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Beta-cell replication promoting compounds and methods of their use

A technology of β cells and pancreatic cells, applied in biochemical equipment and methods, pancreatic cells, animal cells, etc., can solve the problem of human insulin deficiency, primary β cells do not have the same effect, and reduced pancreatic β cell mass and function And other issues

Inactive Publication Date: 2012-11-28
PRESIDENT & FELLOWS OF HARVARD COLLEGE +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Type 2 diabetes results from a combination of insulin resistance and impaired insulin secretion, but many people with type 2 diabetes eventually show a marked reduction in pancreatic beta cell mass and function, which in turn makes people with type 2 diabetes A "relative" deficiency of insulin because the beta cells of the pancreas still produce some insulin, but this insulin is either too little or not working properly to get enough glucose into the cells for energy
The main disadvantage of this approach is that the compounds identified by this screening method may not have the same effect on primary β cells, that is, the compounds identified are only specific for growth arrest, reversible immortalization induced proliferation in mouse β cells

Method used

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  • Beta-cell replication promoting compounds and methods of their use
  • Beta-cell replication promoting compounds and methods of their use
  • Beta-cell replication promoting compounds and methods of their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0443] Example 1: Screening Analysis

[0444]Rat islets were isolated as previously described in Gotoh M, Maki T, Kiyoizumi T, Satomi S and Monaco AP, An improved method for isolation of mouse pancreatic islets, Transplantation, 40, 437-438, 1985; The contents of which are hereby incorporated by reference in their entirety. The isolated islets were cultured overnight in a tissue culture incubator. The next morning, islets were trypsinized into colonies of 1-3 cells, which were resuspended in islet medium (Mediatech 99-786-CV; 10% FBS serum (Valley Biomedial BS3033); 8.3 mM glucose (Sigma G7528); 1X Penicillin / Streptomycin (Invitrogen 15070-063); 1X Glutamax (Invitrogen 35050-079)), and to a 96-well plate coated with 804G (rat bladder cancer cell line) conditioned medium (Sigma CLS3904) mid-hole spot plate. Cells were plated at a density of 60k cells / well, and greater than 95% of the cells were confirmed to be viable when plated. Islet cells were allowed to attach for 48 ho...

Embodiment 2

[0446] Example 2: PH3 induction by A10 and B8 production

[0447] β cells were treated with A10 (2 μM) or B8 (15 μM) using a protocol similar to that described in Example 1. Proliferating cells were visualized using a phospho-histone 3 antibody (Millipore 06-570). like figure 1 As shown in , both A10 and B8 increased the ratio of PH3 to PDX-1 relative to DMSO treatment of the control.

Embodiment 3

[0448] Example 3: A10 specifically increases β-cell replication

[0449] β cells or mouse skin were induced with 10 μM, 5 μM, 2.5 μM, 1.25 μM, 0.625 μM, 0.3125 μM, 0.156 μM, 0.078 μM, 0.04 μM, or 0.019 μM A10 using a protocol similar to that described in Example 1. Fibroblasts are processed. like figure 2 As shown in a, the percentage of Ki-67-positive β-cells increased in a dose-dependent manner. However, if figure 2 As shown in b, the percentage of Ki-67-positive mouse skin fibroblasts did not change when treated with A10. These results are consistent with little or no ADK expression in mouse fibroblasts (relative to mouse islets) observed by Western blot analysis (data not shown).

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Abstract

In the invention provides for a method of stimulating or increasing beta-cell replication or growth, by contacting a beta-cell with an inhibitor of adenosine kinase (ADK), an inhibitor of S-Adenosylhomocysteine hydrolase (SAHH) or an activator of AMP activated protein kinase (AMPK).

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit under 35 U.S.C. §119(e) of US Provisional Application No. 61 / 288,001 filed December 18, 2009, the contents of which are hereby incorporated by reference in their entirety. [0003] governmental support [0004] This invention was made with Government support under Grant Nos. DK072505 and DK084206 awarded by the National Institutes of Health. The US Government has certain rights in this invention. technical field [0005] The present invention relates to compositions and methods for promoting replication and / or growth of beta cells. Background technique [0006] There are two forms of diabetes: (1) insulin-dependent diabetes or type 1 diabetes (aka, juvenile onset diabetes, fragile diabetes, insulin-dependent diabetes (IDDM)) and (2) non-insulin-dependent diabetes or 2 type diabetes mellitus (aka NIDDM). Type 1 diabetes most often occurs in adolescents but can occur in adults. Ty...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/071C12N5/02A61K31/7042A61K35/39A61P3/10
CPCC12N2501/65C12N2500/40C12N5/0676G01N33/507A61K31/7042A61P3/10C12N5/0602C07D487/04G01N33/15
Inventor 贾斯廷·P·安斯道格拉斯·A·梅尔顿李·L·鲁宾戈登·韦尔
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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