, and this will target our adipocytes and muscle tissue to take up glucose. It also acts on the liver. It causes cessation of glucose output. So as a result, the glucose output is reduced because we're trying to get it back to our homeostatic level, so as a result, we decrease blood plasma glucose level. So basically the muscles kind of soak up, we want them to and the liver stops releasing glucose from its stores. So the mechanism of action of how insulin allows this to happen is very important.

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So imagine. Insulin and glucose, we've eaten the meal.. So glucose wants to get into the muscle, but it's the insulin that kind of knocks on the door and then it opens itself to allow the glucose in. And without that process, if there is enough insulin we won't get into the muscle.

So the mechanism of action of insulin is mediated by specific insulin receptors. So this is an example in the muscle. So we have insulin and the insulin receptors on the muscle. Basically, there's some cellular changes that happen. So when insulin binds to the insulin receptor, it activates tyrosine kinase, and as a result, that's basically a transport complex. It can transport glucose via GLUT4 and convert this into glycogen. So the effects of insulin on target cells, it does have effect on solute transport, and the aim is to increase cellular transports of glucose, amino acids and fatty acids.

It also modulates the key intracellular metabolic pathway by increasing the synthesis of glucose proteins of the synthesis and nucleic acids. So basically, insulin just there facilitates the transport of glucose in our target muscles, and it does these via specific transporters. So insulin receptors need to be alert after time. After time and it's related to obesity, they might become less sensitive. And that's where the problem is when there's not enough, even if there's a lot of blood glucose, it might not be able to get into the actual muscles because insulin is not knocking at that door, allowing the door to open because it's become less sensitive.

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So it's really important to think about the control of insulin and how it's regulated.

So we know it's producing the beta cells. So if we get an increase in insulin secretion, what controls those factors?

So actually, we get an increase in incidence of secretion through these various where there is positive sign. So the first one, obviously, is an increase in plasma glucose. If we're going to increase in plasma amino acids or GIP which is glucose dependent insulinotropic peptide. These factors all will facilitate or increase the secretion of insulin. Parasympathetic activity also plays a part. Its sympathetic activity or plasma adrenaline actually will have a negative effect, and that decreases the secretion of the insulin.

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Glucose is happening freely doing its thing. We've got glucose, we've got triglycerides and fatty acids and monoglycerides and we have got amino acids. So the green indicates an increase in plasma insulin and the red indicates a decrease in plasma. So let's think about what happens in the liver first and then we'll look at the other organs. So in the liver, we get when there's an increase in plasma insulin, what it does, it converts glucose into glucose six phosphate. This is then converted into pyruvate and acetyl CoA and stored as fat if there is too much excess.

When there is a decrease in plasma insulin, we get some opposite effects happening. So the acetyl CoA can be converted into ketones and we can use ketones to help us to get energy as it is an energy source. So pyruvate is converted back into glucose six phosphate and then it's converted into glucose, and glycogen also can be converted into glucose six phosphate as well. So that's what happens in the liver.

In the adipose tissue, when there is an increase in plasma insulin , you get more fat storage. So we get the glucose converted into fatty acids. When there is a drop, triacylglycerols are converted back into alpha glycerol- phosphate and fatty acids, so we can actually start using those as energy substrates as well. The fats also come in from our diet. So it's not only glucose that goes through the pathway, it is also the fat in our bloodstream as well, that we've got from food that we've just eaten.

In exam situation, if you're talking about target organs, you must refer to the liver, adipocytes and muscles. These are the three target organs that are involved in glucose metabolism uptake.

So amino acids are very important, of course, for muscle building. So when a drop in plasma insulin, amino acids from my bloodstream are converted into proteins. And here the glucose that comes in from the blood (if there is an increase in glucose), it can also be stored as glycogen in the muscles. Now if there is a drop in glucose, we need to use this, proteins can be converted back into amino acids and then we can actually start utilising this in some extreme situation where there's a lack of food resources available in our body. So the glycogen is also then converted back into glucose, and we can use glucose in our muscles. So go back to your aerobic and anaerobic respiration, and then that will help you understand the whole process as well. So, that's what happens with glucose and insulin and they have a very close relationship

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Glucagon also has a close relationship with glucose.

