• BMB Reports
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• v.52 no.5
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• pp.295-303
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• 2019

Breakthroughs in stem cell technology have contributed to disease modeling and drug screening via organoid technology. Organoid are defined as three-dimensional cellular aggregations derived from adult tissues or stem cells. They recapitulate the intricate pattern and functionality of the original tissue. Insulin is secreted mainly by the pancreatic ${\beta}$ cells. Large-scale production of insulin-secreting ${\beta}$ cells is crucial for diabetes therapy. Here, we provide a brief overview of organoids and focus on recent advances in protocols for the generation of pancreatic islet organoids from pancreatic tissue or pluripotent stem cells for insulin secretion. The feasibility and limitations of organoid cultures derived from stem cells for insulin production will be described. As the pancreas and gut share the same embryological origin and produce insulin, we will also discuss the possible application of gut organoids for diabetes therapy. Better understanding of the challenges associated with the current protocols for organoid culture facilitates development of scalable organoid cultures for applications in biomedicine.

• Journal of Acupuncture Research
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• v.26 no.5
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• pp.39-47
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• 2009

목적 : 정상 췌장조직 속에 존재하는 췌장 소도세포들을 파괴시켜 고혈당을 유발시키고 복령 물추출물로 약침을 시술하여 췌장 조직의 보호효과와 항당뇨 효과를 살펴보고자 실험을 진행하였다. 방법 : 5주령의 Sprague-Dawley rat을 통제된 실험실 환경에 적응시킨 후 1주일간 복령약침액(125mg/kg 복령약침군 및 250mg/kg 복령약침군)을 좌우 신수($BL_{23}$)에 교대로 각각 피하에 약침하고 streptozotocin을 복강내 주사하여 3일 후 diabetes mellitus 유도 정도를 평가하고 2주일간 추가 치료를 진행 한 뒤, 혈액지표(plasma glucose, insulin, TG, TC, NEFA, sGOT, sGPT, ALP, BUN, CRE)와 췌장조직의 형태학적 분석 및 염증 관련 단백질의 발현을 평가하였다. 결과 : 복령약침군(125mg/kg 복령약침군 및 250mg/kg 복령약침군)에서 insulin과 triglyceride, NEFA 수치가 유의하게 감소하였으며 간 기능 효소수치인 sGOT가 감소하는 경향을 나타내었으나, 신장기능지수는 유의한 감소를 나타내지 않았다. 특히 250mg/kg 복령약침군에서 streptozotocin 투여로 인한 pancreatic islet의 형태학적 변성이 현저하게 개선되었다. Western blot 결과 JNK-2, P-JNK-2, P-JNK-1, ERK1/2 및 phosphorylated ERK1의 발현이 감소되었다. 결론 : 복령약침이 고인슐린혈증과 고지질질혈증을 개선시키고 streptozotocin에 의한 pancreatic islet의 파괴를 억제하며, 이는 inflammation-related transcription factor인 NF-kB와도 관련이 있는 것으로 판단된다. 향후 복령약침의 항당뇨 효과와 그 기전에 관한 추가 연구가 필요할 것으로 사료된다

• Korean Journal of Veterinary Research
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• v.42 no.1
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• pp.21-28
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• 2002

The regional distribution and relative frequency of the pancreatic endocrine cells in the ICR mouse were studied by immunohistochemical (PAP) method using four types of specific antisera against insulin, glucagon, somatostatin and human pancreatic polypeptide (PP). The pancreas of mice could be divided into three portions; pancreatic islets, exocrine and pancreatic ducts. Pancreatic islets, furthermore, were subdivided into three regions (central, mantle and peripheral region) according to their located types of immunoreactive cells. In the pancreatic islet portions, insulin-immunoreactive cells were located in the central and mantle regions but most of somatostatin-, glucagon- and PP-immunoreactive cells were detected in the mantle and peripheral regions with various frequencies. In addition, PP-immunoreactive cells were also found in the central regions of pancreatic islets of ICR mouse. In the exocrine portions, all four types of immunoreactive cells were demonstrated in the ICR mouse. In the pancreatic duct portions, insulin- and glucagon-immunoreactive cells were situated in the epithelial lining of ICR mouse with a few and rare frequencies, respectively. In addition, rare PP-immunoreactive cells were also demonstrated in the subepithelial regions of the pancreatic duct. However, no somatostatin-immunoreactive cells were demonstrated.

