Repaglinide Preserves Nutrient-Stimulated Biosynthetic Activity in Rat Pancreatic Islets

Viñambres, Concepción; Villanueva-Peñacarrillo, María Luisa; Valverde, Isabel; Malaisse, Willy

doi:10.1006/phrs.1996.0068

Cited by 29 publications

(14 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, although both drugs have effects similar to glibenclamide in terms of stimulating insulin secretion, it appears that nateglinide and repaglinide are less toxic for ␤-cells. This is in line with previous findings demonstrating other distinct effects among sulfonylurea, repaglinide, and nateglinide (31,(43)(44)(45). The reason for these differences may be related to different binding characteristics to the K ATP channels (30,31,46).…”

Section: Discussionsupporting

confidence: 88%

Sulfonylurea Induced β-Cell Apoptosis in Cultured Human Islets

Maedler

Carr

Bosco

et al. 2005

The Journal of Clinical Endocrinology & Metabolism

314

214

View full text Add to dashboard Cite

Loss of beta-cell mass and function raises a concern regarding the application of sulfonylureas for the treatment of type 2 diabetes because previous studies have shown that agents that cause closure of inwardly rectifying K(+) sulfonylurea receptor subtype of ATP-sensitive potassium channels, such as tolbutamide and glibenclamide, induce apoptosis in beta-cell lines and rodent islets. Therefore, we investigated the effect of the new insulin secretagogues, repaglinide and nateglinide, and the sulfonylurea, glibenclamide, on beta-cell apoptosis in human islets. Human islets from six organ donors were cultured onto extracellular matrix-coated plates and exposed to glibenclamide, repaglinide, or nateglinide. The doses of the three compounds were chosen according to detected maximal effects, i.e. efficacy. Exposure of human islets for 4 h to 0.1 and 10 microm glibenclamide induced a 2.09- and 2.46-fold increase in beta-cell apoptosis, respectively, whereas repaglinide (0.01 and 1 microm) did not change the number of apoptotic beta-cells. At low concentration (10 microm), nateglinide did not induce beta-cell apoptosis. However, at high concentration of 1000 microm, it induced a 1.49-fold increase in the number of apoptotic beta-cells. Prolonged exposure for 4 d of the islets to the secretagogues induced beta-cell apoptosis. The increase was of 3.71- and 4.4-fold at 0.1 and 10 microm glibenclamide, 2.37- and 3.8-fold at 0.01 and 1 microm repaglinide, and of 3.2- and 4.6-fold at 10 and 1000 microm nateglinide, respectively. Glibenclamide at 0.1-10 nm (doses that were less efficient on insulin secretion) did not induce beta-cell apoptosis after 4 h incubation as well as 0.1 nm after 4 d incubation. However, 1 and 10 nm glibenclamide for 4 d induced a 2.24- and 2.53-fold increase in beta-cell apoptosis, respectively. Taken together, closure of the inwardly rectifying K(+) sulfonylurea receptor subtype of ATP-sensitive potassium channels induces beta-cell apoptosis in human islets and may precipitate the decrease in beta-cell mass observed in patients with type 2 diabetes.

show abstract

Section: Discussionsupporting

confidence: 88%

Sulfonylurea Induced β-Cell Apoptosis in Cultured Human Islets

Maedler

Carr

Bosco

et al. 2005

The Journal of Clinical Endocrinology & Metabolism

314

214

View full text Add to dashboard Cite

show abstract

“…When rats were given an intravenous injection of 1 nmol/kg of the VPAC1-selective agonist [K15, R16, L27]VIP(1-7)/ GRF (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), it increased plasma insulin levels by twofold, but, consistent with the role of VPAC1 in enhancing hepatic glucose production, it also increased blood glucose levels by 14% 30 min after an IPGTT (data not shown). The VPAC1-selective agonist displayed dosedependent effects on intestinal water retention that were identical to those of VIP, whereas the effect of the VPAC2-selective agonist was much less.…”

Section: Vpac2 Agonist For Type 2 Diabetesmentioning

confidence: 71%

“…Insulin biosynthesis was studied in isolated rat islets using a modification of a previously described protocol (20). After an overnight culture, groups of 20 islets were preincubated in RPMI 1640 containing 3 mmol/l glucose for 30 min.…”

mentioning

confidence: 99%

A Potent and Highly Selective VPAC2 Agonist Enhances Glucose-Induced Insulin Release and Glucose Disposal