Glucagon is a catabolic hormone, and it's a 29 amino acid peptide.

Glucagon protects the body from hyperglycemia that is low blood glucose level. So in a way, you can think of it as having an opposite action to insulin. It functions to raise blood glucose levels, so decrease in blood glucose would trigger pancreatic alpha cells to release glucagon. And as a result, a plasma glucagon has the following effects in the liver: increasing glycogenolysis, gluconeogenesis and increasing ketone synthesis.And as a result, we've got an increase in plasma glucose and increasing ketones.

Now let's start thinking about the different types of diabetes, so there's Type 1 and Type 2 and gestational diabetes which is very similar to Type 2.

So let's look at type one diabetes. Ithappens during puberty if it's not related to obesity, and all of those factors would be correct. Type one diabetes is the least common of the main two types of diabetes mellitus and accounts for about five to 15% of the people with diabetes. This is an autoimmune disease, and it does usually manifest itself during young adulthood or when puberty begins. So what causes it? It's an autoimmune disease because there is selective destruction of beta cells so beta cells are important for releasing insulin, so this selective destruction causes very little or no insulin that's secreted in our body and therefore the food that we have in terms of the glucose and amino acids and fats, they will be there hanging around in the body, but they won't be able to be taken up by the target organs appropriately.

So Type two diabetes. Well, this is more related to adults. It is related to obesity. . Type 2 diabetes is the most common form of diabetes. It counts for at least 85 to 95% of people who have diabetes mellitus

What causes is is that it develops when the body cannot make enough insulin. Or when insulin released becomes resistant. The insulin receptors and the transporter system that becomes resistant . So they are less sensitive to insulin.

So there's two reasons, insulin not made enough or insulin resistance. So this is thought to be related to obesity. And it can also be correlated with certain ethnicities, and it could be therefore genetic and also dietary.

Although I say that Type two diabetes is an adult onset, there are some individuals now and it has become more and more apparent these days that young teenagers are also being diagnosed with type two diabetes and again that goes back to obesity. So this is the most common form of age of onset for Type two diabetes which is over 40. But just be mindful that even young individuals are now developing Type two diabetes.

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it's because there is hyposecretion which is low secretion of insulin which means this insulin deficiency and as result you get diabetes mellitus. So I need to think about the symptoms now. What happens to that individual before they know that there's something wrong and they may go to the GP to present their symptoms

These symptoms are all correlated so chronic hyperglycemia so there is more glucose in the body which causes glycosuria and this is polyuria which means they go to the toilet quite frequently, so there will be increase in urination as a result that triggers the thirst centre so there is polyphagia which is related to an increasing hunger or system although the person feels hungry and they are eating appropriately and what they need. The actual target organs do not get the nourishment it requires because insulin isn't there to facilitate the process of glucose or amino acids and fats to enter the target organs because insulin is in deficiency. So that's why the individual feels hungry. There could be wastage of muscles and that's because glucose is not available so the proteins will be converted back into amino acids and used as a substrate. This also is related to ketosis

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So again, that's just reiterating some of those symptoms, this unexplained weight loss and that's due to muscle metabolism.Increasing hunger, feeling tired, blurred vision, irritability, increased thirst, you are eating more frequently than usual.

These symptoms are correlated. So with high glucose levels in the blood, some of the glucose is going to be leaving the urine, which means its going to change the osmotic pressure because there is more glucose in the urine. So when glucose is passed into the urine, it is going to take some of the water with it because the osmotic pressure has changed that triggers the thirst centre in the brain, because we were gonna feel dehydrated and we're going to feel more thirsty and as a result we're going to go to the toilet more because more water is being lost because of the osmotic diuresis.

We're going to feel tired and irritable. Unexplained weight loss is unexplained because the individual doesn't know why they're losing weight until their diagnosis. It's related to imbalance in insulin release. Muscle wasting is linked with ketosis because of the fat metabolism of ketones being used as an energy source.

