JC33, 34 (Medicine) - Diabetes Flashcards
Physiology of blood glucose control in fed and fasting state
Fed state: High glucose level increases insulin secretion:
- Utilization of glucose by tissue uptake
- storage of AA, glucose, FA by ↑hepatic and
tissue uptake and conversion into storage form
Fasting state: Low glucose level increase glucagon, adrenaline secretion
- breakdown of tissue stores of glycogen, fat and proteins
- Increase level of ketone bodies, FA, glucose for use
Physiology of insulin secretion
Site: pancreatic islet β cells (core)
Process: high glucose → Increased GLUT-2 uptake into pancreatic cell → glycolysis make ATP → K+ ATP channel activation → depolarization → insulin secretion
Insulin from cleaving of C-peptide from pro-insulin
Causes of DM
- Type 1: immune-mediated β-cell destruction → absolute insulin insufficiency
- Type 2: insulin resistance → relative insulin insufficiency gradually becoming an absolute insulin deficiency
- Genetic defects of β-cell dysfunction or insulin action, eg. MODY
- Secondary diabetes:
- Pancreatic diseases (affecting β cells directly): chronic pancreatitis, CA pancreas, pancreatectomy, haemochromatosis
- Iron overload from transfusion
- Overproduction of hormonal antagonists of insulin (eg. acromegaly, Cushing’s)
- Drug-induced: glucocorticoids, thyroid hormones, thiazides, α/β-agonists, phenytoin, pentamidine, nicotinic acid…etc
Risk factors of type I DM
Genetics
→ HLA-DR and –DQ susceptibility haplotypes (20% if HLA identical)
→ Other genes, eg. proinsulin
Environment: triggering events that cause presentation of β-cell antigen to immune system
→ Viruses, eg. mumps, Coxsackie B
→ Bovine serum albumin (BSA) in cow’s milk in infancy (↑risk of T1DM if on cow’s milk early)
→ Toxins, eg. nitrosamines
Immunological: key in pathogenesis
→ Hygiene hypothesis
→ A/w other autoimmune disorders, (eg. thyroid (2-5%), celiac disease, Addison’s, pernicious anaemia, vitiligo)
Pathogenesis of Type I DM
Initiation: environmental triggers cause T-cell-mediated autoimmunity towards pancreatic islet β cells
Onset:
- Insulitis: lymphocytic infiltrate of pancreatic islets
- Autoantibodies:
- Anti-islet cell antibodies, eg. anti-glutamic acid decarboxylase antibody (GAD)
- Anti-insulin antibody
Result: absolute insulin deficiency
- Progressive destruction of β-cells → ↓insulin secretion
- Hyperglycaemia when 80-90% of insulin-secreting ability is loss
- Hyperglycaemia is toxic to β-cells → further worsen insulin secretion
Clinical presentation of Type I DM
Abrupt Onset of Hyperglycaemic symptoms: polydipsia, polyuria, nocturia, fatigue
Rapid weight loss
Complications:
- Diabetic ketoacidosis
- Urogenital infections/symptoms, eg. UTI, pruritus vulvae (F), balanitis (M)
Pathophysiology of hyperglycaemic symptoms
Hyperglycaemia
→ glycosuria
→ osmotic diuresis
→ polyuria, nocturia
→ dehydration
→ polydipsia, fatigue
Risk factors of Type II DM
Genetics: MZ twins concordance rate = 70-90% (higher than T1DM!)
