p38 MAPK Activators for Glucose Tolerance

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Solution Overview

Problem

Current treatments for type 2 diabetes and obesity are inadequate, and there is a need for effective methods to reduce endoplasmic reticulum stress and lower blood glucose levels in individuals with these conditions.

Innovation Solution

The development of compositions and methods that increase p38 MAPK activity in the liver to enhance X-box binding protein 1 (XBP1) phosphorylation and nuclear translocation, using specific activators of MKK3, MKK4, MKK6, p38 MAPK, and MK2 to reduce blood glucose levels by promoting glucose tolerance.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments for type 2 diabetes and obesity are used, then existing therapeutic options are maintained, but blood glucose levels remain inadequately controlled and endoplasmic reticulum stress persists

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoidcomplexity of signaling pathway modulation

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent changes the biochemical parameter of kinase activity by administering compounds that activate MKK3, MKK4, or MKK6, which in turn activate p38 MAPK. This parameter change leads to increased phosphorylation of XBP1 and improved glucose tolerance, providing a novel therapeutic mechanism that differs from existing diabetes treatments.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses specific kinase activators as intermediary substances that mediate between the administered compound and the downstream effects on glucose metabolism. These intermediaries (MKK3/4/6 and p38 MAPK) transmit the therapeutic signal through the signaling pathway to achieve glucose lowering effects.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If stress-activated protein kinase (SAPK) signaling is enhanced, then XBP1 phosphorylation and nuclear translocation increase improving glucose tolerance, but conventional wisdom suggests SAPK signaling is detrimental to metabolic homeostasis

Engineering Contradiction:

Improveglucose toleranceVSAvoidmetabolic disruption

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the traditionally viewed harmful SAPK signaling into a beneficial therapeutic mechanism. By selectively activating MKK3/4/6-p38 MAPK-XBP1 pathway, the invention harnesses what was considered detrimental stress signaling to improve glucose tolerance and treat diabetes, effectively converting a harmful pathway into a therapeutic tool.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS10226514B2Methods and compositions for reducing blood glucose levels

Publication Date: 2019.03.12 CHILDRENS MEDICAL CENT CORP

AI summary

A method of reducing blood glucose in a subject has been developed. In preferred embodiments, the method involves administering to the subject a specific activator of endogenous mitogen-activated protein kinase kinase 6 (MKK3), mitogen-activated protein kinase kinase 6 (MKK4), mitogen-activated protein kinase kinase 6 (MKK6), p38 mitogen-activated protein kinase (p38MAPK), mitogen-activated kinase-activated protein kinase 2 (MK2), or a combination thereof, in an effective amount to reduce blood glucose in a subject. In other embodiments, the method involves administering to the subject a specific activator to increase X-box binding protein 1 (XBP1) phosphorylation on Thr48 and Ser61 in an effective amount to reduce blood glucose in the subject. Methods of identifying agents for reducing blood glucose in a subject are also provided.