These are all related with early symptoms of diabetes mellitus, the late clinical features develop when the symptoms have been already identified and the patient perhaps has been on medication, but it's maybe not regulated. But even if it's regulated, some of these late clinical features can occur. So this happens much later on during the pathology of the disease. So do not get these two symptoms confused, so you've got the early symptoms and the late symptoms come. Late symptoms are associated with macrovascular complication, which is to do with the large vessels or blood vessels in our body. It's also associated with microvascular complication, which is related to the finer blood vessels. Now dermopathy is to the vessel in the skin, and peripheral neuropathy has to do with the nerve cells. This is also correlated with microvascular complications.

So let's think about what I mean by macrovascular complications. So, as I said, this is related to the large blood vessels in the body, such as the coronary blood vessels or cerebral arteries and some peripheral vessels, and they become hardened because there is more glucose in the blood because of insufficient insulin, there's going to be more fat that's also lurking around. Fats clog the system which leads to the hardening of the arteries and can cause heart attack, stroke or poor circulation in the feet so it can result in ischemic heart disease which is the leading cause of diabetes related to death, and people with diabetes are more likely to get a kind of secondary heart disease as well and 2 to 4 times higher rate than people without diabetes. So this is quite a poor outlook. Also, people with diabetes at 2 to 4 times have a higher risk of developing a stroke due to cerebral vascular disease.

Peripherally, it also can have a huge impact. Diabetes can cause amputation of the lower limbs such as the feet because of poor circulation.

Atherosclerosis of the aorta. This is quite a poor outlook for patients without diabetes who have not been controlled properly. It can lead to microvascular complication, which is related to these various coronary or cerebrovascular diseases

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The microvascular complications are associated with the fine blood vessels. What is that glucose going to do to those fine vessels? It's going to make them sticky which is not good for perfusion, so things might not be able to be pumped around more efficiently in the fine vessels. It's going to affect the fine vessels in our eyes, which is related to retinopathy. It's going to affect our kidney function so the fine vessels in the kidney are affected so that's referred to nephropathy. Neuropathy is related to the damage it does to the nerve cells.

So basically high blood glucose damages small vessels because of the thickening of capillaries, makes the blood sticky and causes small blood vessels to leak.

But, you know, as a professional pharmacist, it's important that you see and you become aware of. So this is an example off the damage to somebody's feet, patient with diabetes. So this is peripheral nerve tissue damage. So it's a combination. It's a microvascular complication associated with dermopathy and they also could involve a loss of neuronal cells so it is neuropathy. So here we have reduced blood flow and also damage to vessels. So patients who have been diagnosed with diabetes, are not allowed to cut their own toenails. They must see a podiatrist who would deal with the feet appropriately. Gangrene may develop. If such a condition occurs, one of the most extreme conditions is to have the limbs amputated or foot amputated. Things like this happen less, but nevertheless they still do occur if it's not controlled properly.

People don't usually associate it with nerves and diabetes. But you know there is a huge thing, and that's because you know nerve cells are fine, obviously we need to also supply blood to the nervous tissue, all the things it does to fine blood vessels making them sticky and harder, similar things happen to our neurons peripherally.

So this is an example of what happens to our nerves from a healthy, huge individual to progression of diabetes. And this, as you can see the lesions forming here that can lead to the patient having their foot amputated.

You can see gradual loss of only blood supply. The vessels are kind of retracting here, but there's also loss of nerve cells as well. So circulation of nerve cells are affected.

And he has an illustration of micro vascular damage to blood vessels in the skin that can cause lesions in this year. So here we got huge ed lesions basically. And that's because of the damage to nerves and also fine blood vessels in the skin.

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Retinopathy is related to the eyes and diabetes mellitus is one of the leading causes of blindness. So here we have, um, the example of the spots that because this is a haemorrhage and we get a cotton wool like effect in patients with diabetes and also there is nerve tissue damage. There are huge cellular changes in patients with diabetes, so having the correct medication and dosage, protecting them from these damages, protects our eyes, our kidneys, and coronary blood flow. So it's really important people are diagnosed accordingly and treated properly.