→ Altered regulation of β-cell mass
→ Check first-degree relative with Hx of DM
Obesity: 10× risk for BMI >30
Metabolic syndrome: HTN, hyperlipidaemia, PCOS, NAFLD
Previous conditions: pre-diabetes, gestational DM
Age >45y
Pathogenesis of Type II DM
Central obesity:
- Adipocytes release large amounts of FFA → insulin resistance
- Adipocytes release adipokines → insulin resistance
- Low physical activity decrease AMPK activation → ↓glucose uptake + ↓FFA metabolism
Progression:
- Hyperinsulinemic euglycaemia: ↑insulin resistance and insulin secretion
- Impaired glucose tolerance: β-cells cannot handle metabolic load → gradual β-cell failure
Early T2DM: Relative insulin deficiency→ hyperglycaemia and hyperlipidaemia cause toxicity to β-cell
Late T2DM: absolute insulin deficiency
Clinical presentation of Type II DM
Commonly asymptomatic at dx
- Hyperglycaemic symptoms: fatigue ± polyuria/polydipsia
- Weight loss: usually none (insulin level sufficient to suppress lipolysis/glycogenolysis)
- Body habitus: obese or non-obese
- Complications:
→ Hyperglycaemic hyperosmolar state (HHS)
→ Urogenital infections
Monogeneic forms of DM
Subtypes
- Permenant neonatal DM (PNDM) - permanent activation of K-ATP channel in Pancreatic B-cell > cannot depolarize and release insulin
- Maternally inherited diabetes with deafness (MIDD) - Mutation of mitochondrial genome
- MODY2 - Inactivating glucokinase gene mutation > cannot make ATP for depolarization and insulin release
- MODY1,3,5 > Transcription factor mutations > cannot express components of TCA cycle, glucose transport, insulin
Maturity onset diabetes of the young (MODY)
- Presentation
- Diagnosis
- Cause
- Management
Presentation: early onset (<25y) non-obese NIDDM patients with -ve islet cell autoAb
Dx: Genetic testing
Cause: various mutations interfering with pancreatic β-cell’s ability to secrete insulin
Inheritance: monogenic AD,
Management: no treatment for MODY2 (long-term outcome similar to healthy), sulphonylureas for MODY1/3
Acute complications of DM
Acute complications: Diabetic ketoacidosis (DKA) in T1DM
Hyperglycaemic hyperosmolar state (HHS) in T2DM
Stress hyperglycaemia: unmasked by infections, pregnancy, steroid therapy or stroke
Infections eg. urogenital infection
Diagnostic criteria of DM
Single measurement of random glucose ≥11.1mmol/L with classic DM symptoms or in hyperglycemic crisis
Two positive tests on different days if asymptomatic
→ Venous plasma glucose-based: Fasting glucose ≥7 mmol/L with ≥8h of fasting; 2h post-prandial glucose ≥11.1 mmol/L in a 75g OGTT
→ HbA1c ≥6.5%
Diagnostic Criteria of pre-diabetes
Pre-diabetes: ↑risk of DM and macrovascular Cx but no ↑risk of microvascular Cx
□ Impaired fasting glucose (IFG): fasting glucose 5.6-6.9 mmol/L (6.1-6.9 for WHO)
□ Impaired glucose tolerance (IGT): 2h PPG 7.8-11.0mmol/L after 75g OGTT
□ A1c-based: HbA1c 5.7-6.4%
Outline screening for DM
Screening: indicated in BMI ≥23 + more than 1 risk factor
- First-degree relative with
- High risk ethnicity
- History of CVD, HT, HL
- History of PCOS (female)
- Physical inactivity
- Medical conditions with insulin resistance
Yearly test for pre-diabetes
3 yearly test for gestational DM
Yearly testing for normal people over 45, with 3 yearly check-up if normal
Compare type I and II DM
- Age of onset
- S/S onset
- Presentation
Compare type I and II DM
- Significant medical diseases
- Family history of certain diseases
- First-line investigations
Type II DM does not present with weight loss and DKA
True or False?
How to definitely diff. Type I and II DM?
