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

Abstract

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].

The mechanisms underlying the unique pharmacodynamics of nateglinide

“…Glipizide and glyburide were considerably less effective than nateglinide in reducing glucose excursions but both produced substantial hypoglycaemia that did not resolve within the 6-h experimental period [24]. Similar results with nateglinide have been found in the monkey in vivo, as highlighted in this supplement [34], and in recent clinical studies [35,36,37].…”

Use and Importance of Nonhuman Primates in Metabolic Disease Research: Current State of the Field

“…Therefore, fasting insulin concentrations can be used as an index of insulin sensitivity in NHP studies in which clamps and glucose tolerance tests are not logistically possible. In addition to clamps and IVGTTs, oral glucose tolerance tests and meal tolerance tests, either by orogastric gavage or free-fed in chair-trained animals, can be used to assess glucose tolerance, insulin secretion, and nutrient-induced pancreatic and gastrointestinal hormone release before and during interventions in NHPs (Cummings et al 2013;D'Alessio et al 2001;Dunning et al 2003).…”

“…In this section, we will highlight a number of selected examples in which studies performed in NHP models have been valuable as translational studies of novel therapeutics for metabolic diseases. Specifically, NHPs have been used to evaluate the pharmacological profiles of several new compounds for the treatment of type 2 diabetes, including the insulin secretogogue nateglinide (Dunning et al 2003) and gemigliptin (LC15-0444), a novel dipeptidyl peptidase-4 inhibitor (Kim et al 2016). NHP models are also useful to assess potential toxicities in new and approved agents for the treatment of type 2 diabetes.…”

The role of oral antidiabetic agents: why and when to use an early-phase insulin secretion agent in Type II diabetes mellitus

“…Nateglinide, like repaglinide and sulphonylureas, acts directly on the pancreatic beta cell to stimulate insulin secretion that is rapid, of short duration, and is dependent on ambient glucose [30,31]. Experimental evidence shows that nateglinide restores early-phase insulin secretion even faster than the benzoic acid derivative, repaglinide, in diabetic animals [32]. Nateglinide given to Type 2 diabetic patients just before meals decreases mealtime glucose excursions which improves overall glycaemic control with a minimal risk of hypoglycaemia [33].…”