Human duct cells contribute to β cell compensation in insulin resistance.

Citation
Dirice, E., et al. “Human Duct Cells Contribute To Β Cell Compensation In Insulin Resistance.”. Jci Insight.
Center Joslin Diabetes Center
Author Ercument Dirice, Dario F De Jesus, Sevim Kahraman, Giorgio Basile, Raymond Ws Ng, Abdelfattah El Ouaamari, Adrian Kee Keong Teo, Shweta Bhatt, Jiang Hu, Rohit N Kulkarni
Keywords Cell Biology, diabetes, Endocrinology, Islet cells, Mouse models
Abstract

The identification of new sources of β cells is an important endeavor with therapeutic implications for diabetes. Insulin resistance, in physiological states such as pregnancy or in pathological states such as type 2 diabetes (T2D), is characterized by a compensatory increase in β cell mass. To explore the existence of a dynamic β cell reserve, we superimposed pregnancy on the liver-specific insulin receptor-KO (LIRKO) model of insulin resistance that already exhibits β cell hyperplasia and used lineage tracing to track the source of new β cells. Although both control and LIRKO mice displayed increased β cell mass in response to the relative insulin resistance of pregnancy, the further increase in mass in the latter supported a dynamic source that could be traced to pancreatic ducts. Two observations support the translational significance of these findings. First, NOD/SCID-γ LIRKO mice that became pregnant following cotransplantation of human islets and human ducts under the kidney capsule showed enhanced β cell proliferation and an increase in ductal cells positive for transcription factors expressed during β cell development. Second, we identified duct cells positive for immature β cell markers in pancreas sections from pregnant humans and in individuals with T2D. Taken together, during increased insulin demand, ductal cells contribute to the compensatory β cell pool by differentiation/neogenesis.

Year of Publication
2019
Journal
JCI insight
Volume
4
Issue
8
Date Published
12/2019
ISSN Number
2379-3708
DOI
10.1172/jci.insight.99576
Alternate Journal
JCI Insight
PMID
30996131
PMCID
PMC6538348