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Tuesday, March 19, 2024
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HomeHealthDIABETES: The Silent Killer Part 2

DIABETES: The Silent Killer Part 2

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Second of Two Parts

Diabetes is due to one of two mechanisms, inadequate production of insulin (which is made by the pancreas to lower the blood glucose by helping it to move into the cells) and / or inadequate sensitivity of cells to the action of Insulin. The mechanism of action of insulin is explained in relative detail in the first part of Explainer: Diabetes part 1, generally it serves as an “on switch” for processes of the body to utilize the food it takes in order for it to be stored / used as energy – thus diabetics, no matter how much food they eat, will always feel starved (and some go thin and weak) because the body fails to uptake glucose due to the lack of insulin’s function. 

THE TYPES of DIABETES

There are three (3) main types of Diabetes.

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Type 1 diabetes, previously called insulin-dependent diabetes and juvenile diabetes, stems from the pancreas unable to produce enough insulin due to loss of beta cells. The loss of beta cells are thought to be caused by an autoimmune destruction – the exact cause is unknown but some speculate it to be viral of origin, and the immune system has an over reactive response to whatever irritated the pancreas, ending up destroying the beta cells.

Type 2 diabetes, previously called adult onset diabetes, starts as an insulin resistance type of condition, in which cells fail to respond to insulin properly. Basically the Beta cells of the pancreas have no problems producing insulin but the cells of the body itself has defective insulin receptors. (obesity and a sedentary lifestyle is a cause of insulin resistance – excessive fat is said to decrease insulin signaling) Insulin resistance may be accompanied by decreased insulin production, increased glucagon production, and also decreased incretin – another type of hormone that serves to augment insulin release and function. 

Diabetes by Nick Youngson CC BY-SA 3.0 Alpha Stock Images
Diabetes by Nick Youngson CC BY-SA 3.0 Alpha Stock Images

Hyperinsulinemia is common in type 2 diabetes, in which due to increased blood glucose, the normal pancreatic beta cells continue to pump out insulin in response. Like machinery that gets broken due to excessive use, the beta cells tire out, and some of them die which overtime produces insulin slower – ultimately leading to both insulin resistance and insulin deficiency, aggravating the disease.  

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Obesity, lack of exercise, and a diet composed of processed food, sweetened drinks, and saturated fats are known to cause the development of Type 2 diabetes. Increased inflammatory mediators from fat tissue like Tumor Necrosis Factor alpha (TNF-a) releasing retinol binding protein 4 (RBP4) has said to lead to insulin resistance by either or both impairing insulin action or insulin receptor’s sensitivity.  Adiponectin a hormone that promotes insulin sensitivity and has a protective effect to various cardiovascular diseases are released by healthy fat cells but engorged fat cells in DMType2 produce less adiponectin, further aggravating the disease.

Gestational diabetes (GDM) is the third main form, and occurs when pregnant women without a previous history of diabetes develop high blood sugar levels – the exact pathophysiology is currently being studied, but proposed mechanisms go for insulin resistance due to pregnancy hormones blocking the insulin receptors. While insulin resistance physiologically occurs normally on the second trimester of pregnancy, a pregnant woman’s body does compensate perhaps by increasing fat stores / or increasing the size (hypertrophy) of beta cells to produce more insulin etc. but in GDM, the balance is skewed and the pregnant women’s bodies are unable to maintain it.

To explain briefly, untreated, GDM poses a risk to both mother and child. There may be problems with delivery, and the child may be unhealthily big and may even grow to become obese and diabetic. Lifestyle changes are the first line of treatment for GDM and then medications (insulin) are given if blood glucose remain elevated. Funny enough, and always a trick question by Obstetricians and Gynecologist, delivering the baby almost always treats GDM.

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DIABETES TYPE 1 and DIABETIC KETOACIDOSIS (DKA)

In diabetes, when there’s not enough glucose inside the cells because they are stuck circulating in the blood, the cells are starved for energy. The body is going to look for available sources to compensate, and thus breaks down the triglycerides in fat cells (lipolysis). Glycerol and free fatty acids are the products of these breakdown – but free fatty acids may be further broken down by beta oxidation into acetyl CoA. The next step usually is acetyl CoA goes into the Kreb’s cycle to produce energy but sometimes there’s an excess of acetyl CoA and these excesses undergo ketogenesis to produce ketone bodies specifically acetoacetate and beta hydroxybutarate. These ketone bodies get released into the blood stream making the blood more acidic.

Additionally, one of these two, acetoacetate, may be broken down into acetone, and absorbed into the lungs and exhaled. This increases the respiratory rate causing what’s called Kaussmaul breathing, and the exhaled gas which contains acetone has a fruity odor. 

DIABETES TYPE 2 and HYPEROSMOLAR HYPOGLYCEMIC STATE (HHS)

In a diabetic individual besides a decreased insulin supply, there’s an increased insulin demand and this can be essentially interpreted as increased stress in the body’s cells. Other things that aggravates diabetes and are essentially risk factors for getting into a hyperosmolar state (or Diabetic Ketoacidosis as they can go hand in hand) are Infections like Pneumonia, Urinary Tract Infection and Cellulitis, Inflammation of the organs like pancreatitis, Intoxication like recreational drugs or alcohol, Infarctions perhaps in CVA’s like heart attack and stroke, or Iatrogenic stress like Surgery and Steroid prescriptions, but the risks are not limited to these causes alone.

