20 - Pathology of the Thyroid I

Question 1

What is the definition of diabetes mellitus?

**

Answer 1

A CHRONIC disorder of carbohydrate, fat and protein metabolism due to defective or deficient INSULIN secretory response

Question 2

Describe the population statistics of diabetes mellitus

Answer 2

• 3% of the world’s population (that’s a lot)
• 16 million in US, only 8 million diagnosed
• 1 million new cases per year
• 50,000 deaths/year in the US

Diabetes is the 7th leading cause of death ***

Question 3

What causes diabetes mellitus?

Answer 3

Many different causes

• Destruction of islets due to pancreatitis
• Tumors
• Drugs (steroids, thiazides, etc.)
• Hemochromatosis (“bronze diabetes” due to hemosiderin deposition in the pancreas)
• Surgery
• Infections (e.g. congenital rubella, CMV, coxsackievirus)
• Endocrinopathies (pituitary, adrenal, pregnancy)
• Gestational diabetes
• Idiopathic

Question 4

What are the four types of diabetes?

Answer 4

• Type 1
• Type 2
• Gestational
• MODY

Question 5

Describe type 1 diabetes

Answer 5

• Beta cell destruction which leads to ABSOLUTE insulin deficiency ***
• Immune mediated
• Idiopathic

Question 6

Describe type 2 diabetes

Answer 6

• Insulin resistance with relative insulin deficiency ***

- Onset usually >40 years old

Question 7

What is MODY?

Answer 7

Maturity Onset Diabetes of the Young

• 2-5% of patients have been found to have genetic abormalities which cause a primary defect in beta cell function ***
• No loss or change in the number of beta cells
• Usually autosomal dominant with high penetrance
• Early onset usually less than 25 years old
• No obesity
• No insulin resistance and no antibodies to glutamic acid decarboxylase ***

Question 8

What are normal blood glucose values?

Answer 8

Blood glucose values are normally maintained in a very narrow range (usually 70 - 120 mg/dL)

Question 9

Describe the diagnostic values for diabetes mellitus

Answer 9

The diagnosis of diabetes is established by noting elevation of blood glucose by any one of four criteria:

1 - HbA1c of 6.5% or more

2 - Fasting plasma glucose of 126 mg/dL or higher

3 - 2 hour plasma glucose of 200 or more during an oral glucose tolerance test

4 - Random (“casual”) glucose of 200 or more in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis

Question 10

What do you need to keep in mind when testing these lab values?

Answer 10

If any of the first three lab values come back positive (HbA1c 6.5, fasting 126 or glucose test 200), RETEST, just in case the lab results were wrong

Always do this in the absence of unequivocal hyperlycemia to make sure the diagnosis is correct

Question 11

What does it mean in the patient’s fasting blood glucose level is between 120 and 126?

Answer 11

Suspicious for diabetes, but not diagnostic

Question 12

What is the MOST COMMON leading cause of death in diabetics?

Answer 12

MI

DM causes MI

It does NOT matter which type of diabetes the aptient has –> this applies to all diabetics

Question 13

What are the other common causes of death in diabetics?

Answer 13

• Renal failure
• Cerebrovascular disease
• Hypertensive heart disease
• Infections

Question 14

Describe the pathogenesis of type 1 diabetes

Answer 14

A combination of genetic predisposition and environmental insult contribute to autoimmune attack and ultimately diabetes

Question 15

Describe the genetic predisposition in type 1 diabets

Answer 15

HLA-linked genes and other genetic loci put the patient at risk of developing type 1 diabetes

Question 16

Describe the environmental insult in type 1 diabetes

Answer 16

There can be a viral infection inducing molecular mimicry AND/OR damage to beta cells

Question 17

What do both the genetic predisposition and environmental insult lead to?

Answer 17

Immune response against normal beta cells AND/OR immune response against altered beta cells

This overall leads to autoimmune attack, beta cell destruction and type 1 diabetes

Question 18

What are the two morphological changes we see in type 1 diabetes?

