Endocrinology: Pathology - Endocrine pancreas

Question 1

How many islets of Langerhans are found within the pancreas?

Answer 1

~1 million

Question 2

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?

Answer 2

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

Question 3

What are the two main physiologic effects of pancreatic polypeptide on the GIT?

Answer 3

1. Increased secretion of gastric/intestinal enzymes
2. Inhibition of GI motility

Question 4

What are the two main physiologic effects of vasoactive intestinal peptide?

Answer 4

Increased glycogenolysis -> hyperglycaemia
Increased GI fluid secretion -> secretory diarrhoea

Question 5

Which of the cell types found in the endocrine pancreas can cause carcinoid syndrome?

Answer 5

Enterochromaffin, via release of 5HT

Question 6

Criteria for diabetes mellitus diagnosis

Answer 6

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

Question 7

Describe the classification of diabetes in terms of primary vs secondary

Answer 7

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)

Question 8

Five causes of secondary diabetes mellitus

Answer 8

Pancreatitis
Pancreatectomy
Pancreatic cancer
Cystic fibrosis
Haemochromatosis

Question 9

What % of primary diabetes mellitus is type I vs type II?

Answer 9

Type I 5-10%
Type II 90-95%

Question 10

Describe the three regulatory mechanisms of normal glucose homeostasis

Answer 10

1. Degree of hepatic glucose production
2. Degree of glucose uptake and utilisation by peripheral tissues (especially skeletal muscle)
3. Actions of insulin and counter-regulatory hormones (e.g. insulin) on glucose uptake and metabolism

Question 11

What are the two main metabolic complications seen in diabetes mellitus? Which of these is more common in type I vs type II?

Answer 11

1. Diabetic ketoacidosis (more common in type I)
2. Hyperosmolar nonketotic coma (more common in type II)

Question 12

Describe the pathogenesis of diabetic ketoacidosis

Answer 12

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

Question 13

Describe the pathogenesis of hyperosmolar nonketotic coma

Answer 13

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

Question 14

How long post onset of diabetes mellitus does it typically take for longterm complications to arise?

Answer 14

15-20yrs

Question 15

Five metabolic effects of insulin

Answer 15

1. Increased glucose uptake/utilisation in tissues (especially skeletal muscle)
2. Increased glycogen synthesis (hepatic and skeletal muscle)
3. Decreased gluconeogenesis
4. Increased lipogenesis
5. Increased protein synthesis

Question 16

Two metabolic effects of glucagon

Answer 16

1. Increased hepatic gluconeogenesis, glycogenolysis
2. Decreased hepatic glycogen synthesis

Question 17

Seven macrovascular complications of diabetes mellitus

Answer 17

1. Generalised large artery atherosclerosis
2. Increased risk of coronary and cerebral ischaemic events (e.g. MI, stroke)
3. Aortic aneurysm formation
4. Arterial insufficiency and lower limb gangrene
5. HTN
6. Dyslipidaemia
7. Renal vascular insufficiency

Question 18

Six microangiopathic complications of diabetes mellitus

Answer 18

1. Diabetic nephropathy
2. Visual loss: diabetic retinopathy, cataracts, glaucoma
3. Peripheral neuropathy (affecting both motor and sensory neurons)
4. Autonomic neuropathy (can cause impotence, postural hypotension)
5. Mononeuropathy (wrist drop, foot drop, cranial nerve palsy)
6. Increased infection risk

Question 19

In what % of diabetic patients does infection cause death?

Answer 19

5%

Question 20

What % of diabetic patients will develop diabetic nephropathy?

Answer 20

30-40%

Question 21

What % of diabetic patients will develop diabetic retinopathy?

Answer 21

60-80%

Question 22

Describe the pathogenesis of type I diabetes mellitus

Answer 22

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

Question 23

What % of islet cells must be destroyed before hyperglycaemia and ketosis result?

Answer 23

90%

Question 24

Three antibodies present in type I diabetes mellitus

Answer 24

1. Anti-GAD
2. Anti-ICA512
3. Anti-insulin

Question 25

What are the two pathogenic hallmarks of type II diabetes?

Answer 25

1. 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
2. B cell destruction:
   - Initial compensatory hyperinsulinaemia that gives way to B cell failure and mild to moderate insulin deficiency

Question 26

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

Answer 26

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

Question 27

Compare and contrast the genetics of type I vs type II diabetes mellitus, in terms of twin concordance and HLA linkage

Answer 27

TYPE I DM:
- 50% twin concordance
- HLA-D linked

TYPE II DM:
- 90-100% twin concordance
- No HLA association

Question 28

Compare and contrast the pathogenesis of type I vs type II diabetes mellitus

Answer 28

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

Question 29

Compare and contrast the histological findings seen in type I vs type II diabetes mellitus

Answer 29

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