Beta-3 Adrenergic Agonist Screening for Glucose Uptake Without cAMP

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Solution Overview

Problem

Current treatments for type 2 diabetes, particularly those targeting insulin-independent pathways, face challenges due to adverse effects associated with beta-adrenergic receptor agonists, such as increased cAMP levels leading to cardiovascular issues and glucose output from the liver, making them unsuitable for effective glucose uptake stimulation in peripheral tissues.

Innovation Solution

A method for screening compounds that increase GLUT translocation without elevating cAMP production, using cells expressing beta-adrenergic receptors and GLUT, to identify beta-adrenergic receptor ligands that stimulate glucose uptake in muscle cells without the adverse effects of cAMP elevation, thereby improving glucose homeostasis.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If beta-adrenergic receptor agonists are used to stimulate glucose uptake in peripheral tissues, then glucose uptake is improved, but cAMP levels increase causing adverse effects such as tachycardia, palpitation, tremor, sweats, agitation, and increased glucose levels in the blood

Engineering Contradiction:

Improveglucose uptakeVSAvoidadverse effects

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the pharmacological parameter by using selective beta-3 adrenergic receptor agonists instead of non-selective beta-agonists. This selective activation of beta-3 receptors in brown adipose tissue produces glucose uptake stimulation without the systemic cAMP-mediated adverse effects (tachycardia, palpitation, tremor) associated with traditional beta-1 and beta-2 agonists, thus resolving the contradiction between improving glucose uptake and avoiding harmful side effects

Inventive Principle:

Principle #35Parameter changes

2Productivity

If beta-adrenergic receptor agonists are used to increase glucose uptake in skeletal muscle, then glucose clearance is improved, but liver glucose output increases due to cAMP elevation

Engineering Contradiction:

Improveglucose clearanceVSAvoidglucose output from liver

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by targeting beta-3 adrenergic receptors specifically in brown adipose tissue, which is rich in mitochondria and capable of fatty acid oxidation. This localized activation produces glucose uptake stimulation in peripheral tissues without the systemic cAMP-mediated effects on the liver, thus improving glucose clearance while avoiding increased liver glucose output

Inventive Principle:

Principle #3Local quality

3Productivity

If standard adrenergic agonists are used to treat diabetes, then glucose uptake is stimulated, but the treatments have several drawbacks and side effects making them unsuitable for effective treatment

Engineering Contradiction:

Improveglucose uptake stimulationVSAvoidsuitability for treatment

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent changes the receptor selectivity parameter from non-selective beta-agonists to selective beta-3 agonists. This parameter change results in a compound (BRL 37344) that activates glucose uptake pathways in brown adipose tissue without the harmful side effects of traditional adrenergic agonists, thereby improving both the productivity of glucose uptake stimulation and the reliability of treatment suitability

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

This approach allows for the identification of compounds that enhance GLUT4 translocation and glucose uptake in skeletal muscle, potentially reducing the need for insulin and minimizing life-threatening complications associated with type 2 diabetes, while avoiding the side effects of traditional treatments.

Implementation Method 1

activating certain GLUTs. For example for diseases such as type 2 diabetes it is vital to activate GLUT4 translocation to the plasma membrane and thus glucose uptake

Methodology Applied

Scientific EffectGLUT translocation:

Implementation Method 2

beta-adrenergic receptor ligands that do not cause an increase of the cAMP production in a cell expressing a beta-adrenergic receptor, but that cause an increase of the GLUT translocation in the cell

Methodology Applied

Scientific EffectBeta-adrenergic receptor signaling:

Implementation Method 3

Facilitative glucose transporters (GLUT) mediate glucose uptake into most cells. GLUT are transporter proteins that mediate transport of glucose and/or fructose over the plasma membrane down the concentration gradient

Methodology Applied

Scientific EffectFacilitative glucose transport:

Data Source

PatentUS9891212B2Screening method, a kit, a method of treatment and a compound for use in a method of treatment

Publication Date: 2018.02.13 ATROGI

AI summary

A method to identify a candidate compound for use in the treatment of a condition involving dysregulation of glucose homeostasis or of glucose uptake in a mammal, by identifying a candidate compound that causes an increase in translocation of GLUT without causing an increase in the production of cAMP. A kit for use in such a method. A method of treatment of a condition involving dysregulation of glucose homeostasis or of glucose uptake in a mammal and a compound for use in such a method.