This lecture is a comprehensive walk-through of all chronic diabetic complications — not just the eye — and the pharmacological arsenal used to prevent and treat them. It starts with the eye as the entry point (because diabetic retinopathy is the archetypal microvascular complication), then expands to cover nephropathy, neuropathy, macrovascular disease, and the full management framework including diet, oral hypoglycaemic agents, incretins, SGLT2 inhibitors, and insulin. The lecture is co-taught by Endocrinology (Prof Karen Lam) and Ophthalmology (Prof Christopher Leung), reflecting the multidisciplinary nature of diabetic care. ^[1]

1. List ocular complications of diabetes mellitus
2. Classify diabetic retinopathy (NPDR vs. PDR) and describe fundoscopic findings
3. Explain the pathogenesis of chronic diabetic complications
4. Outline the principles of treating chronic complications at subclinical and overt stages
5. Describe the pharmacology of all major anti-diabetic drug classes
6. Know the side effects of every anti-diabetic drug (high yield)
7. Understand insulin types, their kinetics, and indications for insulin therapy
8. Describe the comprehensive management approach to T2DM (ADA framework)

DMO can occur at ANY stage of DR and is a major cause of central visual loss in people with diabetes. [6,14]

DMO occurs when there is breakdown of the blood-retinal barrier near the macula, leading to fluid and lipid accumulation (hard exudates) in the macular region. The fovea is the centre of the macula responsible for fine central vision, so even mild oedema here dramatically reduces visual acuity.

2025 MCQ Q11 tested this directly: a patient with dot/blot haemorrhages + hard exudates at the macula (especially fovea), no new vessels → answer = Diabetic macular oedema (not vitreous haemorrhage, not neovascular glaucoma, not tractional retinal detachment). ^[4]

"Growth of new vessels on iris extending to the angle of the anterior chamber, leading to high intraocular pressure and optic nerve degeneration" ^[1]

Why does this happen? Severe retinal ischaemia drives VEGF production and rubeosis iridis. Fragile new vessels and their fibrovascular membrane spread across the iris and angle, first impeding outflow and later contracting into peripheral anterior synechiae and secondary angle closure. The result can be a painful eye with very high IOP and rapid optic-nerve damage. ^[8]

The image shows ptosis with a divergent eye (CN III pattern), failure of abduction (CN VI pattern), painful ophthalmoplegia, and foot drop as examples of acute focal neuropathy ^[1]. A microvascular CN III palsy is often pupil-sparing, whereas a dilated poorly reactive pupil raises urgent concern for compression such as a posterior communicating artery aneurysm. Pupil sparing does not safely exclude an aneurysm or other compression: a new acute CN III palsy requires prompt neuro-ophthalmic/neurologic assessment and usually vascular neuroimaging ^[22]. Do not attribute diplopia to diabetes before excluding stroke, aneurysm, mass, myasthenia and other causes.

"Activation of pentose (polyol) pathway leads to accumulation of sorbitol within the lens" ^[8]

Aldose reductase converts glucose to sorbitol in the lens. Sorbitol cannot easily diffuse out, causing osmotic water influx into the lens → lens swelling → opacification. Diabetic cataracts tend to occur at a younger age and progress faster than age-related cataracts.

"PREVENTION IS ALWAYS THE BEST CURE!!!" ^[1]

Panretinal photocoagulation (PRP) works by deliberately destroying peripheral ischaemic retina. This reduces the total retinal oxygen demand, decreases VEGF production, and causes regression of new vessels. Side effects include loss of peripheral vision, poor night vision (dark adaptation), and mild reduction in visual acuity. ^[9]

Anti-VEGF agents are given intravitreally. For PDR they can produce visual outcomes comparable or superior to PRP in trials, but they demand reliable repeated follow-up; lapses can lead to poor outcomes. For centre-involved DMO with visual impairment, anti-VEGF is more effective than laser monotherapy. If vision remains good despite DMO, close observation with treatment if vision worsens can be reasonable. Bevacizumab is commonly used off-label; other approvals and availability vary by jurisdiction ^[14].

The classic diagram suggests normal → hyperfiltration → moderately increased albuminuria (UACR 3–30 mg/mmol) → severely increased albuminuria → falling eGFR → kidney failure. Real diabetic kidney disease does not always follow this sequence: eGFR can decline without albuminuria, albuminuria may regress, and another kidney disease may coexist. Prefer diabetic kidney disease (DKD) over the assumption-laden label "diabetic nephropathy."

