Application of Grb10 as key negative regulation factor of beta cell dysfunction

A dysfunctional, β-cell technology, applied in the field of biomedicine, can solve problems such as unclear specific mechanisms

Inactive Publication Date: 2020-08-07
THE SECOND XIANGYA HOSPITAL OF CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these findings suggest that the mTORC1 signaling pathway plays a key role in regulating β-cell mass, the specific mechanism by which mTORC1 signaling regulates β-cell mass and function remains unclear

Method used

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  • Application of Grb10 as key negative regulation factor of beta cell dysfunction
  • Application of Grb10 as key negative regulation factor of beta cell dysfunction
  • Application of Grb10 as key negative regulation factor of beta cell dysfunction

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1 human body study

[0046] The study used islets from 13 human organ donors, including 6 minors (under 18 years old) and 7 adults (over 18 years old). Grb10 expression was compared between islets younger than 18 years old and adult donors (greater than 18 years old). Human pancreases were obtained from deceased non-diabetic donors by the Department of Urology, Department of Organ / Liver Transplantation, Second Xiangya Hospital, Central South University.

[0047] Use collagenase P to digest and isolate human islets, carefully clean the adipose tissue, lymph nodes, blood vessels and fascia around the pancreas, trim the human pancreas, inflate the pancreatic duct with a 5ml syringe, and inject 1mg / mL collagenase P through the pancreatic duct Hanks Balanced Salt Solution (HBSS), the amount of collagenase solution used is equivalent to twice the weight of the pancreas. The pancreas was taken out and placed in collagenase P solution and digested at 37°C for about...

Embodiment 2

[0049] Embodiment 2 animal model

[0050] β-cell-specific Grb10 knockout mice Grb10KO (KO) were generated by breeding homozygous Grb10 female (loxP) mice on a C57BL / 6J background with female homozygous Ins2-Cre mice . Ins2-Cre was expressed in pancreatic β cells but not in hypothalamic neurons. loxP littermates and Ins2-Cre littermates were used as controls (WT). Ins2-Cre mice were provided by Zhang Weiping (Tianjin Medical University). All mice were housed in the Specific Pathogen Free Facility (SPF) of the Animal Health Center, Xiangya Second Hospital, Central South University, under a 12-h light-dark cycle. All procedures using animals were performed in accordance with the Animal Care and Use Committee of Xiangya Second Hospital and Central South University.

Embodiment 3

[0051] Example 3 Body Weight, Food Intake and Body Composition

[0052] Mice were fed a normal diet (ND) (Hunan SilaikeJingda Laboratory Animal Co Ltd) containing 19% protein, 5% fat and 5% fiber or a high fat drink (HFD) containing 20% ​​protein; 60% fat; 20% carbohydrate Compound (D12492, ResearchDiets Inc.) was continued for 16 weeks. Mouse body weight and food intake were monitored weekly at the same time points. Mice were analyzed for lean and fat mass by a MQ Minispec 7.5HZ live mouse analyzer (MinispecLF50; BRUKER Optik GmbH; Germany).

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Abstract

The invention relates to the field of biological medicine, in particular to application of Grb10 as a key negative regulation factor for pancreatic beta cell dysfunction. According to the invention, the physiological function of Grb10 in beta cells is researched, wherein the results show that Grb10 is highly expressed in pancreas and islets of human and mice, and is highly expressed in islets of diabetic mouse models and islets of old people. In addition, the beta cell specific knockout Grb10 increases the beta cell quality and beta cell function of high fat diet (HFD) mice by promoting beta cell maturation and inhibiting beta cell dedifferentiation. According to the invention, the important role of Grb10-mTORC1 interaction in regulating beta cell dedifferentiation is highlighted, and a new insight is provided for a regulating mechanism of beta cell characteristics and functions.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to the application of Grb10 as a key negative regulator of beta cell dysfunction. Background technique [0002] Decreased β-cell number and / or impaired β-cell function is one of the mechanisms of type 1 diabetes (T1D) and type 2 diabetes (T2D). However, the underlying mechanism of diabetes, beta-cell reduction, remains to be fully determined. [0003] Research has shown that mature and differentiated beta cells are not in a permanent state and that this state can change in response to changes in the environment. Accumulating evidence indicates that islet β-cell dedifferentiation plays a key role in diabetic β-cell loss. Dedifferentiated β cells lose their identity and insulin secretory function, accompanied by downregulation of β cell-specific transcription factors and upregulation of endocrine precursor surface markers. β-cell dedifferentiation into neuron 3 (Ngn3)-like progenitors an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61P3/10C12Q1/6883G01N33/68
CPCA61K45/00A61P3/10C12Q1/6883C12Q2600/158G01N33/6893G01N2800/042
Inventor 刘峰张晶晶
Owner THE SECOND XIANGYA HOSPITAL OF CENT SOUTH UNIV
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