Overview of Disorder
Diabetes Mellitus (DM) is not one, but a variety of chronic disorders affecting people across the lifespan, characterised very generally by either an insulin resistance/deficiency or levels of glucagon. Essentially, this is a disease wherein insulin fails to maintain homeostatic balance. Of course this is a very broad topic overview, however this chapter will delve into the endocrine relevance, what the metabolic process looks like when working normally, versus when we encounter a person either borderline, or with a diagnosis of DM.
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Glucose Homeostasis & DM
In order to achieve cellular respiration (wherein glucose in converted into ATP), the process begins with the consumption of food. I'm not going to go into great detail about these kinds of sugars as of yet, but the sexy Venn diagram above is a good demonstrative starting point for this area of study (yes, we all love a good diagram).
As you may have heard, BGL's (or BSL's) are what we refer to the blood glucose/sugar level, and is what we are referring to when we refer to glucose in circulation. Of course, in greatly high or low (hypo/hyperglycaemia), we may detect a change in plasma osmolarity, and therefore blood pressure, as this is a component in the blood. However for the purpose of this chapter, I'll leave that for another day.
All we must really understand by this point, is that we consume food, which is broken down (in the jejumum if you're curious/your course requires you to know that like mine does), and the breakdown is necessary for the eventual creation of ATP which fuels obviously all functions in the human body.;
A little more detail:
Hexose monosaccharide: a simple sugar with 6 carbon atoms
This sugar will eventually be broken down into 2x 3 carbon molecules
So what?
Why does this sugar shit matter?
Obviously, as mentioned, ATP is necessary for all bodily functions. A good example of this is the Nervous system, or your retinae, which rely solely on glucose to be able to function healthily. Fairly sure ATP is covered in my A&P book in the cell section?
Anyway, it isn't a one way street, and when we put in, must be regulated.
What happens when our bodies regulate BGL's?
The diagram I have pinched above is a good look at what happens to our body after each time we eat.
As whatever the fuck we just stuck in our mouths is taken into our systems, a normal response, can be seen in the line that is blue, the most steady at the bottom. This person, (Sarah lets call her), has a small spike, wherein the levels of glucose in her blood rise with the food she just ate.
But as her body goes oh shit, we have Glucose running around everywhere, floatin' about Willy nilly, the body (simply) goes 'Quick, get the insulin out!' This response in turn helps the body to take the glucose out of the blood, and into the tissues, and thus, we see Sarah's BGL lower back down to normal.
Right. Then in red, we have James.
Now James is what I'm going to call borderline (no, I'm not a doctor, nor am I a lecturer, I have no idea really what's going on, just go with it), and James has just had lunch. His body has gone fuck me look at that, we have GLUCOSE, Shit! Get the insulin quick! Or something like that.
Now the thing that is important, is that James' red line starts high, spikes, and has a drop before he comes back to what his normal, shows is actually higher than Sarah's. I won't go into the patho here, but James is displaying an inefficiency with his insulin (put very simply).
Rip Luke who is green, and is displaying originally high BGL's, with a drastic spike, followed by a catastrophic drop.
Luke's pattern is what we will be looking at in the Patho for Type 2 Diabetes Mellitus (T2DM).
Overall, I like to think of the process as something like this:
Getting a little more in depth
What is a Glucose Transporter?
We have two main types of transporters, and these are:
✨GLUTs✨ - membrane blunt facilitates glucose transporters, and
✨SGLTs✨ - sodium/glucose cotransporters
GLUTs → GLUT-1 is more general, ubiquitously expressed, whereas 2,3&4 are more tissue specific.
SGLTs → Mainly involved in Glucose uptake from the gut, as well as reabsorption in the kidney
Anatomy & Physiology of the Healthy Person
Okay so although we have already talked a lot of biology/physiology in the body, I would now like to talk about how we regulate our BGL on a physiological level, for a normal homeostatic response to rising glucose levels.
We already know insulin facilitates and promotes glucose uptake into cells. This is our glucose storage. We aren't really using this (yet).
How do we access and use it then?
Glucagon is a peptide hormone secreted from the alpha cells in the Islets of Langerhans.
(Yes, this guy: Paul Wilhelm Heinrich Langerhans. A German pathologist, physiologist and biologist, he was the chad who solidified his name in the history books by not one, but two discoveries he made in the span of his career. In 1896, he was credited after his discovery of the cells within the pancreas that secrete - da da daaaa, ✨insulin✨, resulting in the naming of the Islets of Langerhans. {And if you're curious, he discovered stuff about cells in the skin too. See, Chad})
Enough about this dude and the omegaverse he created.
