Endocrine JC033: Polyuria And Polydipsia: Glucose Metabolism, Diabetes Mellitus, Diabetic Ketoacidosis

Question 1

Diabetes mellitus

Answer 1

• Chronic disorder characterised by ↑ blood glucose level, secondary to ***complete / relative lack of insulin
• 10% HK adults

3 main S/S (3”P”s):
1. Polyuria
- ***glycosuria —> osmotic diuresis

2. Polydipsia
   - loss of water through urination —> ↑ thirst
3. Polyphagia
   - brain cells perceive ***inadequate glucose level in cells as signal to ↑ intake
   - weight loss despite ↑ appetite

DDx of Polyuria Polydipsia (Self notes):
- Diabetes insipidus
- Conn’s syndrome (HypoK, HyperCa, Lithium —> Nephrogenic DI)
- HyperCa

Question 2

DM Presentation

Answer 2

1. ***Asymptomatic (50%)
   - incidental glycosuria / hyperglycaemia
2. Classical symptoms (3”P”s) —> indicate more severe hyperglycaemia / underlying disease (common in patients in undiagnosed / poorly controlled DM)
   - Polyuria
   - Polydipsia
   - Polyphagia: Weight loss despite ↑ appetite (marked weight loss suggests more severe DM / presence of TB)
3. Presenting with complications (∵ undiagnosed DM)
   - Acute / Chronic
   - **Microvascular: Retinopathy, Nephropathy, Neuropathy
   - **Macrovascular: Stroke, IHD, PAD
4. Unmasked by infection, pregnancy, steroid therapy, stroke
   - Infection, Steroid, Stroke —> **↑ in Catecholamines, Glucocorticoid, Cortisol —> ↑ Insulin resistance
   - Pregnancy —> **↑ Counter-regulatory hormone from placenta —> ↑ Insulin resistance
5. Others
   - Candidiasis (e.g. vaginal thrush, pruritis vulvae)

Question 3

Diagnosis of Diabetes

Answer 3

WHO / ADA (American Diabetes Association) 2019 guideline

記: 7, 11, 6.5

Based on **Venous Plasma Glucose
- Fasting glucose **>=7 mmol/L (fast >=8 hours)
- 2-hour glucose **>=11.1 mmol/L during 75g OGTT
- Random plasma glucose **>=11.1 mmol/L in presence of classic ***symptoms of DM / hyperglycaemic crisis (e.g. DKA)

(mmol/L to mg/dl: multiply by 18)

Based on **HbA1c
- **>=6.5%
- must be based on standardised HbA1c assays with stringent quality assurance
- HbA1c <6.5% does NOT exclude DM based on blood test

Diagnosis of DM:
- Require **2 abnormal test results from **same sample (e.g. fasting glucose + HbA1c) / **2 separate samples unless **clearly symptomatic / ***hyperglycaemic crisis

Treatment target (UpToDate):
- HbA1c <=7
- FG <=7.2
- 2 hour PPG <=10

Question 4

Prediabetes

Answer 4

Category of increased risk for DM

記: 5678, 5.7

Based on Blood glucose:
- IFG (Impaired fasting glucose): **5.6/6.1 <= FG < 7 mmol/L (ADA, WHO)
- IGT (Impaired glucose tolerance): **7.8 <= 2 hour glucose (during 75g OGTT) < 11.1 mmol/L
—> both carry ↑ risk of developing DM, CVS disease

Based on HbA1c criteria:
- ADA only: ***5.7-6.4%

Question 5

HbA1c (Glycosylated haemoglobin)

Answer 5

• **Non-enzymatic glycosylation of N-terminal **valine of Hb ***β-chain
• Objective index of overall blood glucose control in preceding ***2-3 months
• Good correlation with average blood glucose

Exceptions:
1. Variable effect on HbA1c: Genetic / Chemical alterations in Hb in different individuals (e.g. Thalassaemia)

