Transgenic Pig Islets Enhancing Glucose-Responsive Insulin Secretion

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Solution Overview

Problem

Current treatments for Type I diabetes using pig islet xenotransplantation are limited by the weak response of pig islets to glucose stimulation, requiring high numbers of islets for effective insulin production, which is inefficient and raises ethical concerns.

Innovation Solution

Transgenic pig beta cells with constitutively activated PKC and PKA pathways, combined with expression of a constitutively active muscarinic receptor and GLP-1, enhance insulin secretion synergistically, improving glucose responsiveness.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If pig islet xenotransplantation is used to treat Type I diabetes, then insulin production is restored, but the response to glucose stimulation is weak requiring high numbers of islets

Engineering Contradiction:

Improveinsulin production capabilityVSAvoidglucose responsiveness

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent changes the biochemical parameters of pig beta cells by overexpressing specific proteins (glucokinase, phosphofructokinase, pyruvate kinase) that control glycolytic flux. This modifies the metabolic pathway parameters to enhance the conversion of glucose to insulin, thereby improving glucose responsiveness while maintaining reliable insulin production

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite cellular system by combining pig beta cells with overexpressed metabolic enzymes and co-culture with accessory cells (alpha, delta, PP cells). This composite approach synergistically enhances glucose sensing and insulin secretion capabilities, resolving the contradiction between reliable insulin production and improved glucose responsiveness

Inventive Principle:

Principle #40Composite materials

2Reliability

If high numbers of pig islets are transplanted to achieve effective insulin production, then diabetes treatment efficacy is improved, but the number of pigs required increases raising ethical concerns

Engineering Contradiction:

Improvediabetes treatment efficacyVSAvoidnumber of islets required

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

By modifying metabolic pathway parameters through overexpression of key enzymes (glucokinase with increased Km, phosphofructokinase with enhanced activity), the patent increases the insulin secretion efficiency per islet. This reduces the total quantity of islets needed to achieve effective diabetes treatment, thereby lowering the number of pigs required and addressing ethical concerns

Inventive Principle:

Principle #35Parameter changes

3Reliability

If pig islet transplantation is performed, then insulin production is restored, but the number of pigs needed per patient is high

Engineering Contradiction:

Improveinsulin production restorationVSAvoidnumber of pigs per patient

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent alters the metabolic parameters of pig beta cells by introducing and overexpressing human metabolic enzyme genes (glucokinase, phosphofructokinase, pyruvate kinase). This enhances the glucose-stimulated insulin secretion efficiency, allowing fewer pig islets to be transplanted per patient, thereby reducing the number of pigs needed while maintaining reliable insulin production restoration

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The transgenic pig islets exhibit significantly increased insulin secretion in response to glucose, potentially reducing the number of islets needed for transplantation and improving treatment efficacy.

Implementation Method 1

the PKC and PKA pathways are transgenically modified, preferably are constitutively activated

Methodology Applied

Scientific EffectSignal transduction pathway activation:

Implementation Method 2

the synthesis and secretion of insulin in response to blood glucose levels may involve two pathways: (i) the PKC pathway, and (ii) the PKA pathway

Methodology Applied

Scientific EffectInsulin secretion:

Implementation Method 3

the expression of a constitutively active muscarinic receptor and GLP-1, enhance insulin secretion synergistically

Methodology Applied

Scientific EffectReceptor activation:

Implementation Method 4

GLP-1, enhance insulin secretion synergistically

Methodology Applied

Scientific EffectHormone action:

Data Source

PatentUS11160836B2Transgenic pig islets and uses thereof for treating diabetes

Publication Date: 2021.11.02 GIANELLO PIERRE

AI summary

The present invention relates to an isolated transgenic pig beta cell wherein the PKC and the PKA pathway are constitutively activated; to a transgenic pig islet comprising said transgenic pig beta cell; and to a transgenic pig comprising said transgenic pig beta cell or said transgenic pig islet. Another object of the invention is a device comprising a transgenic pig beta cell or a transgenic pig islet of the invention. The present invention also relates to the use of said transgenic pig beta cell, said transgenic pig islet, or said device for treating a disease, disorder or condition related to the impaired function of endocrine pancreas or of beta cell.