POTASSIUM CHANNEL INHIBITORS PHARMACODYNAMICS PATHWAY (PW:0000725)
Description
Nateglinide and repaglinide are used as
blockers of the ATP-sensitive potassium channels (KATP ) to
promote insulin secretion and lower blood glucose levels in patients with type
2 diabetes mellitus (T2D). In response to elevated
levels of circulating glucose; insulin is secreted from the pancreatic beta
cells. This effect is counteracted by glucagon when the glucose levels are low
- the two hormones act to maintain glucose homeostasis. The secretion of
insulin from the islets of Langerhans is biphasic; the first and better
understood phase is completely lost in diabetic patients while the second is
severely impaired
. The first phase is largely
dependent on the K
ATP channels. In normal individuals, glucose is
rapidly taken up by the beta cells and metabolized. The resulting increase in
ATP concentration triggers closure of K
ATP channels leading to
membrane depolarization and opening of voltage-gated calcium channels. The
increase in calcium concentration induces fusion of the insulin-granules with
the plasma membrane and SNARE-mediated insulin exocytosis. Insulin binding to
its receptor sets in motion the insulin pathway which in turn activates
downstream signaling pathways to regulate glucose transport, insulin expression
and a range of other gene expression and cellular events.
Uptake,
metabolism and release of the drug are generally referred to as the
pharmacokinetics of the drug while the action exerted on the target and the
subsequent events are generally referred to as its pharmacodynamics. Nateglinide
and repaglinide potentiate the closure of the KATP channels; they
have similar pharmacodynamic profiles with some differences in the interaction
with and the effect upon the K
ATP channels. Both drugs depend on
glucose and do not seem to exert any effect in the fasted state; nateglinide
action appears to be the more sensitive one to increased glucose concentration.
The drugs are loosely categorized as members of the meglitinide family by
virtue of functional rather than structural relationships. Meglitinide is the
non-sulfonylurea portion of glibenclamide molecule - the regulatory subunits of
K
ATP channel are receptors for sulfonylureas. Repaglinide is the
benzoic acid derivative of meglitinide; nateglinide is a D-phenylalanine
derivative. The drugs have been administered alone as well as in combination
with other drugs and appear to be safe for patients with renal impairment. Studies
indicate that they have similar actions in humans and in animal models
investigated. An advantage of these drugs is the fact that they don¿t appear to
give rise to hypoglycemic effects, most likely due to their rapid uptake,
metabolism and release. A disadvantage is that their metabolism appears to be
carried out in a species-specific manner thus making in difficult to study adverse
drug effects using animal models. [To access the PharmGKB diagram page click
here ]
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Pathway Diagram:
Genes in Pathway:
G
Abcc8 ATP binding cassette subfamily C member 8
ISO SMPDB SMP:00453 SMP:00454
NCBI chr 1:96,598,568...96,679,563
G
Cacna1a calcium voltage-gated channel subunit alpha1 A
ISO SMPDB SMP:00453 SMP:00454
