Hello everyone, I am Dr. Trupti. Welcome to my YouTube channel Enjoy Biochemistry. In the previous video on diabetes, we have studied the classification of diabetes, its diagnostic criteria, pathogenesis of diabetes, various metabolic changes seen in the diabetes.
In this video, we will see the various molecular mechanisms which will lead to complications associated with diabetes. The complications associated with diabetes can be acute and chronic. The acute complications are diabetic ketoacidosis which most commonly occur in type 1 diabetes. However, it can also occur in type 2 diabetes and hyperosmolar hyperglycemic state it is most common in type 2 diabetes.
The various chronic complications associated with diabetes they are macrovascular complication, microvascular complications and other complications. Macrovascular complications mainly involve large vessels such as arteries and veins. And these macrovascular complications lead to coronary heart disease, cerebrovascular disease and peripheral vascular disease.
Microvascular complications involve small vessels such as capillaries and they clinically manifest as diabetic retinopathy, diabetic nephropathy i.e. diabetic kidney disease and diabetic neuropathy. The other complications can be cataract, glaucoma, infections, foot ulcers leading to gangrene, various skin infections and fungal infections. Let's see few differences between diabetic ketoacidosis and hyperglycemic hyperosmolar state. Diabetic ketoacidosis is more common in type 1 diabetes. However, it can also occur in type 2 diabetes.
It is characterized by hyperglycemia, dehydration, there is ketosis. So it is characterized by both ketonemia that is increased ketone bodies in the blood as well as they are excreted in the urine which is called as ketoneuria. And there is metabolic acidosis which is increased anion gap acidosis.
There is hyperventilation which is a compensatory mechanism and fruity odor due to presence or exhalation of acetone through breath. It gives fruity odor. Then it is also characterized by hyponatremia and hyperkalemia. So these are few important features of diabetic ketoacidosis.
Now in hyperglycemic hyperosmolar state which is more common in type 2 diabetes, it is also associated with hyperglycemia, dehydration, there is increased plasma osmolarity but there is no ketosis, no ketonuria, anion gap is normal and there is no significant acidosis. Diabetes is the independent risk factor for development of atherosclerosis which further leads to various macrovascular complications involving large vessels such as arteries and it affects the arteries of brain, heart and peripheral vessels leading to cardiovascular diseases and then cerebrovascular diseases and peripheral vascular diseases. So the hyperglycemia it leads to Glycation of LDL that is low density lipoprotein and there is increase in glycated LDL. Hyperglycemia also leads to formation of reactive oxygen species and it also leads to formation of oxidized LDL. So there is increase in glycated LDL as well as oxidized LDL.
In diabetes there is also increase in small dense LDL and there is decrease in HDL. So all these four factors that is increase in glycated LDL, increase in oxidized LDL, increase in the small dense LDL and decrease in HDL all these processes lead to formation of atheroma and this atheroma further leads to formation of atherosclerosis which is the underlying pathology of macrovascular complications and this topic of atherosclerosis it has been already explained in a video I am giving the link. in the description.
Now let's study the molecular mechanisms of macro and microvascular complications associated with diabetes. Endothelial dysfunction is being increasingly recognized as the principal mediator of both micro and macrovascular complications and these molecular mechanism they include hyperglycemia induced activation of various metabolic pathways, the release of growth factors and cytokines, the hyperglycemia glycaemia induced oxidative stress and various epigenetic mechanisms so hyperglycaemia it induces Release of various growth factors and then oxidative stress and epigenetic mechanisms are also activated and ultimately there is endothelial dysfunction which is the principal mediator of all the complications associated with diabetes, macrovascular as well as macrovascular. Now the major growth factors which are released they are vascular endothelial growth factor and angiopoietins. They stimulate extracellular matrix production and accumulation and it leads to Deposition of excess basement membrane material. In addition to this, various components of metabolic syndrome also lead to endothelial dysfunction.
And those components are diabetes, raised fasting plasma glucose, obesity, high triglyceride and high blood pressure. Hyperglycemia in diabetes also induces various epigenetic mechanisms. Epigenetic mechanism is They deal with the changes in DNA molecule due to causes outside the DNA molecule i.e. changes in the cellular environment. And there is complex interaction between genetic factors and environmental interactions, especially dietary habit, lifestyle and this can accelerate or slow down the disease progression. And these environmental factors, they mainly trigger an inflammatory response and thereby they promote inflammation-mediated insulin resistance as well as endothelial dysfunction.
So the true nuclear factor kappa b the inflammation response is promoted and which further mediate insulin resistance and there is endothelial dysfunction. So hyperglycemia through the epigenetic mechanism also lead to endothelial dysfunction. Hyperglycemia also induces various metabolic pathways and it further leads to endothelial dysfunction and then later macro and microvascular complications. So let's see which are those four pathways which are activated by hyperglycemia.
The first pathway is glyoxylation pathway and in this pathway there is formation of advanced glycation end products. And these advanced glycation end products they non-enzymetically modify various intracellular proteins, extracellular matrix proteins and components as well as plasma proteins. The second pathway is protein kinase C pathway.
