Pathway Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics

Pharmacodynamics perspective
Representation of anti-diabetic drugs repaglinide, nateglinide and sulfonylurea effects on insulin secretion in pancreatic cells.
Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics
repaglinide nateglinide sulfonylurea slc2a2 gck abcc8 kcnj11 vdcc ins ins insr irs1 irs2 p13k akt1 hnf4a tcf1 tcf2 pdx1 mafa isl1 neurod1
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Description

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 beta-cells to regulate blood glucose concentration. When blood glucose rises, glucose is transported into the beta-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 beta 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.

Authors: Li Gong.
Citation:
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
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History:
Therapeutic Categories:
  • Endocrine and Metabolic Disease agents

Entities in the Pathway

Genes (28)

Drugs/Drug Classes (3)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
ABCC8_KCNJ11 (ABCC8, KCNJ11) ABCC8_KCNJ11 (ABCC8, KCNJ11) ATP, nateglinide, repaglinide, sulfonamides, urea derivatives 10773014, 11728565, 11742410
AKT1 AKT1 PIK3C2A, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R5 11742410
Glucose Glucose-6-P GCK 11742410
HNF1A HNF1A AKT1 11742410
HNF1B HNF1B AKT1 11742410
HNF4A HNF4A AKT1 11742410
ISL1 ISL1 AKT1 11742410
MAFA MAFA AKT1 11742410
NEUROD1 NEUROD1 AKT1 11742410
PDX1 PDX1 AKT1 11742410
PIK3C2A, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R5 PIK3C2A, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R5 INSR_IRS1_IRS2 (INSR, IRS1, IRS2) 11742410
CACNA1A, CACNA1C, CACNA1D CACNA1A, CACNA1C, CACNA1D ABCC8_KCNJ11 (ABCC8, KCNJ11)
INS INSR_IRS1_IRS2 (INSR, IRS1, IRS2) 11742410
Glucose-6-P ATP, pyruvate 11742410
pyruvate ATP, CO2 11742410
Ca++ Ca++ CACNA1A, CACNA1C, CACNA1D 15585596
Glucose Glucose SLC2A2 11742410
INS INS Ca++ 15585596
K+ K+ ABCC8_KCNJ11 (ABCC8, KCNJ11) 16416420, 18566517

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