Endocrinology: Pathology - Endocrine pancreas Flashcards
How many islets of Langerhans are found within the pancreas?
~1 million
Four major and two minor cell types of the endocrine pancreas, and the hormones they release. Which of these cells are also found scattered throughout the exocrine pancreas?
Major:
- B cells: insulin
- a cells: glucagon
- d cells: somatostatin
- PP cells*: pancreatic polypeptide
Minor:
- D1 cells: VIP
- Enterochromaffin cells: 5HT
- also scattered throughout exocrine pancreas
What are the two main physiologic effects of pancreatic polypeptide on the GIT?
- Increased secretion of gastric/intestinal enzymes
- Inhibition of GI motility
What are the two main physiologic effects of vasoactive intestinal peptide?
Increased glycogenolysis -> hyperglycaemia
Increased GI fluid secretion -> secretory diarrhoea
Which of the cell types found in the endocrine pancreas can cause carcinoid syndrome?
Enterochromaffin, via release of 5HT
Criteria for diabetes mellitus diagnosis
Random glucose >200mg/dL (11.1mmol/L) with classic signs and symptoms
Fasting glucose >126mg/dL (7mmol/L) on more than one occasion
Abnormal OGTT glucose >200mg/dL (11.1mmol/L) 2hrs after standard glucose load
Describe the classification of diabetes in terms of primary vs secondary
Primary:
- Type I: AI disease characterised by B cell destruction and absolute insulin deficiency
- Type II: peripheral insulin resistance and inadequate secretory response by B cells
Secondary:
- Due to other identifiable causes of islet cell destruction or insulin dysfunction (e.g. pancreatitis, pancreatic cancer)
Five causes of secondary diabetes mellitus
Pancreatitis
Pancreatectomy
Pancreatic cancer
Cystic fibrosis
Haemochromatosis
What % of primary diabetes mellitus is type I vs type II?
Type I 5-10%
Type II 90-95%
Describe the three regulatory mechanisms of normal glucose homeostasis
- Degree of hepatic glucose production
- Degree of glucose uptake and utilisation by peripheral tissues (especially skeletal muscle)
- Actions of insulin and counter-regulatory hormones (e.g. insulin) on glucose uptake and metabolism
What are the two main metabolic complications seen in diabetes mellitus? Which of these is more common in type I vs type II?
- Diabetic ketoacidosis (more common in type I)
- Hyperosmolar nonketotic coma (more common in type II)
Describe the pathogenesis of diabetic ketoacidosis
Insulin deficiency and glucagon excess leads to decreased peripheral utilisation of glucose and increased gluconeogenesis
Resultant hyperglycaemia causes an osmotic diuresis -> dehydration
Activation of ketogenesis increases lipolysis and mobilises free fatty acids which are then converted to ketone bodies -> ketoacidosis
Describe the pathogenesis of hyperosmolar nonketotic coma
Severe dehydration results from sustained osmotic diuresis caused by hyperglycaemia
There are sufficient insulin levels to prevent unrestricted hepatic free fatty acid oxidation and therefore formation of ketone bodies -> no ketoacidosis
How long post onset of diabetes mellitus does it typically take for longterm complications to arise?
15-20yrs
Five metabolic effects of insulin
- Increased glucose uptake/utilisation in tissues (especially skeletal muscle)
- Increased glycogen synthesis (hepatic and skeletal muscle)
- Decreased gluconeogenesis
- Increased lipogenesis
- Increased protein synthesis
Two metabolic effects of glucagon
- Increased hepatic gluconeogenesis, glycogenolysis
- Decreased hepatic glycogen synthesis
Seven macrovascular complications of diabetes mellitus
- Generalised large artery atherosclerosis
- Increased risk of coronary and cerebral ischaemic events (e.g. MI, stroke)
- Aortic aneurysm formation
- Arterial insufficiency and lower limb gangrene
- HTN
- Dyslipidaemia
- Renal vascular insufficiency
Six microangiopathic complications of diabetes mellitus
- Diabetic nephropathy
- Visual loss: diabetic retinopathy, cataracts, glaucoma
- Peripheral neuropathy (affecting both motor and sensory neurons)
- Autonomic neuropathy (can cause impotence, postural hypotension)
- Mononeuropathy (wrist drop, foot drop, cranial nerve palsy)
- Increased infection risk
In what % of diabetic patients does infection cause death?
5%
What % of diabetic patients will develop diabetic nephropathy?
30-40%
What % of diabetic patients will develop diabetic retinopathy?
60-80%
Describe the pathogenesis of type I diabetes mellitus
Autoimmune disease due to islet destruction by immune effector cells reacting against B-cell antigens (insulitis)
Due to failure of self-tolerance in T cells (type IV hypersensitivity reaction), likely as a result of genetic susceptibility (HLA-D) +/- environmental insult (e.g. viral infection)
Antibodies are present but it is unclear whether they are causal or are produced as a consequence of injury
What % of islet cells must be destroyed before hyperglycaemia and ketosis result?
90%
Three antibodies present in type I diabetes mellitus
- Anti-GAD
- Anti-ICA512
- Anti-insulin
What are the two pathogenic hallmarks of type II diabetes?
- Insulin resistance (in which obesity plays a central role):
- Decreased responsiveness of peripheral tissues due to decreased number of receptors and impaired intracellular receptor signalling - B cell destruction:
- Initial compensatory hyperinsulinaemia that gives way to B cell failure and mild to moderate insulin deficiency
Compare and contrast the clinical presentation of type I vs type II diabetes mellitus, in terms of age of onset, weight, blood insulin levels, presence of absence of autoantibodies, and frequency of DKA
TYPE I DM:
- Onset in childhood/adolescence
- Normal weight or weight loss
- Decreased blood insulin levels
- Autoantibodies present (anti-insulin, anti-GAD, anti-ICA512)
- DKA occurs in absence of insulin therapy
TYPE II DM:
- Usually adult onset
- Obesity in 80%
- Increased blood insulin in early disease, normal or decreased in late
- No autoantibodies
- DKA rare
Compare and contrast the genetics of type I vs type II diabetes mellitus, in terms of twin concordance and HLA linkage
TYPE I DM:
- 50% twin concordance
- HLA-D linked
TYPE II DM:
- 90-100% twin concordance
- No HLA association
Compare and contrast the pathogenesis of type I vs type II diabetes mellitus
TYPE I DM:
- T cell dysfunction -> breakdown in self-tolerance to islet cell antigens
TYPE II DM:
- Insulin resistance in peripheral tissues
- Failure of B cell compensation leads to decreased insulin secretion in late stage
- Multiple obesity-associated factors
Compare and contrast the histological findings seen in type I vs type II diabetes mellitus
TYPE I DM:
- Insulitis (inflammatory infiltrate of T cells and macrophages)
- B cell depletion, islet atrophy
- Fibrosis
TYPE II DM:
- No insulitis
- Focal atrophy and amyloid deposition in islets
- Mild B cell depletion
