Tissue barriers and novel approaches to achieve hepatoselectivity of subcutaneously-injected insulin therapeutics

ABSTRACT

Current subcutaneously (s.c.)-injected insulin (INS) products result in a hyperinsulin exposure to peripheral tissues (skeletal muscle and adipose) while INS hardly accesses to liver after injection. This unphysiological distribution raises risks of hypoglycemia episode and causes weight gain after long term treatment. An ideal INS replacement therapy requires the distribution or action of exogenous INS to more closely mimic physiological INS in terms of its preferential hepatic action. However, there are 2 factors that limit the ability of s.c. injected INS to restore the liver: peripheral gradient in INS deficient diabetes patients: (1) the transport of INS in capillary endothelium and peripheral tissues from the injection site; and (2) peripheral INS receptor (IR) mediated INS degradation. In this review, the tissue barriers against efficient liver targeting of s.c. injected INS are discussed and current advances in developing hepatoselective insulin therapeutics are introduced.

KEYWORDS:

• diabetes
• hepatic-directed vesicle INS
• hepatoselectivity
• IR-B selective INS analog
• Peglispro
• proinsulin-transferrin
• subcutaneously-injected insulin
• thyroxyl-INS analog

Abbreviations

Rd	=	peripheral glucose disposal rate
Ra	=	hepatic glucose production rate
PGD	=	peripheral glucose disposal

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Funding

Studies of ProINS-Tf in this review were supported by NIH grant GM063647 and USC Bensussen Innovative Challenge Grant.