DM - Aetiology, presentation + diagnosis

Question 1

What are the potential secondary causes of DM?

Answer 1

1. Pancreatic disease (Pancreatitis, Trauma, Neoplasia etc)
2. Endocrine disease (Acromegaly, Cushing’s, Glucogonoma etc)
3. Drug-induced (Glucocorticoids, B-blockers, Thiazides)
4. Genetic defects of B-cell function
5. Infections (Congenital rubella, CMV etc)
6. Gestational diabetes

Question 2

Compare T1DM and T2DM.

Answer 2

T1DM:

• ketosis prone
• insulin deficient
• autoimmune (GAD + ICA antibodies)
• acute onset
• non-obese
• juvenile onset (usually <35)
• HLA DR3 + DR4
• FHx +ve in 10%

T2DM:

• non-ketosis prone
• insulin resistance ± deficiency
• non-autoimmune (metabolic syn)
• insidious onset
• obesity associated
• onset usually >35
• no HLA relation
• FHx +ve in 30%

Question 3

What is the pathogenesis of T2DM?

Answer 3

• complex interaction of environmental factors (obesity, lack of physical activity) and diabetogenic genes (contribute to insulin resistance)
• both factors cause insulin resistance and B-cell failure, which are exacerbated by hyperglycaemia
  → ‘glucose toxicity’ = high levels of glucose lead to poorer B-cell function leading to reduced insulin secretion
• ‘Thrifty gene hypothesis’ = favour fat storage + insulin resistance (protective mechanism in times of famine)

Question 4

Define metabolic syndrome.

Answer 4

1. Central obesity
2. Any 2 of the following:
   - low HDL concentration
   - high BP
   - high triglycerides
   - high fasting glucose

Question 5

What is the pathogenesis of T1DM?

Answer 5

1. Characterised by pancreatic B-cell destruction, usually leading to absolute insulin deficiency
   - autoimmune destruction of pancreatic islets in predisposed individuals (usually islet cell and glutamic acid decarboxylase antibodies +ve
   - may be idiopathic (antibody -ve)
2. Environmental factors:
   - peak age of 5-7
   - puberty
   - seasonal variations
   - coxsackie or parvovirus exposure
3. Genetic:
   - HLA DR3/4
4. Combination of genetic + environmental factors result in the development of insulitis (inflammation of pancreatic B-cells)
   - infiltration of activated T-lymphocytes
   - develop symptoms of DM when >90% of B-cells are destroyed

Question 6

What is a normal HbA1c? What HbA1c level indicates good glycaemic control in a diabetic patient?

Answer 6

1. Normal HbA1c: <42 mmol/mol

2. Good glycaemic control in a diabetic: <53 mmol/mol

Question 7

What results would you expect in a diabetic patient in the following tests?

(a) Fasting plasma glucose (mmol/L)
(b) 2h plasma glucose after OGTT (mmol/L)
(c) Resting plasma glucose (mmol/L)
(d) HbA1c (mmol/mol) (%)

Answer 7

(a) ≥7.0
(b) ≥11.1
(c) ≥11.1
(d) ≥48 (6.5%)

Question 8

What results would you expect in impaired glucose tolerance in the following tests?

(a) Fasting plasma glucose (mmol/L)
(b) 2h plasma glucose after OGTT (mmol/L)
(c) HbA1c (mmol/mol) (%)

Answer 8

(a) <7.0
(b) 7.8-11.0
(c) 42-47 (6.0-6.4%)

Question 9

What results would you expect in impaired fasting glucose in the following tests?

(a) Fasting plasma glucose (mmol/L)
(b) 2h plasma glucose after OGTT (mmol/L)

Answer 9

(a) 6.1-6.9

(b) <7.8

Question 10

What results would you expect in a diabetic patient in the following tests?

(a) Fasting plasma glucose (mmol/L)
(b) 2h plasma glucose after OGTT (mmol/L)
(c) Resting plasma glucose (mmol/L)
(d) HbA1c (mmol/mol) (%)

Answer 10

(a) ≤6.0
(b) <7.8
(c) <7.8
(d) <42 (5.9%)

Question 11

How do people with diabetes often present (T1 + T2)?

Answer 11

T1DM (classic ‘osmotic’ symptoms):

• polyuria
• polydipsia
• noturia
• weight loss
• fatigue
• blurred vision
• pruritis
• recurrent urinary and genitourinary tract infections
• may present acutely as DKA

T2DM:

• symptoms tend to be more vague, subclinical and of longer duration
• polyuria
• poldipsia
• may present acutely with HHS
• may present with complications: skin infections, foot problems, retinopathy, acute MI/stroke

Question 12

Describe the relationship between obesity and insulin resistance.

Answer 12

• Obesity causes excessive growth of adipose depots with adipocyte hypertrophy and hyperplasia
• This fat overload results in the activation of stress/inflammatory pathways and subsequent paracrine/autocrine-mediated insulin resistance
• This is turn increases adipocyte FFA release which stimulates resident macrophages and adipocytes causing increased expression of pro-inflammatory cytokines
• Additionally, these hypertrophied unstable adipocytes eventually die and release their lipid contents causing additional migration of macrophages to clear dead or dying adipocytes
• All of these events result in adipose tissue inflammation, impaired insulin signalling and insulin resistance