Characterisation of Age-Dependent Beta Cell Dynamics in the Male db/db Mice

Abstract

AimTo characterise changes in pancreatic beta cell mass during the development of diabetes in untreated male C57BLKS/J db/db mice. MethodsBlood samples were collected from a total of 72 untreated male db/db mice aged 5, 6, 8, 10, 12, 14, 18, 24 and 34 weeks, for measurement of terminal blood glucose, HbA1c, plasma insulin, and C-peptide. Pancreata were removed for quantification of beta cell mass, islet numbers as well as proliferation and apoptosis by immunohistochemistry and stereology. ResultsTotal pancreatic beta cell mass increased significantly from 2.1 ± 0.3 mg in mice aged 5 weeks to a peak value of 4.84 ± 0.26 mg (P < 0.05) in 12-week-old mice, then gradually decreased to 3.27 ± 0.44 mg in mice aged 34 weeks. Analysis of islets in the 5-, 10-, and 24-week age groups showed increased beta cell proliferation in the 10-week-old animals whereas a low proliferation is seen in older animals. The expansion in beta cell mass was driven by an increase in mean islet mass as the total number of islets was unchanged in the three groups. Conclusions/InterpretationThe age-dependent beta cell dynamics in male db/db mice has been described from 5-34 weeks of age and at the same time alterations in insulin/glucose homeostasis were assessed. High beta cell proliferation and increased beta cell mass occur in young animals followed by a gradual decline characterised by a low beta cell proliferation in older animals. The expansion of beta cell mass was caused by an increase in mean islet mass and not islet number.

Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis

“…Stereological quantification of pancreas mass was carried out in collaboration with Gubra (Gubra ApS, Hørsholm, Denmark (13). Ductal epithelial cells were detected with a rat anti-cytokeratin 19 antibody (ck19, 1:100; Hybridoma Bank, TROMA-III, University of Iowa, Iowa City, IA) and visualized with 3,39-diaminobenzidine.…”

Structural and functional changes of pancreatic beta-cells during the progression of disease in the Leprdb model of type 2 diabetes

“…For the beta-cell mass component, there is substantial evidence for the proliferative ability of the pancreatic islets in response to the body's increased insulin demand in both human (obesity, pregnancy) and animal models (genetic or diet induced obesity) (Hull, Kodama et al 2005;Sachdeva and Stoffers 2009;Dalbøge, Almholt et al 2013;Saisho, Butler et al 2013). For example, short-term glucose infusion (96 hours) can stimulate 50% increase in beta-cell mass in rats which confirmed the plasticity of postnatal beta-cell mass (Bonner- Weir, Deery et al 1989).…”

“…It is conceivable that the impairment of beta-cell function in diabetes is much greater than could be explained by the rate of beta-cell apoptosis which makes beta-cell death unlikely to be the main contributor to the disease progression (Ashcroft and Rorsman 2012;Dalbøge, Almholt et al 2013). An alternative mechanism for the loss of functional beta-cell mass which has received considerable attention recently is the beta-cell dedifferentiation (Weinberg, Ouziel-Yahalom et al 2007;Talchai, Xuan et al 2012;Blum, Roose et al 2014;Wang, York et al 2014).…”

“…Page | 33 transparent appearance, intra-islet amyloid/ fat deposition or even collapsing islets (Nugent, Smith et al 2008;Dalbøge, Almholt et al 2013). …”

“…Performing the glucose tolerance test on single db/db mice, each mouse was classified into one of four stages of disease from prediabetes (stage 1) to severe diabetes (stage 4). Even though there is evidence for increased betacell mass in early disease of db/db mice (Dalbøge, Almholt et al 2013), the underlying morphological changes of the pancreatic islet and beta-cell over the disease course are unclear which will be addressed in chapter 4.…”