1. Pathophysiology and drug targets.
Pathophysiology and drug targets. T2D is a heterogeneous disorder with a complex pathophysiology, in which genetic and environmental factors contribute to dysfunction of various organ systems that control glucose homeostasis (5,6). Insulin resistance of liver, adipose, and skeletal muscle tissue results in respectively impaired insulin-induced reduction of HGP, lipolysis, and impaired insulin-stimulated glucose uptake (5). Hyperglycemia evolves when pancreatic β-cells are unable to secrete sufficient insulin to overcome insulin resistance (i.e., β-cell failure). In addition, α-cell dysfunction, characterized by fasting and postprandial hyperglucagonemia, stimulates HGP, which further augments hyperglycemia. Moreover, the efficacy of gut-derived incretin hormones GLP-1 and GIP to facilitate meal-related insulin release and glucagon suppression is impaired. The kidneys contribute to hyperglycemia by increasing tubular glucose reabsorption, presumably through upregulation of SGLT2 and increased renal gluconeogenesis (7). Last, in the development of T2D, impaired activation of satiety centers in the brain stimulates excessive food intake, and insulin resistance in the brain may alter central control of metabolic homeostasis (45). Pleiotropic drug effects are illustrated by the frame and color of the boxes. Green indicates body weight loss, blue indicates body weight neutrality, and red indicates body weight gain. A dotted frame indicates blood pressure reduction, and a solid frame indicates blood pressure neutrality. SU, sulfonylurea; TZD, thiazolidinedione.
Michaël J.B. van Baar et al. Dia Care 2018;41:
©2018 by American Diabetes Association