NCBI chr19:23,520,741...23,819,971
G
Cacna2d2 calcium voltage-gated channel auxiliary subunit alpha2delta 2
ISO SMPDB SMP:00453 SMP:00454
NCBI chr 8:108,072,208...108,203,516
G
Cacnb1 calcium voltage-gated channel auxiliary subunit beta 1
ISO SMPDB SMP:00453 SMP:00454
NCBI chr10:82,998,182...83,018,838
G
Ins2 insulin 2
ISO SMPDB SMP:00453 SMP:00454
NCBI chr 1:197,843,277...197,992,522
G
Slc2a2 solute carrier family 2 member 2
ISO SMPDB SMP:00453 SMP:00454
NCBI chr 2:111,609,798...111,639,930
Pathway Gene Annotations
Disease Annotations Associated with Genes in the potassium channel inhibitors pharmacodynamics pathway
Abcc8 atrial heart septal defect , brain edema , Brain Injuries , cardiac arrest , Colorectal Neoplasms , Congenital Hyperinsulinism , congestive heart failure , cryptorchidism , diabetes mellitus , Dwarfism , Endotoxemia , epilepsy , familial hyperinsulinemic hypoglycemia 1 , familial hyperinsulinemic hypoglycemia 2 , gastroesophageal reflux disease , genetic disease , Growth Disorders , hyperinsulinemic hypoglycemia , hyperinsulinism , Hyperplasia , hypertension , hypoglycemia , intellectual disability , leucine-sensitive hypoglycemia of infancy , Macrocephaly , maturity-onset diabetes of the young , maturity-onset diabetes of the young type 1 , maturity-onset diabetes of the young type 13 , middle cerebral artery infarction , Muscle Hypotonia , Myocardial Reperfusion Injury , Necrosis , neonatal diabetes , Neonatal Hypoglycemia, Simulating Foetopathia Diabetica , Neuraminidase Deficiency , newborn respiratory distress syndrome , Parkinsonism , permanent neonatal diabetes mellitus , Permanent Neonatal Diabetes Mellitus 3 , polyhydramnios , Pulmonary Arterial Hypertension , Retrognathia , sciatic neuropathy , Spinal Cord Injuries , status epilepticus , Stroke , Subarachnoid Hemorrhage , transient neonatal diabetes mellitus , Transient Neonatal Diabetes Mellitus, 2 , Transient Neonatal Diabetes Mellitus, 3 , Traumatic Subarachnoid Hemorrhage , type 1 diabetes mellitus , type 2 diabetes mellitus Cacna1a Aicardi-Goutieres Syndrome 4 , alpha-mannosidosis , Alternating Hemiplegia of Childhood 1 , amyotrophic lateral sclerosis , Ataxia , attention deficit hyperactivity disorder , Auditory Neuropathy , autism spectrum disorder , autistic disorder , bone marrow disease , cerebellar ataxia , cerebral palsy , cerebral venous thrombosis , Charcot-Marie-Tooth disease dominant intermediate B , childhood absence epilepsy , childhood electroclinical syndrome , combined immunodeficiency , combined T cell and B cell immunodeficiency , developmental and epileptic encephalopathy 1 , developmental and epileptic encephalopathy 2 , developmental and epileptic encephalopathy 42 , developmental and epileptic encephalopathy 52 , Developmental Disabilities , disorder of sexual development , Dysarthria , epilepsy , episodic ataxia , episodic ataxia type 2 , exfoliation syndrome , familial hemiplegic migraine , familial hemiplegic migraine 1 , generalized dystonia , Generalized Epilepsy , genetic disease , glutaric acidemia I , intellectual disability , Lambert-Eaton myasthenic syndrome , learning disability , Marshall-Smith syndrome , migraine , migraine with aura , Muscle Spasticity , Muscle Weakness , myelitis , myoclonic-atonic epilepsy , Nervous System Malformations , neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures , Neurodevelopmental Disorders , neurogenic bladder , Neurologic Gait Disorders , progressive bulbar palsy , spastic ataxia , Spastic Paraparesis , spinocerebellar ataxia type 6 , Spinocerebellar Ataxias , Sporadic Hemiplegic Migraine , subependymal giant cell astrocytoma , sudden infant death syndrome , temporal lobe epilepsy , Tremor , vascular dementia Cacna2d2 Ataxia , Cardiac Arrhythmias , Cerebellar Atrophy with Seizures and Variable Developmental Delay , childhood absence epilepsy , choreatic disease , COVID-19 , developmental and epileptic encephalopathy , early infantile epileptic encephalopathy , epilepsy , Female Infertility , Generalized Epilepsy , genetic disease , Hearing Loss , Myocardial Ischemia , primary ciliary dyskinesia Ins2 acute kidney failure , Acute Liver Failure , adenoma , Albuminuria , Alzheimer's disease , Beckwith-Wiedemann syndrome , bipolar disorder , bladder disease , cardiac arrest , cholangiocarcinoma , cognitive disorder , congestive heart failure , cystic kidney disease , delta beta-thalassemia , developmental and epileptic encephalopathy , diabetes mellitus , Diabetic Cardiomyopathies , diabetic ketoacidosis , Diabetic Nephropathies , diabetic retinopathy , disease of metabolism , early infantile epileptic encephalopathy , Edema , Experimental Liver Cirrhosis , generalized dystonia , genetic disease , gestational diabetes , glucose intolerance , hepatitis , hepatocellular carcinoma , hyperglycemia , hyperinsulinism , Hyperkalemia , Hyperproinsulinemia , hypertension , Hypertriglyceridemia , hypertrophic cardiomyopathy , hyperuricemia , hypoglycemia , Hypoinsulinemia , hypokalemia , Hypotension , immunodeficiency 39 , Insulin Resistance , insulinoma , kidney disease , kidney failure , Lewy body dementia , liver disease , maturity-onset diabetes of the young , maturity-onset diabetes of the young type 1 , maturity-onset diabetes of the young type 10 , Memory Disorders , metabolic dysfunction-associated steatotic liver disease , Metabolic Syndrome , Micronuclei, Chromosome-Defective , MPTP Poisoning , muscular disease , neonatal diabetes , Neoplasm Invasiveness , neural tube defect , neuronal ceroid lipofuscinosis , obesity , osteoarthritis , pancreatic cancer , pancreatic ductal carcinoma , pancreatitis , panic disorder , Paralysis , Paresthesia , Parkinson's disease , permanent neonatal diabetes mellitus , Permanent Neonatal Diabetes Mellitus 4 , Phelan-McDermid syndrome , polycystic ovary syndrome , prostate cancer , Prostatic Neoplasms , Rhabdomyolysis , Segawa Syndrome, Autosomal Recessive , steatotic liver disease , Tachycardia , transient neonatal diabetes mellitus , type 1 diabetes mellitus , type 1 diabetes mellitus 2 , type 2 diabetes mellitus , Type 2 Diabetes Mellitus 1 , Ventricular Dysfunction, Left , Ventricular Fibrillation , Ventricular Outflow Obstruction , Weight Loss Slc2a2 Breast Neoplasms , diabetes mellitus , Experimental Diabetes Mellitus , Fanconi syndrome , Fanconi-Bickel syndrome , Fetal Growth Retardation , gastrinoma , genetic disease , Glucagonoma , glycogen storage disease , hepatocellular carcinoma , insulinoma , long QT syndrome , maturity-onset diabetes of the young type 1 , neural tube defect , pancreatic ductal carcinoma , steatotic liver disease , type 2 diabetes mellitus
