L25- Endocrine Pathology V (pancreas) Flashcards
describe the maturation of insulin
1) Preproinsulin
- -> Endoplasmic Reticulum
2) cleavage of N-terminal + production of 2 disulfide bonds => Proinsulin
- -> Golgi Apparatus
3) cleavage of proinsulin => Insulin + C-peptide (both stored in granules and released together)
what is the key laboratory difference from over-injection of insulin versus an insulinoma
Injection: low glucose, high insulin, LOW C-peptide
Insulinoma: low glucose, high insulin, HIGH C-peptide
describe the effects of insulin (hint- 3 tissues affected, 3 main effects each)
Liver:
- inc glycogen synthesis
- inc lipogenesis
- dec gluconeogenesis
Muscle:
- inc glucose uptake
- inc glycogen synthesis
- inc protein synthesis
Adipose:
- inc glucose uptake
- inc lipogenesis
- dec lipolysis
describe the types of Presentations DM may have
1) asymptomatic: elevated blood glucose
2) classical symptoms: polyuria, polydipsia, elevated glucose
3) severe presentation / coma
what are the normal glucose values (fasting and random)
Fasting: 70 - 100 mg/dL (4.0-5.6 mmol/L)
Random: 79-140 mg/dL (4.4-7.8 mmol/L)
list some secondary causes of DM
-pancreatic disease (no insulin production)
- hormonal antagonists to insulin (cortisol, GH, catecholamines)
- drug / chemical induced
- Infections: CMV, mumps, coxsackie B
- Genetics: down syndrome, turner syndrome
- Gestational DM (typically resolved after delivery)
Features of DM I:
- (1)% of DM cases
- (2) age of onset
- (3) rate of onset
- (4) weight of patient
- (5) prevalence of ketosis
- (6) insulin levels
- (7) link to HLA?
- (8) auto-antibodies?
1- 10% 2- <40 y/o 3- rapid 4- lean / normal 5- prone to ketosis 6- low to absent insulin levels 7- presence of HLA link 8- commonly linked to auto-antibodies
Features of DM II:
- (1)% of DM cases
- (2) age of onset
- (3) rate of onset
- (4) weight of patient
- (5) prevalence of ketosis
- (6) insulin levels
- (7) link to HLA?
- (8) auto-antibodies?
1- 90% 2- >40 y/o 3- slow 4- obese 5- rarely in ketosis 6- high (normal or reduced) insulin 7- no HLA link 8- no auto-antibody link
list / describe the genetic factors affecting DM I
- 40% concordance between monozygotic twins
- association with HLA-: DR3, DR4, DQA1, DQB1
list the environmental factors affecting DM I
Viruses: coxsackie B, rubella, CMV, mumps
drugs and toxins
DM I Autoimmunity:
- arises from a failure of (1)
- most antibodies are considered (2)
- (3) occurs and is defined as DM I once (4) has happened
1- failure T-cell self-tolerance
2- islet cell antibodies (ICA)
3- long pre-diabetic phase (destruction of β-cells)
4- 90% of β-cells are destroyed
describe the etiological hypothesis of DM type I
1) viral / chemical attack on β-cells
2) exposure of new β-cell Ags OR molecular mimicry of viral / β-cell structures
3) Ags –> activate T-cells in pancreatic lymph nodes
4)
- CD4+ (Th) / CD8+ (Tc) cells are involved in β-cell damage
- HLA system is involved in Ag presentation
- CKs from Th1 can activate B-cells –> Ig production against β-cell Ags
what are the two key factors involved in DM type II etiopathogenesis
- insulin resistance
- β-cell exhaustion / failure
describe the genetic factors involved with DM II
- > 90% concordance between monozygotic twins
- 5-10x inc risk if 1st degree relative has it
-typically polygenic disorder –> simultaneous presence of several genes + environmental factors
(NO HLA association)
describe the environmental factors involved in etiopathogenesis of DM II
Obesity:
- 80% Pts are obese
- risk increases with BMI
- fat distribution- higher risk with central obesity (apple shaped) > peripheral obesity (pear shaped))
Lack of Exercise
-independent from obesity
describe Obesity’s role in DM II etiopathogenesis
Contributes to insulin resistance + β-cell dysfunction:
1) free FA production antagonizes insulin action
2) change in adipokines levels
3) inflammation: IL-1, amyloidosis w/in islets
describe appearance of pancreas in DM I
selective destruction of insulin secreting β-cells
insulitis- chronic inflammation infiltrate of islets (mainly insulin containing islets)
describe appearance of pancreas in DM II
moderate reduction in islet tissue
variable degrees of amyloid deposition
list some of the long-term complications of DM
- nephropathy
- neuropathy
- retinopathy
- heart disease
- stroke
- feet issues
list the biochemical signs of DM (lab signs)
- hyperglycemia, glycosuria
- ketoacidosis, ketonuria
- hyperlactatemia
- hyperlipidemia
- hypovolemia, hyperosmolarity
classic triad of DM Sxs (indicate more in DM I or II)
(prominent in DM I > II)
-polyuria / nocturia (osmotic diuresis)
- polydipsia (thirst)- dehydration
- polyphagia (persistent catabolic state)
list the non-triad DM symptoms
- weight loss (type I more, catabolic state)
- tiredness (muscular weakness due to proteolysis and dec glucose)
- blurred vision (dehydration of lens, aqueous/vitreous humoe)
Severe:
- vomiting (ketones stimulating area postrema)
- hyperventilation (Kussmaul breathing- compensation to metabolic acidosis)
list the criteria required for DM diagnosis (ADA / WHO)
(one of the following)
1) random glucose >200, plus classical signs/Sxs
2) fasting glucose > 126
3) 2hr plasma glucose > 200 during OGTT
4) HbA1c > 6.5%
describe OGTT
(oral glucose tolerance test)
- fast overnight (8hrs)
- measure basal glucose (time 0)
- give 75g glucose water
- measure glucose at 2hrs
<140, normal
140-199, pre-diabetic
>200, DM
