ALT Type 2 diabetes is characterised by insulin resistance involving multiple tissues including liver, kidney, skeletal and cardiac muscle, vasculature, adipose tissue, and β cells. The insulin resistance is genetic in origin and can be shown early in life in lean, glucose-tolerant individuals, long before the onset of overt diabetes. Excess caloric intake exacerbates the underlying genetic cause of the insulin resistance, placing stress on the β cells, which themselves are genetically predisposed to dysfunction. GLP-1 receptor agonists can reverse the component of insulin resistance that is related to obesity and lipotoxicity, but cannot correct the genetic component of insulin resistance, which only can be reversed by insulin-sensitising drugs that address the basic genetic or molecular causes of insulin resistance. HGP=hepatic glucose production. ASCVD=atherosclerotic cardiovascular disease. GLP-1 RA=glucagon-like peptide-1 receptor agonist.