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. This is an example to show you the nephropathy to do with the kidney function. So this is a healthy example of a section of the kidney. So here's a diabetic patient. We get leakage of proteins so there is more protein and glucose in the urine which changes the osmotic pressure. So just to reiterate all of the complications associated with diabetes. So we have looked at the microvascular complications of the microvascular complications, and I don't mind telling you that this is being frequently used. It comes up as a short exam question. It could be part of a long exam question. Andi, the only mistake people make is getting the immediate symptoms confused with long term complications. Don’t get them confused. So general symptoms of diabetes we talked about and then we separated the long term complication when diabetes is not treated

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Now let's think about the type of screening test for diabetes that we can offer a patient who thinks they've got diabetes and these are people walking to the local pharmacy. They can get a blood glucose test done. All it is is pricking the finger index finger, usually drawing a small amount of blood and testing that using this blood to look at some coloured charts to look, which would indicate the level of glucose in that.

And the patient would be referred to the GP if the result comes up to them with high blood sugar level..

Similar tests can be done from urine where glucose sensitive strips can be used. And so you can get the level of glucose , the level of ketones and the protein in the urine.

Some of these charts also measure blood cell counts as well, and these are used in hospital use. This is the usual scenario in hospitals.

Now what else can be done in the hospital is the glucose tolerance test. Now this is when a patient comes in and from overnight fasting and their blood glucose levels are taken at rest, and then they're given a 75 gram glucose drink and then the blood is taken at regular intervals. Now, the patient with diabetes is shown in green. The normal healthy patient is shown in purple here. So what you see is that there's an increase in blood sugar level, but then this then levels out. But however in the diabetic patient, the amount of blood sugar level remains quite high and it seems like an almost steady state for a very long time and doesn’t get back to the baseline level, the homeostatic level. So that's when we know the glucose metabolism is impaired.

So fasting glucose tests can be very useful. Other tests that we could do, which are more sensitive if you'd like to see are the C-Peptide test. The chains of insulin are linked by the C peptide chain and when an insulin is released from proinsulin , and then you get the release of C peptide and then that becomes a diagnostic test to look at the amount of C peptide chain change. And it's a very useful test for both type one and type two diabetes. And it will investigate whether there's insulin resistance and to monitor insulin production after removal of tumour of the pancreas, for example. So it is a more sensitive test offered in certain situations such as these.

Also, this is a very sensitive test that can diagnose patients with diabetes or late autoimmune diabetes. So this is when an autoimmune part of diabetes comes into effect, if you like, but this is shown in adulthood and not during puberty. So it's a useful test, and it can be used in the following scenarios. GAD test is a blood test, which measures whether the body produces a type of antibody which destroys its own GAD cells, useful for adults over 30 who are not overweight and where type two diabetes diagnosis is in doubt. So there's some ambiguity to whether the patient has diabetes or not. It's useful to determine whether gestational diabetes may be type one diabetes as well. The test can also be used to measure the progression of type one diabetes or indicate the risk of type one diabetes or late onset adult diabetes.

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So let's now think about the treatment of diabetes. The first line of treatment is diet and exercise so it does play a huge part in patients. And the nice guidelines that patients should be given the chance to actually rectify that impaired glucose level through diet and exercise for up to three months at least. . So the major aims of treatments will include maintaining blood glucose level near normal values as possible. And the important thing is that we have to ensure that patients maintain normal body weight and the patient has enough energy or sufficient energy source to to get through the day. So all of this can be achieved through a diet and lifestyle change, not crash diets, but a lifestyle change so long term change in the way they eat the food, what type of food they eat and daily exercise. So this has to become an integral part of their daily activity throughout their life.

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And sometimes it might be difficult for patients to do it if they have a certain body weight. It might be difficult for them to move around at a certain age. So we also have to cater the treatment according to the patient's needs.

