Superior Glycemic Control With a Glucose-Responsive Insulin Analog: Hepatic and Nonhepatic Impacts

Author:

Moore Mary Courtney12ORCID,Kelley David E.3,Camacho Raul C.3,Zafian Peter3,Ye Tian3,Lin Songnian3,Kaarsholm Niels C.3,Nargund Ravi3ORCID,Kelly Terri M.3,Van Heek Margaret3,Previs Stephen F.3,Moyes Christopher3,Smith Marta S.1,Farmer Ben12,Williams Phil24,Cherrington Alan D.12

Affiliation:

1. Department of Molecular Biology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN

2. Diabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, TN

3. Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ

4. Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN

Abstract

We evaluated the hepatic and nonhepatic responses to glucose-responsive insulin (GRI). Eight dogs received GRI or regular human insulin (HI) in random order. A primed, continuous intravenous infusion of [3-3H]glucose began at −120 min. Basal sampling (−30 to 0 min) was followed by two study periods (150 min each), clamp period 1 (P1) and clamp period 2 (P2). At 0 min, somatostatin and GRI (36 ± 3 pmol/kg/min) or HI (1.8 pmol/kg/min) were infused intravenously; basal glucagon was replaced intraportally. Glucose was infused intravenously to clamp plasma glucose at 80 mg/dL (P1) and 240 mg/dL (P2). Whole-body insulin clearance and insulin concentrations were not different in P1 versus P2 with HI, but whole-body insulin clearance was 23% higher and arterial insulin 16% lower in P1 versus P2 with GRI. Net hepatic glucose output was similar between treatments in P1. In P2, both treatments induced net hepatic glucose uptake (HGU) (HI mean ± SEM 2.1 ± 0.5 vs. 3.3 ± 0.4 GRI mg/kg/min). Nonhepatic glucose uptake in P1 and P2, respectively, differed between treatments (2.6 ± 0.3 and 7.4 ± 0.6 mg/kg/min with HI vs. 2.0 ± 0.2 and 8.1 ± 0.8 mg/kg/min with GRI). Thus, glycemia affected GRI but not HI clearance, with resultant differential effects on HGU and nonHGU. GRI holds promise for decreasing hypoglycemia risk while enhancing glucose uptake under hyperglycemic conditions.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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