Abscisic Acid and TZD Combination Therapy for Insulin Sensitivity

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Solution Overview

Problem

Current treatments for insulin resistance, cardiovascular disease, impaired glucose tolerance, diabetes, and inflammation, such as thiazolidinediones (TZDs), are limited by side effects like weight gain and congestive heart failure, and biguanides have risks like lactic acidosis, necessitating the exploration of alternative compounds that can activate peroxisome proliferator-activated receptor γ (PPAR γ) without these adverse effects.

Innovation Solution

Combining abscisic acid (ABA) with thiazolidinediones (TZDs) to enhance their efficacy and safety, allowing for lower concentrations of each compound, thereby reducing side effects and increasing insulin sensitivity and glucose tolerance while inhibiting inflammation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If thiazolidinediones (TZDs) are used to activate PPAR γ and improve insulin sensitivity, then glucose tolerance is improved, but weight gain and congestive heart failure occur

Engineering Contradiction:

Improveinsulin sensitivityVSAvoidweight gain and congestive heart failure

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent combines abscisic acid (ABA) with thiazolidinediones (TZDs) to create a synergistic therapy. ABA activates PPAR γ through a cAMP/PKA-dependent mechanism, while TZDs activate PPAR γ through direct binding. Together, they produce enhanced insulin sensitivity and glucose tolerance at lower doses, reducing the harmful side effects associated with TZD monotherapy.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

Abscisic acid acts as an intermediary compound that activates PPAR γ through a different mechanism than TZDs. ABA increases cAMP levels, which activates PKA, which in turn activates PPAR γ. This intermediary pathway allows for PPAR γ activation without the direct side effects of TZDs, particularly weight gain and heart failure.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If thiazolidinediones (TZDs) are used to reduce inflammation, then anti-inflammatory effects are achieved, but fluid retention and congestive heart failure occur

Engineering Contradiction:

Improveanti-inflammatory effectVSAvoidfluid retention

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent combines the anti-inflammatory effects of TZDs with abscisic acid to achieve synergistic inflammation reduction. ABA has been shown to reduce adipose tissue inflammation and improve insulin sensitivity without causing fluid retention. The combination allows for enhanced anti-inflammatory effects while avoiding the fluid retention side effect.

Inventive Principle:

Principle #5Merging (Combining)

3Reliability

If higher concentrations of TZDs are used to enhance therapeutic effects, then insulin sensitivity improves, but side effects increase

Engineering Contradiction:

Improveinsulin sensitivityVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent combines ABA with TZDs to achieve synergistic effects, allowing for lower concentrations of each compound to be used. The synergistic interaction between ABA and TZDs produces enhanced insulin sensitivity and glucose tolerance at reduced doses, thereby minimizing side effects such as weight gain, fluid retention, and congestive heart failure.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The patent changes the concentration parameters of the therapeutic compounds by using lower doses of TZDs in combination with ABA. This parameter change achieves the same or better therapeutic effects while reducing the harmful side effects associated with higher TZD concentrations.

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 combination of ABA and TZDs demonstrates synergistic effects in improving insulin sensitivity, glucose tolerance, and reducing inflammation, with ABA activating PPAR γ and other nuclear receptors, potentially treating diabetes, cardiovascular disease, and obesity-related inflammation without the side effects associated with TZDs alone.

Implementation Method 1

ABA increases pancreatic insulin secretion through a cyclic AMP (cAMP)/protein kinase A (PKA)-dependent mechanism

Methodology Applied

Scientific EffectcAMP/PKA-dependent mechanism:

Implementation Method 2

The combination of ABA and TZDs demonstrates synergistic effects in improving insulin sensitivity, glucose tolerance, and reducing inflammation

Methodology Applied

Scientific EffectSynergistic effect:

Data Source

PatentEP2391360B1Method of synergistically enhancing the therapeutic efficacy and safety of medications through a combination therapy

Publication Date: 2017.09.06 VIRGINIA TECH INTELLECTUAL PROPERTIES INC

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Figure 3A~3B

AI summary

The present invention provides combinations, for treatment of subjects suffering from or at high risk of developing diseases and disorders involving expression of peroxisome proliferator-activiated receptors (PPAR). The combinations include abscisic acid and one other bioactive agent, which together provide synergistic effects toward treatment or blocking of development of the disease or disorder. In exemplary embodiments, a combination of abscisic acid and a thiazolidinedione (TZD) is provided for increased insulin sensitivity and improved (i.e., reduced) obesity-induced inflammation.