Journal
ACTA DIABETOLOGICA
Volume 54, Issue 8, Pages 737-747Publisher
SPRINGER-VERLAG ITALIA SRL
DOI: 10.1007/s00592-017-1001-2
Keywords
Islet; Hypoglycemia; Human; Gastro-entero pancreatic factors
Categories
Funding
- Juvenile Diabetes Research Foundation
- American Society of Metabolic and Bariatric Surgery
- Graetz Foundation
- Novo Nordisk Foundation
- KG Jebsen Foundation
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
- [RC1 DK086918]
- [R56 DK095451]
- [RCN FRI-MEDBIO 240788]
- [RO1 DK67536-10]
- [RO1 DK10321501]
- [P30 DK036836]
- Novo Nordisk Fonden [NNF14OC0010659, NNF16OC0021050, NNF15OC0016330] Funding Source: researchfish
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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 is 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 beta-cell proliferation or apoptosis is altered in RYGB + NG. Methods We performed an observational study to analyze markers of proliferation, apoptosis, 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 beta-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 beta-cell proliferation in some individuals may contribute to increased beta-cell mass observed in severely affected patients.
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