False - Type II DM can progress to absolute insulin insufficiency and present with acute complications
Definitive tests:
- Auto-Ab: anti-islet cell, anti-GAD (70-80%), anti-insulin (60-75%), anti-IA-2 (65-75%), anti-ZnT8 (70-80%)
- C-peptide: ↓C-peptide in T1DM, ↑/N C-peptide in T2DM
- Glucagon stimulation test: inadequate stimulation of insulin secretion in T1DM
Follow-up checks for Type I DM
Aims of DM management
Patient education
Tx DM with individualized choices
Tx associated coronary risk factors
Regular check for complications
Assessment of glycaemic control
HbA1c - 6 monthly if stable, 3 monthly if unstable
Home blood sugar monitoring (HBSM) - Insulin use, before eating, sleeping, exercise
Continuous glucose monitoring (CGM) - nocturnal hypoGly, Postprandial hyperGly, Morning hyperGly
Target HbA1c for DM patients
Limitations of HbA1c
Alternative
Usually good correlation with average blood glucose except:
→ Variable effect: genetic/chemical alterations of Hb (eg. HbF, HbH (↑), Hbpathies (↓))
→ Falsely High HbA1c: ↑glycation (eg. chronic renal failure), ↓erythropoiesis
→ Falsely Low HbA1c: ↓RBC lifespan (eg. blood loss, haemolysis, hypersplenism), transfusion
Alternative: serum fructosamine (glycosylated serum protein)
→ Use: objective index of overall BG control in the preceding 1-3w
→ Need to correct for serum Alb level if <3.0mmol/L
Treatment outline for Type 1 and II DM
T1DM: lifestyle measures + insulin
T2DM:
→ Lifestyle measures alone in early stages (1st line)
→ Lifestyle measures + oral hypoglycaemics if relative insulin insufficiency
→ Lifestyle measures + insulin if absolute insulin insufficiency (advanced)
- First line: Metformin
- High risk CVD and CKD > SGLT2 inhibitor or GLP-1
- No CVD or CKD: DDP-4 inhibitor, SGLT2 inhibitor, TZD, GLP-1RA
- Need weight loss: SGLT2 inhibitor or GLP-1RA
Dietary management for DM
Energy content: 30kcal/kg ideal body weight per day
Composition:
→ 40-50% carbohydrates, 30% fat (<7% saturated/trans fat), 20-30% protein
→ 20-35g/d fibre intake
Other advice:
→ Personalized according to individual preference and culture
→ Consistency of meal timing and quantity
→ Emphasis on ↑fibre food, low-fat dairy products and fresh fish
→ Minimize high energy food, esp those with high glycemic index (GI) and glycemic load (GL)
→ Hypocaloric diet for obese T2DM pt
List all classes of drugs for DM
- Insulin secretagogues
- Incretin mimetics
- DDP-4 inhibitors
- Insulin sensitizers
- a-glucosidase inhibitors
- SGLT2 inhibitors
Insulin secretagogues
Examples
MoA
Sulfonylureas (SUs)
- 1G: chlorpropamide, tolbutamide
- 2G: gliclazide (Diamicron), glibenclamide, glipizide
Meglitinide analogues
- Repaglinide
- Nateglinide
MoA
Blocks K+ ATP channel of pancreatic β cells
→ ↑depolarization → ↑insulin secretion
Insulin secretagogues
S/E
Cautions
Sulfonylureas:
- Risk of weight gain
- High risk Hypoglycaemia
- C/O poor renal function (high risk hypoGly)
- No cardiovascular or renal benefits
Meglitinide analogues
- Risk of weight gain
- Small risk of Hypoglycaemia
- No cardiovascular or renal benefits
Incretin mimetics
Examples
MoA
GLP-1 analogues
- Exenatide (weekly)
- Liraglutide (QD)
Mimics endogenous incretin action → ↑insulin secretion from pancreatic β cells
Slow gastric emptying and weight loss
Incretin mimetics
Benefits, S/E and caution
Benefits:
- Atherosclerotic CVD (dulaglutide, liraglutide)
- Slow progression of Diabetic nephropathy
S/E:
Pancreatitis
Injection site reaction
Thyroid C-cell tumor
C/O very poor renal function (eGFR < 35)
DPP-4 inhibitors
Examples
MoA
S/E
DPP-4 inhibitors
- Sitagliptin (Januvia)
- Linagliptin (Trajenta)
- Vildagliptin (Galvus)
Inhibits DPP-4-mediated breakdown of endogenous incretins → prolong incretin action on β cells
S/E
↑risk of acute pancreatitis and pancreatic CA or neuroendocrine tumours
