Heterogeneity of proliferative markers in pancreatic β-cells of patients with severe hypoglycemia following Roux-en-Y gastric bypass

Abstract

Aims Severe postprandial hypoglycemia with neuroglycopenia is an increasingly recognized, debilitating complication of Roux-en-Y gastric bypass (RYGB) surgery. Increased secretion of insulin and incretin hormones are implicated in its pathogenesis. Histopathologic examination of pancreas has demonstrated increased islet size and/or nuclear diameter in post-RYGB patients who underwent pancreatectomy for severe refractory hypoglycemia with neuroglycopenia (RYGB+NG). We aimed to determine whether β-cell proliferation or apoptosis are altered in RYGB+NG. Methods We performed an observational study to analyze markers of proliferation, apoptosis, and cell cycle, and transcription factor expression in pancreatic tissue from affected RYGB+NG patients (n=12), normoglycemic patients undergoing pancreatic surgery for benign lesions (controls, n=6, and individuals with hypoglycemia due to insulinoma (n=52). Results Proliferative cell nuclear antigen (PCNA) expression was increased in insulin-positive cells in RYGB+NG patients (4.5-fold increase, p<0.001 vs. controls) and correlated with β-cell mass. Ki-67 immunoreactivity was low in both RYGB+NG and controls, but did not differ between groups. Phospho-histone H3 levels did not differ between RYGB+NG and controls. PCNA and Ki-67 were both significantly lower in both controls and RYGB+NG than insulinomas. Markers of apoptosis and cell cycle (M30, p27, and p21) did not differ between groups. PDX1 and menin exhibited similar expression patterns, while FOXO1 appeared to be more cytosolic in RYGB+NG. Conclusions Markers of proliferation are heterogeneous in patients with severe post-RYGB hypoglycemia. Increased β-cell proliferation in some individuals may contribute to increased β-cell mass observed in severely affected patients.

Human duct cells contribute to β cell compensation in insulin resistance

“…This may explain, in part, the absence of nuclear MAFA expression in pancreas sections from T2D patients while expression remained in human ducts that were obtained from controls without diabetes and transplanted into mice. Alternatively, this may be an example of heterogeneity that is observed in pathological conditions affecting the pancreas (53).…”

Hypoglycemia After Gastric Bypass Surgery: Current Concepts and Controversies

“…Subsequent analyses revealed no differences in overall b-cell mass when the same samples were compared with autopsy specimens (36). Other studies revealed substantial variability in both b-cell area and markers of proliferation (37). Whether these differences reflect heterogeneity in the population under study or are unrelated to functional differences in mealstimulated insulin responses remains uncertain.…”

Roux-en-Y Gastric Bypass Is Associated With Hyperinsulinemia But Not Increased Maximal β-Cell Function

“…However, a small study involving Goto-Kakizaki rats showed no increase in β -cell mass after sleeve gastrectomy and duodenal-jejunal bypass [33]. In a human study, pancreatic tissue obtained from patients with symptomatic postprandial hypoglycemia after RYGB did not show increased β -cell mass [34], although others have reported opposite results [3, 4, 35]. Given these discrepant results, the important question of whether RYGB causes changes in β -cell mass is still open.…”