The ATP-sensitive K+ channel is a complex protein consisting of eight subunits, with four of them being ATP-binding subunits called SUR subunits. These subunits are targeted by sulfonylurea drugs, which not only close the K+ channel but are also commonly used as oral hypoglycemic drugs to treat hyperglycemia in patients with impaired beta cell function. However, excessive or incorrect use of sulfonylurea drugs in combination with other medications can lead to hypoglycemia due to excessive insulin release.

Currently, both DPP-4-resistant analogues of GLP-1 and inhibitors of DPP-4 are approved for the treatment of patients with type 2 diabetes mellitus and some beta cell function. Importantly, these drugs allow glucose to act on the beta cell and therefore only weakly increase insulin secretion in the absence of glucose. As a result, GLP-1 analogues induce hypoglycemia much less frequently compared to sulfonylurea drugs.

The insulin receptor (InsR) belongs to the receptor tyrosine kinase (RTK) gene family and plays a crucial role in insulin's effects on metabolism. Insulin primarily activates the protein kinase Akt, which has diverse actions on cell metabolism.

The InsR is present on the cell membrane as a homodimer, where each monomer contains a tyrosine kinase domain. The metabolic actions of insulin include utilizing glucose for ATP production and anabolic pathways, storing fatty acids as triglycerides, protein synthesis from amino acids, macromolecular synthesis (such as RNA, DNA, and lipids), organelle formation, and cell proliferation/renewal. Insulin also has mitogenic actions.

The actions of insulin/InsR-activated Akt kinase can be summarized in the simplified diagram of the Akt kinase and MAPK pathways downstream of the InsR. The insulin gene expression and islet cell biogenesis rely on several transcription factors specific to the pancreas, liver, and kidney. These transcription factors include hepatocyte nuclear factor 4α (HNF-4α), HNF-1α, insulin promoter factor 1 (IPF-1), HNF-1β, and neurogenic differentiation 1/beta cell E-box trans-activator 2 (NeuroD1/β2). Mutations or heterozygous null mutations in any of these factors lead to inadequate insulin production and maturity-onset diabetes of the young (MODY) before the age of 25. MODY is characterized by nonketotic hyperglycemia, often asymptomatic, that begins in childhood or adolescence. Mutations in glucokinase also contribute to the development of MODY.

The proglucagon molecule exhibits divergent proteolytic cleavage patterns, resulting in the formation of glucagon, glucagon-like peptide (GLP), and glucagon-related polypeptide (GRPP).
TheATP-sensitiveK+ channelisanoctamericproteincomplexthatcontainsfourATP-bindingsubunitscalledSUR subunits. Thesesubunitsareboundbysulfonylurea drugs, whichalsoclosetheK+ channelandarewidelyusedasoralhypoglycemicstotreathyperglycemiainpatientswithpartiallyimpairedbetacellfunction.Hypoglycemiaisasignificantsideeffectofsulfonylureadrugsifusedinexcessorincorrectlyincombinationwithotherdrugs,owingtoinappropriatelyhighreleaseofinsulin.
BothDPP-4–resistant analogues of GLP-1 andinhibitors of DPP-4 arecurrentlyapprovedfortreatmentofpatientswithtype2DMwithsomebetacellfunction.Importantlythesedrugsarepermissive totheactionsofglucoseonthebetacellandthusonlyweaklyincreaseinsulinsecretionintheabsenceofglucose.ThusGLP-1analoguesinducehypoglycemiamuchlessfrequentlythansulfonylureadrugs.
The insulin receptor (InsR) is a member of the receptor tyrosine kinase (RTK) gene family (see ). Most of the actions of insulin on metabolism involve activation of the protein kinase Akt, which in turn has pleiotropic actions on cell metabolism.
The InsR is expressed on the cell membrane as a homodimer, with each monomer containing a tyrosine kinase
B InsRec IRS protein Metabolic actions Anabolic actions of insulin • Utilization of glucose for ATP & anabolic pathways • Storage of FFAs as TG • Protein synthesis from AAs • Macromolecular synthesis (e.g., RNA, DNA, lipids) • Organelle formation • Cell proliferation/renewal Mitogenic actions Merabolic actions PIP2PIP3 RAS/ RAF MAPK/ ERK PI3K Akt
GLUT 4 Translocation Glucose import Glycolysis, Glycogenesis, PDH, DNL Glucogenolysis Gluconeogensis FFA ˜ oxidation Ketogenesis Lipolysis Proteolysis autophagy Protein synthesis Gycolysis, PPP, DNL Gluconeo-genesis, VLDL export Protein phoshatases mTORC1 SREBP-1C FOX01 Akt •Fig. 39.9 A,Structureofdimerizedinsulinreceptorincellmembrane.B,SimplifieddiagramoftheAktkinaseandMAPKpathwaysdownstreamoftheInsR.C,Summarizedactionsofinsulin/InsR-activatedAktkinase.
Insulingeneexpressionandisletcellbiogenesisaredependentonseveraltranscriptionfactorsspecifictothepancreas,liver,andkidney.Thesetranscriptionfactorsincludehepatocyte nuclear factor 4α (HNF-4α), HNF-1α, insulin promoter factor 1 (IPF-1), HNF-1β, and neurogenic differentiation 1/beta cell E-box trans-activator 2 (NeuroD1/β2). Aheterozygousnullmutationofoneofthesefactorsresultsinprogressivelyinadequateproductionofinsulinandmaturity-onset diabetes of the young (MODY) beforetheageof 25.MODYischaracterizedbynonketotichyperglycemia,oftenasymptomatic,thatbeginsinchildhoodoradolescence.Inadditiontothefivetranscriptionfactors,mutationsinglucokinase alsogiverisetoMODY.
•Fig. 39.10 Divergentproteolyticcleavagepatternsoftheproglucagonmolecule.GLUC,glucagon;GLP,glucagon-likepeptide;GRPP,glucagon-relatedpolypeptide.
domain on the cytosolic side (see