Human duct cells contribute to β cell compensation in insulin resistance
Ercument Dirice, … , Jiang Hu, Rohit N. Kulkarni
Ercument Dirice, … , Jiang Hu, Rohit N. Kulkarni
Published April 18, 2019
Citation Information: JCI Insight. 2019;4(8):e99576. https://doi.org/10.1172/jci.insight.99576.
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Research Article Cell biology Endocrinology

Human duct cells contribute to β cell compensation in insulin resistance

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.

Authors

Ercument Dirice, Dario F. De Jesus, Sevim Kahraman, Giorgio Basile, Raymond W.S. Ng, Abdelfattah El Ouaamari, Adrian Kee Keong Teo, Shweta Bhatt, Jiang Hu, Rohit N. Kulkarni

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Figure 1

Compensatory islet hyperplasia in pregnant LIRKO mice.

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Compensatory islet hyperplasia in pregnant LIRKO mice. (A) Serum insulin...
(A) Serum insulin (n = 3–9 mice per group, 2-tailed Student’s t test) and (B) blood glucose levels (n = 3–7 mice per group, 2-tailed Student’s t test) in female control and LIRKO mice measured before gestation (G0), during (G15.5, G17.5) pregnancy, and after (P4 and P10) pregnancy. (C) Blood glucose values following an oral glucose tolerance test (2.5 g/kg BW) (n = 4–7 mice per group, 2-tailed Student’s t test) and (D) glucose levels plotted as percentage of basal values, following i.p. injection of insulin (1 U/kg BW) (n = 3–6 mice per group, 2-tailed Student’s t test). Solid line indicates control, and dashed line indicates LIRKO mice. Nonpregnant mice are shown as circles and pregnant mice as squares. (E) Representative immunofluorescence images of pancreatic sections stained with a cocktail of antibodies against insulin (shown in red), glucagon (shown in blue), and somatostatin (shown in green) as described in Methods. Scale bar: 100 μm. Original magnification, ×20. Insets show enlarged endocrine cells. (F) Average number of β cells per islet. A total of 20 randomly selected islets were analyzed per group for all time points (n = 3 mice per group, 2-tailed Student’s t test). (G) Quantification of the islet endocrine cell content. α, β, and δ cell numbers were counted per islet, and 20 randomly selected islets were analyzed per mouse in each group for all time points and presented as the percentage of total islet endocrine cells (n = 3 mice per group, 2-tailed Student’s t test). (H) Representative images of pancreatic sections obtained from nonpregnant and pregnant (G15.5) control and LIRKO mice stained for insulin (red), proliferation marker Ki67 (green), and nuclear marker DAPI (blue). Insets point to Ki67+ cells. Scale bar: 100 μm. (I) Quantification of Ki67+ β cells (n = 3–5 mice per group, 2-tailed Student’s t test) (for quantification, see Supplemental Table 1) (J) Representative pancreas sections with insets showing insulin+ (red) islets. Scale bar: 4 mm. (K) Morphometric analysis of β cell mass as described in Methods (n = 3–4 mice per group, 2-tailed Student’s t test). Scale bars: 100 μm (A and B), 4 mm (J). #Control versus control, *control versus LIRKO, and §LIRKO versus LIRKO. Data are expressed as mean ± SEM. #P, §P, and *P < 0.05; ##P, §§P, and **P < 0.01; and §§§P and ***P < 0.001.