Differential effects of short and long duration insulinotropic agents on meal‐related glucose excursions

Souza, C. J. De; Russo, Patrícia A.; Lozito, Robert J.; Dunning, BE

doi:10.1046/j.1463-1326.2001.00114.x

Cited by 15 publications

(17 citation statements)

References 32 publications

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“…However, when the pharmacodynamics of these two agents have been compared directly in the perfused rat pancreas [10] or in vivo in rodents [11] it was found that the effects of nateglinide are more rapidly manifest and shorter in duration than are the effects of repaglinide. As reviewed recently [12], marked differences in the kinetics of ligand/receptor interactions and closure of the K + ATP channel seem to, at least in part, underlie the kinetic differences observed in vivo.…”

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confidence: 99%

Pharmacologic restoration of the early insulin response in pre-diabetic monkeys controls mealtime glucose excursions without peripheral hyperinsulinaemia

Gutiérrez

et al. 2003

Diabetologia

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Aims/hypothesis. This study sought first to compare the pharmacodynamics and pharmocokinetics of two rapid-onset, rapidly-reversible insulinotropic agents, nateglinide and repaglinide, in pre-diabetic Cynomolgus monkeys and second to use these agents to assess the metabolic effects of early insulin secretion on prandial glucose control. Methods. First, equipotent doses of nateglinide (20 mg/kg) and repaglinide (0.1 mg/kg) or vehicle were given intragastrically to overnight-fasted ketamine-anesthetized pre-diabetic Cynomolgus monkeys and samples were obtained for measurement of plasma glucose, insulin, glucagon, NEFA and drug concentrations. Second, nateglinide, repaglinide or vehicle were administered 10 min before a glucosesupplemented liquid meal and prandial glucose and insulin profiles were compared. Results. Although oral administration of nateglinide and repaglinide elicited similar maximum increments of plasma insulin (+403 and +448 pmol/l, respectively), the effects of nateglinide were more rapidly manifest and less prolonged. With nateglinide, insulin increased within 10 min and returned to baseline within 50 min. After repaglinide, the first increase occurred at 30 min and insulin concentrations remained increased for 3.5 h post-dose. When given 10 min before a meal, nateglinide increased early, but not total insulin release (AUC 0-210 =108 vs 150 nmol/l min for nateglinide and vehicle, respectively) and reduced prandial glucose excursions by 78%. Repaglinide increased total insulin release (AUC 0-210 =298 nmol/l min) and reduced glucose excursions by 53%. Conclusion/interpretation. Nateglinide is more rapidacting and rapidly-reversible than is repaglinide. By restoring a more physiologic insulin profile, nateglinide is more effective than repaglinide in controlling prandial glucose excursions with less hyperinsulinaemia. It has been shown convincingly that in Type 2 (noninsulin-dependent) diabetes mellitus [1,2] and even in precursors thereof [3] the kinetics of insulin secretion are disrupted despite the existence of absolute (if not relative) hyperinsulinaemia. The disrupted insulin secretory kinetics can be confirmed by either the absence of the acute insulin response to i.v. glucose [4] or a sluggish insulin response to oral glucose [5] or a meal [6]. The impaired early insulin response leads to a marked impairment of the suppression of endogenous glucose production normally seen after glucose administration or a meal [5,6] and to a lesser extent, a later decrease of peripheral glucose utilization [6].

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confidence: 99%

Pharmacologic restoration of the early insulin response in pre-diabetic monkeys controls mealtime glucose excursions without peripheral hyperinsulinaemia

Gutiérrez

et al. 2003

Diabetologia

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“…Glyburide failed to influence early insulin release and mealtime glucose excursions, but augmented postmealtime insulin concentrations and caused delayed hypoglycaemia. Although, glipizide and repaglinide both increased early as well as total insulin exposure and prevented mealtime glucose excursions [33] they caused delayed hypoglycaemia. These findings not only attest to the importance of early insulin release to mealtime glucose control but also suggest that nateglinide will have an improved safety and tolerability profile and greater potential to exert better mealtime glucose control, than either short-acting or long-acting SUs or repaglinide.…”

