Aula 11 - Diabetes Mellitus

Question 1

What is Diabetes Mellitus?

Answer 1

Chronic metabolic disease characterized by high leves of glucose in the blood (hyperglicemia).

Question 2

Is diabetes a preventable disease?

Answer 2

Yes, diabetes type 2, which is the most common type of diabetes, is a multifactorial disease that can be prevented through a healthy lifestyle and diet. However, diabetes type 1 is an autoimmune disease, that cannot be prevented.

Question 3

Distinguish type 1 and type 2 diabetes.

Answer 3

• Type 1 Diabetes: autoimmune disease characterized by the autoimmune destruction of the beta pancreatic cells, which are the ones responsible for producing insulin, leading to insulin insuficiency.
• Type 2 Diabetes: chronic metabolic disorder characterized by hyperglycemia and resulting in insulin resistance.

Question 4

Describe what you imagine to be a patient with type 2 diabetes.

Answer 4

Elderly, obese, arteriosclerotic and hypertensive patient.

Question 5

Describe what you imagine to be a patient with type 1 diabetes.

Answer 5

Young, thin, non arteriosclerotic patient with normal blood pressure.

Question 6

Regarding the manifestation of the symptoms, diabetes type 1 usually appears:
a) sudden and acute
b) slow and insidious

Answer 6

a) sudden and acute

Question 7

What is gestational diabetes?

Answer 7

It’s a condition characterized by high glucose levels in the blood (hyperglicemia) of a pregnant woman that develops during pregnancy and usually disappears after giving birth.

Question 8

What is maturity-onset-diabetes in the young (MODY)?

Answer 8

An hereditary type of diabetes caused by mutations to a single gene which disrupts insulin production.

Question 9

Can diabetes type 1 be idiopathic?

Answer 9

Yes!

Question 10

What are the two types of autoimmune diabetes type 1?

Answer 10

• Fast type (children and teens)
• Slow type: latent autoimmune diabetes in adults (LADA)

Question 11

What are the three main antibodies found in autoimmune diabetes type 1?

Answer 11

• Anti-Glutamic Acid Decarboxylase Antibodies (anti-GAD)
• Anti-Islet Cell Antibodies (ICA)
• Anti-Insulin Antibodies (IA)

Question 12

What are the two main antigens found in autoimmune diabetes type 1?

Answer 12

HLADR3 and HLADR4

Human leukocyte antigens (HLA) are genes in major histocompatibility complexes (MHC) that help code for proteins that differentiate between self and non-self.

Question 13

Type 1 Diabetes is:
a) insulin resistant
b) insulin deficient

Answer 13

b)

Question 14

What is the most common complication in diabetes type 1?

Answer 14

Diabetic ketoacidosis coma, which is characterized by uncontrolled hyperglycemia, metabolic acidosis, and increased body ketone concentration.

Question 15

Briefly describe the mechanisms that lead to the destruction of beta pancreatic cells and the deveolpment of type 1 diabetes.

Answer 15

The activation of the auto-antibodies against beta pancreatic cells is determined by genetic susceptibility (HLADR3 and HLADR4) as well as environmental factors (such as toxins or virus), which can cause damage to the beta pancreatic cells. This results in an immune attack against beta pancreatic cells by the auto-antibodies and lymphocytes. As these cells are responsible for the production of insulin, their destruction leads to a decrease in insulin synthesis, which ultimately causes insulin deficiency and, thus, type 1 diabetes.

Question 16

Name some of the metabolic alterations and symptoms of type 1 diabetes.

Answer 16

• Loss of muscle mass
• Increase of triglycerides and fatty acids in circulation
• Hyperglycemia (high glucose levels in blood) and Glycosuria (glucose in urine)
• Polydipsia (excessive thirst) and Polyphagia (excessive hunger)
• Metabolic acidosis, with the presence of ketone bodies in urine

Question 17

What causes hyperglycemia and glycosuria in type 1 diabetes?

Answer 17

The destruction of beta pancreatic cells leads to insulin deficiency. Insulin is responsible for transporting glucose out of the blood and into the tissues, in order to be stored and used as energy. Therefore, in the absence of insulin, glucose remains in the blood, causing increased blood glucose levels (hyperglycemia). Consequently, this raises the oncotic pressure in the blood, which makes water leave the tissues and enter the blood, increasing blood volume. As a result, there is an increased production of urine and, since glucose is accumulated in the blood, there will be a high concentration of glucose in urine as well (glycosuria).

Question 18

What causes extreme thirst (polydipsia) in type 1 diabetes?

Answer 18

Hyperglycemia raises the oncotic pressure in the blood, which makes water leave the tissues and enter the blood, increasing blood volume. As a result, there is an increased production of urine. Uncontrolled hyperglycemia results in a large amount of water leaving the tissues and, consequently, the body (through urine), which can cause serious dehydration and lead to extreme thirst.

