Immunology of T2 Diabetes Flashcards
Describe metabolism in the fed state
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
Describe metabolism in the fasting state
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
What happens in T1 diabetes.
no insulin, high glucagon. Uncontrolled protein breakdown. Excessive gluconeogenesis. Excessive production of ketone bodies. They are excreted by kidneys.
What are the metabolic effects of insulin
glycogen synthesis in liver and muscle. Glycogenesis in liver and muscle. Glucose uptake by muscle and adipose. Fatty acid synthesis inhibited. Lipolysis inhibited.
What is the mechanism of action of insluin
Insulin binds the receptor
Receptor is auto phosphorylated
IR catalyses tyrosine phosphorylation of insulin receptor substrates
IRS-1 activates several signalling pathways
What does PI3K pathway lead to
protein, carbohydrate and fat metabolism
What odes MAP kianse pathway lead to
involved in cell growth and differentiation through Ras
What happens after pathways are acitvated
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
How is Akt/PKB activated
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
How is glycogen made
GS needs to be non-phosphorylated. Insulin activates Akt/PKB phosphorylates glycogen synthase kinase and makes it inactive, making GS active.
How is lipolysis inhibited
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
How is the insulin signal terminated
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
What is insulin resistance
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
How does Free FA impair insulin sensitvity
Interfere with IRS activation
How does TNFa imapir insulin sensitivity
Interfere with IRS activation
What does leptin do
increases insulin sensitivity but obese often leptin resistant
What does adiponectin do
increases insulin sensitivity, decreased in obesity
What is metabolic syndrome
3 of: Abdominal obesity High blood pressure High blood glucose High serum TAG Low high density lipoprotein concentrations
What does DAG do in muscles and liver
In muscle and liver intracellular accumulation of lipids such as DAG triggers activation of protein kinases which impair insulin signalling
How does Ras pathway affect gene expression
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
What is the pathology of T1DM
pseudoatrophic islets; small, devoid of beta cells, but retaining glucagon and somatostatin
What is the significance of anti-GAD65
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
What are the targets of Islet Cell Antibodies
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
What do C peptide levels reflect
Beta cell mass
What immunotherapies can are used for T1DM
Autologous hematopoietic stem cell transplantation to restart immune system
Humanised monoclonal antibodies: anti-CD4 targets T cells, anti CD20 targets B cells
