Diabetes Mellitus Causing Microvascular Changes
PKGhatak, MD
Diabetes mellitus is a disease that lasts lifelong. People with diabetes follow their fasting blood sugars and some also understand the value of HbA1c in the management of diabetes. However, there is a silent killer working incessantly and burning away the smallest arterial branches like a smoldering brush fire. This killer is called Microvascular complications of diabetes.
Diabetes is actually of two types. Type I diabetes is due to a complete lack of Insulin. Type II diabetes is much more complex to categorize in one sentence. There are several reasons why a person develops diabetes in adult life; some due to insulin resistance, others the presence of insulin antibodies, and still there are more causes. But no matter which one is responsible for diabetes, in the long run, diabetics are at risk of developing one or more organ damages, which may happen in 50% of cases. It may result in visual impairment, renal failure, peripheral neuritis, skin ulcers and loss of a foot, heart disease and many other diseases.
Pathological changes in organs from diabetes are well described, but the way the changes happen is still not fully understood. Scientists experiment on lab animals, usually on mice, and not all their findings are squarely applicable to humans.
Blood sugar is Glucose. Besides blood glucose, the liver and muscles store glucose in a different chemical form called glycogen. The liver also turns excess fat and some amino acids into glucose. The heart uses glucose for energy and also uses fatty acids and ketones for the same purpose.
The blood sugar is kept between 80 to 100 mg in a fasting state by the interactions of several hormones. The chief among them is Insulin. Insulin combines with certain components of the cell membrane and makes a passage for glucose molecules to enter the interior of cells. The glucose molecule goes to mitochondria where the oxygen molecule reacts with glucose to release energy.
Like anything in excess amount does not always bring happiness, excess sugar has a dark secret. It burns the tissue, slowly and steadily.
In the biological system, all chemical reactions are the results of enzyme actions similar to Catalysts in chemical reactions. In diabetes, due to high blood glucose, the Superoxide, Sorbitol and Glycation of the substrate are overproduced. These substances are responsible for the thickening of the basement membrane, increased endothelial permeability, extravascular protein deposition and coagulation.
The microvascular changes in the eyes can be observed under direct vision with an Ophthalmoscope and so it is well documented but similar changes are also happening in other organs but the severity varies from individual to individual. In addition to the eyes, kidneys, Peripheral nerves, autonomic nerves the heart and skeletal muscles are affected.
Researchers have identified multiple biochemical pathways through which microvascular changes take place. The important among them are Protein Kinase C (PKC), Mitogen Activated Protein Kinase (MAPK), Diacylglycerol Kinase (DAG), Activated Protein Kinase (AMPK), Polyop pathway, and non-enzymatic Glycation End Products (GEPs), Kallikrein-Bradykinin system, Renin-Angiotensin system, and others. Hypertension acts as an accelerator of change.
PKC.
PKC is a family of closely related enzymes active with messenger calcium irons and DAG. PKC upregulates the Endothelial Growth Factor (EGF) through NADPH (nucleotide adenosine dehydrophosphatase hydrogen). The final result is the increased production of endothelin I, Vascular endothelial growth factor and connective tissue growth factor IV. The functional alterations are endothelial leaks, increased vascular permeability, angiogenesis, cell growth and apoptosis. And deregulation of cellular functions, dilation of small vessels, extracellular matrix expansion, and altered fatty acid metabolism.
MAPK.
MAPK is involved in the direct cellular response to mitogen, osmotic stress, gene expression, cell differentiation, mitosis, and cell survival.
DGK
DGK is an enzyme family, used in the phosphorylation of diacylglycerol (DG) and transforming it to phosphatidic acid (PA). Both DG and PA are important signal molecules.
AMPK.
AMPK acts as a master switch regulating glucose and fatty acid metabolism. It is capable of sensing energy needs. It is activated by skeletal muscle contraction and cardiac ischemia. In the liver, it enhances fatty acid oxidation and decreases the production of glucose, cholesterol and triglycerides.
NAD/NADH and NADP/NADPH systems.
These are coenzymes, which act as hydrogen ions and electron donors and receivers. NADP/NADPH is issued in anabolic (formation of new products) reactions and NAD/NADH is active in catabolic reactions.
Dextrose Monophosphate Shunt.
This is an alternate but parallel path through which glucose is utilized to 5-carbon pentose sugars. As the pentose is metabolized it generates Ribose and deoxyribose used in nucleoprotein synthesis.
Polyol / Sorbitol Pathway.
In diabetes, the hyperactive stage of this pathway leads to the accumulation of NADPH and reduced glutathione which are responsible for the overproduction of collagen fibers.
In diabetes, the above enzyme systems are overactive. The consequence is the following - Cell signaling dysfunction. Toxic AGE, Oxidants and Methyl glycol accumulation in the tissues. Altered osmols and redox potentials.
These are stressful situations within the cells and the response is manifested by the release of inflammatory cytokines and leukotrienes, decreased Insulin effectiveness, Kallikrein-Bradykinin activation. The end results are vascular changes of diabetes.
Organ changes in Diabetes mellitus.
Kidneys.
The initial change is the expansion of the mesangium and increased matrix production. The thickening of the basement membrane of the glomeruli is the result of it. Glomerular sclerosis and hyalinization of glomeruli lead to glomerular atrophy and hypertension and renal insufficiency.
Eyes.
Retinal changes are observable by an ophthalmoscope or retinoscope.
Micro aneurysm formation, retinal flame shaped hemorrhage, exudate and arterial atrophy, and macular edema are usual in various combinations and seventies in individual cases. This is the primary cause of visual loss and blindness.
Nervous system
The central, peripheral and autonomic nervous systems are affected in diabetes.
The changes are in the tiny arterioles supplying blood to the nervous tissues. Lack of oxygen and nutrients break down myelin sheath and in advanced cases, the axon is also damaged.
Cranial nerve palsy leads to double vision, and paralysis of the lateral rectus muscle is seen. The long peripheral nerves supplying the toes and fingers are the first to suffer damage. Loss of pain, touch and vibration sensations are lost initially then temperature sensations. Muscle weakness may develop due to motor nerve palsy. Neuritis pain in the legs is distressing for patients. Skin cuts and bruises and cigarette burns produce chronic ulcers and ultimately may end up requiring an amputation. Autonomic nervous system involvement produces impotence in men and postural hypotension. Nonspecific Gastric and intestinal symptoms may occur, and some also develop bladder and bowel evacuation difficulties.
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The changes in the heart, muscles and pancreas, liver and other organs can be found in previous blogs.
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