↑risk of IBD, deranged LFT and rarely joint pain
Caution:
Dose adjustment in CKD (except linagliptin)
Risk of HF (saxagliptin only)
Insulin sensitizers
Examples
MoA
Biguanides
- Metformin HCl (Glucophage)
↑AMPK activity → ↓gluconeogenesis, ↑FA utilization, ↓FA synthesis
Thiazolidinediones
- Rosiglitazone
- Pioglitazone (Actos)
↑PPARγ action in adipocytes → ↓inflammation, ↑insulin sensitivity,
preferential differentiation of pre-adipocytes to increase FA uptake
Biguanides/ Metformin
Benefits
S/E
Caution
Benefits:
- Weight loss
- Benefit against ASCVD
S/E
- GI S/E (dyspepsia, diarrhea) and B12 deficiency
Caution
- Risk of lactic acidosis: eGFR <30, alcohol abuse, severe liver disease,
unstable HFrEF or uncontrolled sepsis at risk of hypoperfusion - Dose adjustment at eGFR 30-45
- Withhold 48h before and after contrast CT
Thiazolidinediones
S/E
Caution
S/E:
- weight gain
- derange LFT
- Increase LDL-C (Rosiglitazone)
- Bladder Cancer (Pioglitazone)
Caution:
- Increase fluid retention and risk of congestive HF
- C/O Chronic kidney disease
α-glucosidase inhibitors
Examples
MoA
S/E
α-glucosidase inhibitors
- Miglitol
- Acarbose
Competitive inhibitors of GI α-glucosidase → ↓digestion and absorption of starch and disaccharides from small intestines → ↓postprandial blood glucose level
Lower risk of ASCVD
S/E:
Flatulence and diarrhea due to high glucose in feces
Poor hypoglycaemic effect/ performance
SGLT2 inhibitor
Example
MoA
Benefits
S/E
SGLT2 inhibitor
- Canaglifozin
- Dapaglifozin (Forxiga)
- Empaglifozin (Jardiance)
Inhibits SGLT2 in PCT of kidney tubule → ↓glucose reabsorption → ↑glucose excretion
Benefits:
- Weight loss
- No hypoglycaemia
- Reduce ASCVD and Diabetic nephropathy
S/E:
- Urogenital infections
- Postural hypotension (osmotic diuresis)
- Osteoporosis (Canagliflozin)
- CA bladder (Dapagliflozin)
- High LDL-C
- Euglycaemic DKA
Insulin therapy
Indication
T1DM: Immediately from Dx
T2DM:
→ Features of absolute insulin insufficiency, eg. marked recent weight loss, marked ketosis
→ Failed oral Tx
→ Clinically ill, eg. dehydrated, infection, MI
→ Pregnancy
Features of absolute insulin deficiency: Ketosis, Marked recent weight loss, Underweight/ critically ill
Severe hyperglycemia at Dx: HbA1c >10%, Fasting glucose >16.7mmol/L
Forms of insulin
□ Rapid-acting analogues, eg. insulin Aspart (Novorapid), insulin Lispro (Humalog)
□ Short-acting insulins, i.e. regular human insulin eg. Actrapid, Humulin R
□ Intermediate-acting analogues, eg. insulin NPH (protaphane)
□ Long-acting analogues, eg. insulin degludec (Tresiba), insulin glargine (Lantus)
□ Pre-mixed insulins, eg. Protamine/Aspart (Novolog 70/30), Lispro protamine/Lispro (Humalog mix 75/25 and 50/50), NPH/regular (Humulin mix 70/30, Novolin mix 70/30)
3 types of insulin regimens
2 monitoring methods
Basal insulin only: suitable for patients with fasting hyperglycemia only
→ Examples: protaphane bedtime, Tresiba/Lantus OM/bedtime
Daily/BD insulin: suitable for patients with daytime hyperglycemia
→ Examples: protaphane , pre-mixed
Basal-bolus insulin: suitable for patients with difficult titration or T1DM or long term type 2 DM with worsening insulin deficiency
→ Examples: Tresiba + Novorapid
fasting Haemstix for fasting glycemic control
Regular HbA1c for postprandial control
4 acute diabetic complications
Diabetic ketoacidosis (DKA) ± coma
Hyperglycaemic hyperosmolar state (HHS) ± hyperosmolar nonketotic coma (HONK)
Hypoglycaemia
Infections: pulmonary TB (due to ↓WBC function), UTI (glycosuria), others
Triggers of DKA and HHS
Reason: inability to ↑insulin appropriately to compensate for stress hyperglycaemia
Triggers:
→ Physiological stress: infection, operation, trauma, MI, stroke (esp if elderly)
→ Emotional stress if severe
→ Drug administration, eg. steroids
DKA
Which type of DM presents with DKA?
Precipitating factors?
Severity levels?