2. Falsely high HbA1c
   - **↑ Glycation (e.g. acidosis in chronic renal failure)
   - **↓ Erythropoiesis (prolonged turnover of RBC e.g. Fe deficiency)
   - Assay issue (e.g. ↑ Bilirubin in ***obstructive jaundice)
3. Falsely low HbA1c
   - **↓ RBC life span (e.g. blood loss, haemolysis, hypersplenism, chronic renal failure) —> compensatory production of new RBC which has lower HbA1c concentration
   - **Blood transfusion from non-diabetic donor

—> If in doubt: check Serum ***Fructosamine

Question 6

Serum Fructosamine

Answer 6

• Glycosylated serum proteins
• Objective index of overall blood glucose control in preceding ***1-3 weeks (shorter t1/2 than RBC)
• Correct for serum albumin level (if <3 mmol/L)

Question 7

Subjects at ↑ risk of DM

Answer 7

1. DM in ***1st degree relatives
2. History of ***gestational DM
3. ***Age >45 (∵ ↑ insulin resistance + ↓ insulin secretion)
4. Obesity, Hypertension, Dyslipidaemia

Question 8

***Metabolic syndrome

Answer 8

Aka ***Insulin resistance syndrome

Cluster of metabolic disorders caused / linked by **insulin resistance + associated with **accelerated atherosclerosis

***5 components (三高+中央肥胖):
1. Glucose intolerance / Type 2 DM
2. Hypertension
3. Hypertriglyceridaemia (Dyslipidaemia)
4. ↓ HDL cholesterol (Dyslipidaemia)
5. Central obesity

Diagnosis of Metabolic syndrome: >=3 of above

Question 9

Gestational DM (GDM)

Answer 9

1. Transient diabetes / Impaired glucose tolerance during pregnancy
   - in women with underlying genetic predisposition
   - during pregnancy —> ↑ counter-regulatory hormone from placenta (e.g. ***Placental growth hormone (PGH)) —> ↑ insulin resistance —> abnormal glucose level
2. Normal glucose tolerance after delivery (∵ placenta left body)
3. ***50% DM on long term follow-up (5 fold risk than normal pregnant women)

Question 10

Classification of DM

Answer 10

Type 1: ***β-cell destruction
- insulin deficiency
- life-long insulin dependency

Type 2: ↓ insulin ***secretion + sensitivity
- less severe insulin deficiency —> maintain good glycaemia without insulin
- diet +/- oral drugs +/- insulin

Other (Secondary diabetes):
- **Pancreatic diseases (e.g. after total pancreatectomy)
- **Endocrine disease (e.g. phaeochromocytoma, Cushing’s syndrome)
- ***Drugs (e.g. glucocorticoids, immunosuppressants)
—> may remit after underlying cause removed

(From ERS42:
Type 1:
- Autoimmune destruction of β cells
- Insulin dependent (IDDM)
- Lack of insulin production
- Onset usually before 20 yo
- Absolute requirement for exogenous insulin

Type 1B:
- Idiopathic

Type 2:
- Major form (>90% of Asian)
- NIDDM
- Combined defect of insulin secretion and insulin resistance
- Obesity-associated

Gestational (GDM):
- Pregnancy-associated

Latent autoimmune diabetes (LADA) (1.5 type):
- >10%
- caused by Type 1 + Type 2

Maturity Onset Diabetes of Young (MODY):
- caused by genetic mutation)

Question 11

***Comparison of clinical, genetic, immunologic features of Type 1 and Type 2 DM

Answer 11

Type 1 DM
- Prevalence: Caucasians 10-20%, Chinese 5%
- Onset: Abrupt
- Endogenous insulin: Low - Absent (check serum **C-peptide)
- Ketosis: Common (DKA)
- Age of onset: Usually children / young adults
- Symptoms: **Severe, dramatic weight loss (∵ severe insulin deficiency)
- Body mass: Usually non-obese
- Treatment: Insulin (Lifelong)
- Family history: 10-15%
- Twin concordance: 25-50%
- Human leukocyte antigen (HLA): **HLA-DR + DQ associations
- **AutoAb: Usually present at onset (>85%) (against insulin / islet antigens) (Not a must due to Clinical diagnosis)