Pathology: diabetic glomerulosclerosis — diffuse mesangial expansion, nodular glomerulosclerosis (Kimmelstiel-Wilson nodules), arteriolar hyalinosis (afferent and efferent). ^[11]

Red flags for non-diabetic nephropathy in a diabetic (i.e., don't just blame diabetes — think about biopsy): ^[12]

• Gross haematuria / active urine sediment
• Rapid decline in GFR
• Short duration of diabetes (< 5 years in T1DM)
• Absence of diabetic retinopathy, especially in T1DM, lowers the likelihood but does not exclude DKD—particularly in T2DM
• Abrupt heavy proteinuria/nephrotic syndrome or systemic features inconsistent with the usual trajectory

The slide's "amyotrophy" photograph appears to show upper-limb/shoulder wasting, whereas the syndrome usually meant in diabetes is a painful lumbosacral radiculoplexus neuropathy. Do not learn the photograph as the defining distribution. Diabetic peripheral neuropathy is also a diagnosis of exclusion: consider alcohol/toxins, neurotoxic drugs, B12 or other nutritional deficiency, hypothyroidism, kidney disease, paraproteinaemia, infection, inflammatory and inherited neuropathies—especially with acute, asymmetric, non-length-dependent or motor-predominant findings ^[14].

• Coronary disease / heart failure
• Stroke and other cerebrovascular disease
• Peripheral artery disease, with ulcer, infection and neuropathy jointly contributing to amputation risk

The fixed historical risk multipliers vary greatly by population, era and prevention. The enduring lesson from the body diagram is systemic atherosclerotic risk: manage blood pressure, atherogenic lipids, smoking, weight, kidney disease, physical inactivity and thrombosis risk as well as glycaemia.

1. Non-enzymatic glycation of proteins → formation of AGEs (advanced glycation end-products) → cross-linking of collagen, endothelial dysfunction, pro-inflammatory signalling
2. Polyol (sorbitol) pathway activation → aldose reductase converts glucose to sorbitol → osmotic stress → damage in lens (cataract), Schwann cells (neuropathy), pericytes (retinopathy)
3. PKC activation → altered vascular permeability, abnormal angiogenesis
4. Hexosamine pathway → altered gene expression in endothelial cells

Understanding pathogenesis explains why strict glycaemic control prevents microvascular complications (DCCT/UKPDS trials), why hypertension accelerates all complications, and why certain drugs (ACEI, ARB, SGLT2i, GLP-1RA, finerenone) have specific protective effects beyond glucose lowering.

"Good glycaemic control" ^[1]

"e.g. microalbuminuria — improve glycaemic control, treat other risk factors (BP, smoking), pharmacological intervention: ACEI, ARB, SGLT2i/GLP-1RA, Finerenone" ^[1]

"Microalbuminuria is reversible" is too absolute. Moderately increased albuminuria can regress, but it is also a cardiovascular/kidney risk marker. Confirm persistence (exclude exercise, infection, marked hyperglycaemia, menstruation and acute illness), calculate eGFR, control risk factors, and follow both UACR and eGFR.

"Progression slowed by: ↑glycaemic control, risk factor management (hypertension, hyperlipidaemia, smoking). Specific: nephropathy — renin-angiotensin blockade, SGLT2i, GLP-1RA, finerenone. Symptomatic — dialysis/transplant, pain relief. Prevention of drastic consequences — laser therapy, foot care" ^[1]

Current ADA guidance states there is no ideal universal percentage of calories from carbohydrate, protein or fat. Base the plan on the person's usual foods, culture, access, preferences, medicines, kidney function, metabolic goals and risk of malnutrition. The type and quality of food matter more than hitting the slide's fixed macronutrient percentages ^[17].

