type 1 and type 2 diabetes Flashcards
pathogenesis of type 1 diabetes and what are the main infiltrators
- pancreatic beta cell destroyed by an autoimmune process
- T cell mediated autoimmune and also get B cells
- T lymphocytes destroy beta cells directly eg cytotoxic eg CD
- B cells secrete antibodies
- loss of beta cells and loss of function leading to reduced insulin
- also get increased resistance to insulin
autoantibodies assoc to type 1 dm 4
- anti GAD glutamic acid decarboxylase
- antibodies to insulin
- antibodies to islet cell surface IA2 antibodies
- protein tyrosine phosphatase antibodies
what % do symptoms occur of beta cells lost
80-90%
which one has a more genetic implication type 1 or type 2
type 2 dm
prevalence of dm 1
0.5% of population
what genes is type 1 dm assoc too
HLA
-Dr3 and Dr4 in caucasians
risk of diabetes in father, mother, non hla identical sibling, hla identical sibling, non identical twin and identical
9% 3 3 16 20 35
other than genetics what other factors trigger dm1
- environment: exposure to cow milk, viruses
- geographic variation
- seasonal variation: peaks in winter
- inverse assoc. to BMI and age of onset
children who are younger at dx are more likely to over weight
childhood obesity increase risk
what is the accelerator hypothesis of type 1 dm
obesity causes insulin resistance and hence greater insulin secretion leading to increased exposure of immune system to insulin and the pancreas so increase auto-immune response
what other autoimmune diseases is diabetes assoc. too
coeliac disease addison hypothyroidism grave's rheumatoid arthritis
symptoms of type 1 dm
- fatigue
- polyuria: as glucose pulls water with it and more glucose in renal then can be absorbed
- kussmaul breathing
- nocturia
- thirst
- polydipsia
- tachycardia
- hypotension
- weight loss as unrestrained lipolysis
- ketoacidosis: elevated H+ drives out K+
what does LADA stand for
latent autoimmune diabetes of adulthood
ie as usually presents 5-7 years old 1dm
-defined as the presence of islet autoantibodies in high titre, without rapid progression to insulin therapy
what is kussmaul respiration
increased rate of breathing- greater total expiration of CO2 to blow off co2 and raise Ph of blood due to ketoacidosis
acute presentation of DM1
- usually <40
- failure to grow
- short hx of florid osmotic symptoms and rapid weight loss
what is uncontrolled in diabetes
ie get uncontrolled glucagon
-uncontrolled gluconeogenesis as unsuppressed glucagon release
-uncontrolled lipolysis
-uncontrolled ketone generation
-uncontrolled glycogenolysis
-decreased protein synthesis and lipogenesis
so overall get weight loss as insulin
glucagon or insulin which is anabolic and which is catabolic
insulin is anabolic ie it builds
glucagon is catabolic ie it breaks down
what happens in renal failure with ketoacidosis
if there is severe dehydration then polyuria goes to oligouria
ketones accumulate so get ketoacidosis
how are ketones made
- uncontrolled lipolysis-> FFA accumulation
- uncontrolled hepatic beta oxidation means accumulation of acetyl coA
- acetyl coA build up is shunted to the ketone pathway
If we see lots of lymphocytes destroying the beta cells in the pancreatic islets, what name would we give to this inflammatory process affecting the islets?
