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Application of mTORC1 in medicines for regulating and controlling functions and conversion of pancreatic beta cells

A technology of β cells and pancreatic islets, applied in the field of diabetes

Inactive Publication Date: 2018-02-13
SHANGHAI INST FOR ENDOCRINE & METABOLIC DISEASES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, what signaling pathways may be involved in the transdifferentiation of α-cells and β-cells has not been reported yet.

Method used

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  • Application of mTORC1 in medicines for regulating and controlling functions and conversion of pancreatic beta cells
  • Application of mTORC1 in medicines for regulating and controlling functions and conversion of pancreatic beta cells
  • Application of mTORC1 in medicines for regulating and controlling functions and conversion of pancreatic beta cells

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1, Construction of GFP-tracked β cell-specific Raptor knockout mice and GFP sorting and purification of β cells tower

[0032] In order to exclude the interference of other endocrine cells in the islets, this example constructed β cell-specific Raptor knockout GFP tracer mice. The β cell-specific Raptor knockout GFP tracer mice were constructed by the CRE-LoxP system and the Rosa26-LoxP-STOP-LoxP-EGFP system, and the purified β cells were obtained by flow sorting technology to exclude the interference of other endocrine cells in the islets.

[0033] Specifically: the currently widely used ROSA26-EGFP is adopted f mouse system. The ROSA26 gene is located on chromosome 6 of the mouse and is an antisense long-chain non-coding RNA gene, which has been shown to be expressed in most tissues and cells. A -LoxP-STOP-LoxP-EGFP-sequence is specifically inserted in this region, usually after the -STOP-sequence is transcribed, RNA synthesis will stop. The ROSA26 mice...

Embodiment 2

[0036] Example 2. Effects of β cell-specific knockout of Raptor on glucose homeostasis and β cell quality

[0037] 2.1 Raptor knockout mice had significantly elevated blood glucose at four weeks

[0038] From 2 weeks after the birth of the mice, the body weight and random blood glucose of the male mice were continuously monitored every 2 weeks, and the 6-hour fasting blood glucose of the mice was monitored from the 4th week until the mice were 12 weeks old. In this experiment, male WT mice (cre Raptor w / w g / g) as control, male knockout mouse βRapKO GFP (ere Raptor lox / lox g / g) is the experimental group. There was no difference in body weight between the two groups of mice during the observation period. At 2 weeks, βRapKO GFP The random blood glucose levels of the two groups of mice were similar to those of the WT group, and there were differences from the 4th week (12.53±0.48vs 8.72±0.17mmol / l, PGFP The blood glucose of mice in the control group continued to rise, whi...

Embodiment 3

[0046] Example 3. Changes in β-cell identity after β-cell-specific Raptor knockout

[0047] for research in βRapKO GFP Whether there is a phenomenon of transdifferentiation in mice, this example explored the 8-week-old mice.

[0048] 3.1 Changes in the properties of β cells after β cell-specific Raptor knockout

[0049] ROSA26-EGFP was used to specifically trace the mice, and the GFP-positive cells in the islets were all derived from β cells. In order to study whether β cells are transdifferentiated into α cells, this example carried out co-staining of GFP, glucagon and insulin, and found that some of the GFP-labeled β cells knocked out of Raptor expressed glucagon. We counted and found that there was no difference in the proportion of GFP- and glucagon-positive cells in GFP-positive cells at 2 weeks (WT: 0.17±0.02% vs βRapKO GFP : 0.17±0.01%). At 5 weeks, the GFP and glucagon double-positive cells in the knockout group mice were significantly increased, while the presen...

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Abstract

The invention discloses application of mTORC1 in medicines for regulating and controlling the functions and conversion of pancreatic beta cells; and the functions of pancreatic beta cells are improvedby regulating the activity or regulation bypass of mTORC1 passages and / or the pancreatic non-beta cells are converted into new pancreatic beta cells. The conversion is gene recording without a differentiation process. The invention discloses that the mTORC1 passages are of an important role in identity maintenance of beta cells. The specific Raptor knockout of the beta cells can cause functionaldisorders and cell immaturity of the beta cells as well as hyperglycemia since metabolic requirements cannot be met, and simultaneously causes expression increase of MafB, so that transdifferentiationis caused. The activity of the mTORC1 passages is adjusted, or regulation bypasses of the mTORC1 passages can serve as a new target spot for beta cell therapy, and the functions of the beta cells areimproved, or new beta cells are generated by non-beta cells.

Description

technical field [0001] The invention relates to the technical field of diabetes, in particular to the use of mTORC1 in regulating the function of pancreatic beta cells and transforming drugs. Background technique [0002] Type 2 diabetes is a common metabolic disorder that affects more than 300 million people worldwide. Type 2 diabetes is characterized by pancreatic β-cell dysfunction accompanied by peripheral insulin resistance. [0003] The constituent cells of Langerhans islets include: insulin-producing β-cells, glucagon-producing α-cells, somatostatin-secreting δ-cells, pancreatic polypeptide-secreting PP cells, and ghrelin-producing ε-cells. In the case of overnutrition, the β-cell function is active, especially under the condition of high glucose, which secretes insulin to act on the peripheral tissue liver, muscle and fat to increase the utilization of glucose and reduce the blood sugar level. Glucagon acts opposite to insulin, promoting the decomposition of liver ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61P3/10
CPCA61K45/00
Inventor 宁光汪启迪顾燕云尹庆磊倪启程王翌晨王言秋聂爱芳
Owner SHANGHAI INST FOR ENDOCRINE & METABOLIC DISEASES
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