Insulin-Producing Intestinal K Cells Protect Nonobese Diabetic Mice From Autoimmune Diabetes

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• 作者：Majid Mojibian¹ ; ^&lowast ; ; Ada W.Y. Lam¹ ; ^&lowast ; ; Yukihiro Fujita¹ ; Ali Asadi¹ ; Guntram A. Grassl² ; Peter Dickie³ ; Rusung Tan⁴ ; ⁵ ; Anthony T. Cheung⁶ ; Timothy J. Kieffer¹ ; ^{tim.kieffer@ubc.ca" class="auth_mail" title="E-mail the corresponding author}
• 关键词：GIP ; Autoimmunity ; Gut K Cells ; Glucose-Dependent Insulinotropic Polypeptide
• 刊名：Gastroenterology
• 出版年：2014
• 出版时间：July 2014
• 年：2014
• 卷：147
• 期：1
• 页码：162-171.e6
• 全文大小：5175 K

文摘

Type 1 diabetes is caused by an aberrant response against pancreatic β cells. Intestinal K cells are glucose-responsive endocrine cells that might be engineered to secrete insulin. We generated diabetes-prone non-obese diabetic (NOD) mice that express insulin, via a transgene, in K cells. We assessed the effects on immunogenicity and diabetes development.

Methods

Diabetes incidence and glucose homeostasis were assessed in NOD mice that expressed mouse preproinsulin II from a transgene in K cells and nontransgenic NOD mice (controls); pancreas and duodenum tissues were collected and analyzed by histology. We evaluated T cell responses to insulin, levels of circulating autoantibodies against insulin, and the percentage of circulating antigen-specific T cells. Inflammation of mesenteric and pancreatic lymph node cells was also evaluated.

Results

The transgenic mice tended to have lower blood levels of glucose than control mice, associated with increased plasma levels of immunoreactive insulin and proinsulin. Fewer transgenic mice developed diabetes than controls. In analyses of pancreas and intestine tissues from the transgenic mice, insulin-producing K cells were not affected by the immune response and the mice had reduced destruction of endogenous β cells. Fewer transgenic mice were positive for insulin autoantibodies compared with controls. Cells isolated from mesenteric lymph nodes of the transgenic mice had significantly lower rates of proliferation and T cells from transgenic mice tended to secrete lower levels of inflammatory cytokines than from controls. At 15 weeks, transgenic mice had fewer peripheral CD8⁺ T cells specific for NRP-V7 than control mice.

Conclusions

NOD mice with intestinal K cells engineered to express insulin have reduced blood levels of glucose, are less likely to develop diabetes, and have reduced immunity against pancreatic β cells compared with control NOD mice. This approach might be developed to treat patients with type 1 diabetes.