Type 2 DM:
- Prevalence: Caucasians 80-90%, Chinese >95% diabetic patients
- Onset: Progressive / Insidious
- Endogenous insulin: Normal / ↑ / ↓
- Ketosis: Rare
- Age of onset: Mostly in adults
- Symptoms: May be none
- Body mass: Obese / Non-obese
- Treatment: Diet, Oral drugs, Insulin
- Family history: 30%
- Twin concordance: 70-90%
- Human leukocyte antigen (HLA): **Unrelated
- AutoAb: **Absent

Question 12

Pathogenesis of Type 1 DM

Answer 12

Islet cell destruction (immunologically mediated esp. in most Caucasians)

Genetic factors:
- ***Chromosome 6 DR / DQ susceptibility genes (20% risk in HLA-identical twins)
- Other genes (e.g. Insulin gene)

Environmental factors:
- Exact nature unknown (multi-hit action? e.g. coxzackie B, mumps virus, cow’s milk protein in infancy)

Immunological factors:
1. Presence of **AutoAb against Islet cell Ag + Insulin at onset
2. **Cell-mediated autoimmunity against Islet cells at autopsy of new onset patients
3. ↑ Remission / β cell preservation after **immunosuppressants (e.g. Cyclosporin / Anti-TNFα) in early cases
4. Immunotherapy with **Anti-CD3 Ab targeting T-cell —> delay onset of type 1 DM by 2 years in close relatives of type 1 DM having >=2 diabetes-related AutoAb

Question 13

Pathogenesis of Type 2 DM

Answer 13

3 main defects that lead to Hyperglycaemia
1. Insulin resistance at level of Muscles / Fat
- glucose cannot enter cell —> ***↓ glucose uptake

2. Insulin resistance at level of Liver
   - ***excessive glucose output (gluconeogensis)
3. Insulin **deficiency by Pancreas
   - β cell produce **less insulin —> not enough insulin to overcome insulin resistance
   - α cell produce ***excess glucagon —> stimulate liver to produce glucose

Question 14

Development and Progression of Type 2 DM

Answer 14

Genes (obesity, β-cell dysfunction, insulin resistance) + Environment (physical inactivity, excessive food) —>

Phase 1:
—> Insulin resistance (Hyperinsulinaemia + NGT (normal glucose tolerance))

Phase 2:
—> ***β-cell decompensation
—> IGT

Phase 3:
—> **Progressive β-cell decline (decline accelerated by Glucotoxicity (hyperglycaemia) + Lipotoxicity (∵ excess fat in body) on β-cell)
—> **Hypoinsulinaemia + ↑ Hyperglycaemia
—> Type 2 DM

Question 15

***Complications of DM

Answer 15

Acute:
1. **DKA +/- Coma
2. **Hyperosmolar Non-ketotic Coma
3. ***Infections
- pulmonary TB
- UTI
- others

Chronic:
- **Microvascular: Retinopathy, Nephropathy, Neuropathy
- **Macrovascular: Stroke, IHD, PAD

Question 16

Hyperglycaemic Coma

Answer 16

2 types:
1. DKA (Ketotic)
2. Hyperosmolar hyperglycaemic state (Non-ketotic)

Must exclude **precipitating factors:
1. **Infection, operation, trauma, severe emotional stress
2. **MI, **stroke (esp. in elderly) —> Hyperosmolar Non-ketotic Coma
3. Drug administration (e.g. steroid)

Question 17

Diabetic Ketoacidosis (Ketotic Coma)

Answer 17

1. First manifestation of undiagnosed type 1 DM
2. Result of inadequate insulin treatment in known type 1 DM

***Pathogenesis:

1. **Metabolic acidosis
   Acute insulin deficiency
   —> **Unrestrained lipolysis (∵ insulin suppress lipolysis, lipolysis stimulated by adrenaline)
   —> ↑ Free fatty acids
   —> ***Excess hepatic ketone production
   —> Metabolic acidosis
2. ***HypoNa + HypoK
3. Hyperglycaemia causes osmotic diuresis —> ***Dehydration + Secondary loss of electrolytes (Na, K)
4. Insulin deficiency —> ***Impaired tubular Na reabsorption