et al. 2002

View full text Add to dashboard Cite

Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) activate two shared receptors, VPAC1 and VPAC2. Activation of VPAC1 has been implicated in elevating glucose output, whereas activation of VPAC2 may be involved in insulin secretion. A hypothesis that a VPAC2-selective agonist would enhance glucose disposal by stimulating insulin secretion without causing increased hepatic glucose production was tested using a novel selective agonist of VPAC2. This agonist, BAY 55-9837, was generated through site-directed mutagenesis based on sequence alignments of PACAP, VIP, and related analogs. The peptide bound to VPAC2 with a dissociation constant (K d ) of 0.65 nmol/l and displayed >100-fold selectivity over VPAC1. BAY 55-9837 stimulated glucose-dependent insulin secretion in isolated rat and human pancreatic islets, increased insulin synthesis in purified rat islets, and caused a dose-dependent increase in plasma insulin levels in fasted rats, with a half-maximal stimulatory concentration of 3 pmol/kg. Continuous intravenous or subcutaneous infusion of the peptide reduced the glucose area under the curve following an intraperitoneal glucose tolerance test. The peptide had effects on intestinal water retention and mean arterial blood pressure in rats, but only at much higher doses. BAY 55-9837 may be a useful therapy for the treatment of type 2 diabetes.

show abstract

“…However, in contrast to the sulphonylureas, repaglinide does not stimulate insulin release independently of its effects on beta-cell potassium channels, and does not inhibit insulin biosynthesis. 51,52,64,65 Another pharmacological difference of potential clinical importance between repaglinide and the sulphonylureas is that repaglinide augments insulin release from pancreatic islets in vitro only in the presence of glucose. 51,66 Thus, repaglinide enhances glucosemediated insulin release, and hence may be less likely to cause hypoglycaemia.…”

Section: Repaglinide: the ®Rst Hypoglycaemic Prandial Glucose Regulatormentioning

confidence: 99%

Review of prandial glucose regulation with repaglinide: a solution to the problem of hypoglycaemia in the treatment of Type 2 diabetes?

Nattrass

Lauritzen

2000

Int J Obes

View full text Add to dashboard Cite

Type 2 diabetes mellitus is characterised by abnormal beta-cell function (present at the time of diagnosis) that is often associated with insulin resistance. An important and consistent pathophysiological ®nding is the failure to produce adequate increments in insulin secretion in response to carbohydrate intake. Therefore, insulin secretagogue therapy, particularly when focused on prandial glucose regulation, is a logical approach to treatment because it addresses one of the most fundamental pathophysiological aspects of the disease. However, the traditional secretagogues Ð the sulphonylureas Ð have long been associated with the unwanted effect of hypoglycaemia. This is particularly likely to occur when drugs with lengthy plasma half-lives, prolonged drug ± receptor interactions, active metabolites or a reliance on renal clearance are used. The problem is most prevalent in elderly patients, where sulphonylurea-induced hypoglycaemia may be related to failure to comply with strict mealtimes or the need for supplementary food intake, often in the context of compromised renal function. Data from large-scale outcome studies demonstrate that when tight glycaemic control is achieved through aggressive antidiabetic therapy, late diabetic complications can be signi®cantly reduced. However, the pursuit of stricter HbA lc targets with more aggressive interventions may increase the risk of hypoglycaemia. This is an irony because the clinical need to avoid hypoglycaemia and patients' apprehension of it present barriers to the achievement of bene®cial glycaemic targets. However, an increased risk of hypoglycaemia may not be inevitable with insulin secretagogue therapy. The recently introduced carbamoylmethyl benzoic acid derivative, repaglinide, has pharmacological properties that are well suited to its intended role as a prandial glucose regulator. When taken prior to main meals, the rapid onset and relatively short duration of action of repaglinide aid disposal of the mealtime glucose load, without continued stimulation of pancreatic beta-cells in the postprandial fasting period. Repaglinide is also characterised by hepatic metabolism and elimination, which is an advantage in the context of impaired renal function. Prandial glucose regulation with repaglinide selectively increases insulin secretion, and hence limits glucose excursions, in the prandial phase. If a meal is omitted, so too is the corresponding dose. This more¯exible approach to the management of Type 2 diabetes has a number of advantages when compared with the ®xed daily dosing regimens of sulphonylureas, among them a reduced risk of hypoglycaemia Ð a bene®t that is particularly marked in the context of missed or irregular meals.

show abstract

Repaglinide Preserves Nutrient-Stimulated Biosynthetic Activity in Rat Pancreatic Islets

Cited by 29 publications

References 0 publications

Sulfonylurea Induced β-Cell Apoptosis in Cultured Human Islets

Sulfonylurea Induced β-Cell Apoptosis in Cultured Human Islets

A Potent and Highly Selective VPAC2 Agonist Enhances Glucose-Induced Insulin Release and Glucose Disposal

Review of prandial glucose regulation with repaglinide: a solution to the problem of hypoglycaemia in the treatment of Type 2 diabetes?

Contact Info

Product

Resources

About