These stresses stimulate the sympathetic nervous system and release epinephrine and norepinephrine, aptly called stress hormones, and these two also stimulate glucagon production – increasing the promotion of two processes in the liver: Gluconeogenesis which creates glucose out of non-carbohydrate products and glycogenolysis which breaks down glycogen into glucose. 

Note that epinephrine, norepinephrine and glucagon may also affect fat cells and induce lipolysis, essentially inducing the pathway to ketoacidosis. Now an increased glucose in the blood will promote osmotic diuresis as glucose and water are excreted in the urine (thus the symptom of polyuria, polydipsia and dehydration etc.) – this creates what’s called a hyperosmolar hyperglycemic state (HHS) – and extreme dehydration and extremely starved cells from hyperosmolar hyperglycemic state may sometimes cause altered consciousness and confusion.

While Diabetic Ketoacidosis and Hyperosmolar state may occur together, commonly they are differentiated such that DKA usually occurs acutely, less than a day and in DM type 1 patients, while HSS occurs past a day and occurs more with DM type 2 patients. Various symptoms can be associated with DKA and Hyperosmolar state, excess ketone bodies usually trigger nausea and vomiting, acidosis may lead to elevated potassium levels in the blood – Hyperkalemia – causing arrhythmias, palpitation and chest pain and causing bowel problems and abdominal pain. Similarly in hyperosmolar states where-in excreted glucose and dehydration may be severe – starved muscles may lead to weakness, starved organs, specifically the brain may lead to altered mental status such as confusion, seizures and even coma.

Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic states are medical emergencies.

DIABETES and ATHEROSCLEROSIS

High levels of glucose in the blood usually conjugate with proteins and lipids also circulating in it, a process called glycation and these causes’ inflammatory reactions. Also, glucose may be taken into the endothelium and produce reactive oxygen species (ROS), activation of protein kinase C (PKC) and advanced glycalated products (AGP). 

PKC has numerous effects in the blood vessels:  it stimulates increased production of Vascular Endothelial Growth Factors (VEGF) resulting in angiogenesis or recruitment and development of blood vessels. It stimulates production of endothelin which stimulates platelet aggregation. And also stimulate NF-Kb which is a proinflammatory protein ultimately responsible for increased inflammatory product recruitment and permeability of macrophages into the blood vessels. The increased permeability of the blood vessels will also make cholesterol pass through – these in turn be phagocytozed or eaten by the macrophages leading to the formation of foam cells.

The byproducts of these processes ultimately create a feedback loop of inflammation in the blood vessels, added that a lot of glucose are in the blood which further continually aggravates the situation, leading to damage and eventually the development of atherosclerosis or plaque laden blood vessels and also hyaline deposition or hyaline arteriolosclerosis which is thickening of the vessel wall. These lead to the various macrovascular and microvascular complications od diabetes. 

MICROVASCULAR and MACROVASCULAR COMPLICATIONS of DIABETES

The combination of atherosclerosis and hyaline arteriolosclerosis leads to various complications and physical manifestations. 

Coronary Artery Disease and Myocardial Infarction – Heart Attacks, if these plaques develop in the coronary vessels of the heart.

If they occur in the arteries of the arms and feet, it could lead to peripheral artery disease, decreasing blood flow to the limbs, causing ulcers and claudication. 

If they occur in the arteries of the brain it could lead to stroke. If it affects the vessels supplying the kidneys it may ultimately lead to acute or chronic kidney failure.

If they occur in the vessels of the eye, specifically the retina, it could lead to diabetic retinopathy – which could ultimately cause blindness. Special cases to mention is that, patients usually seek ophthalmologic treatments but treating the diabetes actually clears the view more or less. 

Sometimes, glucose gets converted into sorbitol by aldol reducatase, then into fructose by sorbitol dehydrogenase. In some organs the sorbitol dehydrogenase enzyme is normally absent – so sorbitol accumulates and since it is osmotically active, it pulls excess water causing osmotic cell death. This is also what happens in the lens of the eye which is sorbitol dehydrogenase deficient in which excess sorbitol turns into cataracts.

The accumulation of sorbitol may happen in the tubules of the kidneys causing nephropathy, in the nervous system it damages the schwann cells, which are the cells responsible for producing myelin – which in turn is responsible for the electrical impulses of nerves. Without electrical impulses, various abnormalities occur – such as neurogenic bladder, in which control of urination is affected.  Gastroparesis may also occur in which the contraction of the stomach is affected and this is typically felt as heartburn and feeling ill when eating, along with various stomach problems. 

Perhaps a relatively common event seen are when diabetes affect the somatic nerves that control sensation in the feet and hands. In this situations, combined with high risk of ulcer development and impaired wound healing due to peripheral artery disease (caused by atherosclerosis and hyaline formation), a foot ulcer or injury may be left untreated due to the patient not knowing about the wound due to painlessness and eventually lead to formation of a diabetic foot. These wounds have very high risk of turning ischemic due to lack of blood supply and eventually gangrene, leading to eventual amputation.

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Austin Salameda
Austin Salameda
In pursuit of a career in medicine and the arts, Austin considers himself a non-conformist. he thinks everything returns to a baseline no matter how far things tilt from right to left. Writes sometimes, tells stories often, provokes always.
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