Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists

Margaret Wu,Terri Kelly,Yacob Gomez Llorente,Dmitri Pissarnitski,Pei Huo,Peter Zafian,Danqing Feng,Lin Yan,David E Kelley,Ahmet Kekec,Songnian Lin,Ester Carballo-Jane,Stephen F Previs,Scott A Hollingsworth,Julie Lao,Mark D Erion,Mindy Liu,Giovanna Scapin,Ge Dai,Haihong Zhou,Geoffrey Walford,Ying Chen,Dan Shao,Judith N Gorski ,James Mu

doi:10.1038/s41467-022-28561-9

Abstract

Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, inherent liabilities (e.g. hypoglycemia) of injectable insulin continue to limit the true therapeutic potential of related agents. Insulin dimers were synthesized to investigate whether partial agonism of the insulin receptor (IR) tyrosine kinase is achievable, and to explore the potential for tissue-selective systemic insulin pharmacology. The insulin dimers induced distinct IR conformational changes compared to native monomeric insulin and substrate phosphorylation assays demonstrated partial agonism. Structurally distinct dimers with differences in conjugation sites and linkers were prepared to deliver desirable IR partial agonist (IRPA). Systemic infusions of a B29-B29 dimer in vivo revealed sharp differences compared to native insulin. Suppression of hepatic glucose production and lipolysis were like that attained with regular insulin, albeit with a distinctly shallower dose-response. In contrast, there was highly attenuated stimulation of glucose uptake into muscle. Mechanistic studies indicated that IRPAs exploit tissue differences in receptor density and have additional distinctions pertaining to drug clearance and distribution. The hepato-adipose selective action of IRPAs is a potentially safer approach for treatment of diabetes.

Highlights

Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity
IR partial agonist (IRPA)-1 functions as a human insulin receptor isoform b (hIRb) partial agonist when tested in CHO-hIRb cells and measuring insulin receptor (IR)-mediated phosphorylation of Akt
Partial agonism is expressed as percentage of the maximum phosphorylation of Akt (pAkt) activity induced by recombinant human insulin (RHI), this is due to the robustness of this assay and higher numerical values obtained as compared to IR phosphorylation

Summary

Introduction

Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. Insulin dimers were synthesized to investigate whether partial agonism of the insulin receptor (IR) tyrosine kinase is achievable, and to explore the potential for tissue-selective systemic insulin pharmacology. Control of hepatic glucose production (HGP) and rates of lipolysis, more than stimulation of glucose uptake by muscle and other tissues, are the fulcrum for control of fasting blood glucose, and most glucose utilization during fasting is insulin-independent, notably by the brain[10,11]. This pattern of healthy postabsorptive metabolism has been vexingly difficult to replicate with exogenously administered insulin. In late-stage clinical studies[16], this pegylated insulin reduced nocturnal hypoglycemia and weight gain, failed due to a lack of adequate control of lipolysis and triglyceride regulation[16,17]

Methods

Results

Conclusion