The conscious Göttingen minipig as a model for studying rapid pulsatile insulin secretion in vivo

Abstract

Aims/hypothesis. Pulsatile secretion is important for insulin action and suitable animal models are important tools for examining the role of impaired pulsatile insulin secretion as a possible link between beta-cell mass, function and morphology and insulin resistance. This study examines the vascular sampling site, insulin kinetics, pulsatility and the response to glucose pulse entrainment to evaluate the Göttingen minipig as a model for studying pulsatile insulin secretion. Methods. Basal and glucose entrained insulin secretion was examined in normal minipigs and evaluated by autocorrelation, cross correlation and deconvolution. Results. Cross correlation showed a relation between oscillations in insulin concentrations in the portal and jugular vein in anaesthetised animals (p<0.001 in all animals), confirming the usefulness of jugular vein sampling for pulse detection. Jugular vein sampling in conscious animals showed obvious oscillations allowing estimates of burst shape and insulin kinetics. Glucose entrainment improved the pulsatile pattern (autocorrelation: 0.555±0.148 entrained vs 0. 350±0.197 basal, p=0.054). Deconvolution analysis resolved almost all insulin release as secretory bursts (69±20 basal vs 99.5±1.2% entrained, p<0.01) with a pulse interval (min) of 6.6±2.2 (basal) and 9.4±1.5 (entrained) (p<0.05) and a pulse mass (pmol/l per pulse) which was higher after entrainment (228±117 vs 41.2±18.6 basal, p<0.001). Conclusion/interpretation. The ability to fit kinetic parameters directly by deconvolution of peripheral endogenous insulin concentration time series in combination with the suitability of jugular vein sampling, rapid kinetics and entrainability makes the Göttingen minipig ideal for mechanistic studies of insulin pulsatility and its effects on insulin action. [Diabetologia (2002[Diabetologia ( ) 45:1389[Diabetologia ( -1396 Keywords Pulsatile insulin secretion, insulin kinetics, deconvolution, in vivo model, insulin action. dent) diabetes mellitus is characterized by defects in both insulin secretion and action, impaired pulsatile secretion could be an important link between beta-cell malfunction and impaired insulin action [8]. When addressing the cause of these impairments in humans, studies are often influenced by long-term impaired metabolism, and therefore demonstrate that defects could be secondary. This problem can, to some extent, be circumvented by studying first degree relatives of diabetic patients who are at risk of the disease but are still not affected by the effects of hyperglycaemia [9]. However, animal models are a valuable research tool for examining the relation between beta-cell mass, function and morphology on the one hand and insulin It is well documented that insulin concentrations show large amplitude oscillations in the peripheral circulation with a periodicity of 5 to 15 min [1,2,3], and it has been shown that these oscillations are of importance for insulin action in liver [4], muscle [5,6] and adipose tissues [7]. Since Type II (non-insulin-depen-

Effects of subtotal pancreatectomy and long‐term glucose and lipid overload on insulin secretion and glucose homeostasis in minipigs

“…Current commercial pigs for meat production are the results of generations of selective breeding that targeted a phenotype able to store energy for later consumption by humans, likely making them protected against the deleterious effects of a “diabetogenic” environment. 22 But some minipig strains, such as the Göttingen one, on which the physiology of insulin secretion is similar to humans, 23 , 24 or the Ossabaw, recognized to be a natural model of metabolic syndrome, 25 were found to be more susceptible to metabolic issues. Because of this, various studies have attempted in the past to develop preclinical diabetic pig models from these strains.…”

A Unifying Organ Model of Pancreatic Insulin Secretion

“…Starting with the seminal work of Grodsky [ 1 ] experiments have been carried out on explanted animal pancreata, subjected to carefully controlled time-varying glucose concentrations, measuring the resulting insulin secretion [ 2 , 3 ]. Other experiments have been carried out on animal models (monkeys [ 4 , 5 ], dogs [ 6 , 7 ], minipigs [ 8 ], rats [ 9 ]) as well as human subjects [ 10 – 15 ], administering variable amounts of glucose in different ways, and observing the corresponding insulin serum concentrations.…”