title: Insulin Delivery Into the Peripheral Circulation: A Key Contributor to Hypoglycemia in Type 1 Diabetes.
abstract: Hypoglycemia limits optimal glycemic control in type 1 diabetes mellitus (T1DM), making novel strategies to mitigate it desirable. We hypothesized that portal (Po) vein insulin delivery would lessen hypoglycemia. In the conscious dog, insulin was infused into the hepatic Po vein or a peripheral (Pe) vein at a rate four times of basal. In protocol 1, a full counterregulatory response was allowed, whereas in protocol 2, glucagon was fixed at basal, mimicking the diminished α-cell response to hypoglycemia seen in T1DM. In protocol 1, glucose fell faster with Pe insulin than with Po insulin, reaching 56 ± 3 vs. 70 ± 6 mg/dL (P = 0.04) at 60 min. The change in area under the curve (ΔAUC) for glucagon was similar between Pe and Po, but the peak occurred earlier in Pe. The ΔAUC for epinephrine was greater with Pe than with Po (67 ± 17 vs. 36 ± 14 ng/mL/180 min). In protocol 2, glucose also fell more rapidly than in protocol 1 and fell faster in Pe than in Po, reaching 41 ± 3 vs. 67 ± 2 mg/dL (P < 0.01) by 60 min. Without a rise in glucagon, the epinephrine responses were much larger (ΔAUC of 204 ± 22 for Pe vs. 96 ± 29 ng/mL/180 min for Po). In summary, Pe insulin delivery exacerbates hypoglycemia, particularly in the presence of a diminished glucagon response. Po vein insulin delivery, or strategies that mimic it (i.e., liver-preferential insulin analogs), should therefore lessen hypoglycemia.
authors.affiliation: Ian M. Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN justin.m.gregory.1@vanderbilt.edu.
authors.forename: Justin M
authors.identifier: http://orcid.org/0000-0003-2700-0062
authors.initials: JM
authors.lastname: Gregory
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Kraft
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Melanie F
authors.initials: MF
authors.lastname: Scott
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Doss W
authors.initials: DW
authors.lastname: Neal
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Ben
authors.initials: B
authors.lastname: Farmer
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Marta S
authors.initials: MS
authors.lastname: Smith
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Jon R
authors.initials: JR
authors.lastname: Hastings
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Allen
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: E Patrick
authors.initials: EP
authors.lastname: Donahue
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Noelia
authors.initials: N
authors.lastname: Rivera
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Winnick
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Dale S
authors.initials: DS
authors.lastname: Edgerton
authors.affiliation: Novo Nordisk, Copenhagen, Denmark.
authors.forename: Erica
authors.initials: E
authors.lastname: Nishimura
authors.affiliation: Novo Nordisk, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Fledelius
authors.affiliation: Novo Nordisk, Copenhagen, Denmark.
authors.forename: Christian L
authors.initials: CL
authors.lastname: Brand
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Cherrington
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D004285:Dogs; D005934:Glucagon / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced*; D007328:Insulin / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D011169:Portal Vein; D013004:Somatostatin / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D013004:Somatostatin; D005934:Glucagon; D005947:Glucose