acute kidney failure Ins2 Acute Liver Failure Ins2 adenoma Ins2 Aicardi-Goutieres Syndrome 4 Cacna1a Albuminuria Ins2 alpha-mannosidosis Cacna1a Alternating Hemiplegia of Childhood 1 Cacna1a Alzheimer's disease Ins2 amyotrophic lateral sclerosis Cacna1a Ataxia Cacna1a , Cacna2d2 atrial heart septal defect Abcc8 attention deficit hyperactivity disorder Cacna1a Auditory Neuropathy Cacna1a autism spectrum disorder Cacna1a autistic disorder Cacna1a Beckwith-Wiedemann syndrome Ins2 bipolar disorder Ins2 bladder disease Ins2 bone marrow disease Cacna1a brain edema Abcc8 Brain Injuries Abcc8 Breast Neoplasms Slc2a2 cardiac arrest Abcc8 , Ins2 Cardiac Arrhythmias Cacna2d2 cerebellar ataxia Cacna1a Cerebellar Atrophy with Seizures and Variable Developmental Delay Cacna2d2 cerebral palsy Cacna1a cerebral venous thrombosis Cacna1a Charcot-Marie-Tooth disease dominant intermediate B Cacna1a childhood absence epilepsy Cacna1a , Cacna2d2 childhood electroclinical syndrome Cacna1a cholangiocarcinoma Ins2 choreatic disease Cacna2d2 cognitive disorder Ins2 Colorectal Neoplasms Abcc8 combined immunodeficiency Cacna1a combined T cell and B cell immunodeficiency Cacna1a Congenital Hyperinsulinism Abcc8 congestive heart failure Abcc8 , Ins2 COVID-19 Cacna2d2 cryptorchidism Abcc8 cystic kidney disease Ins2 delta beta-thalassemia Ins2 developmental and epileptic encephalopathy Cacna2d2 , Ins2 developmental and epileptic encephalopathy 1 Cacna1a developmental and epileptic encephalopathy 2 Cacna1a developmental and epileptic encephalopathy 42 Cacna1a developmental and epileptic encephalopathy 52 Cacna1a Developmental Disabilities Cacna1a diabetes mellitus Abcc8 , Ins2 , Slc2a2 Diabetic Cardiomyopathies Ins2 diabetic ketoacidosis Ins2 Diabetic Nephropathies Ins2 diabetic retinopathy Ins2 disease of metabolism Ins2 disorder of sexual development Cacna1a Dwarfism Abcc8 Dysarthria Cacna1a early infantile epileptic encephalopathy Cacna2d2 , Ins2 Edema Ins2 Endotoxemia Abcc8 epilepsy Abcc8 , Cacna1a , Cacna2d2 episodic ataxia Cacna1a episodic ataxia type 2 Cacna1a exfoliation syndrome Cacna1a Experimental Diabetes Mellitus Slc2a2 Experimental Liver Cirrhosis Ins2 familial hemiplegic migraine Cacna1a familial hemiplegic migraine 1 Cacna1a familial hyperinsulinemic hypoglycemia 1 Abcc8 familial hyperinsulinemic hypoglycemia 2 Abcc8 Fanconi syndrome Slc2a2 Fanconi-Bickel syndrome Slc2a2 Female Infertility Cacna2d2 Fetal Growth Retardation Slc2a2 gastrinoma Slc2a2 gastroesophageal reflux disease Abcc8 generalized dystonia Cacna1a , Ins2 Generalized Epilepsy Cacna1a , Cacna2d2 genetic disease Abcc8 , Cacna1a , Cacna2d2 , Ins2 , Slc2a2 gestational diabetes Ins2 Glucagonoma Slc2a2 glucose intolerance Ins2 glutaric acidemia I Cacna1a glycogen storage disease Slc2a2 Growth Disorders Abcc8 Hearing Loss Cacna2d2 hepatitis Ins2 hepatocellular carcinoma Ins2 , Slc2a2 hyperglycemia Ins2 hyperinsulinemic hypoglycemia Abcc8 hyperinsulinism Abcc8 , Ins2 Hyperkalemia Ins2 Hyperplasia Abcc8 Hyperproinsulinemia Ins2 hypertension Abcc8 , Ins2 Hypertriglyceridemia Ins2 hypertrophic cardiomyopathy