Type 1 Diabetes Mellitus Flashcards
Define T1 DM
Autoimmune condition in which insulin-producing beta cells attacked and destroyed by immune system resulting in partial/complete deficiency of insulin causing hyperglycaemia. This requires life-long insulin treatment.
What is the overlap in diabetes classification?
- Autoimmune diabetes leading to insulin deficiency can present later in life = latent autoimmune diabetes in adults (LADA)
- T2DM may present in childhood
- Diabetic ketoacidosis can be a feature of T2DM
- Monogenic diabetes can present phenotypically as Type 1 or Type 2 diabetes (eg. MODY, mitochondrial diabetes)
- Diabetes may present following pancreatic damage or other endocrine disease
What are the stages of development of T1 DM?
Patient may have a genetic predisposition. A potential precipitating event occurs. Followed by overt immunological abnormalities but normal insulin release. Progressive loss of insulin release occurs but glucose is normal. Overt diabetes occurs but C-peptide present (usually stage at which detected). Finally no C-peptide present as endogenous insulin no longer produced.
Quantify stages of T1 DM development
- Genetic risk - 15x higher in those with relatives who have disease
- Immune activation - beta cells attacked
- Immune response - development of single autoantibody
- Stage 1 - normal blood sugar >2 autoantibodies
- Stage 2 - abnormal blood sugar >”
- Stage 3 - Clinical diagnosis
- Long standing T1D
Why is the immune basis of T1D important?
- Indicates increased prevalence of other autoimmune conditions
- Risk of autoimmunity in relatives
- More complete destruction of B-cells
- Autoantibodies can be clinically useful
- Immune modulation offers possibility of novel treatment
Describe immune response in T1DM
- Auto-antigen presented to autoreactive CD4+ T lymphocytes
- CD4+ activates CD8+
- CD8+ travels to islets and lyse beta cells expressing auto-antigen
- Exacerbated by release of pro-inflammatory cytokines
- Defects in regulatory immune system fail to suppress autoimmunity
What alleles indicate genetic susceptibility?
Certain HLA-DR alleles increase risk - DR2,6 and 8 have protective effects while DR3+4 have significant risk. 7 and 9 hold risk to those of african descent and asian respectively.
What environmental factors can precipitate T1 DM?
Causality has not yet been established. Enteroviral infections, cow’s milk protein exposure, seasonal variation and changes in microbiota can play a role.
What auto-antibodies can be detected in the pancrease indicating T1 DM?
Detectable in the sera of people with T1 diabetes but not generally needed for diagnosis:
- Insulin antibodies (IAA)
- Anti-glutamic acid decarboxylase (GAD) - enzyme that converts glutamic acid to GABA
- Insulinoma-associated-2 autoantibodies (IA-2A)-Zinc-transporter 8 (ZnT8)
What are symptoms of T1DM?
Polyuria, nocturia, polydipsia, blurring of vision, recurrent infections (thrush), weight loss, fatigue
What are signs of T1 DM?
Dehydration, Cachexia, Hyperventilation, Smell of ketones, glycosuria, ketonuria
What is T1 DM diagnosis based on?
DIAGNOSIS IS BASED ON CLINICAL FEATURES and presence of ketones (in some cases pancreatic autoantibodies / C-peptide may be measured)
What are the effects of insulin deficiency?
- Proteinolysis - amino acids released
- Increased hepatic glucose output
- Lipolysis - Glycerol and NEFAs produced
How are ketone bodies produced?
No negative feedback from insulin. Lack of glucose means acetyl CoA formed from fatty acids cannot enter Krebs Cycle so end up forming ketone bodies.
What are the 4 aims of treatment in T1 DM?
- Maintain glucose levels without excessive hypoglycaemia
- Restore a close to physiological insulin profile
- Prevent acute metabolic decompensation
- Prevent microvascular and macrovascular complications
How is T1 DM managed?
Insulin Treatment
Dietary support / structured educations
Technology
Transplantation
Draw physiological insulin profile
Prandial peak has 2 phases and insulin never fully suppressed - a flat baseline level of insulin exists