Disease relevance of Meglitinide

• These two meglitinide derivatives, commonly called glinides, have been developed for improving insulin secretion of patients with type 2 diabetes mellitus [1].
• The secretion of PP was stimulated by HB 699 before the onset of hypoglycemia, whereas, following glipizide administration, PP secretion increased only after the onset of hypoglycemia [2].

High impact information on Meglitinide

• It is suggested that HB 699 decreases K+ permeability of the B-cell membrane, thereby causing a depolarization which leads to activation of voltage-dependent Ca channels and Ca2+ influx, and eventually increases insulin release [3].
• In contrast, while tolbutamide caused a significant (45 +/- 12%) but short-lived increase in plasma somatostatin concentrations, HB 699 had no significant effect [4].
• The meglitinide-class drug nateglinide is metabolised by CYP2C9 [5].
• This effect was not specific for meglitinide, as tolbutamide was also unable to prevent MgADP activation of Kir6.2/SUR128 currents [6].
• These include insulin lispro, amylin analogues, alpha-glucosidase inhibitors and meglitinide analogues [7].

Biological context of Meglitinide

• The molecular structure of (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionic acid (KAD-1229), a hypoglycemic drug of the meglitinide family, was studied by nuclear magnetic resonance (NMR) and molecular modeling [8].
• It is concluded that compound HB 699 contains two active sites, both of which can trigger insulin release by decreasing K+ permeability of the B-cell membrane [9].

Anatomical context of Meglitinide

• Relationships between the Na(+)/K(+) pump and ATP and ADP content in mouse pancreatic islets: effects of meglitinide and glibenclamide [10].
• Glibenclamide and meglitinide block the transport of low molecular weight solutes into malaria-infected erythrocytes [11].
• 1 Patch-clamp recording techniques were used to examine the effects of tolbutamide, glibenclamide, meglitinide and thiopentone on KATP in CRI-GI insulin-secreting cells in the presence and absence of Mg2+ [12].
• Thus, HB 699 was compared with glibenclamide for the effect on the small-intestinal absorption of sugars and amino acids in vitro (everted-sac and tissue-accumulation technique) and in vivo (single-pass perfusion of the jejunum) [13].
• 2. When KATP-channels in caudate nucleus were activated in cell-attached patches by inhibition of mitochondrial energy production, meglitinide (a benzoic acid derivative), Hoe36320 (a sulphonylurea of low lipophilicity) and glipizide reduced KATP-channel activity half-maximally at 0.4 microM, 0.4 microM and about 0.5 nM, respectively [14].

Associations of Meglitinide with other chemical compounds

• In search of modulators of CFTR, we investigated the effects of the non-sulphonylurea hypoglycaemic agents meglitinide, repaglinide, and mitiglinide (KAD-1229) on CFTR Cl- channels in excised inside-out membrane patches from C127 cells expressing wild-type human CFTR [15].
• 4. Analysis of the dwell time distributions of single channels indicated that both meglitinide and mitiglinide greatly decreased the open time of CFTR [15].
• Control of insulin secretion by sulfonylureas, meglitinide and diazoxide in relation to their binding to the sulfonylurea receptor in pancreatic islets [16].
• In this study glibenclamide and meglitinide were shown to inhibit the induced transport of a sugar alcohol (sorbitol), an amino acid (threonine), an inorganic anion (Cl-) and an organic cation (choline) into human erythrocytes infected in vitro with Plasmodium falciparum [11].
• Modulation of glycogen phosphorylase activity and fructose 2,6-bisphosphate levels by glibenclamide and meglitinide in isolated rat hepatocytes: a comparative study [17].

Gene context of Meglitinide

• Repaglinide, a meglitinide analogue antidiabetic, is metabolised by CYP2C8 and CYP3A4 [18].
• The data favour the idea that meglitinide binding to SUR1 impairs either MgADP binding or the transduction pathway between the NBDs and Kir6.2, and that TMs 8-11 are involved in this modulatory response [6].
• 2. When added to the intracellular solution, meglitinide and mitiglinide inhibited CFTR Cl- currents with half-maximal concentrations of 164+/-19 microM and 148+/-36 microM, respectively [15].
• In contrast, sulphonylureas, meglitinide derivatives and thiazolidinediones are extensively metabolised in the liver via the CYP system and thus, may be subject to drug-drug metabolic interactions [19].
• In inside-out patch-clamp experiments compound II inhibited ATP-sensitive K(+)-channels of the SUR1/K(IR)6.2-type (characteristic of beta-cells) with an IC(50) value of 0.16 microM which is 6-fold lower than the corresponding value for meglitinide [20].

Analytical, diagnostic and therapeutic context of Meglitinide

• 2. Using the conventional whole-cell recording configuration, activation of the outwardly-rectifying, DIDS-sensitive conductance was induced by glibenclamide (10 microM) but not by tolbutamide (100 microM) nor by meglitinide (20 microM) [21].

References