Presentation:
- Usually T1DM or in advanced, insulin-deficient T2DM
- Presenting manifestation of undiagnosed T1DM
- Inadequate insulin Tx in known T1DM
Precipitating factors:
- Infections (30-40%)
- Non-compliance with treatment (25%)
- Alterations to insulin dose (13%)
- Newly diagnosed DM (10-20%)
- MI (<1%)
Severity:
Mild: pH 7.25-7.3, HCO3 15-18, alert
Moderate: pH 7-7.25, HCO3 10-15, mild drowsiness
Severe: pH <7, HCO3 <10, stupor/coma
Biochemical profile in DKA
□ Ketoacidosis: hyperketonemia and ketonuria with metabolic acidosis
□ Hyperglycaemia: ≥11mmol/L
□ Dehydration and electrolyte disturbances
Mild: pH 7.25-7.3, HCO3 15-18, alert
Moderate: pH 7-7.25, HCO3 10-15, mild drowsiness
Severe: pH <7, HCO3 <10, stupor/coma
Pathogenesis of DKA
- Acute insulin deficiency → unrestrained lipolysis → ↑blood FFA → ↑hepatic ketogenesis → ↑↑blood ketones (a fasting state response) → metabolic acidosis
- HyperGly → profound osmotic diuresis → dehydration + Na/K loss
- 2o hyperaldosteronism → ↑↑K loss → net K deficit
- Metabolic acidosis → H+/K+ intracellular shift
- ↑↑Glc/ketones → hyperosmolar hyponatremia or normonatremia
Clinical presentation of DKA
Clinical presentation: can be fulminant or mild but generally evolve rapidly
□ S/S of hyperglycaemia: polyuria, polydipsia, polyphagia, marked fatigue
□ S/S of dehydration/electrolyte disturbance: orthostatic hypotension or even shock
□ S/S of ketoacidosis:
→ Fruity smelling breath
→ Kussmaul’s respiration, leg cramps
→ Acute abdomen: diffuse abdominal pain, nausea, vomiting (due to ileus, usu only if severe acidosis)
→ Altered mentation: ↓consciousness, confusion, coma
Diagnostic criteria of DKA
□ Hyperglycaemia: plasma glucose >14mmol/L
□ HAGMA: arterial pH <7.3, plasma HCO3- <15mmol/L ± ↑AG
□ Ketosis: moderate ketonuria or ketonaemia or ↑serum β-hydroxybutyrate (BHBA)
First-line investigations for suspected DKA
- Urine and plasma glucose
- Urine ± plasma ketones or BHBA (urine ketone is useless)
- Na, K, PO4 ± Mg
- Anion gap (AG)
- Urea, creatinine, Hb
- ABG
If indicated, look for underlying cause:
- CXR, ECG (MI)
- Blood and MSU C/ST (Infection*)
- Urine/serum osmolality (New DM)
- PT, aPTT
How to monitor DKA
Q1H:
- BP/P,
- RR,
- GCS,
- UO (Urine output)
- ± CVP (Central venous pressure)
Temperature - Q2H
Aspirate stomach if unconscious or vomiting ± ETT for airway protection if necessary
Foley’s catheter and set CVP as indicated
Abx if evidence of infection, treat hypotension and shock as appropriate
Treatment of DKA
Rehydration - 1-2L 0.9% normal saline
- Monitor serum Na
- Keep under 10% body weight infusion over 12h
- Watch out for fluid overload and CHF
Insulin - Regular human insulin
- IV bolus + Infusion by insulin pump
- Aim to decrease plasma glucose by 3-4mmol/L/h
- Change to maintenance insulin when Anion Gap normalize
Potassium - 10-20mmol/h
- Maintain serum K at 4-5mmol/L
- Calcium gluconate
- First priority of treatment
Sodium Bicarbonate
- Only if pH under 7.0
- Monitor serum K, maintain until over pH 7.0
Hyperglycaemic Hyperosmolar State (HHS)
Which DM presents with HHS?
Which patients at high risk?
Pathogenesis?