Net result:
∵ Dehydration —> Serum Na, K level usually **normal on admission
—> After rehydration + Insulin therapy
—> insulin stimulated glucose transport into cell accompanied by inward K shift
—> **Hypokalaemia becomes evident
—> Monitoring + replacement of K important in management of DKA

Question 18

Treatment of DKA

Answer 18

(記: Insulin + K + HCO3 + ECG/CVP monitoring)

1. Replace salt + **water deficit
   - IV normal saline (ALL patients without hyperNa) + **K supplement (unless patient has low urine output) (guided by serum K + renal function)
2. Insulin
   - Low dose (5-10 unit/hour) by continuous IV infusion
   - ↓ rate of infusion when blood glucose <13 mmol/L
   (- D/I drip: Dextrose is buffer for Insulin to prevent hypoglycaemia)
3. **Correct acidosis
   - pH usually rises with rehydration + insulin (ketones excreted through urine + ketone production suppressed by insulin infusion)
   - **Bicarbonate infusion if pH ***<7
4. Identify + Treat the ***cause of DKA
5. Monitoring of clinical response, BP, pulse, urine output
   - **CVP and **ECG as indicated (CVP in renal impairment / worried of over-replacement of fluid; ECG if severe K abnormality (hypoK: tachycardia), myocarditis)
6. Emergency measures / Care of unconscious patient

Question 19

Hyperosmolar hyperglycaemic state (Non-ketotic Coma)

Answer 19

• Usually mild, undiagnosed type 2 DM
• Insidious onset (days / weeks)
• Ketosis usually absent (∵ just sufficient insulin to suppress lipolysis / ketogenesis; severe hyperosmolality may ↓ lipolysis)
• Severe hyperglycaemia (>33 (IM handbook)) + **Dehydration (∵ osmotic diuresis) —> **Severe hyperosmolality
• ***Depression of sensorium (when serum osmolality >340 mmol/L) —> Lack of thirst response
• ***High mortality

Tendency to hyperosmolality may be worsened in elderly people
- ∵ reduced appreciation of thirst
- difficulty in drinking enough water to compensate for their osmotic diuresis
- may be on diuretics (further aggravate hyperosmolality)

Question 20

Treatment of Hyperosmolar coma

Answer 20

(記: Fluid (1/2 normal saline) + Prophylactic heparin)

Same as for DKA except:
1. ***Less insulin required

2. ***Water deficit more severe
3. Fluid replacement should be guided by ***CVP / Pulmonary wedge pressure monitoring (esp. if elderly / underlying cardiac / renal disease)
4. If Na >150 mmol/L —> use ***1/2 normal saline for more rapid correction of Na level (instead of normal saline)
   - do NOT use water for injection —> Na ↓ too rapidly —> Cerebral edema
5. **Thrombosis is more common with hyperosmolality —> Clinical vigilance required
   - **Prophylactic heparin + Early ambulation
   - esp. in Caucasians: DVT, PE
   - Chinese: Arterial thrombosis e.g. Stroke, MI

Question 21

DKA vs HHS vs Poorly controlled DM (SpC Medicine)

Answer 21

DKA:
- ↑↑ Haemstix
- Ketoacidosis
- Mild dehydration

HHS:
- ↑↑↑ Haemstix (Extreme hyperglycaemia >33)
- ???Lactic acidosis
- Severe dehydration (Water deficit 5L)

Poorly controlled DM:
- ↑ Haemstix
- No acidosis
- Mild dehydration

Question 22

Hypoglycaemia

Answer 22

Definition (Davidson):
- <3.5 mmol/L

Causes:
1. Too much sulfonylurea / insulin
2. Too little carbohydrate
3. Too much exercise
- ***Renal impairment must be excluded —> patient might have developed diabetic nephropathy already (∵ kidney responsible for clearance of sulfonylurea / insulin)

Other causes (Davidson + SpC Medicine):
- Alcohol
- Critical illness
- Adrenal insufficiency
- Insulinoma
- Large HCC, Mesothelioma, Retroperitoneal sarcoma

