Decreased expression of insulin and increased expression of pancreatic transcription factor PDX-1 in islets in patients with liver cirrhosis: a comparative investigation using human autopsy specimens.
BACKGROUND
Glucose intolerance in patients with liver cirrhosis (LC), known as hepatogenous diabetes, is thought to be distinct from type 2 diabetes (T2DM) in some aspects. Hyperinsulinemia and/or insulin resistance in liver disease is associated with hepatocarcinogenesis, growth of hepatocellular carcinoma, and poor prognosis. However, the pathophysiological processes in islets that are responsible for hyperinsulinemia in LC are still not precisely known. Therefore, we investigated the histopathological differences in islets of Langerhans cells between LC and T2DM.


METHODS
A total of 35 human autopsy pancreatic tissue samples were used in this study (control, n = 18; T2DM, n = 6; LC, n = 11). The expression of insulin, glucagon, somatostatin, pancreatic duodenal homeobox-1 (PDX-1), proliferating cell nuclear antigen (PCNA), and Ki-67 was examined using immunohistochemistry and quantitated by image analysis.


RESULTS
Islet hypertrophy and a significant increase in PCNA-positive cells in islets were observed in the tissues from LC cases. The insulin-positive areas in islets were significantly decreased in LC cases compared with control and T2DM cases (P = 0.001, P = 0.035, respectively), whereas the PDX-1-positive area was significantly increased in LC cases (P = 0.001) compared with the control. Furthermore, disorganization of pancreatic endocrine cells and nucleocytoplasmic translocation of PDX-1 were both seen in the LC subjects.


CONCLUSIONS
In LC, islets undergo hypertrophy and exhibit paradoxical expression of insulin and PDX-1. In the subjects autopsied, insulin expression was decreased, whereas expression of the pancreatic transcription factor PDX-1 was increased in LC. These results point to important distinctions between LC and T2DM.
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan. sakata_masahiro@med.kurume-u.ac.jp
Masahiro
M
Sakata
Akihiko
A
Kawahara
Takumi
T
Kawaguchi
Jun
J
Akiba
Tomoki
T
Taira
Eitaro
E
Taniguchi
Mitsuhiko
M
Abe
Hironori
H
Koga
Masayoshi
M
Kage
Michio
M
Sata
D000368:Aged; D001706:Biopsy; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D005260:Female; D005934:Glucagon / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012189:Retrospective Studies; D013004:Somatostatin / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*
D018398:Homeodomain Proteins; D007328:Insulin; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D013004:Somatostatin; D005934:Glucagon