Pathophysiology

Pathophysiology

I-10. Microvascular complications of diabetes mellitus

糖尿病の細小血管合併症

Diabetic Complications — Overview

Acute metabolic derangements

  1. Hypoglycemia
  2. Diabetic ketoacidosis (DKA)
  3. Hyperglycemic hyperosmolar state (HHS) / coma

Chronic complications

  • Microvascular: retinopathy, nephropathy, neuropathy.
  • Macrovascular (atherosclerotic CVD): heart disease (IHD, MI), cerebrovascular disease (stroke, TIA), peripheral/lower-extremity arterial disease.

Hyperglycemia-Induced Microvascular Injury

  • Targets: retinopathy (microvascular endothelial cells), nephropathy (mesangial cells), neuropathy (Schwann cells).
  • Microvessels = diameter <200 µm. The problem is nutrient transport, not perfusion; damage is predominantly ROS-mediated. Endothelial dysfunction → secondary parenchymal damage.

Mechanism in endothelial cells

  1. Glucose crosses endothelial cells concentration-dependently to feed parenchyma; they can’t downregulate glucose transporters → can’t store glucose → it is transported out.
  2. Endothelial cells rely on anaerobic glycolysis (low O₂ use) → parenchyma highly dependent on them; glucose & fat (FFA, LDL, HDL) also pass transcellularly.
  3. High glucose → oxidative stress → endothelial damage/death → vascular dysfunction (retinal cell proliferation → retinopathy).
  4. Parenchymal injury: ROS consumes NO (↓vasodilation); inflammation (TNF, IL-1) → procoagulant state (↑tissue factor, ↓heparan sulfate, ↓thrombomodulin); immunosuppression.
  • Root cause: excess glucose → mitochondrial superoxide → activates alternative oxidative pathways → ROS + glycation end products (NADH depletion, ↓glutathione). Superoxide can’t be blocked → glycemic control is the best treatment.

Diabetic Retinopathy

  • Usually the first clinically recognized microvascular injury; main cause = poor glycemic control; leading cause of blindness in adults (severe form ~30%).
  • Pathogenesis: hyperglycemia → capillary occlusion (abnormal endothelial proliferation + death) → disrupted blood-retina barrier.
    • Behind occlusion (↑pressure): microaneurysms, soft exudates (“cotton wool spots,” nerve-fiber infarcts), hard exudates (“yellow spots,” lipid extravasation), hemorrhages (“blots and dots”).
    • In front (hypoxic): ↑VEGF + bone-marrow progenitors → neovascularization (proliferative retinopathy).
  • Further problems: severe visual impairment/blindness, retinal detachment (tractional, proliferative), macular edema (disrupts central vision).

Diabetic Nephropathy

  • Both T1DM and T2DM → chronic kidney disease with 3 signs: proteinuria, diminished GFR, hypertension (in T1DM HTN usually from nephropathy; in T2DM HTN often present at diagnosis). Prevalence ~30% (T1DM), ~40% (T2DM).
  • Poor glycemic control central; retinopathy usually precedes nephropathy.
  • Proteinuria hypothesis: onset = microalbuminuria → progression = albuminuria (↓renal function). GFR first rises, then falls as proteinuria worsens.
    • Treatment by stage: glycemic control (normal GFR, no microalbuminuria) → ACE inhibitor/ARB (microalbuminuria) → salt restriction + diuretics (macroalbuminuria).
  • Causes of proteinuria: mesangial expansion → ↑intraglomerular pressure → podocyte injury → damaged slit diaphragms → leak larger proteins → glomeruli/tubuli loss → end-stage failure. CKD also ↑CV risk (dyslipidemia).

Diabetic Neuropathy

  • Affects long peripheral nerves (legs/feet), both somatic & autonomic; symptoms start distally; ~30% prevalence in both types.
  • Forms: distal symmetrical polyneuropathy (DSPN — pain/loss of sensation, “diabetic foot syndrome”); autonomic neuropathy (postural hypotension, cardiac).
  • Pathogenesis: microvascular damage (neuropathy) + Schwann-cell injury (schwannopathy) + axon degeneration (axonopathy); neuropathic pain likely from satellite glial cell activation.
    1. Hyperglycemia → oxidative damage to endothelial & Schwann cells → disrupted nerve blood flow.
    2. Myelin loss (Schwann damage) → secondary axonopathy.
    3. Vascular injury disrupts the blood-nerve barrier.

