Pathogenesis of Type I DM Flashcards
most common type of diabets
type II
TIDM: primarily a result of pancreatic __ cell destruction with consequent __
deficiency, which is prone to __. This form includes cases due to an autoimmune process and those for which the etiology of __ cell destruction is unknown
primarily a result of pancreatic beta cell destruction with consequent insulin
deficiency, which is prone to ketoacidosis. This form includes cases due to an autoimmune process and those for which the etiology of beta cell destruction is unknown
- ABSOLUTE INSULIN DEFICIENCY
- REQUIRES INSLUIN TO SUSTAIN LIFE
What type of diabetes is Ketosis more common?
type I DM. Ketosis is less common in Type 2 dm.
Type 2 diabetes:
• May range from predominant insulin resistance with relative insulin deficiency to
a predominant secretory defect with insulin resistance. Ketosis is not as common. (Diabetes Canada 2018 practice guideline)
• Relative insulin deficiency
• May require insulin to improve metabolic control later in disease process
___ is used as a marker of endogenous insulin production. Why?
Cpeptide. marker of endogenous insulin production because it is created when pro-insulin(can only be made in the body) is cleaved to form insulin in its active form
which country has the highest T1DM rate?
canada
gender differences of type I DM based on age
before puberty, girls = boyds. peak age 12-14, and after 20, men>women
starting symptoms of type I DM
it’s actually not due to dysglycemia. you usualy start with indigestion and GI stuff
outline some genes that contribute to the T1DM polygenic inhertiance pattern
HLA-DQ and Dr, pre-proinsulin, PTPN22, IL2receptor, CTLA-4, interferon-induced helicase
outline the role of the HLA antigen-class I and II molecuels
class I HLAs are on most nucleated cells, presents cytosolically, and presents proteins to CD8+ t cells.
Class II HLAs are on APCs, Macrophages, B cells and activated T cells. presents proteins to CD4+ T cells
90% of T1D patients are DR3-DQ2 or DR4-DQ8
outline how MHC complexes on Bcells and APCs cause Betaislet cell destruction
In pancreas, there are beta cells in the islets that produce insulin. B cels and APCs have MHC antigens on them. The MHC allow the B cells of APC to bind to antigen and present to a T cell which can activate CD4 or CD8 T cells which can turn on an cause islet cell destruction.
outline the role of the insulin gene on type I DM
• Only known pancreatic beta cell specific antigen • Variable number of tandem repeats (VNTR) in the promoter region of insulin gene
- fewer repeats = lower insulin expression.
genetic contribution to the risk of D1Dm based on offspring, siblings or identical twins
name a few autoantibodies that contributes to islet-targeted autoimmunity
• Insulin (IAA)
• Glutamic acid decarboxylase (GAD) – present in islets, CNS, and testes
• Insulinoma-associated antigen 2 (IA-2) – protein tyrosine phosphatase
(PTP) related protein
- Zinc transporter 8 (ZnT8A)
- Islet Cells (ICA)
5 diseases that T1Dm is also associated with
- autoimmune thyroidoitis
- celiac disease
- addisons disease
- autoimmune polyglandular syndrome type 2
- IPAX
viruses associated with Type I diabets
rotavirus, rubella, mumps and coxsaxkie/enterovirus can cause direct destruction of beta cells,
relationship between cows milk, vitamin D exposure, cereal, and omega3 fatty acids to T1DM
cowsmilk; Early exposure to cow’s milk associate with higher risk of T1DM (in some
studies)
Vitamin D; reduced T1Dm risk
Cereals; Studies found increased risk of islet cell antibodies if exposure to cereal
before age 3 months or after 7 months
Omega 3 fatty acids: (animal studies) protective role in the inflammatory response associated
with islet autoimmunity. (Human clinical trial underway).
how does the gut microbiota differ between someone with type I DM and someone ne hehealthy
• Low abundance of butyrate-producing species in autoantibody
positive children
• Increased gut epithelial permeability, or a ‘leaky gut’, has been observed
in T1D, and it pre-dates onset of T1D
Pathophysiology of T1D-related complications:
5 pathways that cause overall cellular stress that hyperglycemia triggers
hyperglycemia causes activation of:
- ROS
- polyol pathyway
- hexosamine pathway
- PKC pathway
- Advanced glycation end product (AGE) pathway
strategies for prevention of T1DM
Secondary Prevention: Abatacept (CTLA4-Ig) preserved c-peptide in age <18 but not age>18
secondary and primary preventsion of T1D
primary; anticd3
secdonary; preservation of cpeptide via abatacept
outline the general pathway of insulin secretiong
glucose enters the pancreatic cell via GLUT2, causing ATP to increase and ATP-sensitive K+ channel to release K+, DEPOLARIIZNG the cell. depolarization opens the voltage dependent Ca2+ channel, causing ca2+ to enter the cell. this rush of calcium promotes vesical release, releasing insulin into the blood.
• Which of the following MODY does not require treatment?
1. Glucokinase 2. HNF1A 3. HNF4A 4. HNF1B
Glucokinase • No long term complications • No need for treatment