Section: Insulin Secretion In Vitromentioning

confidence: 95%

“…In the fasted state the insulin-stimulating effect of nateglinide is remarkably rapid in onset and short in duration [33]. This rapid on-off pharmacodynamic profile allows nateglinide to reduce or eliminate glucose excursions (during glucose tolerance tests or meals) without sustained or delayed hyperinsulinaemia and/or hypoglycaemia.…”

Section: Insulin Secretion In Vitromentioning

confidence: 99%

“…When administered orally in normal fasted rats, maximal glucose-lowering by nateglinide and tolbutamide occurred 2 and 3 h after administration and euglycaemia was restored within 4 and 6 h, respectively [24]. In another study comparing the pharmacodynamics (effects on both glucose and insulin concentrations) of several insulinotropic agents in chronically-cannulated normal rats, agents at similarly-effective doses (in terms of maximal glucose-lowering) showed markedly different pharmacodynamics following their oral administration [33] (Fig. 3).…”

Section: Insulin Secretion In Vitromentioning

confidence: 99%

“…These findings not only attest to the importance of early insulin release to mealtime glucose control but also suggest that nateglinide will have an improved safety and tolerability profile and greater potential to exert better mealtime glucose control, than either short-acting or long-acting SUs or repaglinide. [33] Nateglinide was also found to be unique in its ability to elicit rapid but transient insulin secretion and mealtime glucose control in rodent models of insulin resistance and impaired glucose tolerance. During OGTTs done in rats fed with high-fat food and in Zucker fatty rats, nateglinide increased insulin concentrations more rapidly than did glipizide but elicited less overall hyperinsulinaemia.…”

Section: Insulin Secretion In Vitromentioning

confidence: 99%

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The mechanisms underlying the unique pharmacodynamics of nateglinide

Boettcher

Dunning

2003

Diabetologia

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Nateglinide, a D-phenylalanine derivative, belongs to a new group of insulinotropic agents with rapid onset and short duration of action. These agents have been developed to reduce the risk of hypoglycaemia associated with pharmacological control and to decrease the likelihood of pancreatic beta-cell exhaustion. Nateglinide mediates the release of insulin from beta-cells by binding to the sulphonylurea receptors, which leads to the closure of ATP-sensitive K + channels. Increasing evidence from receptor binding, mechanistic and in vitro and in vivo insulin studies indicate unique pharmacodynamic and pharmacokinetic properties with nateglinide that are distinct from those of sulphonylureas. The time required by nateglinide to close beta-cell K ATP channels is comparable to that of glyburide but threefold and fivefold faster than repaglinide and glimepiride, respectively. Furthermore, its effects are rapidly reversed with an off-rate at the K ATP channel twice as fast as that of glyburide and glimepiride and five times faster than repaglinide. This results in a rapid and short insulin response characteristic of the physiological pattern of post-mealtime insulin release. Internalisation into beta-cells is not required for the action of nateglinide. Given that the kinetic profile of the agent is associated with selective enhancement of early-phase insulin secretion, nateglinide is expected to minimise post-meal hyperglycaemia with minimal propensity for hypoglycaemia. [Diabetologia (2003)

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Should Diabetic Patients Treated Long-term With Sulfonylureas Be Switched to Nateglinide?

Sevinç¹

2003

Arch Intern Med

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Differential effects of short and long duration insulinotropic agents on meal‐related glucose excursions

Cited by 15 publications

References 32 publications

Pharmacologic restoration of the early insulin response in pre-diabetic monkeys controls mealtime glucose excursions without peripheral hyperinsulinaemia

Pharmacologic restoration of the early insulin response in pre-diabetic monkeys controls mealtime glucose excursions without peripheral hyperinsulinaemia

The mechanisms underlying the unique pharmacodynamics of nateglinide

Should Diabetic Patients Treated Long-term With Sulfonylureas Be Switched to Nateglinide?

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