The Ultimate Guide To Type 2 Diabetes Pathophysiology

Welcome to this short lecture on type 2 diabetes mellitus this lecture will essentially just quickly go through the disease explains the pathophysiology and how the manifestations generally come about.

The Ultimate Guide To Type 2 Diabetes Pathophysiology

So firstly let's just go into how the system works normally so with your gastrointestinal system or the GIT you

ingest food. Now, in this case, we'll just talk about carbohydrates so you inject in just food like starches or so forth like bread or potatoes or pasta and spoking down in your JoT and absorbed into the blood on the way to the liver.

I recommended for you this article for know T2D Step by step.

However, this breakdown product of carbohydrates, in this case, glucose will be picked up by the pancreas and particularly the beta cells will release something is known as insulin now with the combination of insulin and glucose will be taken to the liver through the portal system and the liver will start to store that glucose to try

and bring down the level of glucose furthermore the glucose and the insulin will be in the systemic system so

insulin will come out and it will go to the big issues like fats and muscles in the body and with the help of insulin it will open up the door or carrier channels for glucose and so what will essentially happen the glucose will then
flood into these cells and be created into ATP for energy and places like muscles can store excessive glucose
in glycogen and muscle and fat cells can store the excess glucose as fat and the liver can stall the excessive levels of glucose as glycogen.

What is the pathophysiology of diabetes?

Table 1

Oral agents used in the management of type 2 diabetes mellitus:

Class	Mechanism of action	Indication(s)
Sulfonylureas and repaglinide	Increase insulin secretion	Insulinopenia
Biguanides	Decrease hepatic gluconeogenesis	Obesity+ insulin resistance
	Decrease peripheral insulin resistance
Thiazolidinediones	Decrease peripheral insulin resistance	Insulin resistance
	Reduce fatty acids
α-glucosidase inhibitors	Slow absorption of carbohydrates	Postprandial hyperglycemia

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So all these issues together with the help of insulin can bring the sugar levels of the glucose levels back to a normal range.

type 2 diabetes physiology

Now in the state of type 2 diabetes:

• However, there are generally two problems that come about is either insulin the cells in the body that we just spoke about insensitive to insulin so they don't react to it, therefore, the channels don't open therefore glucose doesn't go in that's one of the pancreases just doesn't release enough glucose but enough insulin anymore so, therefore, the insulin is not in the mix or it could be a combination of both.

Type 2 Diabetes

okay so let's have a look at how it happens

How does diabetes Work Type 2?

• Now the risk factors that go with type 2 diabetes so these are the risks that would predispose you to those cases of insensitivity decreased release or both so the big ones are obesity so the size on an in terms of fat that the amount of fat in the body lack of physical activity hypertension dyslipidemia and also genetics so these are the ones that will predispose an individual to possible type 2 diabetes.

How does diabetes Work Type 2?

Now, what would happen let's go for the insensitive case, to begin with?

• So the glucose still comes in as normal and the pancreas still releases insulin and as it goes to the liver and throughout the body instead the insulin doesn't bind to its receptors, therefore, the muscle and the fat don't uptake glucose.
• So glucose tries to get in but can't and therefore it stays within the blood and because the cells in your body and getting the glucose they aren't making energy so probably one of the first signs is fatigue so because you're not making ATP you'll standard if you feel tired and fatigued and that's the lack of ATP produced by glucose.
• Now your liver will try to counteract this by because it thinks you're starving or running out of sugar so it will release more sugar with the help of breaking down glycogen and so forth.

Type 2 Diabetes Pathophysiology

How does type 2 diabetes affect the body?

But this is only going to make the matter worse now the pancreas will try to counteract this because the blood
sugar is still high by releasing more insulin and so you're releasing lots and lots more insulin the pancreas beta cells will sometimes become bigger and they make more of them so hyperplasia and hypertrophic.

But eventually, the pancreas will also run out of fuel and it will lose its ability to release insulin so it now becomes insulin insufficiency.

So that will won't be able to release its insulin anymore and so as a result now we've got well in the initial case
when we have that increased amount of insulin you might have a kind of an early section that we call high insulin a meal.

But that's in the early stages until the pancreas gets exhausted and then we have an insufficiency now once the problem with the insensitivity and the lack of insulin then you can't take these up in the body and ultimately what the next main problem is just too much sugar in the blood which is what we call hyperglycemia which is just huge amounts of sugar in the blood.

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How does type 2 diabetes affect the body?

Now what eventually will happen is that blood will be taken to the kidneys?

Just can't handle this amount of sugar and a lot of it will just pass through and go into the toilet and so this is going to lead to another sign which we call gly cause urea glycoSuria is essentially the sugar in your urine now because sugar is a big molecule it will be pulled will pull water out with it and so the person will develop another

symptom called polyurea which is just excessive urination high amounts of fluid in their urine now because sugars still everywhere it's going to draw fluid okay from all the cells in the body which is going to dehydrate them okay even in the brain and that's going to make more fatigue and problems with pinky and so forth and that's because that's caused by the hyperosmolar roaring effect.

the hyperosmolar roaring effect

Now this hyperosmolar effect will also make a person first and so that's called polydipsia and possibly also hungry and that's going to be another sign hunger but the other double effect could be a huge amount of
sugar could affect the eyes and the person might also become or develop blurred vision and so these are
generally the most common presentations with the early stages of type 2 diabetes.

And a lot of it's driven just by the high amounts of sugar in the blood now we've seen how it comes about we've seen that the causes can be a combination of insensitivity because your insulin receptors are just not
responding to it anymore and that was driven by the risk factors of obesity lack of exercise hypertension dyslipidemia and maybe genetics and once that you have that lack of or you're more insensitive to insulin your pancreas will try to overcome it by releasing more insulin which is the hyper inter Lamia.