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Now these treatments differ if your patient has type one or type two. So let's think about type one diabetes and how we're going to treat that patient. So insulin is inactivated by the enzymes in the gut and so giving the injection by subcutaneous routes would be better for the patients, so they cannot take it orally. So insulin injections and monitoring of blood glucose level is the preferred treatment in type one diabetes. So insulin injections can come in the form of pens or metered dose release of insulin from preloaded disposable pens. There has to be a tight control, however, to prevent the patient from going into hypoglycaemia when there's not enough glucose in the blood for them to function appropriately. So these patients need regular blood tests as well to monitor the total glycosylated haemoglobin or specific functions of the HbA1C level.

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Some key points to remember when we are treating patients with type one diabetes. So subcutaneous insulin can be delivered in the upper arm, the thigh buttocks or the abdomen. The site of injection has to be rotated, and that's because it can cause lipodystrophy so basically there's hardening of the skin where the injection is given, so that's why we have to rotate the site of injection. Now there are different insulin preparations.

So there are short duration, rapid onset soluble insulin, intermediate acting insulin, slow in onset, long lasting insulin. So there are quite a few choices here for the treatment of type one diabetes. So the duration of the actual insulin may vary from patient to patient.

So perhaps prevention is better than cure, and there was a study to show that breastfeeding is better for the baby and it can protect the child from various diseases and diabetes type one being one of them. And also, vitamin D is linked to protection against type one diabetes. So children are usually given two thousand units of vitamin D during the first year of their life to reduce the risk of type one diabetes. So these are just peripheral facts for you.

So the key points to remember now going on to the treatment of type two diabetes, and we've said that type two diabetes, particularly type two diabetes, can be monitored or maintained through diet and exercise.

So type two diabetes can be monitored or regulated with a tight control of blood glucose level. Diet and exercise or it could be through pharmacological intervention through oral hypoglycaemic drugs or other antidiabetic agents. Let's look at some of these in detail, because what you need to know for this module is the type of treatment, the first line treatment and the mechanism of action.

Two tablets can be taken together because of the difference in the mechanism of action and if they don't work in an emergency situation, insulin could be given as well to type two diabetic patients.

So if somebody has tried the three month lifestyle change and it has not worked out for them and blood glucose level is quite high, they'll be given a first line pharmacological treatment and this is the standard release metformin. So this is the initial drug given to adults with type two diabetes, and there could be a gradual increase in the dose related standard release metformin over several weeks to minimise the risk of GI side effects in these adults with type two diabetes. So it is quite common for type two diabetic patients to experience GI discomfort with this kind of metformin release. And if that happens, you have to consider a trial of the modified release of metformin as there are different types of metformin. So the standard release is given and then a modified release is given if there are GI complications or side effects, in short. So in adults with type two diabetes, a review of the dose of metformin is estimated from glomerular filtration rate, and if it is below 45 ml/minute, stop taking metformin and prescribe metformin with caution for those at risk of sudden deterioration in kidney function, and also those at risk of increased risk of falling below 45 ml/ minute. So in adults with type two diabetes when metformin is a contraindication and is not tolerated, you have to consider the following other alternative treatments using a DPP-4 inhibitor or pioglitazone or a sulfonylureas and these are very useful treatments that will have different mechanism of action

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but you are not required to know all the intermediate steps here.

Now, how metformin works first, but it can be taken alone or with a sulfonylurea, and it works by controlling blood glucose level by stimulating our target organs such as muscle to uptake glucose and the uptake can also inhibit both the hepatic gluconeogenesis and glucose absorption from the gut. It also has some appetite suppressant action, which is used for patients who are trying to maintain a weight level and particularly if they're in the obese category. Metformin binds to the receptors here, for example and there are some various cellular changes in the mitochondria and that basically triggers various cellular processes. And this is the important thing that you should focus on here. And it improves insulin receptor function, improves glucose transport and reduces fatty acid synthesis. And all of these factors combined results in improved insulin sensitivity. So basically, metformin triggers and improves insulin sensitivity so you can discuss these factors in an exam situation. So give me an overview of the mechanism and some of its added value here, which is appetite suppressant and the overall impact.

Metformin does have side effects and these are just some of them.

So side effects can include nausea, diarrhoea, vomiting, GI discomfort, anorexia and malaise. It rarely also causes a serious side called lactic acidosis when there is too much lactic acid in the body.

This occurs in people who have heart or kidney problems or above 65.

