Sulfonylurea derivatives are a class of antidiabetic drugs that are used in the management of diabetes mellitus type 2 ("adult-onset"). They act by increasing insulin release from the beta cells in the pancreas.
Acetohexamide, Chlorpropamide, Tolbutamide, Tolazamide
Glipizide, Gliclazide, Glibenclamide, Gliquidone
Second-generation sulfonylureas have increased potency by weight, compared to first-generation sulfonylureas. They have decreased side effects but are more expensive.
che senso hanno queste distinzioni? in cosa sono diverse
Sulfonylureas are used in diabetes mellitus type 2 in non obese patients pazienti or in who metformina is counter-indicated or not well tolerated.
cos'è la metformina
Insulin secretion from pancreatic b-cells is essential in glucose homeostasis; it is regulated by many factors, including nutrients, hormones and neurotransmitters, among which glucose is physiologically the most important.
The ATP-sensitive potassium (KATP) channel plays a key role in controlling b-cell membrane potential and insulin secretion. The channels are composed of subunits Kir6.2, which forms the channel pore, and SUR1, which contains binding sites for nucleotides and sulphonylureas and acts as a channel regulator.
Binding of sulphonylureas Glibenclamide to SUR1 leads to conformational changes in citoplasmatic loop 3 and 8 leading to rearrangement of transmembrane helices. These effects are transmitted to Kir6.2 to result in channel closure.
This inhibits a tonic, hyperpolarizing outflux of potassium, which causes the electric potential over the membrane to become more positive. This depolarization opens voltage-gated Ca2+ channels. The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and therefore increased secretion of insulin.
The ATP-sensitive potassium (KATP) channel is composed of:
4 subunit: inward-rectifier potassium ion channel (Kir6.2)
4 subunit: sulfonylurea receptor (SUR1)
perchè tante subunità?
SUR1 is a transmembran protein, member of the ATP-binding cassette superfamily, encoded on ABCC8 on chromosome 11p15.1. that contains structural domains:
- 2 nucleotide binding domains (NBDs)
- 3 transmembrane domains (TDMs)
- 2 binding sites for sulphonylureas Glibenclamide on citoplasmatic loop 3 and 8
SUR1 aminoacidic structur
MIM Gene Map of SUR1
It is an integral membrane protein, termed inwardly rectifying - because they rectify current (positive charge) in the inward direction. This means that under equal but opposite electrochemical potentials, these channels will pass more inward current than they do outward.
Kir6.2 forms the central pore where K+ ions move through the in a concerted single-file.
It contains structural citoplasmatic domain for ATP binding.
SUR1-Kir6.2 molecolar descriction
REGULATION SUBUNITE ACTIVITY
- leptin: stimulatory SUR1 transcription mediated through activation of PI 3-kinase pathway, link to the features .
- free fatt acid: suppresse SUR1 gene expression, link to the features .
-insulin: open Kir6.2 channels through a PI3-K dependent pathway to inhibit further secretion, link to the features .
- ATP/ADP: increase ATP and decrease ADP stimulated by glucose metabolism close Kir6.2 channels, link to the features
oral antidiabetic therapy with sulfonylureas may contribute to iatrogenic QT prolongation and related arrhythmias. (Sulfonylureas blockade of neural and cardiac HERG channels. 1998)
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There are a loto of side efect explain by isoforms of the SUR:
ipose tissue - SUR2B/Kir6.1
cardiac myocytes - SUR2A
skeletal muscle - SUR2A
smooth muscle - SUB2B
SUR2A and SUR2B which are splice variants arising from a single ABCC9 gene encoded by 12p12.1
MIM Gene Map of SUR2
Mutation of SUR2 caused Dilated Cardiomyopathy with ventricular tachycardia, see original reference: ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating
perchè diverse da tessuto a tessuto le subunità subunità?
There is a relation between sulfonylurea drugs and mortality for cardiovascular events in type 2 diabetes mellitus: Simpson SH et al, CMAJ 2006; 174 : 169-74
Mutation of SUR1 causes some sisorders:
- increase susceptibility to type 2 diabetes mellitus: Diabetes Metab. 2002 Feb;28(1):14-9
- Sur1 Hyperinsulinism: mutations in the insulin-secreting cell potassium channel genes: therapeutic consequences.