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Acta Diabetol. 2017 Aug;54(8):737-747. doi: 10.1007/s00592-017-1001-2. Epub 2017 May 17.

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

Author information

1
Research Division, Joslin Diabetes Center, and Harvard Medical School, 1 Joslin Place, Boston, MA, 02215, USA. Mary.elizabeth.patti@joslin.harvard.edu.
2
Research Division, Joslin Diabetes Center, and Harvard Medical School, 1 Joslin Place, Boston, MA, 02215, USA.
3
Department of Surgery, Haukeland University Hospital, 5021, Bergen, Norway.
4
Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, 5020, Bergen, Norway.
5
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, 5020, Bergen, Norway.
6
Department of Pathology, Haukeland University Hospital, 5021, Bergen, Norway.
7
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA.
8
Department of Surgery, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA.
9
Service of Clinical Pathology, Lausanne University Hospital, Institute of Pathology, 1011, Lausanne, Switzerland.
10
Department of Medicine, Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
11
Faculdade de Ciencias Medicas (FCM), Departamento de Clinica Medica, Obesity and Comorbidities Research Center (O.C.R.C.), Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
12
Endocrinology and Metabolic Diseases, Department of Health Sciences, University of Milano, Via A. Di Rudini', 8, 20149, Milan, Italy.
13
Research Division, Joslin Diabetes Center, and Harvard Medical School, 1 Joslin Place, Boston, MA, 02215, USA. Rohit.kulkarni@joslin.harvard.edu.

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 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 β-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 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.

KEYWORDS:

Gastro-entero pancreatic factors; Human; Hypoglycemia; Islet

PMID:
28512677
PMCID:
PMC5515485
DOI:
10.1007/s00592-017-1001-2
[Indexed for MEDLINE]
Free PMC Article

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