type 1 diabetes mellitus Flashcards
what is type I diabetes mellitus?
autoimmune condition
insulin producing beta cells of the pancreas are attacked
results in partial or complete deficiency on insulin production
causes hyperglycaemia
requires life long insulin treatment
what are the classifications of diabetes?
WHO: type I type II hybrid forms other unclassified during pregnancy
there is a bit of a blend between type I and II.
genetic risk comes into both
but I is environmental trigger, and II is more obesity related
why is the distinction of type I and II not that simple
people think you have type I from a young age, and type II when you are older and fatter.
but it isnt that easy
autoimmune diabetes leading to insulin deficiency can present later in life = LADA (latent autoimmune diabetes in adults)
and T2DM can present in childhood
people think diabetic ketoacidosis is only a feature of T1DM, but it can also be present in type 2
monogenic diabetes can present phenotypically as type 1 or 2 (eg. MODY)
diabetes may present following pancreatic damage or other endocrine disease
when is type 1 diabetes usually diagnosed?
usually during childhood or early adulthood
but it is now shown that it can present through any decade of life
more difficult to diagnose type 1 later in life as many more people are presenting with type 2 then
what are the stages of development of type 1 diabetes? (C-peptide)
genetic predisposition -> potential precipitating event
overt immunological abnormalities - normal insulin release
progressive loss of insulin release - but glocose levels are normal
overt diabetes - c peptide is present still (it is mostly here that T1DM is diagnosed)
no C-peptide present
beta cell mass is constant during the first phase, but after the precipitating event, beta cell mass constantly drops till it is so low there is no insulin production
what is C-peptide?
endogenous insulin usually exists as proinsulin
it is then cleaved
this forms C-peptide and insulin
C peptide levels are what is measured
what is the second representation of stages of development of T1DM? (autoantibodies)
genetic risk
immune activation
immune response - development of a single autoantibody
stage 1 - normal blood sugar, more types of autoantibody
stage 2 - abnormal blood sugar, more autoantibodies
stage 3 - clinical diagnosis
stage 4 - long lasting T1DM, by now the immune attack has subsided as most beta cells have been destroyed (so fewer immune cells)
these autoantibodies can be measured to detect T1DM
why is the immune basis of T1DM important?
consider increased prevalence of other autoimmune diseases
risk of autoimmunity in relatives
more complete destruction of beta cells
autoantibodies can be used clinically
immune modulation offers the possibility on new treatments! (not there yet though)
what is an overview of the immunology of T1DM?
involves both innate and adaptive immune system
- presentation of auto-antigen to autoreactive CD4+ T lymphocytes
- CD4+ cells activate CD8+ T lymphocyes
- CD8+ cells travel to islets and lyse beta cells expressing the auto-antigen
- exacerbated by release of pro inflammatory cytokines
- underpinned also by defects in regulatory T cells that fail to suppress autoimmunity
are all beta cells destroyed in people with T1DM?
in many people yes
but in some people there are still some remaining that produce small amounts of insulin
but not enough to fully compensate for insulin resistance, so insulin therapy is still needed
what allele effects the presence of T1DM?
HLA-DR allele
it doesnt increase or decrease risk overtly.
change in risk depends on the locus of the allele
this was discovered from GWAs
what is the role of environmental factors in T1DM?
multiple factors implicated, but no causality has been established
eg: enteroviral infections (eg. coxsackie virus, corona?) cows milk protein exposure seasonal variation (lower in summer) changes in microbiota
what is the significance of pancreatic auto-antibodies in T1DM?
detectable in the serum of people with T1DM at diagnosis
but not needed for a diagnosis in most cases (only when not sure)
eg.
insulin antibodies (IAA)
glutamic acid decarboxylase(GADA) - widespread neurotransmitter
insulinoma-associated-2 autoantibodies (IA-2A)-zinc-transporter 8
what is the presentation of T1DM?
symptoms: polyuria polydipsia nocturia blurred vision (osmotic shifts in lens) recurrent infections eg. thrush weight loss fatigue
signs: dehydration cachexia (fat and muscle wasting) hyperventilation smell of ketones glycosuria ketonuria
what is the diagnosis of T1DM based on?
clinical features and presence of ketones
what are the effects of no insulin?
muscle: stimulates breakdown to form amino acids
liver: increased hepatic glucose output to form glucose
adipocytes: stimulates lipolysis to form glycerol and NEFA
what is the mechanism behind the formation of ketone bodies in T1DM?
NEFA enters the liver glucagon (in lack of insulin) stimulates the reaction turning fatty acetyl CoA into: acetyl CoA acetoacetate acetone + 3 OH-B
these are ketone bodies (these are acidic, and turn the blood acidic)
what are the aims of treatment of T1DM?
people with T1DM require insulin for life
aims:
maintain glucose levels without excessive hypoglycaemia
restore a close to physiological insulin profile
prevent acute metabolic decompensation (ketoacidosis)
prevent microvascular and macrovascular complication
what are the complications of T1DM?
of hyperglycaemia:
acute - diabetic ketoacidosis
chronic-
microvascular;
retinopathy, neuropathy (feet), nephropathy
macrovascular;
ischaemic heart disease, cerebrovascular disease, peripheral vascular disease
of treatment:
hypoglycaemia
how is T1DM managed?
insulin treatment dietary support structured education technology transplantation
it is self managed
what is the physiological insulin profile?
basal insulin has a flat profile (not zero, just level)
prandial peaks at each meal -
this has two phases
insulin is never completely suppressed (if it does, ketones start to be produced)
what is the insulin profile of a typical basal bolus regime?
one long acting at start of day - keeps insulin levels at never zero
three short acting during mealtimes
what is insulin pump therapy?
continuous delivery of short acting insulin analogue via pump
delivery of insulin into subcutaneous space
programme the device to deliver fixed units per hour throughout the day.
actively bolus for meals
what is the insulin profile from a pump like?
not perfect but much more similar to physiological
variable basal rates extended boluses (more like two stages of prandial release) greater flexibility
