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REGUB: Path of T1DM (iii) (T1 (absent/low C peptide, often islet autoAbs…
REGUB: Path of T1DM (iii)
T1
onset: peak incidence 10-14, or 4-6 (juvenile)
AI destruction of islet cells rendered antigenic in genetically susceptible individuals as a consequence of exposure to environmental antigens
can't be prevented
silent progression over months/sometimes longer (subclinical B cell dysfunction)
typically becomes clinical with acute symptoms when critical mass of beta cells lost - hyperglycaemia
polyuria, polydypsia, polyphagia, weight loss, blurred vision, DKA
insulin-dependent always - absolute deficiency
absent/low C peptide, often islet autoAbs (anti-GAD, anti-IA2, anti-insulin) in >90%
autoabs may predate diabetes by yrs (observation of siblings of diabetic children who go on to also get DM)
not restrict to young people - if in adults often misdxed as aggressive T2 (clues: ketosis prone, not obese, early need for insulin)
Not all young people with DM have T1 - consider T2 or MODY if appropriate
Due to acute development of symp disease, vasc comps of T1 rare @ dx (arise 15-20 yrs later)
0.4% risk in general pop but rising
rising incidence, tendency to present @ younger age
excellent animal models of disease (mouse, rat)
lymphocytic inflamm of islets (insulitis) - normal exocrine tissue, B cell selectively targeted
immunosuppression after dx may delay absolute B destruction, but no effective prevent yet possible
A/W other AI disease: all T1 screened for thyroid (abs in 25%) + coeliac (5%)
Genetics of T1
strong a/w HLA DR3+4 genotypes
HLA DR2: protective
monozygotic twins: only 40-50% concordance - environmental trigger significant
if parent affected: 2.5-5% risk of child
if sibling affected: 5-8% risk
85% of patients have no affected relative
marked geographical variation: high in Finland, Norway, Sardinia, UK, Ire - predominant genotypes explain much of this
Environmental trigger in T1
uncertain
possible viral infection - molecular mimicry of islet cell antigens in susceptible individuals, or possible direct cell damage
geographic + seasonal variations in incidence
possible related to breastfeeding/weaning
timing + nature of triggers may be important
MODY
specific gene defects involving insulin secretion
hepatic nucelar factors 1alpha + 4 alpha
glucokinase
rare cause of DM in young
strong family hx - AD
not insulin dependent - tx with sulphonylureas
consider if young, insulin-independent, strong family hx
no phenotypic signs of insulin resistance
Metabolic syndrome
aka insulin resistance syndrome, syndrome x
Clustering of abdo obesity, abnormal lipids (high TGs, low HDL), insulin resistance tending to cause pre-diabetes/T2DM, HTN
major risk factors for CVD/atheroma
syndrome identifies as key CV risks (other than high LDL) that tend to cluster together
but is this a true syndrome (anything other than sum of its parts + their risks?) - management the same
frequency increases with age
T2
strongly a/w obesity, limited physical activity, age, affluence (environmental factors)
initiated by insulin resistance compensated for by high insulin level to main normal glucose levels (high C peptide)
with time, potential progression to pre-diabetes + then overt diabetes with hyperglycaemia
insulin levels remain normal/high, but hyperglyc impairs B cell function + there is eventual B cell loss - impaired insulin secretion contributes more to hyperglyc than the insulin resistance (resistance compounded by secretory problem)
end-organ resistance + later impaired insulin secretion contribute to hyperglyc
inadequate compensatory response: relative insulin deficiency
even @ end stage there is still some insulin secretion, tends to inhibit ketogenesis - hence DKA rare in T2
intrauterine factors: a/w LBW ('thrifty phenoytype', reduced foetal growth a/w some chronic conditions later in life, poor b cell development)
established disease with hyperglyc present many yrs before becoming clinically evident - comps present @ or soon after dx
polyuria, polydipsia, weight loss, fatigue, blurred vision, infections
Comps often are neuropathy, MI, impotence, retinopathy
rarely with acute biochem comps
DKA
HHS (hyperosmolar hyperglycaemic state) - high blood sugar, high osmolarity without ketosis, usually a/w illness (e.g. MI) or infection
screen @ risk patients
identify during long latent phase/pre-diabetes
alter natural hx + avoid progression/comps
over 45: FPG/HbA1c every 3 yrs
earlier if risk factors (e.g. big babies, gest DM, vasc disease, PCOS, previous pre-diabetes)
is pop health measures better? (e.g. tackling obesity)
screen for comps: retinopathy, nephropathy (microalbuminuria)
screen for txable risks: BP + lipids
Genetics of T2
monozygotic twins: 90% concordance
polygenic inheritance: multiple genes controlling insulin response + secretion
40% have 1st degree relative
more frequent in some ethnic groups (black Americans, native Americans, Pacific islanders, south asians)