L39 - Biochemical basis of Diabetes Mellitus I Flashcards
(27 cards)
Describe function of signal peptide and post-translational modification of preproinsulin?
Signal peptide guides translocation into lumen of ER
ER:
- Disulphide bond formation + Proteolytic cleavage of signal peptide
Golgi:
- Further proteolytic cleavage
- Secretory vesicle
Describe the secretion of insulin in B cells?
Glucose enters β cells through GLUT-2
> > glycolysis and TCA cycle (oxidative phosphorylation) in mitochondria to generate ATP
> > inactivates K+ channel protein
> > membrane depolarization
> > opens Ca2+ channel, influx of Ca2+ cause insulin vesicle exocytosis
Define the locus and variability of HLA genes.
MHC/HLA locus = Chromosome 6
Highly polymorphic
Describe how HLA haplotypes can influence the risk of Type 1 DM?
MHC haplotype divided into:
1) Susceptibility alleles = increase occurrence of Type 1 DM
2) Neutral alleles = no difference in occurrence of Type 1 DM
3) Protective alleles = Lower risk of Type 1 DM
Which region of the MHC molecule is most affected by polymorphism?
Antigen binding site
Describe the role of MHC in T cell development?
1) Positive selection: Immature T cells that can bind to self-peptide/ MHC complex on thymic epithelial cells are selected
2) Negative selection in thymus medulla: MHC-restricted T cells binding to self-antigen/ MHC with very high affinity selected against
Describe how the MHC molecules can lead to release of autoreactive T cells to periphery? **
1) MHC-II polymorphism = change peptide binding region = faulty selection of T cells = failure to eliminate T cells that bind to self-antigen close to affinity threshold
» Maturation of autoreactive T cells
2) Faulty selection of Treg in thymus = compromise peripheral tolerance/ anergy of autoreactive T cells
Which gene related to glucose homeostasis is used for T cell selection and maturation?
Proinsulin gene
Describe how Proinsulin gene expression influences T cell selection?
Proinsulin gene has VNTR (variable number of tandem repeats) segment in promoter region
- If mostly class 1 VNTR is expressed in thymus medullary epithelial cells
> > Less proinsulin gene expressed
> > Less insulin made for use as self-antigen to educate T cells
> > Faulty selection of autoreactive T cells and Treg
Describe the VNTR of proinsulin expressed in pancreas?
Pancreas: Express equal amount of Proinsulin with class I and III VNTR
Compare the effects of Class I and III VNTR in proinsulin gene?
Class I = under-expression of insulin = faulty selection of Treg and T cells = increase risk of IDDM
Class III = Increase expression of insulin for T cell selection = Protective against IDDM
List 3 genes apart from proinsulin gene that are implicated in Type 1 DM development?
PTPN22 (protein phosphotyrosine-specific phosphatase)
AIRE (autoimmune regulator)
MODY
Describe the function of AIRE in T cell selection?
AIRE = transcription factor:
regulate expression of peripheral self-antigens in thymic epithelial cells for deleting autoreactive T-cells
Describe how virus can cause beta cell death in type 1 DM?
Virus infect Beta cell
» express protein similar to self-reactive peptide (autoantigen)
» Beta cell express viral antigen on MHC-II and MHC-I:
a) activate autoreactive CD4 T cells»_space; Activate B cells to make anti-B cell antibodies
b) Activate CD8+ T cell
> > Beta cell elimination
Describe how damage to Beta cells (e.g. due to diet, trauma, toxins) can lead to beta cell depletion in Type 1 DM?
Stimuli damage Beta cells
> > damaged beta cells release beta cell proteins (autoantigens)
> > APC acquire and present beta cell autoantigens on MHC-II
> > Activation of autoreactive CD4+ T cell:
- Secretion of TNFα, IFNγ»_space; activates macrophages (secrete IL-1)
- Activation of CD8+ T-cells
Explain the physiological role of MODY2?
Code for Glucokinase:
- Used for rate limiting reaction: Glucose»_space; G 6-P
- Act as threshold and determine level of glucose to trigger insulin release
Explain how MODY2 mutation leads to Type 1 DM?
Inactivate glucokinase
> > loss of regulation on intracellular glucose level
> > loss of regulation on insulin secretion
Explain how MODY3: HNF-1α, MODY1: HNF-4α, MODY5: HNF-1β mutations can lead to Type 1 DM?
Mutation = faulty expression of genes encoding for protein component in TCA-cycle
> > Decrease ATP synthesis, glucose transport
> > Unable to trigger Insulin release
Explain how MIDD mutation causes Type 1 DM?
Maternally Inherited Diabetes with Deafness (MIDD):
mutation of mitochondrial genome = cannot respond glucose, make ATP
No ATP = cannot trigger insulin release
Explain how PNDM mutation causes type 1 DM?
Mutation of Permanent Neonatal Diabetes Mellitus (PNDM):
> > permanent activation of K-ATP channel
cannot depolarize beta cell
. cannot release insulin
Explain how type 1 DM causes weight loss?
Insulin = suppress proteolysis and gluconeogenesis
Depletion of insulin = unopposed increased proteolysis and gluconeogensis
> > Elevated blood glucose not used or uptake by cells (low insulin-dependent glucose transport)
> > weight loss
Explain how Type 1 DM leads to ketoacidosis? ***
Low insulin:
- Loss of inhibition on Hormone Sensitive Lipase (HSL) = Increase conversion of TAG in adipocytes to FA in circulation
- Less Acetyl-CoA converted to Malonyl CoA = loss of inhibition on FA translocation into mitochondria = Increase FA into cell mitochondria
> > Increase B-oxidation»_space; ketone body production more than elimination by TCA cycle»_space; Ketoacidosis
Explain how Type 1 DM leads to dehydration?
Increased blood glucose: Increase osmolarity in serum:
a) increase movement of water from tissue into serum
b) decrease water reabsorption in kidney
> > Polysuria
> > dehydration
List effects of IDDM on brain?
microangiopathy, cerebral vascular infarcts, hemorrhage
