Immunology of T2 Diabetes

Question 1

Describe metabolism in the fed state

Answer 1

Glucose taken up by liver. Glycogen synthesis enzymes activated. Glycogen formed in the liver. Excess glucose converted to sugar. Fat is not stored in liver - goes to bloodstream as VLDL. Glucose goes to brain and erythrocytes. GLUT4 transporters on muscle and adipose tissue takes up glucose.
Fat from diet circulates in the form of chylomicrons. VLDLs and chylomicrons deposit TAG in adipocytes.
AA used for protein synthesis. Excess AA converted to carbohydrates

Question 2

Describe metabolism in the fasting state

Answer 2

High glucagon. Low insulin. Glycogen degradation. Glucose goes into bloodstream.
Glucagon activate TG breakdown so FA goes into blood. Muscle not allowed to take up glucose. FA goes to liver and converted to ketone bodies. Lactate from RBC goes up to liver for gluconeogenesis. Muscle protein goes back to liver for glucose production. This increases urea production.
Ketone bodies can be taken up by muscle and brain

Question 3

What happens in T1 diabetes.

Answer 3

no insulin, high glucagon. Uncontrolled protein breakdown. Excessive gluconeogenesis. Excessive production of ketone bodies. They are excreted by kidneys.

Question 4

What are the metabolic effects of insulin

Answer 4

glycogen synthesis in liver and muscle. Glycogenesis in liver and muscle. Glucose uptake by muscle and adipose. Fatty acid synthesis inhibited. Lipolysis inhibited.

Question 5

What is the mechanism of action of insluin

Answer 5

Insulin binds the receptor
Receptor is auto phosphorylated
IR catalyses tyrosine phosphorylation of insulin receptor substrates
IRS-1 activates several signalling pathways

Question 6

What does PI3K pathway lead to

Answer 6

protein, carbohydrate and fat metabolism

Question 7

What odes MAP kianse pathway lead to

Answer 7

involved in cell growth and differentiation through Ras

Question 8

What happens after pathways are acitvated

Answer 8

An increase in GLUT4 molecules on the plasma membrane of insulin sensitive tissues.
GLUT4 is transported from cellular vesicles to the cell surface
Increased uptake of glucose from blood

Question 9

How is Akt/PKB activated

Answer 9

IRS bind the phosphorylated receptor with their SH2 domain and are themselves phosphorylated and activated
The phosphorylated IRS phosphorylates and activates PI3-Kinase, which is attracted to the membrane by virtue of its pH domain
PI3-K phosphoraltes PI (4.5)P2 to produce PI (3, 4, 5) P3 in the membrane, which activates PDK1, which in turn phosphorylates and activates Akt/PKB

Question 10

How is glycogen made

Answer 10

GS needs to be non-phosphorylated. Insulin activates Akt/PKB phosphorylates glycogen synthase kinase and makes it inactive, making GS active.

Question 11

How is lipolysis inhibited

Answer 11

activation of Akt/PKB and inhibition of hormone sensitive lipase.
Hormone sensitive lipase breaks down TAG and is activated by glucagon.
PKA (cAMP) activates hormone sensitive lipase.
Phosphodiesterase removes cAMP. Phosphodiesterase is activated through Akt/PKB

Question 12

How is the insulin signal terminated

Answer 12

Protein phosphatases and phosphoinositide phosphatases inhibit at several points in the signalling pathway
Phosphorylation of IRS on serine/threonine site is another mechanism for switching off
Emerging as an important link in the aetiology of insulin resistance

Question 13

What is insulin resistance

Answer 13

Condition in which normal amounts of insulin are inadequate to maintain normal concentrations of blood glucose
Both insulin and glucose are high
Often associated with obesity

Question 14

How does Free FA impair insulin sensitvity

Answer 14

Interfere with IRS activation

Question 15

How does TNFa imapir insulin sensitivity

Answer 15

Interfere with IRS activation

Question 16

What does leptin do

Answer 16

increases insulin sensitivity but obese often leptin resistant

Question 17

What does adiponectin do

Answer 17

increases insulin sensitivity, decreased in obesity

Question 18

What is metabolic syndrome

Answer 18

3 of:
Abdominal obesity
High blood pressure
High blood glucose
High serum TAG
Low high density lipoprotein concentrations

Question 19

What does DAG do in muscles and liver

Answer 19

In muscle and liver intracellular accumulation of lipids such as DAG triggers activation of protein kinases which impair insulin signalling

Question 20

How does Ras pathway affect gene expression

Answer 20

The adaptor protein SHC docks at the phosphorylated tyrosine furthest away from the membrane. It activates the anchored protein Ras by phosphorylation
Raf->MEK kinase->MAPK through phosphorylation ->phosphorylates specific transcription factors

Question 21

What is the pathology of T1DM

Answer 21

pseudoatrophic islets; small, devoid of beta cells, but retaining glucagon and somatostatin

Question 22

What is the significance of anti-GAD65

Answer 22

10% of patients initially diagnosed with T2DM have anti-GAD65 antibodies
Very few antibodies to Insulin or IA-2
90% of GAD65-Ab positive type 2 patients requires insulin within 6 year follow up
GAD65-Ab marker - T1 latent autoimmune diabetes in adults

Question 23

What are the targets of Islet Cell Antibodies

Answer 23

Insulin
Glutamic acid decarboxylase
IA-2
Zinc Transporter 8
Each of these can be measured by RIA or ELISA (molecular techniques)
Precise targets of individuals differ therefore may ned to use different therapies
ICA do not cuase T1DM

Question 24

What do C peptide levels reflect

Answer 24

Beta cell mass

Question 25

What immunotherapies can are used for T1DM

Answer 25

Autologous hematopoietic stem cell transplantation to restart immune system
Humanised monoclonal antibodies: anti-CD4 targets T cells, anti CD20 targets B cells