Glycemic Targets

  • Management of metabolic abnormality is the central pillar; glycemic control is priority #1, complemented by CV-risk reduction.
  • Intensive glycemic control ↓microvascular (and tends to ↓macrovascular) complications — though one trial showed ↑mortality with intensive therapy.

一問一答

▶Which cell types are the primary targets in diabetic retinopathy, nephropathy, and neuropathy?

Retinopathy → microvascular endothelial cells; nephropathy → mesangial cells; neuropathy → Schwann cells.

▶Why are endothelial cells especially vulnerable to hyperglycemia?

They cannot downregulate their glucose transporters, so they cannot limit glucose uptake; excess intracellular glucose drives oxidative stress and cell damage.

▶What are the three acute metabolic derangements of diabetes?

Hypoglycemia, diabetic ketoacidosis (DKA), and hyperglycemic hyperosmolar state (HHS)/coma.

▶What defines a microvessel, and what is the main problem in microvascular injury?

Microvessels have a diameter <200 µm. The problem is impaired nutrient transport (not perfusion), and damage is predominantly ROS-mediated through endothelial dysfunction.

▶What are the three chronic microvascular complications of diabetes?

Retinopathy, nephropathy, and neuropathy.

▶What is the molecular root cause of hyperglycemia-induced microvascular damage?

Excess glucose → mitochondrial superoxide overproduction → activation of alternative oxidative pathways → ROS and advanced glycation end-products (with NADH/glutathione depletion).

▶Why is glycemic control the best treatment for microvascular complications?

Mitochondrial superoxide overproduction cannot be pharmacologically blocked, so reducing the glucose substrate (glycemic control) is the most effective approach.

▶Which microvascular complication is usually recognized first, and why is it important?

Diabetic retinopathy — it is usually the first clinically recognized microvascular injury and the leading cause of blindness in adults.

▶What is the basic pathogenesis of diabetic retinopathy?

Hyperglycemia causes capillary occlusion (abnormal endothelial proliferation plus endothelial death), which disrupts the blood-retina barrier.

▶What retinal findings appear behind a capillary occlusion (high-pressure side) in diabetic retinopathy?

Microaneurysms, soft exudates (cotton-wool spots = nerve-fiber infarcts), hard exudates (yellow lipid spots), and hemorrhages (blots and dots).

▶What drives proliferative diabetic retinopathy?

Hypoxia in front of the occlusion increases VEGF and recruits bone-marrow progenitors, causing neovascularization.

▶What are the three signs of diabetic nephropathy?

Proteinuria, diminished GFR, and hypertension.

▶How does GFR change as diabetic nephropathy progresses?

GFR first rises (hyperfiltration), then falls as proteinuria worsens from microalbuminuria to overt albuminuria.

▶What is the mechanism of proteinuria in diabetic nephropathy?

Mesangial expansion → increased intraglomerular pressure → podocyte injury → damaged slit diaphragms → leakage of larger proteins → loss of glomeruli/tubuli → end-stage failure.

▶What is the stepwise treatment of diabetic nephropathy by stage?

Glycemic control (normal GFR, no microalbuminuria) → ACE inhibitor/ARB (microalbuminuria) → salt restriction plus diuretics (macroalbuminuria).

▶Does diabetic retinopathy or nephropathy usually appear first?

Retinopathy usually precedes nephropathy.

▶What are the two main forms of diabetic neuropathy?

Distal symmetrical polyneuropathy (DSPN — pain/loss of sensation, "diabetic foot syndrome") and autonomic neuropathy (e.g., postural hypotension, cardiac autonomic dysfunction).

▶What are the three components of diabetic neuropathy pathogenesis?

Microvascular damage (neuropathy), Schwann-cell injury (schwannopathy), and axon degeneration (axonopathy); neuropathic pain likely arises from satellite glial cell activation.

▶Why does myelin loss in diabetic neuropathy lead to axonopathy?

Schwann-cell injury causes myelin loss, which secondarily leads to axon degeneration; vascular injury also disrupts the blood-nerve barrier.

▶What is the central pillar of preventing diabetic microvascular complications?

Management of the metabolic abnormality, with glycemic control as the top priority; intensive control reduces microvascular complications (complemented by CV-risk reduction).