Mechanisms & Genetics of Diabetes - Scott Flashcards
What are the 3 pathways that function in normal cells to maintain glucose homeostasis?
Glucose stimulates release of insulin from pancreatic β cells.
Insulin stimulates uptake of glucose by skeletal muscle and adipose tissue
via Glut4.
Insulin stimulates glycogen synthesis and conversion of fatty acids to
triglycerides in liver, inhibits gluconeogenesis
What are the various categories (types) of diabetes?
DM Type 1
DM Type 2
Gestational Diabetes
Maturity Onset Diabetes of the Young (MODY)
What causes Maturity Onset Diabetes of the Young (MODY)?
Rare, autosomal dominant mutations in single genes that disrupt pancreatic β cell function.
Give clues to important functions in β cells.
MODY1 hepatocyte nuclear transcription factor (HNF)-4α
2 glucokinase
3 HNF-1α
4 PDX1 (Insulin Promoter Factor-1
5 HNF-1β
6 NeuroD1
***All are transcription factors that effect pancreatic beta cells.
How is insulin secretion regulated?
Regulated mainly by glucose:
Glucose taken up by GLUT1 or GLUT2
phosphorylated by glucokinase
Glucose-6-phosphate»_space;> ATP
ATP inhibits K+ channel > depolarization
Depolarization > opening of voltage
dependent Ca2+ channels
Influx of Ca2+ > secretion of insulin
MODY 1
HNF-4α- is a β cell transcription factor. Targets include GLUT2 and pyruvate kinase.
MODY 2
Glucokinase catalyzes rate limiting step in regulation of insulin secretion
MODY 4
PDX1 is a β cell transcription factor necessary for early development, and for transcription of insulin, glucokinase, GLUT2.
What is the etiology of Type 1 Diabetes?
Insulin is not made because pancreatic beta cells are
destroyed by an autoimmune process.
Genetics-
Identical twin concordance 40-60%.
50% of genetic risk comes from polymorphisms in MHCII alleles.
Immunological characteristics- Autoantibodies to islet proteins Insulitis- infiltration of T cells. T cells recognize and proliferate in response to β cell antigens. Autoantibodies before development of T1D.
What are the major genetic variants associated with Type 1 Diabetes?
polymorphisms in MHCII genes => alter peptide binding sequences
Specific MHCII alleles are strongly associated with T1D:
DQA10301
DQB10302
DQB1*0201
Why/how are MHC II proteins important in immune system function?
MHCII proteins and the immune response:
MHCII present antigen peptides to T cell with cognate TCR.
TCR interacts with complex of particular MHCII + peptide activates T cell => Initiates adaptive immune response.
MHCII restriction:
Different MHCII alleles encode MHCII proteins with different peptide binding capabilities.
Repertoire of MHCII proteins determines which peptides will be presented to TCR.
Repertoire of MHCII proteins influences immune response and tolerance.
MHCII proteins and tolerance to “self” antigens:
During T cell development MHCII proteins present “self” peptides on cell surface.
T cells expressing TCR that strongly bind to specific MHCII + “self” peptide complex are targeted for apoptosis.
Tolerance requires that individual’s MHCII proteins be able to bind self antigens.
What is the model of Autoimmune etiology of Type 1 Diabetes?
- High risk variants of MHCII can not bind pancreatic beta cell “self” peptides strongly.
- T cell receptors (TCR) recognizing self antigens of pancreatic beta cells are not weeded out during development
- These T cells have the potential to mount an autoimmune attack when the right environmental trigger occurs.
- Specific environmental triggers lead to inflammatory response (possibly specific viral infections or microbiome)
- Autoimmune response:
T cells expressing TCR which recognize beta cell peptides are clonally expanded => mount immune response against beta cells. - Individuals become symptomatic when ~80% of beta cells are destroyed. Only recourse is to supply artificial insulin.
What are four of the immunomodulatory therapies being tested for Type 1 Diabetes treatment?
Teplizumab = Anti-CD3- alters T cell immune response at several levels
Oral insulin as a decoy for anti-insulin antibodies
CTLA4-Ig (Abatacept) for Prevention of Abnormal Glucose Tolerance = Activates CTLA4 leading to T cell inhibition
T1DM Immunotherapy Using CD4+CD127lo/-CD25+ Polyclonal Tregs (Treg) = adoptive transfer of autologous transfer of Tregs to treat recently diagnosed T1D
What is the etiology begin Type II Diabetes?
Excess nutrients at cellular level => Hyperglycemia, circulating free fatty acids =>
Inflammation, dysregulated lipid metabolism =>
Insulin resistance =>
Pancreatic Compensation (no DM) or
Relative insulin insufficiency =>
Beta cell destruction, absolute insufficiency => TYPE II DM
***Each step amplifies the previous step!
What is the genetic risk in Type II Diabetes?
Specific genes not known: Many genes associated with beta cell function with polymorphisms that confer a small risk have been identified mainly through genome wide association studies (GWAS) = TF7L2 Ppar gamma K+channel zinc transporter IRS calpain 10
What are the processes that contribute to insulin resistance? Involved tissues?
Processes: inflammation, dysregulation of lipid metabolism
Tissues: adipose, skeletal muscle and liver