Hyperosmolar Hyperglycemic Nonketotic Syndrome Pathophysiology

But eventually, that will become tired and run out of steam and it can't release the initial anymore, therefore, we have that dual effect and then we get to start to get the signs and symptoms with being tired and fatigued likewise a urea polyuria hyperglycemia which will then bring on these.

So hopefully, that has given you a quick overview of the disease type 2 diabetes and how the clinical manifestations come about based on its disease.

What does pathophysiology mean in simple terms?

• Harris  MI,  Couric  CC,  Reiber  G,  Boyko  E,  Stern  M,  Bennet  P, eds.  1995 Diabetes in America, 2nd ed. Washington DC:  U.S. Printing Office; NIH publication 95–1468.
• Roman  SH, Harris MI.  1997  Management of diabetes from a public health perspective. Endocrinal Metab Clin North Am.  26: 443– 447. Google Scholar Crossref
• Diabetes Control and Complications Trial Research Group. 1993 The effect of intensive treatment of diabetes in the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 329:683–689.Crossref PubMed

Table 2

Selected therapeutic targets of largely untested mechanisms for type 2 diabetes:

Goal	Target	Comments
Increase β-cell secretory function	A. GPR40 (FFAR1)	Activated by medium to long-chain fatty acids TAK-875 first GPR40 agonist in Phase 3 clinical trials178
	B. GPR119	Receptor located an β-cell and intestine, latter resulting in increased incretin hormone release179
Increase β-cell mass	A. Liver-derived proteins, including betatrophin	Two recently discovered proteins increase β-cell mass in animal models180,181 Unclear whether targeting β-cell mass will adequately increase insulin production and secretion
	B. FoxO1	Decreased FoxO1 results in β-cell dedifferentiation in mouse models, with some becoming α-cells182 Redifferentiation may result in cells capable of producing and secreting insulin
Decrease the effect of glucagon	Glucagon receptor antagonists and glucagon antibodies	Block glucagon action lowers glucose144,145 Result in compensatory α-cell hyperplasia and increased plasma glucagon levels183 Associated with dyslipidemia
	Oxyntomodulin	Product of the proglucagon gene Agonist of both glucagon and GLP-1 receptors Induces weight loss in humans by reducing food intake and increasing energy expenditure184
Reduce hepatic glucose production	A. Glucokinase	Aside from reducing glucose production, would also increase insulin secretion due to the critical role of the enzyme in the β-cell Human studies show a favorable effect on glucose-lowering with increased hypoglycemia. Glucose lowering effects not maintained beyond a couple of months185
	B glucose-6-phosphatase C fructose-1,6-bisphosphatase D glycogen phosphorylase	The goal is to decrease glycogenolysis and/or gluconeogenesis186 Unwanted triglyceride accumulation in the liver186
	E. CPT-1	Blocking CPT-1 inhibits fatty acid oxidation and selective inhibition in the liver should decrease gluconeogenesis Teglicar chronically reduces hepatic glucose production without changing peripheral glucose uptake but increases hepatic triglyceride187
Increase insulin action	A. AMPK	Chemical activators, examples of which include thienopyridine family, D-xylose and lipophilic D-xylose derivatives, cilostazol, phytoestrogens, momordicosides, capsaicinoids, furanothiazolidine, AICAR Structurally unrelated compounds, examples of which include chromium picolinate, α-lipoic acid, kainic acid, cannabinoids, long-chain fatty acids, reactive oxygen species, leptin, ghrelin, IL-6
	B. SIRT1	Activation of SIRT1 downregulates the nuclear transcription factor p53, represses PPAR-γ, complexes with PGC-1α and HNF4α; increase insulin sensitivity and insulin secretion in rodents188 Caloric restriction specifically regulates tissue SIRT1 levels - increase in white adipose tissue, muscle, and pancreas; decrease in liver188 Prototype resveratrol, which is in grapes189 used to make wines Conflicting in vitro data whether SIRT1 will act as an oncogene or tumor suppressor188
	C. PTP1B	Inhibition of PTP1B a potential treatment for type 2 diabetes and other insulin resistance-associated conditions Inhibition improves insulin sensitivity and reduces body weight, total cholesterol, and triglycerides in the high fat diet-fed mice189
	D. FGF21	Abundantly expressed in white adipose tissue, liver, and pancreas190 In liver produces a profile similar to fasting by inducing gluconeogenesis, fatty acid oxidation and ketogenesis by inducing PGC-1α190 In humans, FGF21 levels increase with prolonged fasting and are increased in overweight individuals with features of the metabolic syndrome190 Administration of a novel FGF21 variant to diabetic rhesus monkeys reduced body weight, glucose, insulin, LDL cholesterol, triglycerides, and leptin while increasing HDL cholesterol and adiponectin191
Decrease cellular inflammation	A. IKKβ/NF-κB pathway	Studies in humans with type 2 diabetes using salsalate as an inhibitor reduced HbA1c by 0.37% over 48 weeks192 Urinary albumin excretion increases on therapy which reverses with the withdrawal of treatment192
	B. IL-1β receptor antagonists and IL-1β antibodies	The primary target is intra-islet immune response resulting in IL-1β production71 Studies in humans have been mixed with modest effects to lower HbA1c193
Reduce cortisol production	11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)	1 Enzyme generates cortisol from its inactive form cortisone194 2 Enzyme implicated in visceral obesity and the metabolic syndrome195 with increased enzyme activity in adipose tissue in obese and insulin-resistant humans196,197 2 Inhibitors being developed for a variety of effects with glucose-lowering thus far being modest198
Co-agonist therapy	Glucagon and GLP-1	A principal is combining two peptides with different effects199 Increased energy expenditure with GLP-1 ameliorated the effects of glucagon to raise glucose200

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