Diabetic bone fragility through advanced glycation end product-collagen axis: Mechanisms and therapy of sodium glucose cotransporter 2 inhibitors

Table 2 Three metabolic pathways of bone matrix advanced glycation end-product formation and their rate-limiting determinants

Pathway	Key steps	Products/intermediates	Rate-limiting determinants
Classical Maillard reaction	Glucose reacts with epsilon-amino group of lysine, Schiff base, Amadori rearrangement, early Amadori products	Fructosamine, 1-deoxy-1-ketofructose	Blood glucose concentration, temperature, pH
Glyco-oxidative stress	ROS/RNS oxidize sugars or Amadori products, carboxylated side chains	CML, CEL and other “oxidative AGEs”	ROS levels, antioxidant defenses
Carbonyl stress/dicarbonyl pathway	Glucose autoxidation, degradation or lipid peroxidation, MGO, GO, 3-DG, conjugation with lysine/arginine	MG-H1, glucosepane, pentosidine	Glyoxalase-1 activity, glutathione pool

ROS: Reactive oxygen species; RNS: Reactive nitrogen species; MGO: Methylglyoxal; GO: Glyoxal; 3-DG: 3deoxyglucosone; CML: Nepsilon-(carboxymethyl)lysine; CEL: Nepsilon-(carboxyethyl)lysine; AGEs: Advanced glycation end-products; MG-H1: Methylglyoxal-derived hydroimidazolone-1; pH: Potential hydrogen (acidity/alkalinity).