Impact of Sur1 gene inactivation on the morphology of mouse pancreatic endocrine tissue

Abstract

In congenital hyperinsulinism of infancy (CHI), the loss of K-ATP channels (composed of Kir6.2 and SUR1 subunits) in beta cells induces permanent insulin secretion and severe hypoglycaemia. By contrast, Sur1 ( -/- ) mice do not present such defects. We have investigated the impact of Sur1 gene inactivation on mouse islet cell morphology, structure and basic physiology. Pancreata were collected from young, adult and old wild-type (WT) and Sur1 ( -/- ) mice. After immunostaining for hormone, the total endocrine tissue, cell proportion, cell size and intra-insular distribution, hormone content and Glut-2 expression were quantified by morphometry. Basic physiological parameters were also measured. In young Sur1 ( -/- ) mice, the total endocrine tissue and proportion of beta cells were higher (P<0.05) than in WT mice, whereas the proportion of delta cells was lower (P<0.01). In old Sur1 ( -/- ) mice, alpha cells were frequently located in the central regions of islets (unlike WT islets) and their proportion was increased (P<0.05). Glut-2 protein and mRNA levels were lower in old Sur1 ( -/- ) islets (P<0.02). Insulinaemia, fasting insulin and glucagon contents were equivalent in both groups of pancreata. Thus, the islets of Sur1 ( -/- ) mice present morphological modifications that have not been described in CHI and that might reflect an adaptive mechanism controlling insulin secretion in these mice.

Physiological and Pathophysiological Control of Glucagon Secretion by Pancreatic α-Cells

“…The distribution of α-cells can be very different in some transgenic mice. For instance, α-cells are frequently located in central regions of islets in K ATPdeficient mouse models, such as SUR1 (Marhfour et al 2009) or Kir6.2 knockout mice (Seino et al 2000;Winarto et al 2001) or in mice completely or partially deficient in specific adhesion molecule (Esni et al 1999). The reasons for this altered distribution are unknown.…”

Endoplasmic reticulum accumulation of Kir6.2 without activation of ER stress response in islet cells from adult Sur1 knockout mice

“…It has been demonstrated that, despite the total absence of functional K ATP channels, islet β-cells from Kir6.2 -/-and Sur1 -/-mice do not hyper-secrete insulin in vivo (Miki et al 1998;Seghers et al 2000;Nenquin et al 2004;Szollosi et al 2007); however, β-cells from CHI infants hyper-secrete insulin even in the presence of hypoglycaemia (Aynsley-Green et al 1981;Dunne et al 2004). Accordingly, whereas Sur1 -/-β-cells have apparently normal nuclear and cell surface morphology and the same number of insulin granules and proinsulin mRNA levels as WT islets (Marhfour et al 2009;present study), β-cells from CHI infants display many alterations characteristic of hyper-functioning β-cells such as abnormally large nuclei, abundant cytoplasm, greater cell size, high proinsulin (in the Golgi area) and low insulin content (Rahier et al 1984(Rahier et al , 2000Sempoux et al 1998Sempoux et al , 2003.…”

“…Cytoplasmic Kir6.2 staining intensity was similar in both WT and Sur1 -/-islets. Ultrastructure of endocrine cells Despite their abnormal distribution in Sur1 -/-islets (Marhfour et al 2009), endocrine cells were easily identified by the ultrastructural characteristics of their hormone-containing granules in both types of mice (insulin-containing granules, Fig. 3a-b; glucagon-containing granules, Fig.…”

“…Accordingly, the rate of apoptosis/necrosis of Sur1 -/-islet cells is not increased, as indicated by the normal volume density of pancreatic endocrine cells and the normal glucose tolerance of old Sur1 -/-mice (Seghers et al 2000;Nenquin et al 2004;Szollosi et al 2007;Marhfour et al 2009). Therefore, these results markedly contrast with the increase in β-cell apoptosis and the rapid development of diabetes observed in several models in which β-cells are exposed to sustained activation of their ER stress response (e.g.…”

“…Based on the physiological and morphological differences observed between K ATP -channel deficient mouse models (Kir6.2G132S, Kir6.2 -/-and Sur1 -/-: Miki et al 1997Miki et al , 1998Seghers et al 2000;Marhfour et al 2009), we are tempted to speculate that the ER-stress-response and oxidative-stress-response gene expression in islet cells from CHI patients vary according to the type of mutation involved. Thus, mutations that prevent the expression of one channel subunit may only trigger mild ER stress and oxidative stress.…”