So other treatments that we have had available if e different types of metformin are tolerated by the individual include sulfonylurea for adults with type two diabetes and here are some brand names

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They work by basically kickstarting our beta cells so they work by stimulating any residual capacity, the pancreatic beta cell has to produce insulin. In the long term, they also potentiate the action of endogenous insulin on target cells.

So basically, these drugs depolarise the potassium channel and as a result, it basically pushes the release of insulin via the beta cells. So these are the key points you want to remember when looking at this diagram. So it increases/stimulates the insulin secretion that binds to the co receptors of beta cells by the potassium channel which results in depolarization of the cell, increases in calcium, which results the stimulation of insulin secretion, and as a result, it also decreases glucagon secretion. So these are the key points of the mechanism of actions of sulphonylurea.

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Sulphonylureas also have side effects, of course, and these are some of them they may cause weight gain, may cause skin rashes or blood disorders, fever and jaundice, a particular brand called chlorpropamide might can also produce facial flushing in some patients if they drink alcohol. Other antidiabetic agents include the DPP4 inhibitors and these are also quite clever class of drugs designed and these also known as gliptins and these are a class of drug which can help to stimulate the production of insulin and reduce the production of glucagon similar to sulphonylureas particularly during digestion, these processes occur so slightly different in that this occurs during digestion.

DPP4 inhibitors usually are prescribed for people with type two diabetes who have not responded well to metformin or sulfonylurea.They may also be helpful in weight loss control by decreasing blood glucose level and they have been linked with higher rates of pancreatitis which is a negative thing. So DPP4 inhibitors reduce blood glucagon and blood glucose levels. The mechanism is by increasing incretin levels (GLP-1 and GIP), and the incretin inhibits glucagon release.

So DPP4 enzyme activates increatin so normally increatin (GLP-1 and GIP) stimulate the release of insulin and they inhibit the release of glucagon. And as a result, you have a lowering of blood glucose level. The DPP4 inhibitors block this enzyme DPP4 and as a result, you get this outcome here. So it's an alternative mechanism similar to sulfonylureas, but different from metformin.

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Other antidiabetic agents include pioglitazone which is the TZD class of hypoglycemic drugs, they can reduce peripheral insulin resistance, leading to a reduction of blood glucose concentration, and they can be taken either alone or in combination with sulfonylurea, metformin or insulin. They can be added to a sulphonylurea if metformin is contraindicated or not tolerated by the patient. They can be also added to metformin if risk of hypoglycemia with sulfonylureas or it's not tolerated so they can be used in different combinations of these drugs. So the nice guideline recommends that treatment with pioglitazone is continued only if HbA1C are reduced by 0.5 percent within the first six months.

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We also want to think about the acute complication of diabetic therapy. The acute obvious complication is over treating the patients so the patient becomes hypoglycemic. So that's not enough glucose in the body. And for this hypoglycaemic, a glucose injection kit is available to treat when the patient is unable to treat themselves or treatment by mouth has not been successful, so injection is quite appropriate.

Now the other complication is ketoacidosis and diabetic coma. Treatment of diabetic ketoacidosis involves administration of fluids by IV. to rehydrate the patient because they're going to be dehydrated during the ketoacidosis process. Insulin is also required to instantly suppress the ketone bodies that the body manufactures.

. So ketoacidosis or metabolic ketoacidosis is a condition where a pH imbalance occurs in the body and in the body there's an accumulation of acid due to metabolism. And when the acid hasn't cleared up, and so there's not enough bicarbonate to effectively neutralise the effects of the acid and this is characterised by a reduction of serum bicarbonate concentration or a decrease in the partial pressure of carbon dioxide, reduction of blood pH is less than 7.35 hence ketoacidosis.

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I have created the relationship of all the things that metabolism goes wrong in terms of fat, glucose and amino acids that link them to the target organs, muscle, liver and also the symptoms shown in orange and the outcomes shown in this light colour. So if diabetes is not controlled and insulin is not released, it is going to ultimately at the worst case scenario, it's going to be a coma and death set, but there is a series of events that lead up to this.