Ins2 hyperuricemia Ins2 hypoglycemia Abcc8 , Ins2 Hypoinsulinemia Ins2 hypokalemia Ins2 Hypotension Ins2 immunodeficiency 39 Ins2 Insulin Resistance Ins2 insulinoma Ins2 , Slc2a2 intellectual disability Abcc8 , Cacna1a kidney disease Ins2 kidney failure Ins2 Lambert-Eaton myasthenic syndrome Cacna1a learning disability Cacna1a leucine-sensitive hypoglycemia of infancy Abcc8 Lewy body dementia Ins2 liver disease Ins2 long QT syndrome Slc2a2 Macrocephaly Abcc8 Marshall-Smith syndrome Cacna1a maturity-onset diabetes of the young Abcc8 , Ins2 maturity-onset diabetes of the young type 1 Abcc8 , Ins2 , Slc2a2 maturity-onset diabetes of the young type 10 Ins2 maturity-onset diabetes of the young type 13 Abcc8 Memory Disorders Ins2 metabolic dysfunction-associated steatotic liver disease Ins2 Metabolic Syndrome Ins2 Micronuclei, Chromosome-Defective Ins2 middle cerebral artery infarction Abcc8 migraine Cacna1a migraine with aura Cacna1a MPTP Poisoning Ins2 Muscle Hypotonia Abcc8 Muscle Spasticity Cacna1a Muscle Weakness Cacna1a muscular disease Ins2 myelitis Cacna1a Myocardial Ischemia Cacna2d2 Myocardial Reperfusion Injury Abcc8 myoclonic-atonic epilepsy Cacna1a Necrosis Abcc8 neonatal diabetes Abcc8 , Ins2 Neonatal Hypoglycemia, Simulating Foetopathia Diabetica Abcc8 Neoplasm Invasiveness Ins2 Nervous System Malformations Cacna1a neural tube defect Ins2 , Slc2a2 Neuraminidase Deficiency Abcc8 neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures Cacna1a Neurodevelopmental Disorders Cacna1a neurogenic bladder Cacna1a Neurologic Gait Disorders Cacna1a neuronal ceroid lipofuscinosis Ins2 newborn respiratory distress syndrome Abcc8 obesity Ins2 osteoarthritis Ins2 pancreatic cancer Ins2 pancreatic ductal carcinoma Ins2 , Slc2a2 pancreatitis Ins2 panic disorder Ins2 Paralysis Ins2 Paresthesia Ins2 Parkinson's disease Ins2 Parkinsonism Abcc8 permanent neonatal diabetes mellitus Abcc8 , Ins2 Permanent Neonatal Diabetes Mellitus 3 Abcc8 Permanent Neonatal Diabetes Mellitus 4 Ins2 Phelan-McDermid syndrome Ins2 polycystic ovary syndrome Ins2 polyhydramnios Abcc8 primary ciliary dyskinesia Cacna2d2 progressive bulbar palsy Cacna1a prostate cancer Ins2 Prostatic Neoplasms Ins2 Pulmonary Arterial Hypertension Abcc8 Retrognathia Abcc8 Rhabdomyolysis Ins2 sciatic neuropathy Abcc8 Segawa Syndrome, Autosomal Recessive Ins2 spastic ataxia Cacna1a Spastic Paraparesis Cacna1a Spinal Cord Injuries Abcc8 spinocerebellar ataxia type 6 Cacna1a Spinocerebellar Ataxias Cacna1a Sporadic Hemiplegic Migraine Cacna1a status epilepticus Abcc8 steatotic liver disease Ins2 , Slc2a2 Stroke Abcc8 Subarachnoid Hemorrhage Abcc8 subependymal giant cell astrocytoma Cacna1a sudden infant death syndrome Cacna1a Tachycardia Ins2 temporal lobe epilepsy Cacna1a transient neonatal diabetes mellitus Abcc8 , Ins2 Transient Neonatal Diabetes Mellitus, 2 Abcc8 Transient Neonatal Diabetes Mellitus, 3 Abcc8 Traumatic Subarachnoid Hemorrhage Abcc8 Tremor Cacna1a type 1 diabetes mellitus Abcc8 , Ins2 type 1 diabetes mellitus 2 Ins2 type 2 diabetes mellitus Abcc8 , Ins2 , Slc2a2 Type 2 Diabetes Mellitus 1 Ins2 vascular dementia Cacna1a Ventricular Dysfunction, Left Ins2 Ventricular Fibrillation Ins2 Ventricular Outflow Obstruction Ins2 Weight Loss Ins2
