Diabetes

Question 1

What is diabetes?

Answer 1

Chronic hyperglycemia due to insulin dysfunction/deficiency/resistance

• random (>11.1mmol/L)
• fasting (>7 mmol/L)

Question 2

What are the common acute presentations of diabetes (4)?

Answer 2

Triad
1) Polyuria
2) Polydipsia
3) Weight loss

4) Polyphagia

Question 3

What are the common chronic presentations of diabetes (5)?

Answer 3

1) Fatigue
2) Poor wound healing
3) ↑infection
4) Blurry vision (vascular changes)
5) ↓peripheral sensation (Neuropathy)

Question 4

How is glucose sensed by ß-cells of the pancreas?

Answer 4

Glucose → GLUT2

→ Glycolysis → ATP → closes ATP dependent K+ channel

→ ↓K+ efflux → membrane depolarise

→ open voltage-dependent Ca2+ channel → Ca2+ influx

→ exocytosis of insulin from vesicles

Question 5

How is insulin produced?

Answer 5

1) Produced as preproinsulin

2) Signal peptide cleaved → Disulfide bonds between A and B chain → Proinsulin

3) Cleavage of C-peptides → Mature Insulin

Question 6

What are the 3 cell signaling pathways and 2 other intracellular effects of insulin?

Answer 6

Insulin → RTK → P-ed IRS:
1) SREBP → Lipid synthesis

2) MAPK pathway → Cell growth

3) PI3K pathway
a) → inhibit lipolysis and gluconeogenesis
b) → mTOR pathway
i) → protein synthesis
ii) →PP I → Glycogen synthesis
c) inhibit GSK3ß → ↓inhibition of glycogen synthesis

Others:
1) ↑exocytosis of GLUT4 (muscle and adipocytes)
2) K+ influx

Question 7

Is type 1 or 2 DM more common?

Answer 7

Type 2 (90%)

Question 8

True or false:
Type 1 DM is the most common metabolic condition in children.

Answer 8

True

Question 9

What is the pathogenesis of type 1 DM?

Answer 9

Insult during childhood/development
→ Activate T cells
→ Immune-mediated destruction of ß-cells
→ progressive loss of pancreatic secretory capacity until < min. insulin requirement

Genetic predisposition:
Twins (~30-50% chance if one is affected)

Question 10

What are the autoantibodies detected to diagnose type 1 DM?

Answer 10

1) Glutamic acid decarboxylase autoantibodies (GAD)

2) Islet cell autoantibodies (ICA)

Question 11

What are the effects of insulin deficiency on carbohydrate metabolism in type 1 DM (3)?

Answer 11

Insulin deficiency → unopposed glucagon action:
1) ↑Glycogenolysis (only liver)

2) ↑Gluconeogenesis (Liver from muscle ↑proteolysis and adipocyte ↑lipolysis)

3) ↓GLUT4 uptake (muscle and adipocytes)

Question 12

What are the effects of insulin deficiency on lipid metabolism in type 1 DM (3)?

Answer 12

Insulin deficiency → unopposed glucagon action:
1) ↑ß-oxidation (only liver from lipolysis by HSL)

2) ↑TG synthesis → ↑VLDL export (Liver)

3) ↓LPL → ↓chylomicron uptake

4) ß-oxidation and ketolysis for energy (muscle)

Question 13

What is the pathogenesis of the acute-subacute clinical presentation of DM?

Answer 13

1) ↑Glucose → Osmotic diuresis (> renal threshold) → Polyuria + dehydrations

2) ↑Ketogenesis
i) → ketoacidosis
ii) ↑Respiration → acetone in breath (sweet breath)

3) ↑ Lipolysis and proteolysis
i) → WL
ii) → Δmental state
iii) → ↓appetite
iv) → hyperlipidemia

Question 14

What are 6 biochemical changes and their pathogenesis in type 1 DM?

