Requirement for the L-type Ca2+ channel α1D subunit in postnatal pancreatic β cell generation
Yoon Namkung, … , Sung-Sook Kim, Hee-Sup Shin
Yoon Namkung, … , Sung-Sook Kim, Hee-Sup Shin
Published October 1, 2001
Citation Information: J Clin Invest. 2001;108(7):1015-1022. https://doi.org/10.1172/JCI13310.
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Article

Requirement for the L-type Ca2+ channel α1D subunit in postnatal pancreatic β cell generation

Abstract

Pancreatic β cells are the source of insulin, which directly lowers blood glucose levels in the body. Our analyses of α1D gene-knockout (α1D–/–) mice show that the L-type calcium channel, α1D, is required for proper β cell generation in the postnatal pancreas. Knockout mice were characteristically slightly smaller than their littermates and exhibited hypoinsulinemia and glucose intolerance. However, isolated α1D–/– islets persisted in glucose sensing and insulin secretion, with compensatory overexpression of another L-type channel gene, α1C. Histologically, newborn α1D–/– mice had an equivalent number of islets to wild-type mice. In contrast, adult α1D–/– mice showed a decrease in the number and size of islets, compared with littermate wild-type mice due to a decrease in β cell generation. TUNEL staining showed that there was no increase in cell death in α1D–/– islets, and a 5-bromo-2′ deoxyuridine-labeling (BrdU-labeling) assay illustrated significant reduction in the proliferation rate of β cells in α1D–/– islets.

Authors

Yoon Namkung, Nataliya Skrypnyk, Myung-Jin Jeong, Taehoon Lee, Myung-Shik Lee, Hyung-Lae Kim, Hemin Chin, Pann-Ghill Suh, Sung-Sook Kim, Hee-Sup Shin

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Islet morphology. (a) Upper panel: insulin- and glucagon-positive cells,...
Islet morphology. (a) Upper panel: insulin- and glucagon-positive cells, respectively in wild-type and mutant mice. Bars, 100 μm. Lower panel: lower magnification (×40) of pancreatic islets of wild-type and α1D–/– mice. Immunostaining with anti-insulin antibody shows sparse distribution and lack of larger islets in the α1D–/– pancreas. (b) Decreased number of islets in α1D–/– mice, compared with that in littermate controls. Summed islet numbers obtained from examining every fifth section of 20-μm thickness from a whole pancreas. Filled bars, littermate control mice (wild-type for P0, P14, and P30 and heterozygote for 7 months); open bars, α1D–/– mice. The number of animals examined is indicated at the bottom of each bar. *P < 0.05. **P < 0.001. (c) Morphometric analysis of islet area in pancreas from wild-type (filled bars, n = 5) and α1D–/– (open bars, n = 5) female mice at P30. Distribution of islet areas less than 100 cells, 100–150 cells, or more than 150 cells is shown as a percentage of islets measured. The proportion of larger islets (more than 150 cells in a cross-section) was significantly reduced in the α1D–/– pancreas. *P < 0.05. (d) Percentage of β cells in individual islets at P30. Filled bar, wild-type islets (n = 58 islets from five mice); open bar, α1D–/– islets (n = 79 islets from five mice). *P < 0.001.