So What?
Let's talk a few things Pancreas, because I know you want to know.
The pancreas is unique in that it contains both endocrine and exocrine tissue (i.e, ductless, and with ducts). The Islets of Langerhans form the endocrine portion of the pancreas, and represent about 1% of the total weight of the pancreas. There are 1 million Islets, and within just one islet, are 2000 beta cells.
When the serum glucose that passes through the pancreas exceeds 5.5mmol/L, the beta cells will respond immediately by increasing insulin production, and vice versa, when the serum glucose lowers, so too does insulin production. Appropriate regulation of glucose is influenced by the number of beta cells, and thus the importance of this concept in the regulation of glucose homeostasis is invaluable.
What about the alpha cells you say?
Alpha cells, like beta cells, are major hormone producing cells:
Alpha cells → Produce glucagon
Beta cells → Produce insulin
These are opposing hormones. Insulin facilitates glucose uptake, whereas glucagon facilitates usage of glucose stores (to use, when you're starving your ass off and your body is like, for fuck sakes, can't you fucking eat something? No? Well I'll have to just do it myself, with this fucking glucagon then 😠). These are both essential for carbohydrate metabolism, as well as the metabolism of fats and protein.
Fun Terms I love🤢(related to Insulin):
✅Insulin increases:
1. Glycolysis - uptake/use of glucose in tissues (glucose synthesis)
Glyc(o)- → glucose
-olysis → breakdown
2. Lipogenesis - fat synthesis
Lip(o)- → fat
-genesis → production
3. Glycogenesis - glycogen synthesis
Glyc(o)- → glucose
-genesis → production
🚫Insulin inhibits:
4. Lipolysis - fat breakdown
Lip(o)- →fat
-Olysis → breakdown
5. Glycogenolysis
Glycogen(o)- →glycogen
-olysis → breakdown
6. Gluconeogenolysis
Glycogen(o)- → Glycogen
-olysis → breakdown
Pathophysiology
So what happens when things don't work the way they should?
Diabetes Mellitus is the umbrella term applied to the group of metabolic disorders occurring when we have an abnormal secretion and/or action of insulin. Research has probably moved on since I first learned about this, but it was once thought that perhaps some individuals had altered "sensitivity" towards insulin, though it can be said regardless that depending on the individual's larger picture, comorbidities such as obesity may affect the "sensitivity," or action, that insulin plays in their body. (This has to do with fat, and cholesterol, but that can be a nightmare for later).
Where do we start then?
I will make the executive decision to start here:
There are three main kinds of DM:
(I'm a visual learner so ima leave this here)
Starting at the end, because I ✨can✨
Gestational Diabetes (GDM)
Now I won't lie, as of this moment, I won't be going into much detail here, mainly because my course is not focussing on it, an I do not have the time to touch on it just because.
So GDM is a form of diabetes all women in pregnancy (in Australia) are tested for around 26-28 weeks. This test is called Oral Glucose Tollerance Testing (OGTT), and if a woman's BGL's are seen to be abnormal during the pregnancy, then measures to manage this will be put into place.
Often, after pregnancy, a woman will not persist with their GDM, and will return to a normal homeostatic balance.
Type 1 Diabetes Mellitus (T1DM)
Okay, let's get into the Crux of the patho.
T1DM is often something that surfaces in childhood, and must be treated with insulin thereabouts for life. Incurable, in these instances, patients either have insufficient insulin production, or insulin that does not action as it is meant to.
Think of insulin as one of many master keys 🔑 that can open the doors to the cells to let the Glucose in. In our system, we should have enough keys(insulin) to let the glucose (sugar) into the doors (cells). {just fyi, glycogen can be the key to let them out again to be used, but that's irrelevant right now}.
So. In T1DM, we either have not enough keys, or the keys are just plain the wrong fucking key. So what will we see? We will see glucose levels rising, higher and higher and higher, until we get some insulin that works.
We have two classifications of T1DM: We have either autoimmune T1DM, or idiopathic T1DM. Essentially meaning, we have our own cells that don't or can't work as we want them to.
We may be destroying our own beta cells, creating insulinitis, which comes about by the inflammatory response to these destruction. This occurs in approximately 90% of cases, and thus is the one we will be focussing on.
