Long-Term Diabetes Improvement After Duodenal Exclusion in Zucker Diabetic Fatty Rats Is Associated with Prevention of Strain-Specific Pancreatic Remodeling and Increased Beta Cell Proliferation

Abstract

Background Response to metabolic surgery is heterogeneous and the metabolic states that underpin weight loss and metabolic improvement are still unclear. In this study, we investigate parameters of post-bariatric fasting glucoregulation and leverage artificial intelligence-assisted whole-slide image analyses to characterize associated immunohistologic features of the pancreas. Materials and Methods We performed either loop duodeno-jejunostomy (DJOS) with exclusion of 1/3 of total intestinal length, loop duodeno-ileostomy with exclusion of 2/3 of total intestinal length (DiOS), or a sham operation on 8-week-old male obese ZDF rats. Six months post-operative, we measured blood metabolites and hormones. Subsequently, pancreatic and intestinal tissue was removed, formalin fixed, and paraffin embedded. Immunohistologic (IHC) analyses included proliferating cell nuclear antigen (PCNA) to visualize the proliferation fraction and pancreatic and duodenal homeobox 1 (PDX 1) as a measure of pancreatic cell differentiation. For IHC quantification, all slides were digitalized and analyzed using QuPath. All analyzed slides were reviewed by two independent pathologists for correctness. Results DJOS and DiOS were associated with preserved fasting insulin production compared to sham. Histopathologic evaluation showed significantly higher numbers of beta cells and specifically of clustered cell organization in DJOS and DiOS compared to sham. Cell proliferation (PCNA) was significantly elevated in DJOS and DiOS compared to sham. Conclusion In this interventional model of bariatric surgery in severe genetic diabetes, we demonstrate post-operative histologic and immunohistologic features of the pancreas associated with improved fasting glucose homeostasis. Graphical abstract

(-)-Epigallocatechin-3-gallate promotes intestinal epithelial proliferation and barrier function after ischemia/reperfusion injury via activation of Nurr1

“…PCNA is a protein required for DNA synthesis and served as a marker of cell replication (Seifert et al. 2022 ). As showed in Figure 2a–d , I/R injury could reduce the percentage of pH3 positive cells and PCNA expression of intestinal mucosa, and EGCG could significantly increase percentage of pH3 positive cells and PCNA expression of intestinal mucosa.…”

β Cell function after Roux-en-Y gastric bypass surgery or reduced energy intake alone in people with obesity

“…In addition, it is likely that increases in β cell mass and remodeling of β cell ultrastructure also contributed to the improvement in β cell function in the T2D-LCD and T2D-RYGB groups. Studies conducted in obese diabetic rats found that (a) weight loss increases β cell number and total β cell mass ( 29 ), and (b) even a small (11 mg/dL) chronic increase in plasma glucose concentration has adverse effects on the expression of islet cell genes associated with β cell viability and function ( 30 ), whereas decreasing plasma glucose with pharmacotherapy improves β cell ultrastructure and function, independently of weight loss ( 31 ). Although the results from our study appear to contradict previous studies that concluded that weight loss increases β cell function in people with obesity without T2D ( 8 , 18 , 20 , 32 , 33 ), β cell function in those studies was evaluated by using the disposition index or other indices that assessed insulin secretion/insulin concentration in relation to insulin sensitivity ( 34 , 35 ).…”