Answer 14

Diabetic ketoacidosis:
1) ↑glucose + ↑osmolarity (Dehydration)

2) ↑urea (proteolysis and dehydration)

3) ↓pH + ↓HCO3- (ketoacidosis)

4) ↓pCO2 (compensatory respi alkalosis)

5) ↑Na+ (but appears falsely normal coz ↑blood glucose pulls water → dilute)

6) ↓K+ (but appears normal coz acidotic displacement from cells)

Question 15

What are 2 significant abnormal urine finding in poorly controlled type I DM?

Answer 15

1) ↑glucose (blood glucose > renal threshold)

2) ↑ketones

Question 16

What are the 5 management principals for diabetic ketoacidosis?

Answer 16

1) Attend to (i) airway (ii) breathing (iii) circulation

2) Replace fluid/Na+/K+

3) Start insulin replacement (be wary of inward K+ shift)

4) Treat any precipitating cause of presentation (eg. antibiotic)

5) Prevent complication (eg. heparin to ↓clotting due to hypercoagulable state)

Question 17

How is type 1 DM treated chronically?

Answer 17

Provide insulin in similar pattern as healthy individuals
1) Continuous infusion
2) Intermittent dosing via subcut

Question 18

How is glucose monitoring done in DM patients?

Answer 18

Short term:
Home glucose monitoring (finger prick)

Long term:
HbA1C (average blood glucose over 100-120 days)
- 4-6.1% (ideal <7%)

Question 19

Why is central obesity linked to type 2 DM?

Answer 19

Central fat: ↑Visceral fat
1) linked to metabolic syndrome → impaired fasting glucose

2) visceral fat (hypertrophy) → M2 to M1 → FFA + Cytokines → inflammation:
a) TNFα pathway (cytokines)
b) NFκB pathway (cytokines) + FFA → ↑lipid metabolism
bi) → DAG → activate PKC
bii) → Ceramides

TNFα and PKC (via IRS), Ceramides (via PI3K pathway) inhibit insulin signaling

→ risk factor for type 2 DM

Question 20

How does visceral obesity lead to insulin resistance?

Answer 20

Visceral fat (hypertrophy) → M2 to M1→ FFA + Cytokines → inflammation:
a) TNFα pathway (cytokines)
b) NFκB pathway (cytokines) + FFA → ↑lipid metabolism
bi) → DAG → activate PKC
bii) → Ceramides

TNFα and PKC (via IRS), Ceramides (via PI3K pathway) inhibit insulin signaling

Question 21

With px with metabolic syndrome and thus at risk of type 2 DM, compared to a normal individual:
Glucose levels during fast (↑/↓)
Glucose levels after meals (↑/↓)
Insulin levels after meals (↑/↓)

Answer 21

Glucose levels during fast ↑
Glucose levels after meals ↑
Insulin levels after meals 2/3x ↑

Question 22

Describe the pathogenesis of type 2 DM.

Answer 22

Combination of genetic predisposition (twin concordance >50%) and diet/lifestyle:
1) Insulin R → compensatory ↑ in insulin secretion (but fasting blood glucose still normal)

2) ↑glucose/FFA → ß cell toxicity → ↓ß cells → ↓insulin secreting capacity → ↓ability to compensate by ↑insulin → chronic hyperglycemia

Question 23

What is the metabolic difference between type 1 and 2 DM?

Answer 23

Type 1: Absolute insulin deficiency → ketoacidosis

Type 2: Insulin R → (partial insulin response→ sufficient to prevent ketoacidosis

Question 24

What are the pathogenesis of 4 chronic presentations of type 2 DM?

Answer 24

↑glucose → ↑ROS → microvascular pathology via inflammation/proliferation:
a) Polyol pathway (glucose → aldose reductase → sorbitol
b) Glycation → AGE
c) PKC activation

1) Sorbitol → osmotic damage → cataracts → microvascular pathology → loss of vision

2) microvascular pathology → neuropathy
i) Sensory → pain, tingling, loss of sensation
ii) Motor → weakness, muscle wasting
iii) Autonomic → erectile dysfunction

3) Damage to glomerular capillaries → nephropathy → microalbuminuria → HTN → renal failure

Question 25

What are 4 presentations of chronic diabetes?

