[New aspects of pancreatic beta cell functions and their possible therapeutic applications].
Using the metabolic stimulus-secretion coupling of pancreatic beta cells as an example, this review illustrates how new strategies in the treatment of type 2 diabetes mellitus can be developed from the results of basic research. Metabolic stimulus-secretion coupling presupposes the metabolizing of those stimuli of insulin secretion that have the properties of nutritional substances. Changes in the ATP/ADP ratio within the beta cells will then trigger the release of insulin granules from them. Glucokinase, a glucose phosphorylating enzyme, functions as a metabolic glucose sensor, which couples changes in physiological glucose concentration in the pancreatic beta cells and in the liver to the intermediary metabolism, i.e. glycolysis, the citrate cycle and respiratory-chain phosphorylation. In this way insulin secretion and hepatic metabolism are positively influenced. Several pharmaceutical companies (Roche, Merck, Astra-Zeneca, Lilly) have recently developed first examples of glucokinase-activating compounds and demonstrated in animal models their efficacy in the treatment of type 2 diabetes mellitus. These glucokinase activators prevent glucokinase from changing into a catalytically inactive structure. They also increase glucose affinity of the enzyme and stabilize a catalytically active form of glucokinase proteins. In this way glucokinase activators increase glucose-induced insulin secretion and inhibit hepatic glucogenesis. Glucokinase activators are an interesting innovation in the future treatment of type 2 diabetes, because their action on beta cells and the liver is caused by changes in blood glucose concentration.
Tiedge
M
M
Institut für Medizinische Biochemie und Molekularbiologie, Medizinische Fakultät, Universität Rostock, Rostock, Germany. markus.tiedge@med.uni-rostock.de
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism* / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000628:therapy*; D005941:Glucokinase / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D011725:Pyridines / Q000627:therapeutic use
D001786:Blood Glucose; D007328:Insulin; D011725:Pyridines; C520311:glucokinase activator compound 50; D005941:Glucokinase