• Journal of the East Asian Society of Dietary Life
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• v.22 no.3
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• pp.334-340
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• 2012

This study was carried out to investigate the effects of Opuntia ficus-indica complex (OF) on blood glucose, glucose tolerance, plasma insulin level and histopathological appearance of pancreatic islets in streptozotoxin (STZ)-induced diabetic rats. Thirty-two male Sprague-Daweley rats were divided into non-diabetic control (NC), diabetic control (DC), diabetic OF of 2% (OF-2) and diabetic OF of 5% (OF-5) and fed experimental diets for 3 weeks. Compared to the DC group fasting blood glucose levels in the OF-2 and OF-5 groups were significantly (p<0.05) reduced while fasting plasma insulin level in the OF-2 and OF-5 groups were significantly (p<0.05) increased. Glucose tolerance in the OF-2 and OF-5 groups were improved. Histopathological observation of pancreatic islets of the OF-2 and OF-5 groups showed hyperplasia which was very similar to NC. Numbers of ${\beta}$-cells in OF-2 ($47.81{\pm}0.92$) and OF-5 ($81.64{\pm}2.80$) were higher than numbers of ${\beta}$-cells in DC ($13.18{\pm}1.01$). These results imply that the intake of OF improves ${\beta}$-cell proliferation and prevents the death of ${\beta}$-cells in STZ-induced diabetic rats.

• The Korean Journal of Physiology and Pharmacology
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• v.7 no.5
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• pp.261-266
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• 2003

Type 1 diabetes is an organ-specific autoimmune disease caused by the cytotoxic T cells-mediated destruction of the insulin-producing beta cells in the Langerhans pancreatic islets. Hepatocyte growth factor (HGF) is a potent mitogen and a promoter of proliferation of insulin producing beta cells of pancreatic islets. To study the role of HGF via viral vector in the development of streptozotocin (STZ)-induced diabetes in mice, we have developed an adenoviral vector genetically engineered to carry the gene for human HGF (hHGF) and evaluate the change of blood glucose, insulin level, and insulin-secreting beta cells of pancreatic islets. We demonstrate that the treatment with hHGF gene prevented the development of STZ-induced diabetes and increased serum insulin level to above normal range. Furthermore, it preserved pancreatic beta cells from destruction. These in vivo results may support previous findings that HGF is insulinotropic agent for beta cells and HGF treatment renders the cells to be resistant to the development of diabetes from STZ administration. We suggest that an adenoviral mediated hHGF gene therapy is a good candidate for the prevention and treatment of type 1 diabetes.

• IMMUNE NETWORK
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• v.13 no.6
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• pp.235-239
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• 2013

Encapsulation of tissue has been an area of intense research with a myriad number of therapeutic applications as diverse as cancer, tissue regeneration, and diabetes. In the case of diabetes, transplantation of pancreatic islets of Langerhans containing insulin-producing beta cells has shown promise toward a cure. However, anti-rejection therapy that is needed to sustain the transplanted tissue has numerous adverse effects, and the islets might still be damaged by immune processes. Furthermore, the profound scarcity of healthy human donor organs restricts the availability of islets for transplant. Islet encapsulation allows the protection of this tissue without the use of toxic medications, while also expanding the donor pool to include animal sources. Before the widespread application of this therapy, there are still issues that need to be resolved. There are many materials that can be used, differing shapes and sizes of capsules, and varied sources of islets to name a few variables that need to be considered. In this review, the current options for capsule generation, past animal and human studies, and future directions in this area of research are discussed.

• Molecules and Cells
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• v.41 no.10
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• pp.909-916
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• 2018

In pancreatic ${\beta}$ cells, glucose stimulates the biosynthesis of insulin at transcriptional and post-transcriptional levels. The RNA-binding protein, polypyrimidine tract-binding protein 1 (PTBP1), also named hnRNP I, acts as a critical mediator of insulin biosynthesis through binding to the pyrimidine-rich region in the 3'-untranslated region (UTR) of insulin mRNA. However, the underlying mechanism that regulates its expression in ${\beta}$ cells is unclear. Here, we report that glucose induces the expression of PTBP1 via the insulin receptor (IR) signaling pathway in ${\beta}$ cells. PTBP1 is present in ${\beta}$ cells of both mouse and monkey, where its levels are increased by glucose and insulin, but not by insulin-like growth factor 1. PTBP1 levels in immortalized ${\beta}$ cells established from wild-type (${\beta}IRWT$) mice are higher than levels in ${\beta}$ cells established from IR-null (${\beta}IRKO$) mice, and ectopic re-expression of IR-WT in ${\beta}IRKO$ cells restored PTBP1 levels. However, PTBP1 levels were not altered in ${\beta}IRKO$ cells transfected with IR-3YA, in which the Tyr1158/1162/1163 residues are substituted with Ala. Consistently, treatment with glucose or insulin elevated PTBP1 levels in ${\beta}IRWT$ cells, but not in ${\beta}IRKO$ cells. In addition, silencing Akt significantly lowered PTBP1 levels. Thus, our results identify insulin as a pivotal mediator of glucose-induced PTBP1 expression in pancreatic ${\beta}$ cells.