Symptoms of Hypoglycaemia:
(SpC Medicine: Hypoglycaemia can mimic ANY neurological disease —> MUST rule out Hypoglycaemia in ANY neurological symptoms!!!)
1. ***Adrenergic symptoms
- palpitation
- sweating
- tremor

2. ***Neuroglycopenic symptoms
   - hunger sensation
   - restlessness, anxiety
   - numbness in fingers and around mouth
   - altered consciousness, confusion, drowsiness, coma
   - convulsion sometimes
   - focal neurological deficits suggestive of stroke

Question 23

Treatment of Hypoglycaemia

Answer 23

Alert patient
1. Early meal / snack
2. Sweet drinks, glucose tablets

Confused / Drowsy (do NOT feed)
1. **IM glucagon (1g)
2. **IV glucose

Question 24

Prevention of Hypoglycaemia

Answer 24

Balance between exercise, intake, treatment

Question 25

Monitoring of Diabetic glycaemic control

Answer 25

1. Home blood glucose monitoring
   - education, motivation, vigilance
   - **Continuous Glucose Monitoring (CGM): 7 days
   —> reading every minute, direct display, tips for pump adjustment, alarm system
   —> hypoglycaemia unawareness
   —> nocturnal hypoglycaemia
   —> **dawn phenomenon (↑ glucose level due to wearing of insulin + increase in cortisol level) (vs Somogyi phenomenon: rebound phenomenon due to excessive insulin causing low midnight glucose then production of anti-insulin hormone)
   —> post-prandial hyperglycaemia
2. Clinic blood glucose
3. HbA1c, Serum Fructosamine

Question 26

Childhood diabetes

Answer 26

HbA1c goals:
- Adults: **<7%
- <19 yo: **<7.5%

• Individualisation of treatment goals
• ***Greater risk of hypoglycaemia at extremes of age —> less stringent target if multiple co-morbidities / short life expectancy

Metabolic control of DM in adolescence
- often **suboptimal despite insulin injection (HbA1c >8% in major overseas series)
—> ∵ hormonal changes during puberty —> ↑ insulin resistance
- more **psychosocial stress, less cooperative with glucose control
- control can be improved by ***intensive therapy (however associated with 2-4x ↑ in severe hypoglycaemia)

DCCT: Benefits of good control
- Primary prevention: ↓ Retinopathy 53%, ↓ Microalbuminuria 10%
- Secondary prevention: ↓ Retinopathy progression 70%, ↓ Microalbuminuria 70%
- Faster motor + sensory nerve conduction velocities
- Lower total cholesterol levels

Question 27

Screening for Chronic Complications in adolescence

Answer 27

1. Retinopathy, Nephropathy, Neuropathy
   - for pre-pubertal patients (often Type 1 DM) —> annually after ***5 years of DM (∵ Type 1 DM abrupt onset, DM complications not seen within first 5 years)
   - 2 overnight 12 hour urine for microalbumin
2. ***Annual thyroid dysfunction (3-5% may have autoimmune thyroid disease)
3. Annual lipid levels (prevent macrovascular complications)

Question 28

P/E of DM (SpC Medicine, Tally)

Answer 28

General examination:
- BP, Pulse
- BMI
- **Dehydration
- Necrobiosis, hair loss, infection, pigmented scars, atrophy, ulceration, injection sites
- Skin lesions (skin tags, **acanthosis)
- **Muscle wasting
- **Edema (proteinuria)
- ***Acetone on breath

CVS examination:
- Carotid, Femoral, Renal bruit
- Lower limb pulses, Temperature
- Lower limb gangrene, Trophic changes

Neurological examination:
- Visual acuity, Visual field, Fundoscope
- CN3 palsy (Medical CN3 palsy: ophthalmoplegia without pupil)
- Power
- Sensation: Peripheral neuropathy

Urinalysis:
- Glycosuria, ketones, proteinuria

Question 29

Sliding scale (SpC Medicine)

Answer 29

• Frequent monitoring of blood glucose by **Haemstix every **3-4 hours
• Adjust ***Short acting insulin dose according to H’stix result