Answer 18

• Acute islitis

- Insulitis

Question 19

Describe acute islitis

Answer 19

• Infiltration of neutrophils
• You will see this early on in the disease
• There will be inflammation, degranulation of beta cells, and beta cell death
• This is damage and destruction of beta cells

Question 20

Describe insulitis

Answer 20

• In type 1 diabetes, following the acute inflammation, there will eventually be a reduction in number and size of islets, thus a loss of beta cells
• You will see infiltration of islets by lymphocytes
• These sites of lymphocytic infiltration will later become hyalinized

Question 21

Describe the pathogenesis of type 2 diabetes

Answer 21

• There is NO absolute lack of insulin in type 2 diabetes
• There is a RELATIVE lack of insulin ***
• In other words, normal levels of insulin are circulating but cells are not appropriately responding to the insulin
• This is what we call “insulin resistance”

Question 22

What factors lead to the development of type 2 diabetes

Answer 22

Genetic predisposition combines with environmental factors to lead to hyperglycemia, beta cell exhaustion and eventually type 2 diabetes

Question 23

Describe the genetic predisposition seen in type 2 diabetes

Answer 23

Multiple genetic defects can occur, leading to a primary beta cell defect and deranged insulin secretion

Genetics can also (somewhat) lead to peripheral tissue insulin resistance

Question 24

Describe the environmental factors that contribute to type 2 diabetes

Answer 24

Obesity leads to peripheral tissue resistance to insulin

This leads to inadequate glucose utilization throughout the periphery

Question 25

What will you see in the early stages of type 2 diabetes?

Answer 25

Early: - Normal insulin secretion and plasma levels, but loss of pulsatile, oscillating pattern of secretion - NO insulinitis is present

Question 26

What will you see in the later stages of type 2 diabetes?

Answer 26

- Mild or moderate insulin deficiency which may be due to beta cell damage (beta cells may be "exhausted" due to chronic hyperglycemia - This is called "glucose toxicity" - Insulin resistance in the peripheral tissues is also seen in obesity and pregnancy

Question 27

What is amylin? ****

Answer 27

KNOW THIS - Amylin is abnormally packaged and secreted insulin - Amylin tends to accumulate outside of beta cells and is named due to its resemblance to amyloid - You will see the accumulation of amylin in type 2 diabetes

Question 28

What does amylin look like?

Answer 28

Amorphous "cracked plate glass" appearance

Question 29

Describe non-enzymatic glucose glycosylation ***

Answer 29

This means that glucose has a protein attached (glycosylation) IRREVERSIBLY --> it is a stable product that will remain in the blood Once there is a non-enzymatic glycosylation of glucose, it will increase the A1c SLIDE: nonenzymatic glycosylation of the terminal amino group in proteins. A stable fructose derivative is formed in these reactions, Hemoglobin A1c and glycosylated albumin are formed this way.

Question 30

What is the most common underlying cause in the pathogenesis of complications in diabetes? ***

Answer 30

Non-enzymatic glycation of extracellular matrix is the MOST common underlying cause in the pathogenesis of complications in DM ***KNOW THIS***

Question 31

What are advanced glycation end-products or AGEs?

Answer 31

Substances that can be a factor in the development or worsening of many degenerative diseases, such as diabetes, atherosclerosis, chronic renal failure, and Alzheimer's disease. These harmful compounds can affect nearly every type of cell and molecule in the body and are thought to be one factor in aging and in some age-related chronic diseases.

Question 32

What are the three potentially pathogenic effects of AGEs? ***

Answer 32

* ** KNOW THESE *** - Plasma proteins can bind to glycated basement membranes - Can induce cross linking in type IV collagen in basement membranes (i.e. glomerular basement membrane or GBM) - Can trap LDL particles in the artery walls - Can bind to receptors on numerous cell types ***

Question 33

Describe the pathogenic effects of AGEs binding to receptors on numerous cell types ***

Answer 33

Inducing... - Release of cytokines and growth factors from macrophages - Increase in endothelial permeability - Increase in endothelial procoagulant activity - Increase in extracellular matrix production by vascular smooth muscle cells as well as increase in proliferation THIS IS EVEN MORE IMPORTANT ***

Question 34

Describe the effects of AGEs on blood vessels

Answer 34

Blood vessel - Diagram includes endothelium, sub-endothelium and proteins circulating in the blood stream - Sub-endothelium is found under the endothelium, like a basement membrane - Once the AGEs develop, they can bind to collagen fibers in the sub-endothelium - They can then cause other proteins to bind to the endothelial wall, such as albumin – we then get protein accumulation - This leads to a thickening of the basement membrane LDL will also be trapped in the wall of the artery, this can lead to oxidation - This is the bases of a lot of complications seen in diabetes