Diabetes & Metabolism Journal

Original Articles

Proliferation and Differentiation of Pancreatic beta Cells in L-type Calcium Channel alpha(1D) Subunit (Ca(v)1.3) Heterozygous Knock Out Mice After Partial Pancreatectomy.: Yoon Hee Choi, Il Hee Yun, Sun Hee Suh, Dong Jun Lim, Jae Hyuung Cho, Hyuk Sang Kwon, Bong Yun Cha, Ho Young Son, Chung Gyu Park, Kun Ho Yoon; Korean Diabetes J. 2007;31(3):208-219. Published online May 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.3.208

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Abstract PDF: BACKGROUND
S: L-type voltage-dependent calcium channel (LTCC) plays a crucial role in insulin secretion from pancreatic beta cells through Ca2+ influx. In the recent report, LTCC Ca(v)1.3 subtype homozygous knock out mice showed impairment of postnatal pancreatic beta cell development as well as insulin secretion. METHODS: We performed 90% partial pancreatectomy in heterozygous Ca(v)1.3 knock out mice to investigate the effect of partial deficiency of Ca(v)1.3 gene on beta cell regeneration in the adult. Glucose homeostasis, metabolic profiles including serum insulin and lipid levels and morphologic changes of pancreatic islets were studied. RESULTS: 90% Partial pancreatectomy induced glucose intolerance only in the heterozygous knock out mice at 8 weeks after surgery. Distribution of islet size was significantly different between two groups after partial pancreatectomy; median value of islet size of heterozygote was larger than that of wild type (642.8 micrometer2 vs 1459.8 micrometer2, P < 0.01). The frequency of single beta cell unit, considered as a unit of beta cell neogenesis, was much lower in heterozygote than that of wild type (41% vs 23.3%, P < 0.05). CONCLUSION: These data suggest that Ca(v)1.3 gene deficiency is specifically associated with impairment of beta cell regeneration, especially neogensis and eventual glucose intolerance in the 90% partial pancreatectomized mice.

The Changes of Beta Cell Mass and Islet Morphology in OLETF (Otsuka Long Evans Tokushima Fatty) Rats After Partial Pancreatectomy .: Seung Hyun Ko, Kun Ho Yoon, Sun Hee Suh, Yu Bae Ahn, Soon Jib Yoo, Ki Ho Song, Hyun Shik Son, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 2001;25(1):50-62. Published online February 1, 2001

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Abstract PDF: BACKGROUND
Insulin resistance and incomplete beta cell compensation play a major role for development of type 2 diabetes. When insulin resistance were induced by any cause, appropriate beta-cell proliferation is a key factor for maintaining the normal glucose metabolism. Compensatory beta-cell proliferation for adapting to increased insulin resistance might be achieved by neogenesis of beta-cell from duct cells, replication of preexisting beta-cells and also inhibition of beta-cell apoptosis. Previously incomplete beta-cell compensation was observed in OLETF rat, animal model of type 2 diabetes, after partial pancreatectomy, but there were no reports about the underlying pathogenesis. Therefore, this study was designed to study on the mechanism of incomplete beta-cell compensation in OLETF rat after partial pancreatectomy especially focus on beta-cell proliferation. METHODS: 12 week-old OLETF (Otsuka Long Evans Tokushima Fatty) rats weighing 280-320 g were used. 80% partial pancreatectomy was done. Experimental animals were divided into the 4 subgroups by date of killing after surgery: 0, 3, 90 days. After glucose tolerance test, pancreas remnant was excised and immunohistochemical staining was done for insulin to quantify the beta cell mass by point-counting method and also observed the amount of fibrosis of the islets after Masson's trichrome staining of the pancreas. RESULTS: We observed that impaired glucose tolerance or diabetes were developed after 80% pancreatectomy. We observed rapidly proliferating duct cells in the adjacent area of common pancreatic duct and main duct even up to 90 days after partial pancreatectomy. In OLETF rats, beta cell mass was not increased enough compared to LETO rats and some destructive features of islet architectures were noted at 90 days after pancreatectomy. CONCLUSION: The changes of beta cell mass seems to be a dynamic process adjusting to metabolic demand. Severe hyperglycemia and islet disorganization were apparent in OLETF rats despite of existence of beta cell regeneration and renewal process. So it seemed that hyperglycemia accelerated aging process or senescence of beta cells in OLETF rats.

The Changes of Expression of Intermediate Flament in Pancreatic Duct Cells During Proliferation and Differentiation after 90% Pancreatectomy in Rats.: Seung Hyeon Ko, Kun Ho Yoon, Sun Hee Seo, Jung Min Lee, Ki Won Oh, Sang Ah Chang, Hye Soo Kim, Yoo Bae Ahn, Hyun Shik Son, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 2000;24(2):191-201. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Neogenesis of the beta calls from ductal cells is the main mechanism of the increased beta cell mass after partial pancreatectomy. For the transdifferentiation from the duct cells to the beta cells, de-differentiation of the duct cells is needed because duct cells are also terminally differentiated cells already. But there was no clear evidence of de-differentiation of the duct cells during duct call proliferation so far. Herein we report the changes of intermediate filament protein expression in rapidly proliferating duct cells after partial pancreatectomy for the evidence of de-differentiation of the duct cells. METHODS: 45 week-old Sprague-Dawley rats weighing 80~120 g were used. 90% partial pancreatectomy was done. Experimental animals were divided into 5 subgroups by date of killing after surgery: 1, 3, 7, 14, 30 days, Pancreas remnant was excised and immunohistochemical stain was done for pancytokeratin (Pan-CK) as a epithelial cell marker and vimentin (VT) as a mesenchymal cell marker. We observed the double stained slide with pan-CK and VT antibody using confocal microscope for costaining analysis over time. The sections were also immunostained with anti-insulin antibody for the quantification of the beta cell mass by point-counting methods. RESULTS: We observed impaired glucose tolerance and diabetes were developed affer 90% pancreatectomy. Significant increase of the weight of pancreatic remnant, beta cell and duct cell mass were observed about 14 days after pancreatectomy. We observed the co-expression of VT and pan-CK intermediate filament protein in rapidly proliferating duct cells in the area of common pancreatic duct and main duct at one day after partial pancreatectomy. 3 days affer partial pancreatectomy, VT and pan-CK costained duct cells were mainly observed in the rageneration focus of the duct cell proliferation. 30 days after partial pancreatectomy, we could not find any costaining duct calls in the remnant pancreas. CONCLUSION: The vimentin intermediate filament, a marker of mesenchymal cell was expressed in proliferating ductal cells after pancreatectomy. We could suspect that pancytokeratin and vimentin co-expression is a good marker for de-differentiation of proliferating duct cells.

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