The third is polyol pathway and fourth is hexoamine pathway. Glyoxylation pathway leads to formation of advanced glycation end products. And these advanced glycation end products, they are formed by non-enzymatic reaction of glucose with the free amino groups of protein, lipids and nucleic acid.
Now these advanced glycation end products, they can bind to the age receptors. So these age receptors are also called as RAGE, receptors for advanced glycation end products. These edges they are expressed on the various inflammatory cells like macrophages, T lymphocytes, endothelial cells and smooth muscle cells.
Now what happens if these edges they interact with these receptors expressed on these various cells. So the edges bind to the receptors and various pathways occur or various changes occurs. And the first is release of cytokines and growth factor.
like tumor growth factor beta, vascular endothelial growth factor, release of reactive oxygen species by endothelial cells, then trapping of LDL because of endothelial dysfunction there is the LDL is trapped inside the vessel wall. So that is also important factor. Then there is increased coagulant activity because of this advanced glycation end product because it can form the cross links with various proteins. Then there is proliferation of vascular smooth muscles and there is synthesis of extracellular matrix. So these are the various changes that occur because of advanced glycation end product which is a result of glyoxylation pathway.
Second pathway is activation of protein kinase C pathway. So intracellular hyperglycemia leads to increased formation of diacylglycerol from various glycolytic intermediates which will further induces protein kinase C pathway. And it leads to increased concentration of endothelin, musculoendothelial growth factor, tumor growth factor beta and nuclear factor kappa B. As well as there is decrease in nitric oxide synthase and which will ultimately lead to dysregulation of vascular permeability. 3rd is the activation of polyol pathway which leads to formation of sorbitol.
So sorbitol is a polyhydric sugar alcohol and it is formed from glucose by the action of enzyme aldose reductase. In this process NADPH is utilized and further this sorbitol can be converted to fructose by sorbitol dehydrogenase. So whenever there is diabetes mellitus or increased blood glucose level this aldose reductase enzyme is activated because this has high Km4 glucose and there is formation of sorbitol. This aldose reductase it is present in eye lens, kidneys and nervous tissues. While this sorbitol dehydrogenase it is present in the liver seminal vesicle.
So in conditions of diabetes mellitus in case of hyperglycemia in the tissues like the eye lens, kidneys and nervous tissue as there is aldose reductase there is formation of sorbitol but due to this as this tissues lack sorbitol dehydrogenase this sorbitol cannot be converted to fructose so there is accumulation of sorbitol in these tissues and this is osmotically active substance and that's why the accumulation of sorbitol leads to the conditions like cataract nephropathy and neuropathy The fourth pathway which is induced by hyperglycemia and leading to endothelial dysfunction is hexazomine pathway. Normally glucose is converted to pyruvate through the glycolysis and further it is converted to acetyl-CoA and oxidized through TCA cycle. But in this hexazomine pathway glucose is converted to glucose 6-phosphate and then to fructose 6-phosphate and then it takes the other route. and this fructose 6-phosphate is converted to glucosamine 6-phosphate by the action of enzyme glucosamine fructose 6-phosphate amidotransferase and then there is formation of udp and acetyl glucosamine which further causes o-link glycosylation of various proteins as well as n-linked and o-link glycosylation of proteins and this alters the gene expression of various genes And it leads to increased expression of TGF beta and it can also cause modification of endothelial nitrous oxide synthase.
So ultimately it can lead to endothelial dysfunction. So these are the various pathways which are induced by hyperglycemia and ultimately result in the endothelial dysfunction, which is the mediator of various micro as well as macrovascular complications. So let's summarize today's topic. Diabetes is associated with various acute and chronic complications. Diabetic ketoacidosis is the acute complication of type 1 diabetes and hyperosmolar hyperglycemic state is the complication of type 2 diabetes.
The chronic complication involves the macrovascular complications like coronary heart disease, cerebrovascular disease, peripheral vascular disease while microvascular complications include diabetic retinopathy, diabetic nephropathy and diabetic neuropathy. Other complications can also result from diabetes like cataract, glaucoma, infections, gangrene, foot ulcers, various skin infections and fungal infections. There are various molecular mechanisms which lead to macro and microvascular complications. So they are induced by hyperglycemia of diabetes and this hyperglycemia leads to release of various growth factors and cytokines and also there is release of reactants. active oxygen species which will lead to oxidative stress and epigenetic mechanisms are also activated.
These growth factors and cytokines along with the components of various metabolic syndromes and various other mechanisms ultimately lead to endothelial dysfunction. Various epigenetic mechanisms through the inflammatory mechanism also lead to endothelial dysfunction and there is activation of four important metabolic pathways. by the hyperglycemia.
The first pathway is glyoxylation pathway, second is activation of protein kinase C and third is polyol pathway and fourth is hexazomine pathway and all these pathway ultimately lead to endothelial dysfunction and this endothelial dysfunction is the mediator of macro and microvascular complications which are associated with diabetes.