PATHOPHYSIOLOGY TYPE 2 DIABETES MELLITUS

Question 1

What are the factors of T2D?

Answer 1

Genes + environmental influences → insulin resistance + abnormal insulin secretion by beta cells + increased glucose production by the liver

Question 2

Genes associated with T2D include those that code for:

Answer 2

Beta cell mass/function, proinsulin an insulin molecular structure, insulin receptors, hepatic synthesis of glucose an glucagon an cellular responsiveness to insulin stimulation

Question 3

What is required to develop type 2 diabetes?

Answer 3

Relative insulin deficiency
- this means that beta cell dysfunction is always present to some extent

Question 4

What are risk factors for type 2 diabetes?

Answer 4

Obesity, metabolic syndrome an hypertension
- genetically pre disposed to beta cell dysfunction

Question 5

What prevents appearance of diabetes for years?

Answer 5

Compensatory hyperinsulinemia caused by insulin resistance
- eventually beta cell dysfunction leads to a relative insulin deficiency, hyperglycemia, T2DM

Question 6

What does beta cell dysfunction cause?

Answer 6

Relative insulin deficiency in T2DM

Question 7

Beta cell dysfunction may result in what?

Answer 7

A decrease in beta cell mass, abnormal function of beta cells - or combination of these

Question 8

Why is there a progressive decrease in weight an # of beta cells?

Answer 8

1st: beta cells are very sensitive to increased levels of glucose an free fatty acids an undergo apoptocic death in “glucolipotoxic” conditions
2nd: the adipokine leptin decreases insulin synthesis in beta cells
3rd: inflammatory cytokines like TNF-alpha and IL-1 bet which are released from adipocytes are toxic to beta cells
4th: there is beta cell exhaustion from increased demand for insulin biosynthesis - is associated with intracellular oxidative stress and endoplasmic reticulum dysfunction

Question 9

What is insulin resistance? What are the tissues?

Answer 9

Is a suboptimal response of insulin-sensitive tissues to insulin
Tissues: liver, muscle and adipose tissue

Question 10

The mechanisms of insulin resistance:

Answer 10

Abnormality of insulin molecule, high amounts of insulin antagonists, down-regulation of insulin receptor, decreased or abnormal activation of post receptor kinases and alteration of glucose transporter proteins

Question 11

What percentage of people are obese with type 2 diabetes?

Answer 11

60-80%
- 90% of people with type 2 diabetes are overweight

Question 12

Obesity is a contributor to what? Through what?

Answer 12

Insulin resistance and beta cell dysfunction
Through: increased adipokines an expression of peroxisome proliferator-activated receptor gamma

Question 13

What is the function of peroxisome proliferator-activated receptor gamma?

Answer 13

Highly expressed in adipose tissue and responsible for changes in adipokines
- this includes increased levels of serum leptin and resistan and decreased levels of adiponectin

Question 14

What is the function of Adiponectin?

Answer 14

Increases tissue sensitivity to insulin and appears to have anti diabetic, anti inflammatory and antiatherogenic effects
- the changes adipokines have an over all effect of decreased insulin sensitivity

Question 15

What are thiazolidinediones (drug class)?

Answer 15

Modulate activity of PPAR gamma - used to treat T2D

Question 16

Elevated serum FFA’s and intracellular deposits of triglycerides and cholesterol interfere with what?

Answer 16

Intracellular insulin signalling and decrease tissue responses to insulin

Question 17

What does Lipotoxicity cause?

Answer 17

Altered insulin secretion within beta cells

Question 18

What does elevated FFA inhibit?

Answer 18

Glucose uptake and glycogen storage in the peripheral tissues causing insulin resistance and glucose underutilization

Question 19

What does elevation of FFA and triglycerides reduce?

Answer 19

Hepatic glucose production and hyperglycaemia (this is heightened in fasting state)

Question 20

Inflammatory cytokines (TNF-alpha, IL-6) are released from where?

Answer 20

Adipocytes
- and contribute to insulin resistance through a post receptor mechanism