Insulin Dimer-Incretin Conjugates for Lower Hypoglycemia Risk
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Solution Overview
Problem
Current insulin therapies, including long-acting insulins, are not optimized for physiological basal insulin release, leading to increased hypoglycemia risk and limited glycemic control due to relative over-insulinization of peripheral tissues.
Innovation Solution
Development of insulin dimers conjugated to peptides with incretin activity, such as GLP-1 or GIP, through a linking moiety, forming an insulin dimer that acts as a partial agonist at the insulin receptor, providing tissue-specific glucose regulation with reduced hypoglycemia risk.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If long-acting insulins are used to regulate basal glucose levels, then glycemic control is improved, but hypoglycemia risk increases due to over-insulinization of peripheral tissues
Solution Approach 1:
The patent divides the insulin molecule into dimers (two insulin molecules linked together) and further segments functionality by conjugating to incretin peptides. This segmentation allows the insulin dimer to provide basal glucose regulation while the incretin component provides glucose-dependent glucose lowering, reducing hypoglycemia risk through functional division
Solution Approach 2:
The patent creates a composite therapeutic agent by conjugating insulin dimers with incretin peptides (GLP-1, GIP, or glucagon). This composite structure combines the glucose-lowering effects of insulin with the glucose-dependent regulation of incretins, achieving improved glycemic control with reduced hypoglycemia risk through synergistic interaction of multiple components
2Duration of action of moving object
If insulin analogs are developed to improve PK flatness, then duration of action is extended, but relative over-insulinization of peripheral tissues persists
Solution Approach 1:
The patent segments the insulin molecule into dimers and conjugates to incretin peptides, creating a composite agent where the insulin dimer provides extended duration action while the incretin component provides glucose-dependent regulation that prevents peripheral over-insulinization
Solution Approach 2:
The patent changes the molecular parameters of insulin by forming dimers (altering aggregation state) and conjugating to incretin peptides (altering molecular weight and structure). These parameter changes extend duration of action while the incretin component's glucose-dependent mechanism prevents peripheral over-insulinization
3Reliability
If rapid-acting insulin analogs are used to control post-prandial hyperglycemia, then post-meal glucose control is improved, but narrow therapeutic index to hypoglycemia remains
Solution Approach 1:
The patent creates composite insulin dimer-incretin conjugates where the incretin component provides glucose-dependent glucose lowering that expands the therapeutic index. The composite agent maintains effectiveness for post-prandial control while the incretin's glucose-sensing mechanism prevents hypoglycemia, widening the safety margin
Data Source
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AI summary
Insulin dimers conjugated to peptides having at least one incretin activity are disclosed.