Peripherally delivered hepatopreferential insulin analog insulin-406 mimics the hypoglycaemia-sparing effect of portal vein human insulin infusion in dogs.

Autor: Gregory JM; Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, Tennessee., Kraft G; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee., Scott MF; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee., Neal DW; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee., Farmer B; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee., Smith MS; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee., Hastings JR; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee., Madsen P; Global Research Technologies, Novo Nordisk A/S, Maaleov, Denmark., Kjeldsen TB; Global Research Technologies, Novo Nordisk A/S, Maaleov, Denmark., Hostrup S; Global Research Technologies, Novo Nordisk A/S, Maaleov, Denmark., Brand CL; Global Drug Discovery, Novo Nordisk A/S, Maaleov, Denmark., Fledelius C; Global Drug Discovery, Novo Nordisk A/S, Maaleov, Denmark., Nishimura E; Global Drug Discovery, Novo Nordisk A/S, Maaleov, Denmark., Cherrington AD; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee.
Jazyk: angličtina
Zdroj: Diabetes, obesity & metabolism [Diabetes Obes Metab] 2019 Oct; Vol. 21 (10), pp. 2294-2304. Date of Electronic Publication: 2019 Jul 08.
DOI: 10.1111/dom.13808
Abstrakt: Aims: We previously quantified the hypoglycaemia-sparing effect of portal vs peripheral human insulin delivery. The current investigation aimed to determine whether a bioequivalent peripheral vein infusion of a hepatopreferential insulin analog, insulin-406, could similarly protect against hypoglycaemia.
Materials and Methods: Dogs received human insulin infusions into either the hepatic portal vein (PoHI, n = 7) or a peripheral vein (PeHI, n = 7) for 180 minutes at four-fold the basal secretion rate (6.6 pmol/kg/min) in a previous study. Insulin-406 (Pe406, n = 7) was peripherally infused at 6.0 pmol/kg/min, a rate determined to decrease plasma glucose by the same amount as with PoHI infusion during the first 60 minutes. Glucagon was fixed at basal concentrations, mimicking the diminished α-cell response seen in type 1 diabetes.
Results: Glucose dropped quickly with PeHI infusion, reaching 41 ± 3 mg/dL at 60 minutes, but more slowly with PoHI and Pe406 infusion (67 ± 2 and 72 ± 4 mg/dL, respectively; P < 0.01 vs PeHI for both). The hypoglycaemic nadir (c. 40 mg/dL) occurred at 60 minutes with PeHI infusion vs 120 minutes with PoHI and Pe406 infusion. ΔAUC epinephrine during the 180-minute insulin infusion period was two-fold higher with PeHI infusion compared with PoHI and Pe406 infusion. Glucose production (mg/kg/min) was least suppressed with PeHI infusion (Δ = 0.79 ± 0.33) and equally suppressed with PoHI and Pe406 infusion (Δ = 1.16 ± 0.21 and 1.18 ± 0.17, respectively; P = NS). Peak glucose utilization (mg/kg/min) was highest with PeHI infusion (4.94 ± 0.17) and less with PoHI and Pe406 infusion (3.58 ± 0.58 and 3.26 ± 0.08, respectively; P < 0.05 vs Pe for both).
Conclusions: Peripheral infusion of hepatopreferential insulin can achieve a metabolic profile that closely mimics portal insulin delivery, which reduces the risk of hypoglycaemia compared with peripheral insulin infusion.
(© 2019 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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