Question 19

What causes the loss of muscle mass in type 1 diabetes?

Answer 19

The destruction of beta pancreatic cells leads to insulin deficiency. Insulin is responsible for transporting glucose out of the blood and into the tissues, in order to be stored and used as energy. Therefore, in the absence of insulin, glucose remains in the blood, leading to a decreased glucose concentration in the cells. In order to produce energy, the cells will start to use the stored glucose that they have, in a process called glycolysis (breakdown of glycogen, a storage form of glucose).

In uncontrolled type 1 diabetes, proteolysis (the breakdown of proteins into amino acids) can be used as a last-resort energy source, where the body breaks down muscle proteins to produce glucose (via gluconeogenesis) and energy. However, this leads to muscle wasting and, thus, to the loss of muscle mass.

Question 20

What causes extreme hunger (polyphagia) in type 1 diabetes?

Answer 20

In type 1 diabetes, autoimmune destruction of pancreatic beta cells causes insulin deficiency. Without insulin, glucose cannot enter cells and accumulates in the bloodstream. Despite high blood glucose, cells are starved of energy, triggering a compensatory increase in appetite (polyphagia) as the body attempts to obtain more energy from food.

Question 21

What causes high levels of fatty acids and triglycerides in type 1 diabetes?

Answer 21

The destruction of beta pancreatic cells leads to insulin deficiency. Insulin is responsible for transporting glucose out of the blood and into the tissues, in order to be stored and used as energy. Therefore, in the absence of insulin, glucose remains in the blood, leading to a decreased glucose concentration in the cells. In order to produce energy, the cells - in the liver and fat - will start to break down stored glucose (glucogenolysis) and break down fat (lipolysis), producing fatty acids and glicerol, which can also form triglycerides, thus increasing their levels in circulation.

Question 22

What causes metabolic ketoacidosis in type 1 diabetes?

Answer 22

In type 1 diabetes, autoimmune destruction of pancreatic beta cells causes insulin deficiency. Without insulin, glucose cannot enter cells and accumulates in the bloodstream. Despite high blood glucose, cells are starved of energy, and begin to produce energy through alternative ways. For example, in muscle tissue, the cells break down proteins into aminoacids (proteolysis), while in the liver and adipose tissue, they break down fat into fatty acids (lipolysis).

The liver converts fatty acids into acetyl-CoA through a process called beta oxidation. Acetyl-CoA is metabolised into ketone bodies under severe states of energy deficiency, through a process called ketogenesis.

This process leads to an accumulation of ketone bodies, which turn blood acidic, causing a metabolic acidosis, also known in this case as diabetic ketoacidosis.

Question 23

How does metabolic ketoacidosis lead to coma?

Answer 23

In diabetic ketoacidosis, the buildup of ketone bodies causes blood to become acidic. This acidosis, along with severe dehydration and electrolyte imbalances, disrupts brain function, which can lead to confusion, loss of consciousness, and eventually coma.

Question 24

What causes shock in the case of type 1 diabetes?

Answer 24

In type 1 diabetes, shock can result from severe dehydration due to excessive urination (caused by high blood glucose) and from diabetic ketoacidosis. Fluid loss and low blood volume reduce tissue perfusion, leading to hypotension and potentially life-threatening circulatory shock.

Question 25

What causes renal insuficiency in type 1 diabetes?

Answer 25

As a result of hyperglycemia, increased urination leads to dehydration, which lowers blood volume and, consequently, blood pressure (hypotension). This can reduce the amount of blood that reaches the organs, namely the kidneys, which can become hypoperfused, resutling in kidney disysfunction and later renal insufficiency.

Question 26

What causes dysrhythmias and heart attack in type 1 diabetes?

Answer 26

In order to compensate the metabolic ketoacidosis and buffer the excess H⁺ ions (acidity) in the blood, H⁺ enters cells. However, in order to maintain electrochemical balance, K⁺ exits cells in exchange. This can impair muscle contraction and relaxation, especially in the cardiac muscle, leading to dysrhythmias and, eventually, heart attack.

Question 27

What is the most frequent complication in type 2 diabetes?

Answer 27

Hyperosmolar coma (hyperglycemia leads to increased osmolarity in the blood).

Question 28

What causes insulin resistance in type 2 diabetes?

Answer 28

Insulin resistance arises from defects in the insulin signaling pathway. This includes: * Downregulation or impaired phosphorylation of insulin receptors. * Reduced tyrosine kinase activity, limiting downstream signaling. * Dysfunction in signaling intermediates (e.g., IRS-1/2, PI3K, AKT). * Impaired GLUT-4 vesicle translocation and fusion with the membrane, reducing glucose uptake. * In some cases, genetic mutations in receptor or signaling proteins (evidenced by gene knockouts in models) contribute to resistance. * And, of course, obesity.

