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Superior Glycemic Control With a Glucose-Responsive Insulin Analog: Hepatic and
Nonhepatic Impacts.
Authors Moore MC, Kelley DE, Camacho RC, Zafian P, Ye T, Lin S, Kaarsholm NC, Nargund R,
Kelly TM, Van Heek M, Previs SF, Moyes C, Smith MS, Farmer B, Williams P,
Cherrington AD
Submitted By Submitted Externally on 6/4/2018
Status Published
Journal Diabetes
Year 2018
Date Published 6/1/2018
Volume : Pages 67 : 1173 - 1181
PubMed Reference 29540491
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.


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