Islet adaptation to insulin resistance: mechanisms and implications for intervention.
Insulin sensitivity and insulin secretion are reciprocally related such that insulin resistance is adapted by increased insulin secretion to maintain normal glucose and lipid homeostasis. The relation between insulin sensitivity and secretion is curvilinear and mathematically best described as a hyperbolic relation. Several potential mediators have been suggested to be signals for the beta cells to respond to insulin resistance such as glucose, free fatty acids, autonomic nerves, fat-derived hormones and the gut hormone glucagon-like peptide-1 (GLP-1). Failure of these signals or of the pancreatic beta cells to adequately adapt insulin secretion in relation to insulin sensitivity results in inappropriate insulin levels, impaired glucose intolerance (IGT) and type 2 diabetes. Therefore, treatment of IGT and type 2 diabetes should aim at restoring the normal relation between insulin sensitivity and secretion. Such treatment includes stimulation of insulin secretion (sulphonylureas, repaglinide and nateglinide) and insulin sensitivity (metformin and thiazolidinediones), as well as treatment aimed at supporting the signals mediating the islet adaptation (cholinergic agonists and GLP-1). Both, for correct understanding of diabetes pathophysiology and for development of novel treatment modalities, therefore, the non-linear inverse relation between insulin sensitivity and secretion needs to be acknowledged.
Ahrén
B
B
Department of Medicine, Lund University, SE-221 84 Lund, Sweden. boi.ahren@med.lu.se
Pacini
G
G
D000222:Adaptation, Physiological; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018679:Cholinergic Agonists / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D005934:Glucagon / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008687:Metformin / Q000627:therapeutic use; D010446:Peptide Fragments / Q000627:therapeutic use; D011498:Protein Precursors / Q000627:therapeutic use; D013453:Sulfonylurea Compounds / Q000627:therapeutic use
D001786:Blood Glucose; D018679:Cholinergic Agonists; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D013453:Sulfonylurea Compounds; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D008687:Metformin