Early T2DM with relative insulin deficiency
At risk: Elderly with difficulty drinking water, on diuretics, decreased sense of thirst, sudden copious intake of glucose-containing fluid
Pathogenesis:
Severe Hyperglycemia > osmotic diuresis exacerbated by insulin deficiency causing impaired tubular sodium reabsorption > Severe dehydration/ Hyperosmolarity
But no ketosis (unlike DKA): insulin still present + severe hyperosmolar state → suppress lipolysis
Clinical presentation of hyperglycemic hyperosmolar state
Clinical presentation: typically insidious
□ Predisposition: Hx of ↓fluid intake or ingestion of large amounts of glucose-containing fluid
□ S/S of hyperglycaemia: polyuria, polydipsia, polyphagia, marked fatigue
□ S/S of dehydration/electrolyte disturbance: orthostatic hypotension or even shock
□ Neurological: focal neurological signs, seizures, general consciousness decrease, confusion, coma
Diagnostic criteria of HHS
□ Hyperglycaemia: blood glucose >33mmol/L (different from DKA)
□ Non-ketotic: arterial pH >7.3, serum HCO3- >15mmol/L, mild ketonuria/ketonaemia only (complete opposite direction from DKA)
□ Hyper-osmolar: effective serum osmolality >320mOsm/kg (2[Na] + [Glc])
Treatment of HHS
Rehydration with normal saline
Insulin: less aggressive than DKA, switch to maintenance insulin when alert, tolerating diet, osmo <315
Investigations for HHS
Same as DKA panel
- Urine and plasma glucose
- Urine ± plasma ketones or BHBA (urine ketone is useless)
- Na, K, PO4 ± Mg
- Anion gap (AG)
- Urea, creatinine, Hb
- ABG
If indicated, look for underlying cause:
- CXR, ECG (MI)
- Blood and MSU C/ST (Infection*)
- Urine/serum osmolality (New DM)
- PT, aPTT
Complications of HHS
Complications:
→ Risk of thrombosis esp in Caucasians + hyperosmolality
→ Risk of overshoot hypoglycemia and hypokalemia
→ Risk of cerebral oedema in children
Precipitating factors of Hypoglycaemia in DM pt
□ Overtreatment: excessive insulin or insulin secretagogues (sulphonylureas or meglitinides)
□ Treatment with anti-diabetics precipitated by renal impairment
□ Insufficient carbohydrate intake
□ Excessive exercise
Clinical presentation of Hypoglycaemia in DM pt
Adrenergic symptoms from ANS activity (usually occur first)
→ Palpitation, sweating, anxiety, tremor, tachycardia
→ Gradual decrease awareness in recurrent hypoglycaemia (eg. chronic DM)
Neuroglycopenic symptoms from ↓CNS activity due to hypoGly (usually occur later)
→ Hunger sensation
→ Periorbital and finger paraesthesia, seizures
→ Focal weakness, ↓sensation, clouding of vision
→ Depressed consciousness, drowsiness, coma
Diagnostic criteria of Hypoglycaemia in DM pt
Whipple’s triad
□ Symptoms compatible with hypoglycemia
□ Low blood glucose coinciding with time of symptoms
□ Resolution of symptoms with correction of hypoglycemia
Table below is for DM patients, not normal people
Treatment of hypoglycaemia in DM pt
- Oral carbohydrates: sweet drink, early meal or snack, 15-20g oral glucose
- IV dextrose if unconscious
- IM glucagon if cannot obtain IV access
- Monitoring: Haemstix Q1-2h until stable
→ duration depends on L/RFT and type of insulin/drug (in case of overdose)
Prevention of Hypoglycaemia in DM pt
□ Education to keep good balance between exercise, meals and antidiabetic Tx
□ Revise glycaemic target if frequent asymptomatic hypoGly
□ Consider pre-emptive glucagon prescription for those at risk of level 2-3 hypoGly
List Chronic Diabetic complications
List diabetic eye complications
Lacrimal system: ↓tear production
EOM: CN III, IV, VI palsies (as part of mononeuritis multiplex)
Lens: fluctuating refractive errors, cataract
Glaucoma: idiopathic or due to rubeosis iridis
Retina: retinopathy, papillopathy