1. Personalised — according to individual preference and culture
2. Consistency of meal timings and quantity — especially if on insulin (to prevent hypo/hyperglycaemia)
3. Healthy foods consistent with population-wide recommendations
4. Emphasise high fibre (vegetables, fruits, wholegrains, legumes), low-fat dairy, fresh fish
5. Minimise high-energy foods (high saturated fats, sweet desserts, snacks)
6. For a person seeking weight loss, agree a sustainable energy deficit and preserve nutrition/lean mass; avoid stigmatizing or one-size-fits-all "hypocaloric diet" language

Common features of healthful patterns include non-starchy vegetables, whole fruit, legumes, whole grains, nuts/seeds, and appropriate protein sources while minimising sugar-sweetened beverages, refined grains and highly processed foods. Match mealtime insulin to carbohydrate rather than forcing identical meals when the person is trained for flexible dosing. Avoid ketogenic/very-low-carbohydrate eating with an SGLT2 inhibitor because it increases ketoacidosis risk ^[17].

Gut → α-glucosidase inhibitors (↓glucose absorption)
Liver → Biguanides (metformin) (↓hepatic glucose output, ↓insulin resistance)
       → Thiazolidinediones (↓hepatic insulin resistance)
Pancreas → Sulphonylureas, Meglitinides (↑insulin secretion)
           → DPP-4 inhibitors (↑endogenous incretins → ↑insulin, ↓glucagon)
Muscle/Fat → Thiazolidinediones (↓peripheral insulin resistance)
             → Biguanides
Kidney → SGLT2 inhibitors (↓glucose reabsorption)

How to read the organ-target diagram: the yellow centre is the net fall in glucose. Metformin mainly suppresses hepatic glucose production and improves insulin sensitivity; TZDs act on insulin resistance in adipose/muscle and liver; sulfonylureas/meglitinides stimulate pancreatic insulin secretion; DPP-4 inhibitors augment glucose-dependent incretin signalling; acarbose delays intestinal carbohydrate digestion; and SGLT2 inhibitors reduce proximal-tubular glucose reabsorption. The arrows explain why drugs can be combined—but mechanism alone does not determine outcome benefit, safety, or the right patient.

"Incretins physiologically regulate insulin and glucagon in a glucose-dependent manner"

GLP-1 and GIP are gut hormones released after food ingestion. They:

• ↑ Insulin secretion from β-cells (glucose-dependent → no hypoglycaemia when glucose is normal)
• ↓ Glucagon secretion from α-cells (GLP-1)
• Slow gastric emptying (GLP-1)
• Promote satiety

In T2DM, the incretin effect is diminished — partly because GIP's effect on β-cells is reduced, and both GLP-1 and GIP are rapidly degraded by DPP-4. ^[1]

"↓hyperglycaemia by increasing urine glucose loss; ↓weight, fat mass, BP; no hypoglycaemia if monotherapy; Cardio-renal protection; reduces heart failure even in patients without diabetes" ^[1]

The nephron image shows the core mechanism: filtered glucose enters the proximal tubule, SGLT2 blockade reduces reabsorption, and excess glucose is excreted in urine. Heart-failure and CKD benefits extend beyond diabetes and persist at eGFR levels where the glucose-lowering effect is small [15,16].

• Subcutaneous injection (1–4 times/day; pen or syringe): maintenance
• IV infusion of short-acting insulin in selected acute settings (for example DKA under a protocol); intramuscular insulin is rarely used in modern routine practice
• Continuous SC insulin infusion (CSII): insulin pump
• Inhaled rapid-acting human insulin exists in some markets. It is not a basal replacement; it requires pulmonary assessment/spirometry and is contraindicated in chronic lung disease such as asthma or COPD. The slide's "?? increased lung cancer" is a caution signal, not proof of causation ^[25].

The device montage shows the evolution from vial/syringe to pens, tubed pumps and small wearable pumps. The safe-use lesson is more important than the vintage hardware: verify insulin concentration and device compatibility, teach injection/cannula technique and site rotation, and provide a backup plan for device failure.

This slide is extremely high yield for pharmacology MCQs.

The pharmacokinetic curves are schematic, not exact dosing clocks. Absorption varies with dose, formulation/concentration, injection site, temperature, exercise, lipohypertrophy and kidney function; titrate from glucose/CGM patterns and hypoglycaemia, not the picture alone. Efsitora alfa remains investigational as of August 2026, despite positive phase 3 results, and should not be listed as an available insulin ^[26].

"Short-acting analogues: less self-association than human insulin after SC injection"

The depot diagram shows the rate-limiting sequence: crystals/particles dissolve; soluble hexamers dissociate to dimers and monomers; monomers diffuse into capillaries. Lispro swaps proline and lysine at B28–B29; aspart replaces B28 proline with aspartate. These changes reduce self-association after subcutaneous injection, so monomers become available more quickly and the late tail is shorter.

