Insulin Receptor Partial Agonist Dimers for Hypoglycemia Risk Reduction
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Solution Overview
Problem
Current insulin therapies, including long-acting insulins, have a narrow therapeutic index (TI) leading to a high risk of hypoglycemia and body weight gain, limiting their effectiveness and wider adoption for achieving ideal glycemic control in diabetic patients.
Innovation Solution
Development of insulin receptor partial agonist (IRPA) covalent insulin dimers that act as partial agonists at the insulin receptor, reducing the maximum activity and thereby lowering glucose effectively with a lower risk of hypoglycemia, formulated as novel basal insulins for once daily administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional insulin therapies are used to achieve glycemic control, then glucose levels are lowered, but the risk of hypoglycemia increases due to narrow therapeutic index
Solution Approach 1:
The insulin molecule is segmented into a dimeric structure where two insulin molecules are covalently linked through their B-chain regions. This segmentation creates a novel molecular architecture that provides sustained glucose lowering while reducing hypoglycemia risk through partial agonist activity at the insulin receptor.
Solution Approach 2:
The invention creates a composite insulin structure by covalently linking two insulin molecules through a linker molecule. This composite dimeric structure combines the glucose-lowering efficacy of insulin with a modified receptor interaction profile that reduces excessive activation and subsequent hypoglycemia.
2Quantity of substance
If insulin doses are increased to achieve better glycemic control, then HbA1c levels decrease, but body weight gain increases
Solution Approach 1:
By segmenting the insulin activity into a dimeric structure with partial agonist properties, the therapy achieves sustained glucose lowering without the excessive insulin receptor activation that leads to weight gain, allowing for effective glycemic control with neutral or reduced weight effects.
3Duration of action of stationary object
If long-acting insulin analogs are used to regulate basal glucose levels, then fasting glucose control is improved, but the therapeutic index remains narrow leading to hypoglycemia
Solution Approach 1:
The dimeric structure segments the insulin activity to provide prolonged basal action while the partial agonist mechanism ensures that even with extended duration, the maximum receptor activation is limited, thereby maintaining a wider therapeutic index and reducing hypoglycemia risk.
Solution Approach 2:
The insulin dimer acts as a partial agonist, producing submaximal activation of the insulin receptor compared to endogenous insulin. This partial action provides sufficient glucose lowering for basal control while avoiding the excessive activation that leads to hypoglycemia, even with long duration of action.
Data Source
AI summary
Insulin dimers and insulin analog dimers that act as partial agonists at the insulin receptor are disclosed.