Others: ↑eye infections, ↑eye inflammation after ocular operations
Subtypes of Diabetic retinopathy
□ Diabetic retinopathy (DMR): non-proliferative or proliferative
□ Diabetic macular oedema: retinal thickening and oedema involving macula
→ Can occur at any stage of DR
→ Commonest cause of vision loss in DM patients
Risk factors of diabetic retionopathy
□ Long duration of DM: 80% have DMR after 20y of disease
□ Poor DM control
□ Vascular comorbidities, esp HTN, smoking
□ Others: pregnancy, rapid implementation of tight glycemic control
5 pathophysiological processes of diabetic retinopathy
□ Retinal microangiopathy: chronic hyperGly → metabolic changes in retinal vessels → impaired vascular autoregulation → microaneurysm + retinal haemorrhage (‘dot-and-blot’)
□ Retinal ischaemia: endothelial damage → microthrombosis or occlusion → ischaemia → cotton wool spots (retinal nerve infarct) + venous beading (due to ischaemia) + intra-retinal microvascular abnormalities (IRMA) (anastomosis between arterioles and venules)
□ Breakdown of blood-retinal barrier: microangiopathy + microthrombosis → ↑capillary leakage → hard exudates (lipoprotein leakage) + macular edema (if occurring near macula) + retinal edema
□ Vasoproliferative substances: ischaemia → vasoproliferative factor secretion (eg. VEGF) → neovascularization (PDMR) + exacerbates ischaemia + breakdown of B-R barrier
□ Proliferative DMR: neovascularization w/ fragile vessels → vitreous haemorrhage
5 severity levels of diabetic retinopathy
Mild Non-proliferative diabetic retinopathy
- Clinical finding
- Treatment
Moderate Non-proliferative diabetic retinopathy
- Clinical findings
- Treatment
Severe non-proliferative diabetic retinopathy
Clinical finding
Treatment
Proliferative diabetic retinopathy
Clinical findings
Treatment
Macular edema
Clinical finding
Treatment
Clinical presentation of diabetic retionopathy
Asymptomatic: majority with DMR shows no symptoms until very late stages
- Blurred vision of gradual onset: usually due to macular oedema
-
Sudden visual loss indicates complications
→ Vitreous haemorrhage due to neovascularization into vitreous
→ Rubeotic glaucoma due to neovascularization of iris leading to acute angle closure
→ Tractional Retinal detachment due to fibrosis of abnormal vessels
Diabetic nephropathy
Pathogenesis
2 histological types
Pathogenesis:
□ Mechanism: hyperglycaemia → ↑ROS production → chronic damage to glomerular epithelium
□ Histology:
→ Nodular glomerulosclerosis with Kimmelstiel-Wilson nodules
→ Diffuse glomerulosclerosis with ↑mesangial matrix
Clinical presentation of diabetic nephropathy
Onset
□ Onset: microalbuminuria develops 5-15y after T1DM and 15-20y after T2DM dx
□ Albuminuria: slowly progressive from microalbuminuria (30-300mg/d) then to macroalbuminuria (>300mg/d)
□ Progressive CKD with gradual ↓GFR
Management of diabetic nephropathy
□ CVD risk factors control: stop smoking…
□ Glycaemic control: aim A1c <7-8%
→ Prefer SGLT2i and GLP1a
□ BP control (esp by ACEI/ARB)
□ Treat hyperlipidemia (by statins or fibrates)
□ Renal replacement therapy if ESRD
4 types of diabetic neuropathy
Acute diabetic mononeuropathy
Proximal diabetic neuropathy (diabetic amyotrophy, lumbosacral plexopathy)
Diabetic peripheral neuropathy
Diabetic autonomic neuropathy
Acute diabetic mononeuropathy
- Cause
- Site
- Clinical presentation
- Management
□ Cause: likely ischaemic infarction of peripheral nerves
□ Site: most commonly CN III, CN VI, median and common peroneal palsies
□ Clinical presentation: acute onset, usually transient
→ Ptosis and divergent squint (CN III) (typically pupil-sparing)
→ Lateral rectus palsy (CN VI)
→ Upper facial and eye pain (ocular)
→ Foot drop (peroneal n.)
