Mechanisms and Genetics of DM

Question 1

Insulin basics in T2D

Answer 1

initial insulin resistance at cellular level w/ increased overall levels of insulin
leads to later absolute insulin deficiency

Question 2

Which GLUT transporter requires insulin

where are these transporters found

Answer 2

GLUT4

sk muscle and adipocytes

Question 3

Mechanism of insulin secretion in response to glucose

Answer 3

Glc enters β-cells via GLUT1 or GLUT2
Glc phosphorylated by glucokinase
G6P converted ultimately to ATP
ATP inhibits K+ channel
depolarization of cell
Ca2+ enters cell
fusion of insulin vesicles (endocytosis)

Question 4

MHCII variants associated with T1D

according to Scott

Answer 4

DQA10301
DQB10302
DQB1*0201

Question 5

Which GLUT transporter is found on β-cells

Answer 5

GLUT1 and GLUT2

Question 6

T-cell receptor tolerance is determined where

Answer 6

in thymus

Question 7

What % of β-cells need to be destroyed before T1D develops

Answer 7

80%

Question 8

Role of Treg cells in T1D

Answer 8

inhibits autoimmune responses in periphery

Question 9

Etiology of insulin resistance

Answer 9

TNF-α in abbarent adipocytes
macrophage infiltration into adipocytes
(series of changes)
increased free FA release from adipocytes, decreased TAG
TLR2 and TLR4 activated
NFkB activated
JNK promotes nuclear translocation of AP-1
AP-1 is pro-inflammatory transcription factor

Question 10

Diacyl glycerol pathway

of insulin resistance

Answer 10

FA flux –> increase DAG
DAG activates protein kinase C
PKC inhibits IRS adapters via senne phosphorylation
downstream signalling of insulin impaired

Question 11

Oxidative stress in T2D

Answer 11

excess nutrients overloads electron transport chain
interfere w/ complex III transference
ROS builds up in β-cells
destruction of β-cells

Question 12

How are β-cells lost in T2D

Answer 12

buildup of ROS + ER stress
excess nutrients overloads electron transport chain
interferes w/ complex III transference
ROS builds up in β-cells
destruction of β-cells

Question 13

ER stress in T2D

Answer 13

unfolded proteins –> apoptotic pathway
normally ER stress activates set of protective signalling pathway
too much = destruction