So, if we have destruction of beta cells of the islets of Langerhans in the pancreas, which are purposed to create the insulin we need, then without enough/all of them, we will in turn have less insulin, and therefore less keys to open doors around the body.
FYI, it is also thought (as far as I'm aware) that not only beta cells functionality is abnormal, but also alpha cell functions too.
Anyways.
So what happens when we have reduced keys floating around in the blood, and an in turn relatively high amount of glucagon about as well?
*Ignore that here. Clearly I went to write something and just plain forgot about it.
Have a sexy diagram I prepared earlier. There's a lot to unpack in just one confusing diagram, but remember that it is a cycle, and one thing triggers another issue in return.
I will start with untreated, what will happen to the levels of glucose in the blood.
Now this line is probably (very likely) wrong, but point is, it will go up and up, because there is no insulin/very little to take the glucose out of the blood.
Oh look, a better diagram for my mushrooms:
Moving back to my dodgy red line of increasing glucose.
We eat, more glucose comes in. No insulin/ very little brings it into the cells, meaning the glucose builds higher. We have alpha cells potentially still working to bring glucose out of the cells to be used, increasing levels higher, and thus it spikes ridiculously high.
What will this person look like, with untreated T1DM?
A high BGL will indicate hyperglycaemia, if you saw in my sexy pic. And glucose is essentially sugar. So what happens when you put sugar onto a tabletop, and put water onto it?
The sugar is a greedy b and will suck that water up.
This is the same for inside the body.
We will see the glucose drawing the water from the intracelluar(inside the cells) space, and into the general circulation. We will therefore see dehydration of the cells, and in turn, the body.
This will cascade further.
Perhaps I will spew my thoughts into a diagram:
Ends pretty traumatically, but every homeostatic imbalance that is not rectified ends in ⚰️, so what else can I say?
And from this transpiring of events, we can see that the body does try to rectify the problem. There are other things going on here, but this is what we are mainly focussing on.
So in an untreated T1DM patient, depending on severity, we will see manifestations of polyuria (poly - a lot, and uria, urging = a lot of urine output), glucosuria (which I didn't mention, but is essentially glucose in the urine), polydipsia (increased thirst), polyphagia (increased hunger), blurred vision, weight loss, malaise and fatigue.
THerefore, obliviously, to interrupt this process and avoid ending up ☠️, we give insulin (which vaguely from memory is pig insulin? I have no idea I might have just lied), to let the glucose into the cells, and avoid the catastrophic fall of events leading to saying hello to god (or in my case, Lucifer).
Moving on:
Type 2 Diabetes Mellitus (T2DM)
Where T1DM is an inability to create enough or use their insulin supply, T2DM on the other hand is not a condition in which we have impaired insulin development. In T2DM, we tend to see a resistance to the insulin that an individual has made, which is usually and most commonly seen in conditions such as obesity.
Here is a generalised chart that shows the overarching process of a homeostatic imbalance in untreated T2DM:
God my drawings are getting worse and worse ☠️
So, that is a very general display of what happens. But in that last diagram, it shows that our BGLs rise.
Why is this?
So the body recognises that we have glucose in the blood, and hey, we need to make insulin to get it stored and ready for a rainy day and to ✨do things✨ in the body. But as the insulin's function is impaired by a resistance, the body decides to make the pancreas work harder to creature more insulin. When demand exceeds supply, we thus develop T2DM.
So what causes the resistance?
This resistance is essentially a cellular resistance to the effect of insulin, usually increased by comorbidities/presence of obesity, age, illnesses or inactivity. In obesity, we know that weight loss can improve the body's responsiveness to glucose, although the exact reason why weight affects the action of insulin is not known (that I'm aware of. As far as I know, it has to do with the Whole lipid/hydro solubility talk, and with weight comes (usually) higher cholesterol, which is a fat.
Anyways, time to move on.
What happens when our pancreas is working overtime to lock away those floating glucose molecules, and failing? Well, we have increasing levels of insulin, and higher levels of glucose, and that then gives us the diagnosis of hyperglycaemia.
From here, with the deterioration of the patient's homeostasis, we will see a number of things happen.
Here's a terrifying diagram that puts it quite starkly:
So lets go from here:
We now have hyperglycaemia. The liver goes hey, the cells don't have the glucose that they need to do their thang, so it starts the process of breaking down the glycogen stores already present through glucagon, and letting more glucose out and about. But of course, we don't have the insulin to successfully get the glucose to the cells. So we begin to spiral out of control.