□ Mx: generally supportive but may require MRI to r/o stroke
Proximal diabetic neuropathy
- Cause
- Site
- Clinical presentation
- Diagnostic test
- Management
□ Cause: likely ischaemic infarction of lumbosacral nerve roots and peripheral nerves
□ Site: asymmetrical, proximal, usually LL (but can affect UL)
□ Clinical presentation: progressive, typically transient, lasting weeks to months
→ Acute severe asymmetrical progressive proximal weakness and wasting
→ Hyperaesthesia and paraesthesia
→ Associated autonomic failure and weight loss
□ Dx: NCV (axonal degeneration), MRI pelvis (to r/o alternative causes)
□ Mx: 60% with good functional recovery in 12-24mo but mild residual weakness may remain
→ controlling underlying hyperglycaemia
→ Gabapentin/pregabalin/amitriptyline for neuropathic pain
Diabetic peripheral neuropathy
Cause
Site
Clinical presentation
Screening tests (special)
Management
□ Cause: metabolic or osmotic neurotoxicity due to chronic hyperglycaemia
□ Site: symmetrical, distal, usually begins in LL
□ Clinical presentation:
→ Sensory polyneuropathy: glove-and-stocking sensory loss of all modalities or paraesthesia
→ Motor polyneuropathy: ↓tendon reflexes in LL ± weakness, wasting (generally later)
→ Skin and joint: foot ulcers, foot deformities, Charcot arthropathy
□ Screening: by symptoms and monofilament (small fibre) and tuning fork (large fibre) tests
□ Workup: clinical ± NCV study and blood test (to r/o alternative causes, eg. B12)
□ Mx:
→ Optimize glycemic control as mainstay
→ Gabapentinoids (gabapentin/pregabalin) and antidepressants (amitriptyline) for pain
Cardiovascular manifestation of diabetic autonomic neuropathy
Impaired CO control: resting tachycardia (early), failure of exercise-induced ↑HR resulting in exercise intolerance
Orthostatic hypotension due to central/peripheral sympathetic denervation
Postural tachycardia with lightheadedness, dizziness, presyncope
Sudomotor and vasomotor manifestations of diabetic autonomic neuropathy
Distal hypohidrosis with compensatory proximal hyperhidrosis (abnormal excessive sweating)
Thermoregulatory impairment and hyperthermia
Diabetic dermopathy (dryness, itching) and Charcot arthropathy
Gastrointestinal manifestation of Diabetic autonomic neuropathy
GERD
Gastroparesis: N/V, early satiety, bloating, upper abd pain
Diarrhoea: painless watery nocturnal diarrhoea
Genitourinary manifestation of Diabetic autonomic neuropathy
Bladder dysfunction: ↓ability to sense full bladder, incomplete emptying, recurrent UTI, overflow incontinence
Ejactulatory dysfunction: retrograde ejaculation, erectile dysfunction
Dyspareunia due to ↓vaginal lubrication
Diabetic foot ulcer
Cause
Complications
Risk factors
Cause: Diabetic peripheral neuropathy
Common manifestation:
□ Foot ulcers: 25% lifestyle risk, annual risk 2%/y
□ Diabetic foot infections: cellulitis, osteomyelitis
RFs of foot ulcer development:
□ Previous foot ulceration (most important)
□ Neuropathy (80%): loss of monofilament sensation, neuropathy disability score
□ Foot deformity
□ Concomitant vascular disease
Management of diabetic foot
General foot care recommendations:
□ Annual comprehensive foot examination to identify RFs incl inspection + palpation of pulses
→ Refer vascular surgery for patients with significant claudication or +ve ABI
□ General foot self-care
□ Multidisciplinary approach (refer podiatry)
Diabetic neuropathic (Charcot) Arthropathy
Pathogenesis
Pathogenesis:
Lack of proprioception + ligament laxity + joint instability + deformity → prone to damage by minor trauma
vasomotor changes due to autonomic neuropathy lead to exaggerated local inflammatory response → arthropathy
Clinical features of Diabetic neuropathic arthropathy
Clinical features: generally painless
□ Acute arthritis: sudden onset unilateral warmth, erythema, swelling over foot/ankle (often ppt by minor trauma)
→ Joint involved: tarsal/TMTJ > MTPJ/ankle
□ Chronic arthritis: slowly progressing arthropathy with insidious swelling ± acute attacks
□ Foot deformity: collapse of midfoot arch, bony prominences in peculiar places ± pressure ulcerations
Xray features of Diabetic Neuropathic (Charcot) Arthropathy
□ Early: soft tissue swelling, loss in joint spaces
□ Late: forefoot bone resorption, disappearance in MT heads, pencil-pointing of phalangeal/MT shafts
□ Complication features: stress fractures, subluxation/dislocations
Management of Diabetic Neuropathic (Charcot) Arthropathy
□ Short-term immobilization (3-6mo): proven to ↓long-term joint damage and progression
□ Consider antiresorptive agents (bisphosphonates, calcitonin) as adjunct
□ Orthopaedic surgical correction in severe cases
