Hyperglycaemia but not hyperlipidaemia causes beta cell dysfunction and beta cell loss in the domestic cat

Abstract

Aims/hypothesis In vitro studies point to a toxic effect of high glucose and non-esterified fatty acids on beta cells. Whether elevated levels of glucose and lipids induce beta cell loss in vivo is less clear. The domestic cat has recently been proposed as a valuable animal model for human type 2 diabetes because feline diabetes shows several similarities with diabetes in humans, including obesity-induced insulin resistance, impaired beta cell function, decreased number of beta cells and pancreatic amyloid deposition. Methods We infused healthy cats with glucose or lipids for 10 days to clamp their blood concentrations at the approximate level found in untreated feline diabetes (glucose: 25-30 mmol/l; triacylglycerols: 3-7 mmol/l).Results Glucose and lipid levels were adequately targeted. Plasma non-esterified fatty acids were increased by lipid infusion 1.7-fold. A dramatic and progressive decline of plasma insulin levels was observed in glucose-infused cats beginning after 2 days of hyperglycaemic clamp. In contrast, plasma insulin concentration and glucose tolerance test were not affected by hyperlipidaemia. Compared with controls, glucose-infused cats had a 50% decrease in beta cells per pancreatic area. Apoptotic islet cells and cleaved caspase-3-positive beta cells were observed in glucose-infused cats only. Conclusions/interpretation Sustained hyperglycaemia but not hyperlipidaemia induces early and severe beta cell dysfunction in cats, and excess glucose causes beta cell loss via Diabetologia (2009)

ANIMAL MODELS OF DISEASE: Classification and etiology of diabetes in dogs and cats

“…In humans, it has been proposed that oxidative stress and inflammatory cytokines play an important role (Robertson 2009, Donath & Shoelson 2011. In a recent study, glucose-induced lesions in b-cells were investigated in cats (Zini et al 2009). After 10 days of i.v.…”

“…Lipotoxicity may not be as important as glucotoxicity in cats (Zini et al 2009). In Mean serum glucose (A) and insulin (B) concentrations (GS.E.M.)…”

Assessment of six different collagenase-based methods to isolate feline pancreatic islets

“…To identify the isolation protocol providing pancreatic islets with the least amount of residual acinar cells, sections of formalin-fixed paraffin-embedded digestate were prepared and subsequently immunohistochemically double-stained for insulin and glucagon using a polyclonal guinea pig antibody anti-swine insulin (Code A0564, Dako, Glostrup, Denmark) and a polyclonal rabbit antibody anti-human glucagon (Code A0565, Dako), as previously described (Zini et al, 2009). In brief, paraffin sections (3 µm) were deparaffinized in xylene and rehydrated through graded ethanol to water.…”

Effect of hyperlipidemia on 11β-hydroxysteroid-dehydrogenase, glucocorticoid receptor, and leptin expression in insulin-sensitive tissues of cats

“…A cross-reacting porcine insulin radioimmunoassay (Linco, St. Charles, MO, USA) was used to determine insulin concentrations [25]. Serum cortisol was measured by a chemiluminescence immunoassay (ADVIA Centaur ® System, Bayer (Schweiz) AG, Zurich, Switzerland) and leptin levels were determined by a radioimmunoassay (Linco, St. Charles, MO, USA) [26].…”

“…The detailed clinical course (food intake, physical examination, electrolyte monitoring, blood glucose concentrations, plasma triacylglycerol concentrations) has been described by Zini et al 2009. After infusion, body weight decreased slightly in saline-infused cats (average difference: -4.3%) and increased significantly in lipid-infused cats (average difference: +10.7%, p< 0.05) ( Table 3).…”