• Korean Journal of Veterinary Research
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• v.33 no.3
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• pp.369-379
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• 1993

The regional distribution and the relative frequencies of endocrine cells were studied in nine portions of the blue fox GI tract, and the distribution pattern and cell types of the pancreatic endocrine cells were also studied in the pancreas by immunohistochemical method. Six kinds of immunoreactive cells were identified in the GI tract, and four kinds of immunoreactive cells were also identified in the pancreas. Although numerous 5-HT- and somatostatin-immunoreactive cells were seen throughtout the GI tract, somatostatin-immunoreactive cells were a few in the intestine. Very numerous Gas/CCK-immunoreactive cells were restricted generally in the pyloric region and duodenum. Numerous glucagon-immunoreactive cells were found in the stomach except the pyloric region, and generally a few in the intestine. Moderate number of BPP-immunoreactive cells were found in the stomach except the pyloric region, and a few in the large intestine. Numerous porcine CG-immunoreactive cells were restricted to the cardiac and fundic region. In the pancreas, four types of pancreatic endocrine cells-somatostatin-, glucagon-, BPP- and insuline-immunoreactive-were identified in the pancreatic islet and exocrine portion. These results suggest that the regional distribution, the relative frequencies and cell types of the GEP endocrine cells in the GI tract and pancreas varies considerably among the species.

• Journal of Veterinary Science
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• v.21 no.2
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• pp.26.1-26.14
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• 2020

Pancreatic ductal adenocarcinoma is a lethal cancer type that is associated with multiple gene mutations in somatic cells. Genetically engineered mouse is hardly applicable for developing a pancreatic cancer model, and the xenograft model poses a limitation in the reflection of early stage pancreatic cancer. Thus, in vivo somatic cell gene engineering with clustered regularly interspaced short palindromic repeats is drawing increasing attention for generating an animal model of pancreatic cancer. In this study, we selected Kras, Trp53, Ink4a, Smad4, and Brca2 as target genes, and applied Campylobacter jejuni Cas9 (CjCas9) and Streptococcus pyogens Cas9 (SpCas9) for developing pancreatic cancer using adeno associated virus (AAV) transduction. After confirming multifocal and diffuse transduction of AAV2, we generated SpCas9 overexpression mice, which exhibited high double-strand DNA breakage (DSB) in target genes and pancreatic intraepithelial neoplasia (PanIN) lesions with two AAV transductions; however, wild-type (WT) mice with three AAV transductions did not develop PanIN. Furthermore, small-sized Cjcas9 was applied to WT mice with two AAV system, which, in addition, developed high extensive DSB and PanIN lesions. Histological changes and expression of cancer markers such as Ki67, cytokeratin, Mucin5a, alpha smooth muscle actin in duct and islet cells were observed. In addition, the study revealed several findings such as 1) multiple DSB potential of AAV-CjCas9, 2) peri-ductal lymphocyte infiltration, 3) multi-focal cancer marker expression, and 4) requirement of > 12 months for initiation of PanIN in AAV mediated targeting. In this study, we present a useful tool for in vivo cancer modeling that would be applicable for other disease models as well.

• Korean Journal of Veterinary Research
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• v.49 no.4
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• pp.365-368
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• 2009

A six-year-old female cocker spaniel presented with recurring episodes of pelvic limb weakness and intermittent seizures. Laboratory analysis revealed marked hypoglycemia and an elevated serum insulin concentration. A pancreatic beta-cell tumor at stage III ($T_1N_1M_1$) was diagnosed based on serial blood glucose and insulin measurements along with diagnostic imaging. The patient survived for 140 days after diagnosis with medical management, including frequent feeding and prednisolone therapy. On necropsy, necrosis and masses in the peripancreatic omentum and liver were found; pancreatic beta-cell neoplasia with metastasis to the liver was confirmed by histopathologic examination. This case reports hyper-insulinism in a dog presenting with hypoglycemic seizures.