Answer 25

1) Cataracts (loss/blurring of vision)

2) Nephropathy → HTN → Renal failure

3) Neuropathy
i) Sensory → pain, tingling, loss of sensation
ii) Motor → weakness, muscle wasting
iii) Autonomic → erectile dysfunction

Question 26

How is diabetic nephropathy screened for?

Answer 26

Urine albumin

Question 27

What is the most common emergent presentation of type 2 DM?

Answer 27

Hyperosmolar hyperglycemic state

Question 28

What is the most common emergent presentation of type 1 DM?

Answer 28

Diabetic ketoacidosis

Question 29

What are 4 biochemical changes and their pathogenesis in type 2 DM? How are they different from type 1?

Answer 29

Hyperosmolar hyperglycemic state:
1) ↑glucose + ↑osmolarity (Dehydration)

2) ↑urea (proteolysis and dehydration)

3) ↑Na+ (usually higher in type 2 coz ↑Na and water loss in kidney)

4) ↓K+ (but appears normal coz renal loss but no acidotic shift)

• No ketoacidosis, so pH, pCO2, HCO3- all normal

Question 30

What is the significant abnormal urine finding in poorly controlled type 2 DM?

Answer 30

↑ glucose
(no ketones, unlike in type 1)

Question 31

What are 5 management principles of HHS in type 2 DM?

Answer 31

1) Attend to airway, breathing, circulation

2) Replace fluid w care

3) Start insulin replacement after fluid replacement (watch K+ levels as may drop with insulin)

4) Treat precipitate cause of presentation

5) Prevent complications (eg. heparin to ↓thrombotic events)

Question 32

Why must fluid replacement be done with care in acute management of HHS?

Answer 32

Intracellular water loss → compensatory ↑ osmotically active substance to ↓water outflow (Brain)

• Rehydrate too fast → shift of water → cerebral edema
• Insulin before rehydration → ↓blood glucose → water influx into cells → circulatory collapse

Question 33

What are 4 main ways type 2 diabetes managed chronically?

Answer 33

1) ↓weight/adiposity → ↓insulin R

2) ↑insulin effects

3) ↑ insulin secretion

4) ↑Glucose excretion

Question 34

How can a px with type 2 DM ↓weight/adiposity to ↓insulin R (3)?

Answer 34

1) ↓ dietary carbs (> low GI to slow post-prandial spike of glucose)

2) ↓carbs/fat absorption/digestion
a) Drugs: α-glucosidase inhibitor, lipase inhibitor
b) Surgery: gastric bypass

3) Exercise

Question 35

How can a px with type 2 DM ↑insulin effect/response (2)?

Answer 35

1) Metformin → ↑AMP/ATP ratio → AMPK activation
→ Liver: ↑ Gluconeogenesis, ↓TG/FA synthesis
→ Muscle: ↑Glucose uptake

2) Glitazone → ↑PPAR-γ → exp of genes:
→ Fat: ↑lipolysis, ↓FA release
→ Liver/muscles: ↑insulin sensitivity

Question 36

How can a px with type 2 DM ↑insulin secretion (3)?

Answer 36

1) Sulphonylurea and Meglitinide:
close ATP-dependent K+ channels → depolarise ß cells

2) ↑Incretin:
a) GLP-1 agonist → ↑ GLP-1 → ↑insulin ↓glucagon
b) DDP4 inhibitor → ↓degradation of GLP-1

3) Insulin replacement
(incretin and sulphonylurea/meglinitide→ ß cell exhaustion)

Question 37

How can a px with type 2 DM ↑insulin secretion (1)?

Answer 37

SGLT2 → ↓reabsorption of glucose at PCT → ↑glucose excretion