Pathogenesis of Diabetes Complications

Metabolic Abnormalities that Lead to Diabetic Complications

Uncontrolled hyperglycemia is the primary cause of virtually all complications of diabetes

genetic and other risk factors alter the course of complications, as not all patients develop them to the same degree

Five Metabolic Abnormalities that may play a role in pathogenesis:

(1) Polyol Pathway

Normally, most blood glucose is phosphorylated to glucose-6-phosphate for use in glycolysis and the pentose shunt

During hyperglycemia, a substantial amount of glucose is reduced to sorbitol, which is later oxidized to fructose

complications due to Ý sorbitol, ß myoinisitol, and competition for nitric oxide synthase Þ diabetic cataracts and nerve conduction abnormalities

(2) Non-Enzymatic Glycosylation / Maillard Reaction

Any reducing sugar (including glucose) can covalently attach to amino groups (e.g., lysine) via a ketoamine bond

result is an Amadori product (e.g., hemoglobin A1c) – this can happen to proteins, lipids, and possibly DNA

Glucose + Protein/Lipid Þ Amadori Products Þ Dicarbonyl compounds Þ Advanced Glycation End product (AGE)

Amidori products:

impair enzyme activity, conformational changes, and ligand binding
glycated LDLs are not recognized by receptors and are trapped in ECM and arteries)

Advanced Glycation End Products:

contributes to stiffening, thickening, ß digestibility, and ß ECM turnover in diabetes

act as recognition signals for uptake and degradation of proteins by macrophages Þ cytokines/oxidative stress Þ disease

amino guanidine Þ significant inhibition of non-enzymatic glycation

(3) Glucose-mediated activation of PKC

Glucose becomes diacylglycerol which is an activator of PKC.

Excessive Hexose Concentration (Glucose or Galactose) Þ Ý DAG Þ Ý PKC activity

Effects of PKC Activity:

(a) altered enzyme activities

(b) basement membrane and matrix production

(c) cell proliferation and turnover

(d) increased blood flow

(4) Altered Gene Expression

Glucose can activate the Glucose Response Element (CACGTG motif) which alters protein expression

high glucose can thus increase transcription of fibronectin, B1-laminin, and type IV collagen Þ disease (esp. in kidney)

this effect can persist even if glucose is later controlled – possibly permanent alteration at DNA level

(5) Proliferative Growth Factors – such as IGF-1, basic fibroblast growth factor (bFGF), endothelin, TGF-b

these can induce symptoms similar to diabetic complications in laboratory animals, but link to hyperglycemia unknown

How do these Metabolic Abnormalities lead to disease?

much more is known about the pathogenesis of the conditions than the abnormalities that initially cause them

Pathogenesis of Diabetic Retinopathy

Hyperglycemia Þ Metabolic Abnormalities Þ Vaso-occlusion / capillary degeneration Þ Ischemia Þ Vasoproliferative factors (VEGF) Þ Neovascularization and Macular Edema (visual distortions)

note – Anti-hypertensive meds inhibit progression of diabetic retinopathy; aspirin: partial inhibition of prostaglandin

VEGF:

induced by hypoxia

endothelial-specific mitogen

Ý vascular permeability (~ 50,000x more potent than histamine.)

found in Ý conc of vitreous subst.

Pathogenesis of Diabetic Nephropathy

Hyperglycemia Þ Metabolic Abnormalities Þ three effects:

(1) Ý GFR and RPF Þ Intraglomerular hypertension Þ Albuminuria Þ ß GFR Þ renal insufficiency

(2) Mesangial Expansion Þ ß capillary filtering surface Þ renal insufficiency

(3) Ý TGF-b Þ sclerosis Þ renal insufficiency

note – ACE inhibitors ß protein excretion in normotensive type 1 diabetics

effect is on efferent capillary tone in the glomerulus, not systemic blood pressure

Pathogenesis of Diabetic Neuropathy

Hyperglycemia Þ Metabolic Abnormalities Þ two effects:

(1) Impaired Perfusion Þ Ischemia Þ ß conduction velocity (due to ß Na/K ATPase at nodes of Ranvier)

(2) Loss of trophic factors Þ Axon Dwindling and Regeneration and also Segmental Demyelination Þ Sensory loss and Pain

note – Aldose Reductase Inhibitors prevent diabetes-induced conduction velocity defect but have no effect on polyol path

Zopolnestat is statistically helpful but clinically meaningless; Nerve Growth Factor prevents neural defects