Question 29

How does obesity (especially abdominal obesity) contribute to insulin resistance?

Answer 29

* **Adipokines:** Abdominal (or visceral) fat releases pro-inflammatory adipokines (e.g., TNF-α, IL-6) and fewer protective ones (like leptin), causing chronic inflammation and impairing insulin signaling. Additionally, leptin usually acts on the central nervous system to induce saciety, so the decreased production of leptin leads to an increased feeling of hunger, further promoting obesity. * **Free fatty acids:** Obesity also leads to lipid (triglycerides and fatty acid products) accumulation in non-adipose tissues (like liver and muscle), causing cellular stress, inhibiting insulin signaling and worsening insulin resistance.

Question 30

Besides insulin resistance, what is the other main metabolic deficiency in type 2 diabetes?

Answer 30

Beta pancreatic cell dysfunction, which causes inadequate insulin secretion, often as a result of the damage caused by insulin resistance.

Question 31

Briefly describe the pathophysiology of type 2 diabetes.

Answer 31

Type 2 diabetes begins with insulin resistance in peripheral tissues (muscle, liver, fat). To compensate, pancreatic beta cells increase insulin secretion. Over time, chronic demand and glucotoxicity, lipotoxicity, and amyloid deposition impair beta-cell function, damaging these cells and reducing insulin production. The combination of insulin resistance and insufficient insulin secretion leads to hyperglycaemia and glucose intolerance, resulting in type 2 diabetes.

Question 32

What causes hyperosmolar coma in type 2 diabetes?

Answer 32

Hyperosmolar coma is caused by extreme hyperglycemia, which leads to severe osmotic diuresis and dehydration. The high blood glucose increases plasma osmolarity, drawing water out of cells (including brain cells), which can impair consciousness and result in coma. It typically occurs without significant ketoacidosis.

Question 33

Microangiopathy and Diabetic Retinopathy are common complications in diabetes. Briefly describe their pathophysiology.

Answer 33

Chronic high blood glucose damages small blood vessels (microangiopathy) by causing thickening of the basement membrane, endothelial dysfunction, and capillary leakage. In diabetic retinopathy, these changes lead to retinal ischemia, increased vascular permeability, microaneurysms, and neovascularization, resulting in vision impairment.

Question 34

Macrovascular and cardiovascular diseases are also common complications in diabetes. Briefly describe their pathophysiology.

Answer 34

Chronic hyperglycemia also causes hyperlipidemia (accumulation of lipids in the blood) and inflammation (and consequent damage to blood vessel walls) accelerate atherosclerosis. This can then lead to: * hypertension * heart failure (when the heart muscle doesn't pump blood as well as it should) * heart attack (complete or partial blockage of a coronary artery) * intermittent claudication (pain when leg muscles are hypoperfused) * gangrene (tissue death as a result of hypoperfusion)

Question 35

Describe the pathophysiology of diabetic nephropathy.

Answer 35

Chronic hyperglycemia causes thickening of the glomerular basement membrane, mesangial matrix expansion, and accumulation of extracellular matrix proteins. These changes lead to glomerulosclerosis and damage to renal microvasculature (including renal arteriosclerosis). The resulting loss of filtration barrier integrity causes proteinuria. Progressive injury reduces renal function, potentially leading to chronic kidney disease and end-stage renal failure.

Question 36

Describe the pathophysiology of diabetic neuropathy.

Answer 36

* Chronic hyperglycemia leads to metabolic and vascular changes that damage peripheral nerves. Through the polyol pathway, glucose is reduced to sorbitol, which is subsequently oxidized to fructose. Therefore, the accumulation of glucose results in an accumulation of sorbitol and oxidative stress, impairing nerve function. * Microvascular injury reduces blood flow to nerves, causing ischemia. These factors result in demyelination, axonal loss, and impaired nerve conduction, leading to sensory, motor, and autonomic neuropathy.

Question 37

Name some of the consequences of diabetic neuropathy.

Answer 37

* loss of sensation in the extremities * alteration of motor function * oscillations in blood pressure * alterations in gastrointestinal function * erectile dysfunction

Question 38

Who should have their blood glucose tested?

Answer 38

Everyone over 45 years old should be tested every 3 years. Younger people should be tested if they have any risk factors, such: * being obese; * having a first-degree relative with diabetes; * having gestational diabetes or a baby weighing more than 4 kg; * being hypertensive; * having a high level of triglycerides.

Question 39

What lab parameters should be monitored in diabetic patients?

Answer 39

* Hemoglobin A1c - it translates glycemia in the past 120 days. * Microalbuminuria (albumin in urine) - high levels would indicate renal lesion. * Urinary acetone test (Type 1 Diabetes) - to detect ketone bodies in urine and assess metabolic ketoacidosis. * Triglycerides, cholesterol, LDL and HDL - to detect dyslipidemia.