Pharmacokinetics and Alterations in Glucose and Insulin Levels After a Single Dose of Canagliflozin in Healthy Icelandic Horses.

Canagliflozin (CFZ) is a sodium-glucose cotransporter-2 inhibitor that has shown promising results as a drug for the treatment of insulin dysregulation in horses. Even though CFZ is used clinically, no pharmacokinetic data has previously been published. In this study, the pharmacokinetics of CFZ after administration of a single oral dose of 1.8 mg/kg in eight healthy Icelandic horses was examined. Additionally, the effect of treatment on glucose and insulin levels in response to a graded glucose infusion was investigated. Plasma samples for CFZ quantification were taken at 0, 0.33, 0.66, 1, 1.33, 1.66, 2, 2.33, 2.66, 3, 3.5, 4, 5, 6, 8, 12, 24, 32, and 48 h post administration. CFZ was quantified using UHPLC coupled to tandem quadrupole mass spectrometry (UHPLC-MS/MS). A non-compartmental analysis revealed key pharmacokinetic parameters, including a median Tmax of 7 h, a Cmax of 2350 ng/mL, and a t1/2Z of 28.5 h. CFZ treatment reduced glucose (AUCGLU, p = 0.001) and insulin (AUCINS, p = 0.04) response to a graded glucose infusion administered 5 h after treatment. This indicates a rapid onset of action following a single dose in healthy Icelandic horses. No obvious adverse effects related to the treatment were observed.

Characterization of glucose-stimulated insulin release protocols in african green monkeys (Chlorocebus aethiops).

BACKGROUND: Management of diabetes remains a major health and economic challenge, demanding test systems in which to develop new therapies. These studies assessed different methodologies for determining glucose tolerance in green monkeys. METHODS: Twenty-eight African green monkeys between 4 and 24 years old underwent single or repeat intravenous glucose tolerance testing (IVGTT), oral glucose tolerance testing (OGTT), and/or graded glucose infusion testing. RESULTS: Geriatric monkeys exhibited glucose intolerance with impaired glucose-stimulated insulin secretion following IVGTT. Repeat IVGTT and OGTT assessments were inconsistent. Monkeys with low glucose-stimulated insulin secretion after graded glucose infusion exhibited elevated blood glucose levels. CONCLUSION: IVGTT and graded glucose infusion protocols revealed differences in glucose tolerance among green monkeys at single time points, including age-dependent differences suggestive of shifts in pancreatic beta-cell functional capacity, but care should be applied to study design and the interpretation of data in the setting of longitudinal studies.

Linearity of ß-cell response across the metabolic spectrum and to pharmacology: insights from a graded glucose infusion-based investigation series.

The graded glucose infusion (GGI) examines insulin secretory response patterns to continuously escalating glycemia. The current study series sought to more fully appraise its performance characteristics. Key questions addressed were comparison of the GGI to the hyperglycemic clamp (HGC), comparison of insulin secretory response patterns across three volunteer populations known to differ in ß-cell function (healthy nonobese, obese nondiabetic, and type 2 diabetic), and characterization of effects of known insulin secretagogues in the context of a GGI. Insulin secretory response was measured as changes in insulin, C-peptide, insulin secretion rates (ISR), and ratio of ISR to prevailing glucose (ISR/G). The GGI correlated well with the HGC (r = 0.72 for ISR/G, P < 0.01). The insulin secretory response in type 2 diabetes (T2DM) was significantly blunted (P < 0.001), whereas it was significantly increased in obese nondiabetics compared with healthy nonobese (P < 0.001). Finally, robust (P < 0.001 over placebo) pharmacological effects were observed in T2DM and healthy nonobese volunteers. Collectively, the findings of this investigational series bolster confidence that the GGI has solid attributes for assessing insulin secretory response to glucose across populations and pharmacology. Notably, the coupling of insulin secretory response to glycemic changes was distinctly and uniformly linear across populations and in the context of insulin secretagogues. (Clinical Trial Registration Nos. NCT00782418, NCT01055340, NCT01373450).

Comparison of Second-Phase Insulin Secretion Derived from Standard and Modified Low-Dose Graded Glucose Infusion Tests.

OBJECTIVES: Insulin secretion has 2 phases, first-phase and second-phase insulin secretion (SPIS). The purpose of our study was to validate the SPIS derived from the modified low-dose graded glucose infusion test (MLDGGI) by using the standard SPIS derived from the low-dose graded glucose infusion test (LDGGI). METHODS: Fourteen participants were enrolled. The participants underwent the LDGGI for 200 minutes and MLDGGI for 60 minutes. The LDGGI was administered using the standard Polonsky method, which entails 5 40-minute stages of glucose infusion (1, 4, 8, 6 and 24 mg/kg/min). The slopes of the insulin levels vs. the glucose levels obtained during the test were regarded as SPIS (SPIS-I). Furthermore, deconvolution was performed, and slopes of the insulin secretion rate (ISR) against glucose levels during the test (SPIS-D) were obtained and regarded as the gold standard SPIS. The MLDGGI was administered with 3 20-minute stages of glucose infusion (2, 8 and 24 mg/kg/min) for 20 minutes each. The slopes of the insulin levels vs. the glucose levels obtained during the test were regarded as SPIS (MSPIS-I). In addition, deconvolution was performed, and the slopes of the ISR against glucose levels during the test (MSPIS-D) were obtained. RESULTS: Significant correlations were observed between SPIS-I and SPIS-D (r=0.843; p<0.001) and between MSPIS and SPIS-D (r=0.786; p<0.001). CONCLUSIONS: SPIS could be determined simply by using the LDGGI without deconvolution. Moreover, MLDGGI was proved to be useful in estimating SPIS easily on the basis of insulin levels.