"Shift in isoelectric point → precipitates in subcutaneous tissue → forms a slow-releasing depot"

The molecule image shows A21 asparagine replaced by glycine and two arginines added at B31–B32. Glargine is soluble in its acidic formulation and precipitates after injection into near-neutral subcutaneous tissue, creating a slowly dissolving depot. Its action is relatively peakless—not literally flat—and it should not be mixed in the same syringe with other insulins unless a specific product label says otherwise.

• Continuous SC insulin infusion + continuous glucose monitoring system
• Automated insulin delivery (AID) = CGM sends sensor glucose to a control algorithm, which adjusts pump insulin delivery. Most current systems are hybrid rather than fully closed loop: meal boluses and exercise/device decisions still require user input, and interruption of rapid-acting insulin delivery can lead quickly to ketosis. Training, troubleshooting and backup insulin are essential ^[18].

Insulin-requiring patients:

• Marked recent weight loss
• Marked ketosis
• Underweight; clinically ill (dehydrated, infection, infarction)
• Severe hyperglycaemia at diagnosis: HbA1c > 10%, fasting glucose > 16.7 mmol/L
• Pregnancy
• Failed oral therapy (GLP-1RA preferred alternative if HbA1c < 11%, especially if obese, CVD, or CKD)

Current framing: in T2DM, consider insulin for symptomatic hyperglycaemia, catabolism/weight loss, ketosis or hyperglycaemic crisis, or very high values (A1C > 10% or glucose ≥16.7 mmol/L) ^[16]. Without severe hyperglycaemia or crisis, GLP-1–based therapy is usually preferred before insulin for initial/add-on injectable treatment; if insulin is needed, combining it with GLP-1–based therapy can improve glycaemia and weight while reducing hypoglycaemia burden. Pregnancy requires a pregnancy-specific plan—insulin is preferred for type 1 and type 2 diabetes, but do not generalise the slide into an identical regimen for every patient ^[16].

I. Reduction of cardiovascular and kidney risk:

• Established/high-risk ASCVD: use a GLP-1 RA and/or SGLT2 inhibitor with demonstrated benefit, independent of the current A1C when appropriate.
• Heart failure: prioritise an SGLT2 inhibitor with proven HF benefit; avoid TZDs in symptomatic HF and avoid saxagliptin when alternatives exist.
• CKD: prioritise a proven SGLT2 inhibitor; add/select GLP-1–based therapy and finerenone according to eGFR, albuminuria, potassium and residual cardiovascular/kidney risk [15,16].

II. Achievement of weight and glycaemic goals:

• Metformin remains effective, inexpensive and commonly used, but it is not mandatory "first line" ahead of an outcome-directed drug in every person with ASCVD, HF or CKD.
• Treat weight as its own outcome: structured lifestyle support, GLP-1 RA/dual GIP–GLP-1 therapy, and metabolic surgery where indicated.
• Minimise hypoglycaemia: assess need/dosage of SU, meglitinides, insulin
• Initial combination therapy if HbA1c 1.5–2.0% above target
• Consider accessibility and cost

"Patient education + diet/drugs/insulin + treat risk factors (HT, lipids, smoking, obesity) + individualised targets + regular complication assessment"

Ulcer risk is driven by the interaction of loss of protective sensation, repetitive trauma/pressure, deformity, peripheral artery disease and delayed recognition; infection complicates an established wound. Examine feet at least annually, including skin/deformity, pulses/vascular features, and neurologic assessment. Combine the 10-g monofilament with at least one other test (pinprick, temperature or vibration); inspect at every visit if there is sensory loss or previous ulcer/amputation ^[14].

• Genital candidiasis and, in some patients, urinary infection; do not diagnose UTI from nonspecific symptoms or asymptomatic bacteriuria alone
• Candidiasis (oral, genital — also SGLT2i side effect)
• Pulmonary TB
• Mucormycosis (rhinocerebral — classic in DKA)
• Osteomyelitis of foot

Diabetic autonomic/enteric neuropathy and impaired gastric neuromuscular function can delay gastric emptying → early satiety, nausea, vomiting and postprandial fullness. Confirm delayed emptying and exclude obstruction/medicines before labelling gastroparesis; symptoms and emptying rate correlate imperfectly.