Changes in Glucose and Fat Metabolism in Response to the Administration of a Hepato-preferential Insulin Analog

  1. Alan D. Cherrington1
  1. 1Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  2. 2Novo Nordisk, Copenhagen, Denmark
  1. Corresponding Author: Dale S. Edgerton, E-mail: dale.edgerton{at}vanderbilt.edu

Abstract

Endogenous insulin secretion exposes the liver to three times higher insulin concentrations than the rest of the body. Since subcutaneous insulin delivery eliminates this gradient and is associated with metabolic abnormalities, functionally restoring the physiologic gradient may provide therapeutic benefits. The effects of recombinant human insulin (HI) delivered intraportally (Po) or peripherally (Pe) were compared with an acylated insulin model compound (insulin-327) in dogs. During somatostatin and basal portal vein glucagon infusion, insulin was infused portally (PoHI; 1.8 pmol/kg/min; n=7) or peripherally (PeHI; 1.8 pmol/kg/min; n=8) and insulin-327 (Pe327;7.2 pmol/kg/min; n=5) was infused peripherally. Euglycemia was maintained by glucose infusion. While the effects on liver glucose metabolism were greatest in the PoHI and Pe327 groups, non-hepatic glucose uptake increased most in the PeHI group. Suppression of lipolysis was greater in PeHI than PoHI and was delayed in Pe327. Thus, small increments in portal vein insulin have major consequences on the liver, with little effect on non-hepatic glucose metabolism, whereas peripherally delivered insulin cannot act on the liver without also affecting non-hepatic tissues. Peripherally infused insulin-327 functionally restored the physiologic portal-arterial gradient and thereby produced hepato-preferential effects.

  • Received February 17, 2014.
  • Accepted June 9, 2014.

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  1. Diabetes
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