Gluconeogenesis
The metabolic production of new glucose from non-carbohydrate sources (amino acids, lactate, glycerol) primarily in the liver. Gluconeogenesis is inappropriately elevated in type 2 diabetes, contributing to fasting hyperglycaemia. GLP-1 receptor agonists suppress gluconeogenesis partly through glucagon suppression.
Technical Context
Hepatic gluconeogenesis converts non-carbohydrate substrates (lactate, pyruvate, glycerol, amino acids — particularly alanine and glutamine) to glucose through a multistep enzymatic pathway (pyruvate carboxylase → phosphoenolpyruvate carboxykinase/PEPCK → fructose-1,6-bisphosphatase → glucose-6-phosphatase). Gluconeogenesis is the primary source of hepatic glucose output in the fasting state. Regulation: stimulated by glucagon (activates PEPCK and G6Pase gene transcription via cAMP/PKA/CREB pathway), cortisol, and catecholamines; inhibited by insulin (suppresses PEPCK/G6Pase expression via Akt/FoxO1 pathway). In T2D, hepatic gluconeogenesis is inappropriately elevated due to: hepatic insulin resistance (failure of insulin to suppress gluconeogenic gene expression), elevated glucagon (alpha cell dysfunction), and increased gluconeogenic substrate delivery. GLP-1 RAs reduce gluconeogenesis through: glucagon suppression, improved hepatic insulin sensitivity, and weight loss effects.