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Repaglinide, nateglinide and sulfonylurea are agents used for treatment of type II diabetes.
They lower blood glucose levels by blocking ATP-dependent potassium channels in pancreatic
beta cells to stimulate insulin secretion. Repaglinide and nateglinide act in a
dose-dependent manner, and are characterized as having a fast onset, yet with a brief
duration of action. Their action is glucose dependent, and they are taken with meals for
postprandial hyperglycemia. They have been shown to present reduced risk of long-lasting
hypoglycemia. Sulfonylurea has a longer duration of action than repaglinide, with high
potency and is dependent on functioning beta cells in the pancreatic islets. Sulfonylurea
may induce hypoglycemia in elderly patients with impaired liver or renal functions.
In type II diabetes, patients either do not produce enough insulin or their cells are
resistant to insulin action. Insulin is produced by pancreatic β-cells to regulate
blood glucose concentration. When blood glucose rises, glucose is transported into the
β-cells by glucose transporter 2 (SLC2A2/GLUT2). Glucokinase (GCK) then acts as glucose
sensor to catalyze formation of glucose-6-phosphate and controls the rate of entry of
glucose into metabolism. Glucose-6-phosphate then undergoes glycolysis and the Krebs cycle
(in mitochondria) to generate ATP. The elevated ATP/ADP ratio can in turn close the
ATP-sensitive K+ channels (KATP, made up of four subunits of the sulfonylurea 1 receptor
(ABCC8/SUR1) and four subunits of the inwardly rectifying K+ channel Kir6.2 (KCNJ11)). In
addition to glucose, drugs such as repaglinide, nateglinide and sulfonylureas can also lead
to closure of the KATP channels to stimulate insulin secretion. The closure of KATP channels
depolarizes the plasma membrane, and leads to the opening of voltage-dependent Ca2+ channels
(VDCC) resulting in influx of extracellular Ca2+ which then triggers exocytosis and insulin
release from the insulin containing granules located in pancreatic beta cells. The secreted
insulin can bind to insulin receptor (INSR) and triggers activation of PI3K/Akt pathway and
the transcription factors in the β cells (HNF4A, TCF1, TCF2, PDX1, MAFA, ISL1 and
NEUROD1 etc.) which control the expression of insulin (INS) and many other genes that are
important for regulation of insulin secretion such as SLC2A2, GCK.
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