-Insulitis: infiltration of the islets by mononuclear cells containing activated macrophages,helper cytotoxic and suppressor T lymphocytes
do the b or t cells destroy the beta cells
the T cells
what is also found alongisde autoantibodies in diabetes patients and what are the 3 main ones
- Firstly some patients have antibodies in the blood not only to beta cells but also certain viruses that have been implicated in leading to beta cell damage and dm
o Coxsackie B
o Mumps
o Cytomegalovirus
what affects insulin requirenment
meals carbs stress alcohol illness prolonged exercise some drugs
how does alcohol affect insulin requirenment
need less as suppress hepatic gluconeogenensis
how does illness affect insulin requirenment
induces insulin resistance
and increases glucose so need more insulin
stages of diabetes 1 appearance
use up insulin reserve first but later failing pancreas cant produce enough to prevent hyperglycaemia so symptoms start with food
-then can’t control fasting blood glucose and then get ketoacidosis
what is the insulin sick day rule
take 10% of insulin every 2 hours
type 2 dm pathology
- insulin resistance leads to elevated insulin secretion
- however, after a while the pancreatic beta cells are unable to sustain the demand for insulin so develop hyperglycaemia
- get overworking of beta cells leading to dysfunction and can then progress to 1dm
risk factors for 2dm ie things that increase risk of insulin resistance
-obesity
-age-some develop it despite being normal weight when older
-ethnicity
-genetics
sedentary lifestyle
-drugs: steroids
-conditions with insulin resistance eg acromegaly
-multiparity
disorders assoc. too 2dm
- hypertension
- dyslipidemia
- non alcoholic fatty liver
- pcos
how does obesity/ increased adipose tissue increase resistance
- adipocytes release FFA which induce insulin resistance as compete with glucose as fuel supply for oxidation msucles
- adipocytes release adipokines which act on specific receptors to influence insulin sensitivity in other tisues
- venous drainage of visceral adipose tissue to portal vein affecting the liver
- physical inactivity down regulate insulin sensitive kinase promoting ffa accumulation
how much beta cell function has been lost by presentation of 2dm
50%
why are beta cells damaged in 2dm
- overworked
- deposit amyloid in islets
- elevated plasma glucose and ffa exert toxic effects on beta cells
which gene is most important to 2dm and prevalence
TCF7L2
10% of population with 2x risk if 2 copies
what are the genes in 2dm usually related to
involved in beta cell function or turnover suggest mass important
why doesnt everyone with obesity get diabetes
because those who develop it have
- genetically impaired beta cell function
- reduced beta cell mass
- or a susceptibility of beta cells to attack toxic substances
clinical presentation of 2dm
- asyptomatic
- slower onset
- thirst and polyuria
- malaise
- infections eg thrush
- blurred vision as glucose sticks to lens
- complications
what is IAPP
islet amyloid polypeptide that is also secreted by beta cells when overworked but also induces apoptosis
what is the probability of an identical twin also getting 2dm
100% ish so big genetic component
other conditions that also have insulin resistance
- obesity
- pcos
- pregnancy (multiparity)
- acromegaly
- cushing
- cirrhosis
% of people with insulin resistance but will produce enough insulin that they won’t become diabetic
80%
what needs to be present then for the 20% that develop diabetes
amyloid deposition also which causes beta cells to die leading to hyperglycaemia-> insulin resistance and abnormal insulin secretion
what is the risk of developing diabetes if you develop insulin resistance
20%
can you also get insulin resistance in 1dm
yes if matched obesity
what mass can get increased in 2dm
mass of alpha cells so get increased glucagon secretion
why is weight loss and ketoacidosis less common in 2dm then in 1dm
as only a small amount of insulin is needed to suppress lipolysis and proteolysis
3 severe insulin resistance syndromes
leprechaunsim
rabson-mendenhall
type A insulin resistance
causes of secondary 2dm
-genetic defects of beta cell function (MODY)
-genetic defects on insulin action (leprechaunsim)
-pancreatic disease
-excess endogenous of hormonal antagonist to insulin
-drug induced
-unommon forms of immune-mediated dm IPEX
-assoc. to genetic
syndromes eg down’s syndrome, kline and turner
-gestational diabetes
what drugs can induce 2dm
- steroids
- thiazide diuretics
- phenytoid
antagnoist hormones from disorders to insulin
- growth hormone
- steroids in cushing
- glucagon in glucagonoma
- catecholamines in phaeochromocytoma
- thyrotoxicosis-thyroid hormones
what is IPEX
immunodysregulation polyendocrinopathy x syndrome
what is wolfram’s syndrome
didmoad diabetes i diabetes melitus optic atrophy nerve deafness friedrich ataxia