We then begin to see those effects that were mentioned in that sexy diagram for T1DM, where the hyperglycaemia triggers the downwards cascade that ends up... well, 🪦...
We see the blurring vision, polyuria, polydipsia, glucosuria, etc.
But in the long term, which we often see in T2DM sufferers, we also see that a patient may have infections that won't heal, neuropathy, peripheral numbing, kidney damage, and a number of other conditions, all pertaining to the levels of glucose in the blood. Circulation slows down, nutrients is poor, especially in the peripheries, and thus, we introduce a number of risk factors, such as impaired feeling/session in hands and feet, thus running the risk of not being aware when we acquire a small cut under our foot, and also why that may then become a diabetic foot ulcer, as we are unable to heal it properly.
This is all a lot, I know, and there could be a whole book written on this shit. I'm just no the one to do it, because, well, what the fuck do I know about this shit? That's a patho chap for another day.
OH!
One point I did actually forget to mention, is that eventually, the pancreas will throw his/her hands up and go, fuck this shit, I'm done. It will give up, because they cannot keep up with the glucose in general circulation, and will eventually shut down. This person will then obviously have a full dependency on insulin therapy to survive and maintain their homeostatic balance.
Can you tell I'm getting sick of this now?
Great. Me too.
Epidemiology
Look, short point, there's a growing epidemic of instances across the world. If you're interested, have a geese here:
https://www.who.int/health-topics/diabetes#tab=tab_1
A few dot points...
- T1DM most common chronic disease in children
- Evolutional aspect has been removed from management over the years, so genetic prevalence is on the rise.
Great, these are for me, but I guess for you too if you really want:
1. Name a 5 step process to explain how insulin reduces BGL's:
2. What are the 3 types of Diabetes Mellitus & explain the differences between them:
3. Create a chart showing clinical deterioration for T1DM & T2DM
4. Who is the chad who made an important discovery into today's topic, and what was it?
5. What are the alpha cells in the pancreas for?
1. 5 step process:
1. Receptors indicate that BGL is rising
2. This stimulates insulin secretion into systemic circulation
3. Beta cells in the pancreas secrete insulin into circulation wherein it can transport glucose into a cell
4. Glucose enters cell, leaving systemic circulation
5. Reduced amount of glucose in systemic circulation means blood glucose level has reduced.
(Or something like that)
2. DM types:
1. T1DM - insulin deficiency(inability to create)/reduced sensitivity. Autoimmune kind of disease, incurable. Insulin therapy must be administered to avoid homeostatic imbalance and a call to the funeral home. 🪦
2. T2DM - Often with comorbidites such as obesity, we create insulin, but have a reduced sensitivity to it, resulting in hyperglycaemia. More insulin must be administered to lower BGL's and avoid homeostatic imbalance.
3. GDM - develops during pregnancy. Yeah ima leave that there.
3. See above in notes 😊
4. Chad #1 Paul Wilhelm Heinrich Langerhans. A German pathologist, physiologist and biologist with a fantastic chad beard to go with, in 1896, discovered cells within the pancreas that secrete insulin, resulting in the naming of the Islets of Langerhans.
5. Alpha cells secrete the hormone glucogon to "retrieve" glycogen stores to be converted back to glucose and used in the body when we do not have access to glucose it the blood.
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I am never going to create a textbooks, because ✨cringe✨
xxx
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Additional Notes/Points:
Keytosis - Body is breaking down muscle = we will see keystones and glucose in urinalysis
List of Manifestations for T1DM:
- Unexplained weight loss
- Sudden onset symptoms
- Excessive Thirst (polydipsia)
- Polyphasia
- Dry mouth
- Frequent urination (polyuria)
- Blurred vision
- Tiredness/lethargy
- Keytones present
- Abdominal pain/nausea
- Breathing changes
- May have oral/vaginal thrush
Management of T1DM
- Insulin
- BGL monitoring
- Flood/Fluid
- Exercise
List of Manifestations for T2DM
- Polydipsia
- Polyuria
- Tired/lethargic - may look drunk - usually slurred speech
- Blurred vision
- Slow healing of cuts
- Itching, skin infections
- Thrush, UTI
- Some may not have any symptoms
☞ gradual onset of symptoms over months/years
☞ may eventually require insulin
☞ indigenous people more at risk of insulin resistance